ALBERT

Beschreibung:    Extranodal natural killer/T-cell lymphoma (ENKL) has a dismal prognosis. Although L-asparaginase has shown promising efficacy as a frontline therapy, currently there are no treatment options after progression to an L-asparaginase-containing regimen. We report the results of gemcitabine-containing therapy in patients with relapsed or refractory ENKL. We retrospectively reviewed 20 patients with refractory or relapsed ENKL who received a gemcitabine-containing regimen between 2005 and 2011. The overall response rate was 40 % (8 of 20 patients) with a complete response (CR) rate of 20 % ( n  = 4) and a partial response (PR) rate of 20 % ( n  = 4). Four complete responders had a disease-free status for more than 7 months including two patients received autologous stem cell transplantation consolidation and L-aspraginase maintenance, respectively. The median progression-free survival of the 20 patients was 2.3 months; however, it was 7.3 months for eight responders (CR and PR). The median overall survival of the eight responders had not been reached at the time of analysis. Gemcitabine was effective in a subset of pretreated ENKL patients and can be considered as a salvage option. Content Type Journal Article Category SHORT REPORT Pages 1-4 DOI 10.1007/s10637-012-9889-4 Authors Hee Kyung Ahn, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea Seok Jin Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Deok Won Hwang, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Young Hyeh Ko, Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Tiffany Tang, Department of Medical Oncology, National Cancer Center, Singapore, Singapore Soon Thye Lim, Department of Medical Oncology, National Cancer Center, Singapore, Singapore Won Seog Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Erratum to: Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis Content Type Journal Article Category Erratum Pages 1-2 DOI 10.1007/s10637-012-9892-9 Authors Gopalakrishnan Ramakrishnan, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Sundaram Jagan, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Sattu Kamaraj, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Pandi Anandakumar, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Thiruvengadam Devaki, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Objective Certain eligibility criteria for Phase 1 cancer clinical trials may impede successful patient enrollment onto a study. We evaluated patient-specific or study-specific reasons for screen failures on Phase 1 oncology clinical trials and discuss factors which may inhibit subject enrollment. Methods Thirty-eight Phase 1 clinical trials for solid tumors meeting eligibility criteria and opened for enrollment between February 2006 and February 2011 at one oncology Phase 1 program were examined. Categorical reasons for screen failures and patients’ demographics were examined and compared to characteristics of patients that successfully enrolled on a Phase 1 trial. Results There were a total of 583 successful Phase 1 enrollment and dose administration events out of 773 Phase 1 consent events (75.4 % dose success rate). The three most common reasons for screen failure were: out of protocol-specified range for chemistry, development of an interval medical issue that precluded proceeding with study participation, and subject declining participation after signing consent. Living further away from the Phase 1 program and receipt of fewer prior lines of systemic chemotherapy were significantly associated with increased screen failures. Conclusion Screen failures for Phase 1 studies are not uncommon (24.6 %). When a protocol required tumor or host analyte is not required, most screen failures are due to out of protocol-specified range for chemistry or the development of an interval medical issue. Screen failure rates were increased when patients had longer travel distances and fewer prior lines of systemic chemotherapy. Content Type Journal Article Category SHORT REPORT Pages 1-6 DOI 10.1007/s10637-012-9894-7 Authors Alexandra Mckane, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Chao Sima, The Translational Genomics Research Institute, Phoenix, AZ, USA Ramesh K. Ramanathan, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Gayle Jameson, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Cathy Mast, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Erica White, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Sharon Fleck, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Molly Downhour, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Daniel D. Von Hoff, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Glen J. Weiss, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora , has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteine-repressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-13 DOI 10.1007/s10637-012-9888-5 Authors Patrick T. Grogan, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas, KS 66160, USA Kristina D. Sleder, Department of Surgery, University of Kansas Medical Center, Kansas, KS 66160, USA Abbas K. Samadi, Department of Surgery, University of Kansas Medical Center, Kansas, KS 66160, USA Huaping Zhang, Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS 66045, USA Barbara N. Timmermann, Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS 66045, USA Mark S. Cohen, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas, KS 66160, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400–800 mg once daily [QD]) plus erlotinib (100–150 mg QD) doses were evaluated in cohorts of 3–6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib ( N  = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9887-6 Authors Grace K. Dy, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Jeffrey R. Infante, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA S. Gail Eckhardt, Division of Medical Oncology, University of Colorado School of Medicine, 13001 E 17th Place, Aurora, CO 80045, USA Silvia Novello, Department of Clinical & Biological Sciences, University of Turin, Auo San Luigi-Regione Gonzole 10, 10043 Orbassano, Torino, Italy Wen Wee Ma, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Suzanne F. Jones, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA Anne Huff, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA 19426, USA Qiong Wang, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA 19426, USA A. Benjamin Suttle, GlaxoSmithKline Pharmaceuticals, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Lone H. Ottesen, GlaxoSmithKline Pharmaceuticals, Stockley Park West, 1-3 Iron Bridge Road, Uxbridge, UB11 1BT UK Alex A. Adjei, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Howard A. Burris III, Sarah Cannon Research Institute, 250 25th Ave North, Suite 110, Nashville, TN 37203-1632, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. Methods In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m 2 ; Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. Results Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. Conclusion Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-012-9893-8 Authors Thierry Lesimple, Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042 Rennes Cedex, France Julien Edeline, Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042 Rennes Cedex, France Timothy J. Carrothers, Pharsight, Sunnyvale, CA, USA Frédérique Cvitkovic, Hôpital René Huguenin, Institut Curie, Saint-Cloud, France Borje Darpo, Department of Clinical Science and Education, Section of Cardiology, Karolinska Institute, South Hospital, Stockholm, Sweden Jean-Pierre Delord, Institut Claudius Regaud, Toulouse, France Hervé Léna, Service de Pneumologie, Centre Hospitalier Universitaire, Rennes, France Nicolas Penel, Centre Oscar Lambret, Lille, France Geoff J. Edwards, Eisai Ltd, Hatfield, UK Kenneth Law, Eisai Ltd, Hatfield, UK Jantien Wanders, Eisai Ltd, Hatfield, UK Allan Kristensen, Eisai Inc, Woodcliff Lake, NJ, USA Larisa Reyderman, Eisai Inc, Woodcliff Lake, NJ, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Nasopharyngeal carcinoma (NPC) is endemic to Asia and over 40 % of NPC tissues harbor PIK3CA amplifications. This study characterized the preclinical activity of MK-2206, an oral allosteric inhibitor of AKT in 6 NPC cell lines: C666-1, HK1, HONE-1-EBV, HONE-1, CNE-2 and HNE-1. Exposure to increasing concentrations of MK-2206 resulted in over 95 % of growth inhibition in all NPC cell lines with IC 50 values in the low micromolar range. Further experiments were performed in 3 representative NPC cell lines: CNE-2 (harbor PIK3CA mutation and most sensitive to MK-2206), C666-1 (carries PIK3CA amplification), and HONE-1-EBV (least sensitive to MK-2206). MK-2206 induced G 0 /G 1 cycle arrest in all 3 cell lines, but could induce apoptosis only in CNE-2 cells. MK-2206 significantly abrogated AKT signaling in all 3 cell lines by inhibiting the activation of AKT and its downstream effectors (FKHR, GSK3β and BAD). MK-2206 also reduced mTOR signaling by reducing activation of mTOR and its downstream 4E-BP1 and p70S6 kinase. MAPK activation was observed in HONE-1 and C666-1 cells, but not in CNE-2 cells following exposure to MK-2206. The addition of MK-2206 to cisplatin (but not with paclitaxel) has a supra-additive inhibitory effect on growth in vitro. In summary, MK-2206 can inhibit growth and abrogate AKT and mTOR signaling in NPC cell lines. This agent is currently being evaluated in a phase II study in metastatic NPC. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-012-9896-5 Authors Brigette B. Y. Ma, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Vivian W. Y. Lui, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA Connie W. C. Hui, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Cecilia P. Y. Lau, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Chi-Hang Wong, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Edwin P. Hui, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Margaret H. Ng, Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, Hong Kong, China S. W. Tsao, Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong, China Yan Li, Infectious Disease, Oncology, Respiratory & Immunology Clinical Development, Merck Sharp and Dohme Corp, Inc, North Wales, PA, USA Anthony T. C. Chan, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m 2 is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m 2 , 250 mg/m 2 or 200 mg/m 2 for patients with increasing degrees of liver dysfunction. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-012-9878-7 Authors J. P. Delord, Institut Claudius Regaud, Toulouse, France A. Ravaud, Centre Hospitalier Universitaire, Bordeaux, France J. Bennouna, Centre René Gauducheau, Saint Herblain, France P. Fumoleau, Centre George-François Leclerc, Dijon, France S. Favrel, Institut de Recherche Pierre Fabre, Boulogne, France M. C. Pinel, Institut de Recherche Pierre Fabre, Boulogne, France P. Ferré, Institut de Recherche Pierre Fabre, Boulogne, France F. Saliba, Hôpital Paul Brousse, Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    High-mannose type N-linked glycan with 6 mannosyl residues, termed "M6Gn2", displayed clear binding to the same M6Gn2, conjugated with ceramide mimetic (cer-m) and incorporated in liposome, or coated on polystyrene plates. However, the conjugate of M6Gn2-cer-m did not interact with complex-type N-linked glycan with various structures having multiple GlcNAc termini, conjugated with cer-m. The following observations indicate that hamster embryonic fibroblast NIL-2 K cells display homotypic autoadhesion, mediated through the self-recognition capability of high-mannose type glycans expressed on these cells: (i) NIL-2 K cells display clear binding to lectins capable of binding to high-mannose type glycans ( e.g. , ConA), but not to other lectins capable of binding to other carbohydrates ( e.g. GS-II). (ii) NIL-2 K cells adhere strongly to plates coated with M6Gn2-cer-m, but not to plates coated with complex-type N-linked glycans having multiple GlcNAc termini, conjugated with cer-m; (iii) degree of NIL-2 K cell adhesion to plates coated with M6Gn2-cer-m showed a clear dose-dependence on the amount of M6Gn2-cer-m; and (iv) the degree of NIL-2 K adhesion to plates coated with M6Gn2-cer-m was inhibited in a dose-dependent manner by α1,4-L-mannonolactone, the specific inhibitor in high-mannose type glycans addition. These data indicate that adhesion of NIL-2 K is mediated by self-aggregation of high mannose type glycan. Further studies are to be addressed on auto-adhesion of other types of cells based on self interaction of high mannose type glycans. Content Type Journal Article Pages 1-12 DOI 10.1007/s10719-012-9449-3 Authors Seon-Joo Yoon, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Natalia Utkina, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Martin Sadilek, Depart of Chemistry, University of Washington, Seattle, WA 98195, USA Hirokazu Yagi, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori 3-1, Mizuho-ku, Nagoya, 467-8603 Japan Koichi Kato, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori 3-1, Mizuho-ku, Nagoya, 467-8603 Japan Sen-itiroh Hakomori, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Human alpha-1-antitrypsin (α1AT) is a glycoprotein with protease inhibitor activity protecting tissues from degradation. Patients with inherited α1AT deficiency are treated with native α1AT (nAT) purified from human plasma. In the present study, recombinant α1AT (rAT) was produced in Chinese hamster ovary (CHO) cells and their glycosylation patterns, inhibitory activity and in vivo half-life were compared with those of nAT. A peptide mapping analysis employing a deglycosylation reaction confirmed full occupancy of all three glycosylation sites and the equivalency of rAT and nAT in terms of the protein level. N -glycan profiles revealed that rAT contained 10 glycan structures ranging from bi-antennary to tetra-antennary complex-type glycans while nAT displayed six peaks comprising majorly bi-antennary glycans and a small portion of tri-antennary glycans. In addition, most of the rAT glycans were shown to have only core α(1 - 6)-fucose without terminal fucosylation, whereas only minor portions of the nAT glycans contained core or Lewis X-type fucose. As expected, all sialylated glycans of rAT were found to have α(2 - 3)-linked sialic acids, which was in sharp contrast to those of nAT, which had mostly α(2 - 6)-linked sialic acids. However, the degree of sialylation of rAT was comparable to that of nAT, which was also supported by an isoelectric focusing gel analysis. Despite the differences in the glycosylation patterns, both α1ATs showed nearly equivalent inhibitory activity in enzyme assays and serum half-lives in a pharmacokinetic experiment. These results suggest that rAT produced in CHO cells would be a good alternative to nAT derived from human plasma. Content Type Journal Article Pages 1-11 DOI 10.1007/s10719-012-9453-7 Authors Kyung Jin Lee, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Sang Mee Lee, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Jin Young Gil, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Ohsuk Kwon, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Jin Young Kim, Korea Basic Science Institute, Ochang-eup, Cheongwon-gun, Chungbuk 363-883, Korea Soon Jae Park, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Hye-Shin Chung, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Doo-Byoung Oh, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    As one of several biologically active compounds in milk, glycoproteins have been indicated to be involved in the protection of newborns from bacterial infection. As much of the physical and immune development of the tammar wallaby ( Macropus eugenii ) young occurs during the early phases of lactation and not in utero , the tammar is a model species for the characterization of potential developmental support agents provided by maternal milk. In the present study, the N - and O -linked glycans from tammar wallaby milk glycoproteins from six individuals at different lactation time points were subjected to glycomics analyses using porous graphitized carbon liquid chromatography electrospray ionization mass spectrometry. Structural characterization identified a diverse range of glycan structures on wallaby milk glycoproteins including sialylated, sulphated, core fucosylated and O -fucosylated structures. 30 % of N -linked structures contained a core (α1-6) fucose. Several of these structures may play roles in development, and exhibit statistically significant temporal changes over the lactation period. The N -glycome was found to contain structures with NeuGc residues, while in contrast the O -glycome did not. O -fucosylated structures were identified in the early stages of lactation indicating a potential role in the early stages of development of the pouch young. Overall the results suggest that wallaby milk contains structures known to have developmental and immunological significance in human milk and reproduction in other animals, highlighting the importance of glycoproteins in milk. Content Type Journal Article Pages 1-14 DOI 10.1007/s10719-012-9452-8 Authors Katherine Wongtrakul-Kish, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Daniel Kolarich, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Dana Pascovici, Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW 2109, Australia Janice L. Joss, Department of Biological Sciences, Macquarie University, North Ryde, NSW 2109, Australia Elizabeth Deane, Department of Biological Sciences, Macquarie University, North Ryde, NSW 2109, Australia Nicolle H. Packer, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Chaetoglobosin K (ChK) is a natural product that inhibits anchorage-dependent and anchorage-independent growth of ras -transformed cells, prevents tumor-promoter disruption of cell-cell communication, and reduces Akt activation in tumorigenic cells. This study demonstrates how ChK modulates the JNK pathway in ras -transformed and human lung carcinoma cells and investigates regulatory mechanisms controlling ChK’s effect on the Akt and JNK signaling pathways. Human lung carcinoma and ras -transformed epithelial cell lines treated with ChK or vehicle for varying times were assayed for cell growth or extracted for total proteins for western blot analysis using phosphorylation site-specific antibodies to monitor changes in activation of JNK, Akt, and other signaling enzymes. Results show that ChK inhibited both Akt and JNK phosphorylation at key activation sites in ras -transformed cells as well as human lung carcinoma cells. Downstream effectors of both kinases were accordingly affected. Direct upstream kinases of JNK were not affected by ChK. Wortmannin and LY294002, two PI3 kinase inhibitors, inhibited Akt but not JNK phosphorylation in ras -transformed cells. This report establishes the dual inhibitory effect of ChK on both the Akt and JNK signaling pathways in ras -transformed epithelial and human carcinoma cells. The unique effect of ChK on these two key pathways involved in carcinogenesis earmarks ChK for further studies to determine its molecular target(s) and in vivo anti-tumor potential. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9883-x Authors Amna Ali, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Tatyana S. Sidorova, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Diane F. Matesic, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC 0-t and C max of pazopanib was observed. Four partial responses were observed in patients with renal cancer ( n  = 2), giant-cell tumor of the bone ( n  = 1), and thyroid cancer ( n  = 1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9885-8 Authors Maja J. A. de Jonge, Department of Medical Oncology, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Paul Hamberg, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Jaap Verweij, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Shawna Savage, Duke Medical Center, 2100 Erwin Road, Durham, NC 27705, USA A. Benjamin Suttle, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Jeffrey Hodge, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Thangam Arumugham, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Lini N. Pandite, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Herbert I. Hurwitz, Duke Medical Center, 2100 Erwin Road, Durham, NC 27705, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Targeting tumor vasculature represents a rational strategy for controlling cancer. (Z)-(+/−)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (denoted VJ115) is a novel chemical entity that inhibits the enzyme ENOX1, a NADH oxidase. Genetic and small molecule inhibition of ENOX1 inhibits endothelial cell tubule formation and tumor-mediated neo-angiogenesis. Inhibition of ENOX1 radiosensitizes tumor vasculature, a consequence of enhanced apoptosis. However, the molecular mechanisms underlying these observations are not well understood. Herein, we mechanistically link ENOX1-mediated regulation of cellular NADH concentrations with proteomics profiling of endothelial cell protein expression following exposure to VJ115. Pathway Studios network analysis of potential effector molecules identified by the proteomics profiling indicated that a VJ115 exposure capable of altering intracellular NADH concentrations impacted proteins involved in cytoskeletal reorganization. The analysis was validated using RT-PCR and immunoblotting of selected proteins. RNAi knockdown of ENOX1 was shown to suppress expression of stathmin and lamin A/C, proteins identified by the proteomics analysis to be suppressed upon VJ115 exposure. These data support the hypothesis that VJ115 inhibition of ENOX1 can impact expression of proteins involved in cytoskeletal reorganization and support a hypothesis in which ENOX1 activity links elevated cellular NADH concentrations with cytoskeletal reorganization and angiogenesis. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9884-9 Authors Amudhan Venkateswaran, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA David B. Friedman, Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA Alexandra J. Walsh, Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA Melissa C. Skala, Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA Soumya Sasi, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Girish Rachakonda, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Peter A. Crooks, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Michael L. Freeman, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Konjeti R. Sekhar, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Glycosylation effects on cancer development Content Type Journal Article Pages 1-2 DOI 10.1007/s10719-012-9448-4 Authors Sen-itiroh Hakomori, Division of Biomembrane Research, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA Richard D. Cummings, Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Hepatocellular carcinoma (HCC) is the most common liver malignancy still demanding for novel therapeutic options. Since the ion channel inhibitor TRAM-34 (1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole) was shown to block growth in various cancer cells, we investigated anti-tumor effects of TRAM-34 in human HCC cell lines. We found that TRAM-34 reduced HCC cell proliferation without induction of apoptosis. This was due to a decreased mRNA expression of estrogen receptor alpha (ESR1) and a reduced activation of NF-kappaB, which both are implicated in the development of HCC. Therefore, TRAM-34 might represent a novel therapeutic target for the treatment of HCC. Content Type Journal Article Category Short Report Pages 1-6 DOI 10.1007/s10637-012-9879-6 Authors Christian Freise, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Martin Ruehl, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Daniel Seehofer, Department of General, Visceral and Transplantation Surgery, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany Joachim Hoyer, Department of Nephrology, Philipps-Universität Marburg, Marburg, Germany Rajan Somasundaram, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m 2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m 2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9863-1 Authors Amir Mortazavi, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Yonghua Ling, Pharmacoanalytical Shared Resources, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Ludmila Katherine Martin, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Lai Wei, Center for Biostatistics, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Mitch A. Phelps, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Zhongfa Liu, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Erica J. Harper, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA S. Percy Ivy, Cancer Therapeutics Evaluation Program, National Cancer Institute, Rockville, MD 20852, USA Xin Wu, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Bing-Sen Zhou, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Xiyong Liu, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Deidre Deam, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA J. Paul Monk, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA William J. Hicks, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Yun Yen, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Gregory A. Otterson, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Michael R. Grever, Division of Hematology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Tanios Bekaii-Saab, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    We have analyzed the structures of glycosphingolipids and intracellular free glycans in human cancers. In our previous study, trace amounts of free N -acetylneuraminic acid (Neu5Ac)-containing complex-type N -glycans with a single GlcNAc at each reducing terminus (Gn1 type) was found to accumulate intracellularly in colorectal cancers, but were undetectable in most normal colorectal epithelial cells. Here, we used cancer glycomic analyses to reveal that substantial amounts of free Neu5Ac-containing complex-type N -glycans, almost all of which were α2,6-Neu5Ac-linked, accumulated in the pancreatic cancer cells from three out of five patients, but were undetectable in normal pancreatic cells from all five cases. These molecular species were mostly composed of five kinds of glycans having a sequence Neu5Ac-Gal-GlcNAc-Man-Man-GlcNAc and one with the following sequence Neu5Ac-Gal-GlcNAc-Man-(Man-)Man-GlcNAc. The most abundant glycan was Neu5Acα2-6Galβ1-4GlcNAcβ1-2Manα1-3Manβ1-4GlcNAc, followed by Neu5Acα2-6Galβ1-4GlcNAcβ1-2Manα1-6Manβ1-4GlcNAc. This is the first study to show unequivocal evidence for the occurrence of free Neu5Ac-linked N -glycans in human cancer tissues. Our findings suggest that free Neu5Ac-linked glycans may serve as a useful tumor marker. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9435-9 Authors Masahiko Yabu, Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Hiroaki Korekane, Systems Glycobiology Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Hidenori Takahashi, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Hiroaki Ohigashi, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Osamu Ishikawa, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Yasuhide Miyamoto, Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Purpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m 2 /day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CL CR ), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CL CR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CL CR  = 40 mL/min) compared to patients with normal CL CR . Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy. Content Type Journal Article Category PHASE II STUDIES Pages 1-9 DOI 10.1007/s10637-012-9867-x Authors Yumiko Aoyama, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Atsunori Kaibara, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Akitsugu Takada, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Tetsuya Nishimura, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Masataka Katashima, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Taiji Sawamoto, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Sulfatides, 3- O -sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue. Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPARα. To confirm this hypothesis, we treated wild-type and Ppara -null mice with the specific PPARα agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPARα-dependent manner. However, these effects of fenofibrate were absent in the brain or colon. Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPARα has demonstrated that fenofibrate treatment activated PPARα in the kidney, heart, liver, and small intestine but did not affect the brain or colon. These findings suggest that PPARα activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPARα is a possible transcriptional regulator for the mouse CST gene. Content Type Journal Article Pages 1-8 DOI 10.1007/s10719-012-9454-6 Authors Takero Nakajima, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Yuji Kamijo, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Huang Yuzhe, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Takefumi Kimura, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Naoki Tanaka, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Eiko Sugiyama, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Kozo Nakamura, Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, Minami-Minowa, Kami-Ina, Nagano, Japan Mamoru Kyogashima, Division of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, Ina, Kita-Adachi, Saitama, Japan Atsushi Hara, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Toshifumi Aoyama, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC 50  〈 2 μM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5’deoxy-5’fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-012-9891-x Authors Naomi Walsh, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Susan Kennedy, St. Vincent’s University Hospital, Dublin, Ireland AnneMarie Larkin, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Brendan Corkery, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Lorraine O’Driscoll, Molecular Therapeutics for Cancer Ireland, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland Martin Clynes, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland John Crown, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Norma O’Donovan, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Methods Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. Results Fifteen patients were enrolled at weekly doses of 500 U/kg ( n  = 3), 1000 U/kg ( n  = 3), 1600 U/kg ( n  = 3) and 2500 U/kg ( n  = 6). The median age was 57 years (33–74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600–2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for 〉8 weeks in 26.7% of the enrolled patients. Conclusion Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9807-9 Authors Thomas Yau, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China P. N. Cheng, Bio-Cancer Treatment International Limited, Rm 511-513, 5/F, Bio-Informatics Centre, 2 Science Park West Avenue, Hong Kong Science Park, Shatin, NT, Hong Kong Pierre Chan, Department of Medicine, Ruttonjee Hospital, 266 Queen’s Road East, Wan Chai, Hong Kong William Chan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Li Chen, Bio-Cancer Treatment International Limited, Rm 511-513, 5/F, Bio-Informatics Centre, 2 Science Park West Avenue, Hong Kong Science Park, Shatin, NT, Hong Kong Jimmy Yuen, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong Roberta Pang, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China S. T. Fan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Ronnie T. Poon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. Patients and methods Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200–400 mg po days 1–14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6–12 patients each with advanced RCC and NSCLC. Results 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1–14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11–26 %), including 2 who were on treatment for nearly a year. Conclusions Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1–14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9812-z Authors A. Dasari, University of Colorado Cancer Center, Aurora, CO, USA L. Gore, University of Colorado Cancer Center, Aurora, CO, USA W. A. Messersmith, University of Colorado Cancer Center, Aurora, CO, USA S. Diab, University of Colorado Cancer Center, Aurora, CO, USA A. Jimeno, University of Colorado Cancer Center, Aurora, CO, USA C. D. Weekes, University of Colorado Cancer Center, Aurora, CO, USA K. D. Lewis, University of Colorado Cancer Center, Aurora, CO, USA H. A. Drabkin, Medical University of South Carolina, Charleston, SC, USA T. W. Flaig, University of Colorado Cancer Center, Aurora, CO, USA D. R. Camidge, University of Colorado Cancer Center, Aurora, CO, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Effective inhibition of BCR-ABL tyrosine kinase activity with Imatinib represents a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, more than 30 % of patients with CML in chronic phase do not respond adequately to Imatinib and the drug seems not to affect the quiescent pool of BCR-ABL positive leukemic stem and progenitor cells. Therefore, despite encouraging clinical results, Imatinib can still not be considered a curative treatment option in CML. We recently reported downregulation of eukaryotic initiation factor 5A (eIF5A) in Imatinib treated K562 cells. Furthermore, the inhibition of eIF5A by siRNA in combination with Imatinib has been shown to exert synergistic cytotoxic effects on BCR-ABL positive cell lines. Based on the structure of known deoxyhypusine synthase (DHS) inhibitors such as CNI-1493, a drug design approach was applied to develop potential compounds targeting DHS. Here we report the biological evaluation of selected novel (DHSI-15) as compared to established (CNI-1493, deoxyspergualin) DHS inhibitors. We show that upon the compounds tested, DHSI-15 and deoxyspergualin exert strongest antiproliferative effects on BCR-ABL cells including Imatinib resistant mutants. However, this effect did not seem to be restricted to BCR-ABL positive cell lines or primary cells. Both compounds are able to induce apoptosis/necrosis during long term incubation of BCR-ABL positive BA/F3 derivates. Pharmacological synergism can be observed for deoxyspergualin and Imatinib, but not for DHSI-15 and Imatinib. Finally we show that deoxyspergualin is able to inhibit proliferation of CD34+ progenitor cells from CML patients. We conclude that inhibition of deoxyhypusine synthase (DHS) can be supportive for the anti-proliferative treatment of leukemia and merits further investigation including other cancers. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9810-1 Authors Patrick Ziegler, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Tuhama Chahoud, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Thomas Wilhelm, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Nora Pällman, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Melanie Braig, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Valeska Wiehle, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Susanne Ziegler, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Marcus Schröder, Department of Chemistry, Organic Chemistry, Faculty of Sciences, Hamburg, Germany Chris Meier, Department of Chemistry, Organic Chemistry, Faculty of Sciences, Hamburg, Germany Adrian Kolodzik, Center for Bioinformatics, University of Hamburg, Hamburg, Germany Matthias Rarey, Center for Bioinformatics, University of Hamburg, Hamburg, Germany Jens Panse, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Joachim Hauber, Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany Stefan Balabanov, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Tim H. Brümmendorf, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Insulin like growth factor receptor (IGF-1R) targeting became one of the most investigated areas in anticancer drug development during the last decade. Strategies aiming to block IGF-1R activity include monoclonal antibodies, tyrosine kinase inhibitors and anti-ligands antibodies. Initial enthusiasm quickly encountered challenges. Unfortunately the validation of the efficacy of IGF-1R targeted agents in large clinical trials failed, however anecdotal single agent activity was seen in early studies. Consequently, questions regarding the selection of right target population and the appropriate trial design are arising. Despite the plethora of clinical trials conducted no predictive biomarker has been validated so far and resistance mechanisms to IGF-1R inhibitors remain unclear. The other issue to be addressed is how to best combine IGF-1R inhibitors with other therapeutic approaches. This review highlights the most relevant clinical data emphasizing the main tumor types where IGF-1R inhibition showed potential interest. We also tried to extract based on clinical and translational data some candidate biomarkers that could help better to select patient population who potentially could benefit most from this therapeutic approach. Content Type Journal Article Category REVIEW Pages 1-10 DOI 10.1007/s10637-012-9811-0 Authors Andrea Gombos, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Otto Metzger-Filho, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Lissandra Dal Lago, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Ahmad Awada-Hussein, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Erratum to: Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy Content Type Journal Article Category Erratum Pages 1-3 DOI 10.1007/s10637-012-9799-5 Authors Céline Clémenson, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Cyrus Chargari, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Laurent Désiré, Exonhit SA, Paris, France Anne-Sophie Casagrande, Exonhit SA, Paris, France Jean Bourhis, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Eric Deutsch, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28–61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08–1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08–11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population. Content Type Journal Article Category PHASE II STUDIES Pages 1-7 DOI 10.1007/s10637-012-9808-8 Authors Thomas Yau, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Hilda Wong, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China Pierre Chan, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China T. J. Yao, Clinical Trials Centre, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China R. Pang, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China T. T. Cheung, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China S. T. Fan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Ronnie T. Poon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico , in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of 〉 450 Da, a predicted log P (log P) of either 〈2 or 〉 3.5, and a cytotoxicity IC 50 value of 〉 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood–brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570’s resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-012-9806-x Authors Hua Lv, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Fan Wang, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA M. V. Ramana Reddy, Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA Qingyu Zhou, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Xiaoping Zhang, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA E. Premkumar Reddy, Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA James M. Gallo, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Pseudomyxoma peritonei is a disease characterised by the accumulation of mucinous ascites. Thus far, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be effective at eradicating disease. Chemotherapy has been less effective, providing disease stabilization but not demonstrating significant treatment responses. Mucolytic is a potential class of drug that may be exploited in the chemical management of this disease. A variety of potential mucolytic agents are explored in this review providing evidence of basic biochemical evidence of its efficacy with potential translational application. Content Type Journal Article Category REVIEW Pages 1-7 DOI 10.1007/s10637-012-9797-7 Authors Krishna Pillai, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Javed Akhter, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Terence C. Chua, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia David L. Morris, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m 2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m 2 bid for 2 weeks every 3 weeks and cetuximab 250 mg/m 2 weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1–6.8). Conclusion The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9802-1 Authors Sil Kordes, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Dick J. Richel, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Heinz-Josef Klümpen, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Mariëtte J. Weterman, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Arnoldus J. W. M. Stevens, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Johanna W. Wilmink, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose. Dasatinib is an oral tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family and ixabepilone is an epothilone B analog. Synergistic activity has been reported when combining dasatinib with chemotherapy. This study was conducted to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) for this combination. Patients and methods. Patients with metastatic solid tumors who progressed on standard therapy received dasatinib orally daily and ixabepilone IV every 3 weeks at escalating doses using 3 + 3 design. An expansion cohort was studied after reaching the MTD. Pharmacokinetic studies were performed. Results. Nineteen patients were enrolled. No DLTs were observed at dose level (DL) 1 (dasatinib 100 mg and ixabepilone 30 mg/m 2 ). At DL 2 (dasatinib 100 mg and ixabepilone 40 mg/m 2 ), one patient had multiple DLTs. At DL 3 (dasatinib 150 mg and ixabepilone 40 mg/m 2 ), the first patient developed grade 3 AE during cycle 2, the second patient had a DLT and a grade 3 AE during cycle 2. The accrual to DL 3 was halted without reaching the maximally administered dose (MAD) and MTDs were determined to be dasatinib 100 mg and ixabepilone 40 mg/m 2 (DL 2). One patient had a partial response and 12 patients stable disease as their best response. Fourteen patients came off study due to toxicities. Conclusion. The combination of dasatinib and ixabepilone showed modest clinical activity with doses 100 mg orally daily and 40 mg/m 2 IV every 3 weeks, respectively. Treatment related toxicities were seen frequently. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9805-y Authors P. Herbolsheimer, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA R. Kapoor, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA K. L. Smith, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA D. Perry, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA N. Verma, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA I. Veytsman, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA J. Jelinek, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA S. M. Swain, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Background   Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies. Methods This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated. Results A total of 12 patients received saracatinib at doses of 50 ( n  = 3), 125 ( n  = 6), and 175 mg ( n  = 3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67 %), nausea (67 %), decreased appetite (58 %), lymphopenia (50 %) and pyrexia (50 %). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17 %). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased ( n  = 1); and grade 3 hypoxia ( n  = 1). Following a single dose, saracatinib median t max across the doses was 2–4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8–2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n  = 2; 125 mg, n  = 1). Conclusions Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9809-7 Authors Yasuhito Fujisaka, Osaka Medical College, Osaka, Japan Yusuke Onozawa, Shizuoka Cancer Center, Shizuoka, Japan Takayasu Kurata, Osaka Medical College, Osaka, Japan Hirofumi Yasui, Shizuoka Cancer Center, Shizuoka, Japan Isao Goto, Osaka Medical College, Osaka, Japan Kentaro Yamazaki, Shizuoka Cancer Center, Shizuoka, Japan Nozomu Machida, Shizuoka Cancer Center, Shizuoka, Japan Junichiro Watanabe, Shizuoka Cancer Center, Shizuoka, Japan Hitoshi Shimada, AstraZeneca, Osaka, Japan Xiaojin Shi, AstraZeneca, Osaka, Japan Narikazu Boku, Shizuoka Cancer Center, Shizuoka, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Persistent infections with certain high-risk human papillomavirus (HPV) types such as 16 and 18 can result in the development of cervical cancer. Neither of the two prophylactic vaccines against HPV16 and 18 that are in current use have any therapeutic efficacy for prevalent HPV infections. Ablative therapy is widely used for the treatment of HPV cervical dysplasia however disease recurrence is a widely recognized problem. Thus there is a continuing need for therapeutic approaches for the treatment of HPV infections. The HPV16 E6 viral oncoprotein represses surface expression of the cellular adhesion molecule, E-cadherin. Reduced E-cadherin expression on HPV-infected keratinocytes is associated with lowered numbers of antigen-presenting Langerhans cells in the infected epidermis, potentially reducing immune surveillance for HPV. Four chemicals reported to up-regulate E-cadherin were screened for their ability to counteract E6 repression of surface E-cadherin. 5-Aza-2’-deoxycytidine (AzaDC), a DNA methyltransferase inhibitor, and Indole-3-carbinol (I3C), reported to increase E-cadherin through a p21 Waf1/Cip1 -dependent mechanism, had low cytotoxicity and increased or restored E-cadherin expression and adhesive function in HPV16 E6 expressing HCT116 cells. Doxorubicin, also known to induce p21 Waf1/Cip1 , increased E-cadherin in E6 expressing cells but had some associated cytotoxicity. Tamoxifen, which can restore adhesive function of surface E-cadherin, was ineffective in counteracting E6 repression of E-cadherin. AzaDC and I3C both show potential to restore antigen-presenting cells to HPV infected skin by antagonizing E6 repression of E-cadherin, thereby counteracting an important immune evasion mechanism of HPV16 and reinstating immune function at the infected site. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-16 DOI 10.1007/s10637-012-9803-0 Authors Zarina J. D’Costa, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Cheng-Mee Leong, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Justin Shields, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Charles Matthews, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Merilyn H. Hibma, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin. Materials and Methods This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. Results Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90–100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. Conclusions On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9800-3 Authors Pamela L. Kunz, Stanford University School of Medicine, Stanford, CA, USA Aiwu R. He, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA A. Dimitrios Colevas, Stanford University School of Medicine, Stanford, CA, USA Michael J. Pishvaian, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Jimmy J. Hwang, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Pamela L. Clemens, Bristol-Myers Squibb, Princeton, NJ, USA Marianne Messina, Bristol-Myers Squibb, Wallingford, CT, USA Remigiusz Kaleta, Bristol-Myers Squibb, Wallingford, CT, USA Fernanda Abrahao, Bristol-Myers Squibb, Wallingford, CT, USA Branimir I. Sikic, Stanford University School of Medicine, Stanford, CA, USA John L. Marshall, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Proteasome inhibitors are emerging as a new class of anticancer agents. In this work, we examined the mechanisms underlying cytotoxicity, selectivity and adjuvant potential of the proteasome inhibitor MG132 in a panel of glioblastoma (GBM) cells (U138MG, C6, U87 and U373) and in normal astrocytes. MG132 markedly inhibited GBM cells growth irrespective of the p53 or PTEN mutational status of the cells whereas astrocytic viability was not affected, suggesting a selective toxicity of MG132 to cancerous glial cells. Mechanistically, MG132 arrested cells in G2/M phase of the cell cycle and increased p21 WAF1 protein immunocontent. Following cell arrest, cells become apoptotic as shown by annexin-V binding, caspase-3 activation, chromatin condensation and formation of sub-G1 apoptotic cells. MG132 promoted mitochondrial depolarization and decreased the mitochondrial antiapoptotic protein bcl-xL; it also induced activation of JNK and p38, and inhibition of NFkappaB and PI3K/Akt survival pathways. Pre-treatment of GBMs with the mitochondrial permeability transition pore inhibitor, bongkrekic acid, or pharmacological inhibitors of JNK1/2 and p38, SP600125 and SB203580, attenuated MG132-induced cell death. Besides its apoptotic effect alone, MG132 also enhanced the antiglioma effect of the chemotherapeutics cisplatin, taxol and doxorubicin in C6 and U138MG cells, indicating an adjuvant/chemosensitizer potential. In summary, MG132 exerted profound and selective toxicity in GBMs, being a potential agent for further testing in animal models of the disease. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-012-9804-z Authors Alfeu Zanotto-Filho, Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Elizandra Braganhol, Laboratório de Enzimologia, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Ana Maria Oliveira Battastini, Laboratório de Enzimologia, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil José Cláudio Fonseca Moreira, Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Red and brown algae have been shown to produce a variety of compounds with chemotherapeutic potential. A recent report described the isolation of a range of novel polyhalogenated monoterpene compounds from the red algae Plocamium corallorhiza and Plocamium cornutum collected off the coast of South Africa, together with the previously described tetraprenylquinone, sargaquinoic acid (SQA), from the brown algae Sargassum heterophyllum . In our study, the algal compounds were screened for anti-proliferative activity against metastatic MDA-MB-231 breast cancer cells revealing that a number of compounds displayed anti-cancer activity with IC 50 values in the micromolar range. A subset of the compounds was tested for differential toxicity in the MCF-7/MCF12A system and five of these, including sargaquinoic acid, were found to be at least three times more toxic to the breast cancer than the non-malignant cell line. SQA was further analysed in terms of its mechanism of cytotoxicity in MDA-MB-231 cells. The ability to initiate apoptosis was distinguished from the induction of an inflammatory necrotic response via flow cytometry with propidium iodide and Hoescht staining, confocal microscopy with Annexin V and propidium iodide staining as well as the PARP cleavage assay. We report that SQA induced apoptosis while a polyhalogenated monoterpene RU015 induced necrosis in metastatic breast cancer cells in vitro. Furthermore, we demonstrated that apoptosis induction by SQA occurs via caspase-3, -6, -8, -9 and -13 and was associated with down-regulation of Bcl-2. In addition, cell cycle analyses revealed that the compound causes G 1 arrest in MDA-MB-231 cells. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-14 DOI 10.1007/s10637-011-9788-0 Authors Jo-Anne de la Mare, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Jessica C. Lawson, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Maynard T. Chiwakata, Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa Denzil R. Beukes, Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa Adrienne L. Edkins, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Gregory L. Blatch, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72 year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400 mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123 μmol/L to 196 μmol/L and an elevation in whole blood cyclosporine concentrations from 79 μg/L to 139 μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150–186 μmol/L) and cyclosporine concentrations (53–97 μg/L). A prolonged partial response to therapy for 19 months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1 ng/ml and 139 ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration. Content Type Journal Article Category SHORT REPORT Pages 1-3 DOI 10.1007/s10637-011-9769-3 Authors Karen E. Mulder, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Merrill J. Egorin, Departments of Medicine and Pharmacology and Cancer Center, Pittsburgh, Pennsylvania, USA Michael B. Sawyer, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Currently, no prospective data exists to support a “stop-and-go” modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0–2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2–58) with outcomes as follows: complete response, n  = 1; partial response, n  = 23; stable disease, n  = 21; progression, n  = 1; and not evaluated, n  = 4. Median time to treatment failure was 7.7 months (80% CI: 6.2–8.0), and median progression-free survival was 12.8 months (80% CI: 10.8–14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients. Content Type Journal Article Category PHASE II STUDIES Pages 1-6 DOI 10.1007/s10637-011-9779-1 Authors Natsuko T. Okita, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan Taito Esaki, Gasrointestinal and Medical Oncology Division, National Kyushu Cancer Center, Fukuoka, Japan Eishi Baba, Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Daisuke Sakai, Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Shinya Tokunaga, Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan Hiroya Takiuchi, Cancer Chemotherapy Center, Osaka Medical College Hospital, Osaka, Japan Nobuyuki Mizunuma, Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Kengo Nagashima, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan Ken Kato, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC 50 values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-011-9768-4 Authors Euphemia Leung, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Gordon W. Rewcastle, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Wayne R. Joseph, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Rhonda J. Rosengren, Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand Lesley Larsen, New Zealand Institute for Plant and Food Research Ltd, Dunedin, New Zealand Bruce C. Baguley, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (F u ) sorafenib in human plasma and in isolated protein solutions. Unbound sorafenib concentrations were determined in cancer patients receiving the drug orally at a dose of 400 mg and 600 mg twice daily. Sorafenib was extensively bound with mean F u value of 0.3% in both non-cancer and cancer patient’s plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated protein solutions, 99.8% and 79.3% of sorafenib was bound to human serum albumin (HSA) (4 g/dL) and α 1 -acid glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 10 6  M −1 and 1.40 × 10 5  M −1 , respectively. In cancer patients receiving sorafenib, unbound sorafenib was not correlated with patient characteristics or laboratory values. In conclusion, sorafenib is highly protein bound in human plasma with a higher affinity towards albumin and limited free drug may be partly responsible for its borderline clinical activity. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-7 DOI 10.1007/s10637-011-9767-5 Authors Maria Cristina Villarroel, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Keith W. Pratz, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Linping Xu, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA John J. Wright, Investigational Drug Branch/CTEP/NCI, Rockville, MD, USA B. Douglas Smith, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Michelle A. Rudek, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients. Experimental Design Combinations of marizomib and vorinostat were assessed in vitro . Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300 mg daily for 16 days in 28 day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed. Results Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. Conclusions Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone. Content Type Journal Article Category PHASE I STUDIES Pages 1-15 DOI 10.1007/s10637-011-9766-6 Authors Michael Millward, Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia Timothy Price, The Queen Elizabeth Hospital, Adelaide, Australia Amanda Townsend, The Queen Elizabeth Hospital, Adelaide, Australia Christopher Sweeney, Royal Adelaide Hospital, Adelaide, Australia Andrew Spencer, The Alfred Hospital, Melbourne, Australia Shawgi Sukumaran, The Queen Elizabeth Hospital, Adelaide, Australia Angie Longenecker, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Lonnie Lee, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Ana Lay, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Girish Sharma, Department of Medical University of South Carolina, Charleston, SC, USA Robert M. Gemmill, Department of Medical University of South Carolina, Charleston, SC, USA Harry A. Drabkin, Department of Medical University of South Carolina, Charleston, SC, USA G. Kenneth Lloyd, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Saskia T. C. Neuteboom, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA David J. McConkey, MD Anderson Cancer Center, Houston, TX, USA Michael A. Palladino, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Matthew A. Spear, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Glioblastoma represent the most frequent primary tumors of the central nervous system and remain among the most aggressive human cancers as available therapeutic approaches still fail to contain their invasiveness. Many studies have reported elevated expression of the Focal Adhesion Kinase (FAK) protein in glioblastoma, associated with an increase in the rates of both migration and invasion. This designates FAK as a promising target to limit invasiveness in glioblastoma. Thymoquinone (TQ), the main phytoactive compound of Nigella sativa has shown remarkable anti-neoplasic activities on a variety of cancer cells. Here, we studied the anti-invasive and anti-migratory effects of TQ on human glioblastoma cells. The results obtained indicated that TQ treatment reduced migration, adhesion and invasion of both U-87 and CCF-STTG1 cells. This was accompanied by a drastic down-regulation of FAK, associated with a reduction of ERK phosphorylation as well as MMP-2 and MMP-9 secretion. This study provides new data on FAK regulation by a natural product (TQ) which could be of a great value for the development of novel therapies in glioblastoma. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-011-9777-3 Authors Kaouther Kolli-Bouhafs, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Abdelaziz Boukhari, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Abdurazzag Abusnina, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Emilie Velot, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Jean-Pierre Gies, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Claire Lugnier, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Philippe Rondé, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The poly-(ADP-ribose) polymerase (PARP) inhibitor, MK-4827, is a novel potent, orally bioavailable PARP-1 and PARP-2 inhibitor currently in phase I clinical trials for cancer treatment. No preclinical data currently exist on the combination of MK-4827 with radiotherapy. The current study examined combined treatment efficacy of MK-4827 and fractionated radiotherapy using a variety of human tumor xenografts of differing p53 status: Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma. To mimic clinical application of radiotherapy, fractionated radiation (2 Gy per fraction) schedules given once or twice daily for 1 to 2 weeks combined with MK-4827, 50 mg/kg once daily or 25 mg/kg twice daily, were used. MK-4827 was found to be highly and similarly effective in both radiation schedules but maximum radiation enhancement was observed when MK-4827 was given at a dose of 50 mg/kg once daily ( EF  = 2.2). MK-4827 radiosensitized all four tumors studied regardless of their p53 status. MK-4827 reduced PAR levels in tumors by 1 h after administration which persisted for up to 24 h. This long period of PARP inhibition potentially adds to the flexibility of design of future clinical trials. Thus, MK-4827 shows high potential to improve the efficacy of radiotherapy. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-8 DOI 10.1007/s10637-011-9770-x Authors Li Wang, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Kathy A. Mason, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA K. Kian Ang, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Thomas Buchholz, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA David Valdecanas, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Anjili Mathur, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Carolyn Buser-Doepner, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Carlo Toniatti, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Luka Milas, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Erratum to: Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma Content Type Journal Article Category Erratum Pages 1-2 DOI 10.1007/s10637-011-9771-9 Authors Masashi Niwakawa, Division of Urology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi, Shizuoka, 411-8777 Japan Katsuyoshi Hashine, Department of Urology, National Hospital Organization, Shikoku Cancer Center, Ehime, Japan Raizo Yamaguchi, Division of Urology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi, Shizuoka, 411-8777 Japan Hirofumi Fujii, Division of Clinical Oncology, Jichi Medical University, Tochigi, Japan Yasuo Hamamoto, Department of Medical Oncology, Tochigi Cancer Center Hospital, Tochigi, Japan Koichi Fukino, Bayer Yakuhin, Ltd., Osaka, Japan Takahiko Tanigawa, Bayer Yakuhin, Ltd., Osaka, Japan Yoshiteru Sumiyoshi, Department of Urology, National Hospital Organization, Shikoku Cancer Center, Ehime, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. Patients and methods Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off x 3wks q4wks; S2). Results Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2–4) and tremors (Grade 2–3). In S2, DLTs included tremors (Grade 2–3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. Conclusion The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-011-9774-6 Authors Glen J. Weiss, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Manuel Hidalgo, Johns Hopkins, Baltimore, MD, USA Mitesh J. Borad, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Daniel Laheru, Johns Hopkins, Baltimore, MD, USA Raoul Tibes, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Ramesh K. Ramanathan, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Lisa Blaydorn, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Gayle Jameson, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Antonio Jimeno, Johns Hopkins, Baltimore, MD, USA Jeffrey D. Isaacs, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Angela Scaburri, Milano International Oncology (MIO), Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Maria Adele Pacciarini, Milano International Oncology (MIO), Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Francesco Fiorentini, Accelera S.r.l, Nerviano, Milan, Italy Marina Ciomei, Oncology, Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Daniel D. Von Hoff, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Patients and Methods Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m 2 /day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. Results Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m 2 /day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. Conclusion A dosage of 10 mg everolimus daily with TMZ 150 mg/m 2 /day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen. Content Type Journal Article Category PHASE I STUDIES Pages 1-8 DOI 10.1007/s10637-011-9775-5 Authors Warren P. Mason, University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON M5G 2M9, Canada Mary MacNeil, QEII Health Sciences Centre, Halifax, Canada Petr Kavan, Department of Oncology, McGill University, Montréal, Canada Jacob Easaw, Tom Baker Cancer Centre, Calgary, Canada David Macdonald, London Regional Cancer Centre, London, Canada Brian Thiessen, BCCA–Vancouver Cancer Centre, Victoria, Canada Shweta Urva, Novartis Pharmaceuticals Corporation- Oncology Business Unit, Florham Park, USA Zarnie Lwin, University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON M5G 2M9, Canada Lynn McIntosh, NCIC Clinical Trials Group, Kingston, Canada Elizabeth Eisenhauer, NCIC Clinical Trials Group, Kingston, Canada Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The neurotransmitter serotonin is involved in numerous bodily functions via seven different serotonin receptor subfamilies. Serotonin plays a role in gastrointestinal functions like intestinal secretion or peristalsis and neuropsychiatric events like depression or migraine. One of these subtypes has been found on glioblastoma cells, inducing growth promotion. In our study we attempted to target imaging agents to glioblastoma cells via the serotonin receptor. For this we coupled serotonin to the fluorescent dye rhodamine and the magnetic resonance imaging contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The cellular uptake, cytotoxicity and detection sensitivity of the conjugates were evaluated by confocal laser scanning microscopy (CLSM), cell growth analysis, flow cytometry and magnetic resonance relaxometry on U373 human glioblastoma cells. Receptor-dependency of the uptake was confirmed by competition experiments with excess of unmarked serotonin. Cellular uptake of the conjugates was found in CLSM, magnetic resonance relaxometry and flow cytometry experiments. CLSM revealed the cytoplasmic character of the uptake. In cell growth analysis experiments no adverse effect of either conjugate on the cells was observed. Competition experiments performed with the conjugates and unmarked serotonin showed decreased conjugate uptake compared to the experiments without competition. In conclusion the neurotransmitter serotonin could be successfully used to target imaging agents into human glioblastoma cells. This makes it of interest for future glioblastoma imaging methods. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-7 DOI 10.1007/s10637-011-9781-7 Authors Alexander Sturzu, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany Sumbla Sheikh, Peptide Synthesis Laboratory, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany Uwe Klose, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany Hartmut Echner, Peptide Synthesis Laboratory, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany Hubert Kalbacher, Peptide Synthesis Laboratory, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany Martin Deeg, Mass Spectrometry Laboratory, Medicinal Research Centre, University of Tübingen, Tübingen, Germany Thomas Nägele, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany Marius Horger, Department of Radiology, University of Tübingen, Tübingen, Germany Ulrike Ernemann, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany Stefan Heckl, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Gemcitabine has been recognized as a standard chemotherapy in advanced pancreas cancer (APC). We conducted a phase II study of a triple combination regimen (GPT) consisting of gemcitabine (G), cisplatin (P) and erlotinib (T) in patients with APC. Patients and methods Chemotherapy-naïve patients with locally advanced or metastatic, histologically confirmed adenocarcinoma of the pancreas were treated with erlotinib 100 mg daily, 1,000 mg/m 2 of gemcitabine and 25 mg/m 2 of cisplatin administered on days 1 and 8, respectively, every 3 weeks. The primary end point was objective response. Secondary end points included progression-free survival, overall survival and toxicity. The study was designed according to the optimal two-stage design. Results Twenty-two patients were enrolled between June 2009 and August 2010. No complete response was achieved and partial response was observed in 5 patients (26%), Stable disease in 7 (37%), and progressive disease in 7 (37%). The median time to progression was 4.0 months (95% CI: 2.9–5.1 months), and the median overall survival 6.8 months (95% CI: 3.7–9.9 months). The response rate in stage I reached the target (≥3/22, p0 = 10%) established for movement to stage II but this study was determined to close earlier than planned because of unexpected treatment-related deaths (3 patients). Conclusion The triple regimen of GPT is effective for APC. Treatment-related mortalities factored early closure of this GPT protocol. Considering effect and toxicity, this triple regimen seems to offer few benefits to the patients compared with gemcitabine-based doublets. (ClinicalTrials.gov number, NCT00922896). Content Type Journal Article Category PHASE II STUDIES Pages 1-6 DOI 10.1007/s10637-012-9792-z Authors In Gyu Hwang, Department of Internal Medicine, Chung-Ang University College of Medicine, 224 Heukseok-dong, Dongjak-gu, Seoul 156-755, Republic of Korea Joung-Soon Jang, Department of Internal Medicine, Chung-Ang University College of Medicine, 224 Heukseok-dong, Dongjak-gu, Seoul 156-755, Republic of Korea Sung Yong Oh, Department of Medicine, Dong-A University College of Medicine, Dongdaesin-dong 3-ga, Seo-gu, Busan 602-715, republic of Korea Suee Lee, Department of Medicine, Dong-A University College of Medicine, Dongdaesin-dong 3-ga, Seo-gu, Busan 602-715, republic of Korea Hyuk Chan Kwon, Department of Medicine, Dong-A University College of Medicine, Dongdaesin-dong 3-ga, Seo-gu, Busan 602-715, republic of Korea Gyeong Won Lee, Departments of Internal Medicine, Institute of Health Science, School of Medicine, Gyeongsang National University, Chilam-dong, Jinju-si, Gyeongsangnam-do 660-702, Republic of Korea Seil Go, Departments of Internal Medicine, Institute of Health Science, School of Medicine, Gyeongsang National University, Chilam-dong, Jinju-si, Gyeongsangnam-do 660-702, Republic of Korea Myoung Hee Kang, Departments of Internal Medicine, Institute of Health Science, School of Medicine, Gyeongsang National University, Chilam-dong, Jinju-si, Gyeongsangnam-do 660-702, Republic of Korea Young Joo Cha, Medical Device Clinical Trials Center, Chung-Ang University College of Medicine, 224 Heukseok-dong, Dongjak-gu, Seoul 156-755, Republic of Korea Jung Hun Kang, Departments of Internal Medicine, Institute of Health Science, School of Medicine, Gyeongsang National University, Chilam-dong, Jinju-si, Gyeongsangnam-do 660-702, Republic of Korea Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The Aurora kinases (serine/threonine kinases) were discovered in 1995 during studies of mutant alleles associated with abnormal spindle pole formation in Drosophila melanogaster. They soon became the focus of much attention because of their importance in human biology and association with cancer. Aurora kinases are essential for cell division and are primarily active during mitosis. Following their identification as potential targets for cancer chemotherapy, many Aurora kinase inhibitors have been discovered, and are currently under development. The binding modes of Aurora kinase inhibitors to Aurora kinases share specific hydrogen bonds between the inhibitor core and the back bone of the kinase hinge region, while others parts of the molecules may point to different parts of the active site via noncovalent interactions. Currently there are about 30 Aurora kinase inhibitors in different stages of pre-clinical and clinical development. This review summarizes the characteristics and status of Aurora kinase inhibitors in preclinical, Phase I, and Phase II clinical studies, with particular emphasis on the mechanisms of action and resistance to these promising anticancer agents. We also discuss the validity of Aurora kinases as oncology targets, on/off-target toxicities, and other important aspects of overall clinical performance and future of Aurora kinase inhibitors. Content Type Journal Article Category REVIEW Pages 1-22 DOI 10.1007/s10637-012-9798-6 Authors Madhu Kollareddy, Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Palacky University, Puskinova 6, Olomouc, 77520 Czech Republic Daniella Zheleva, Cyclacel Ltd, 1 James Lindsay place, Dundee, DD1 5JJ UK Petr Dzubak, Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Palacky University, Puskinova 6, Olomouc, 77520 Czech Republic Pathik Subhashchandra Brahmkshatriya, Institute of Organic Chemistry and Biochemistry, v.v.i. and Gilead Sciences and IOCB Research Center, Academay of Sciences of the Czech Republic, 166 10 Prague, Czech Republic Martin Lepsik, Institute of Organic Chemistry and Biochemistry, v.v.i. and Gilead Sciences and IOCB Research Center, Academay of Sciences of the Czech Republic, 166 10 Prague, Czech Republic Marian Hajduch, Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Palacky University, Puskinova 6, Olomouc, 77520 Czech Republic Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    ATP-competitive mammalian target of rapamycin (mTOR) inhibitors are in early phase clinical trials. These novel targeted agents, including PP242, are mechanistically distinct from the allosteric, partial mTOR inhibitor, rapamycin. The goal of this study was to evaluate how PP242 best combines with standard chemotherapies for colorectal cancer (CRC), and which subsets of patients are most likely to benefit. The combination index for PP242 plus 5-fluorouracil, oxaliplatin, or irinotecan was determined in CRC cell lines with different mutational backgrounds. In KRAS mutant CRC cell lines, sensitivity to PP242 increases with co-mutation of PIK3CA. Mutation of p53 predicts resistance to chemotherapy, but not PP242. Efficacy of PP242 was comparable to that of standard chemotherapies over the dose range tested. Sensitivity or resistance to PP242 dictates relative synergy or antagonism, respectively, when PP242 is combined with 5-fluorouracil. The same trend exists for PP242 + oxaliplatin, but with a narrower dynamic range. Conversely potency of PP242 and the combination index for PP242 + irinotecan were unrelated, but synergy exists across all dose levels in PP242 and irinotecan sensitive, p53 wild-type cell lines. Overall, our in vitro analysis predicts that mutational status can be used to rank sensitivity to PP242 and standard chemotherapies. Single agent potency can in turn be used to predict the combination index in a drug-specific manner. Our data suggest a clinical trial to determine whether ATP-competitive mTOR inhibitors provide benefit in combination with standard chemotherapies for patients with PIK3CA mutant metastatic CRC, stratified by the presence or absence of KRAS co-mutation. Content Type Journal Article Pages 1-7 DOI 10.1007/s10637-012-9793-y Authors Chloe E. Atreya, Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, University of California, 1600 Divisadero Street, 4th Floor, San Francisco, CA 94115, USA Gregory S. Ducker, Department of Chemistry, University of California, Berkeley, CA, USA Morris E. Feldman, Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA Emily K. Bergsland, Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, University of California, 1600 Divisadero Street, 4th Floor, San Francisco, CA 94115, USA Robert S. Warren, Division of Surgical Oncology, University of California, San Francisco, CA, USA Kevan M. Shokat, Department of Chemistry, University of California, Berkeley, CA, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. Patients and Methods Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. Results No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m 2 . Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m 2 ( n  = 2), 200 mg/m 2 ( n  = 3) and 160 mg/m 2 ( n  = 1). Grade 3/4 transaminase increases ( n  = 3), grade 3/4 central nervous system disorders [confusion ( n  = 2) and ataxia ( n  = 1)], and grade 3 pyrexia ( n  = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m 2 , and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. Conclusion Dose level VIII (200 mg/m 2 ) was considered the MTD, and dose level IX (160 mg/m 2 ) was defined as the RD. Limited antitumor activity was observed. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-011-9772-8 Authors C. Massard, Departement de Médecine, Institut Gustave Roussy, University Paris South XI, SITEP, 39, rue Camille Desmoulins, 94805 Villejuif, France R. Salazar, Institut Català d’Oncologia, Barcelona, Spain J. P. Armand, Departement de Médecine, Institut Gustave Roussy, University Paris South XI, SITEP, 39, rue Camille Desmoulins, 94805 Villejuif, France M. Majem, Institut Català d’Oncologia, Barcelona, Spain E. Deutsch, Departement de Médecine, Institut Gustave Roussy, University Paris South XI, SITEP, 39, rue Camille Desmoulins, 94805 Villejuif, France M. García, Institut Català d’Oncologia, Barcelona, Spain A. Oaknin, Institut Català d’Oncologia, Barcelona, Spain E. M. Fernández-García, Pharma Mar, Clinical R&D, Colmenar Viejo, Madrid, Spain A. Soto, Pharma Mar, Clinical R&D, Colmenar Viejo, Madrid, Spain J. C. Soria, Departement de Médecine, Institut Gustave Roussy, University Paris South XI, SITEP, 39, rue Camille Desmoulins, 94805 Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The potential of EHT 6706, a novel tubulin-binding agent, was investigated in combination with ionizing radiation (IR) and with conventional cytotoxic chemotherapy agents. Cell proliferation, cell cycle, apoptosis and clonogenic assays were performed in five human cancer cell lines: H460 (non small cell lung carcinoma, NSCLC), HCT116 and HCT116 p53-/- (colorectal cancer), MDA-MB-231 (breast cancer), and MiaPaca2 cells (pancreatic cancer). The drug inhibited cell proliferation in all cell lines. This effect was associated with G2/M arrest and activation of apoptosis in a dose-dependent manner. The drug was then tested in combination with chemotherapy and IR in vitro . Effects on proliferation and clonogenic survival were analyzed. EHT 6706 treatment inhibited clonogenic survival synergistically with IR in H460 and MiaPaca2 cell lines. In the remaining cell lines, the effects of EHT 6706 and IR were additive. For H460 and MiaPaca2 cell lines, the highest effect was seen when cells were exposed for 20 h to EHT 6706 before being irradiated. EHT 6706 also exerted additive inhibition of proliferation when given in combination with conventional chemotherapy agents, such as oxaliplatin, cisplatin and gemcitabine in H460 and MiaPaca2 tumor cell lines. These data show that EHT 6706 could act synergistically with IR and additively with chemotherapy in tumor cell lines in vitro . This provides a good rationale to further assess EHT 6706 in combination protocols and confirm these effects in vivo . Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-14 DOI 10.1007/s10637-011-9785-3 Authors Céline Clémenson, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Cyrus Chargari, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Laurent Désiré, Exonhit SA, Paris, France Anne-Sophie Casagrande, Exonhit SA, Paris, France Jean Bourhis, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Eric Deutsch, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-011-9790-6 Authors David A. Proia, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Jim Sang, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Suqin He, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Donald L. Smith, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Manuel Sequeira, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Chaohua Zhang, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Yuan Liu, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Shuxia Ye, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Dan Zhou, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Ronald K. Blackman, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Kevin P. Foley, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Keizo Koya, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Yumiko Wada, Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4–12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n  = 83; Zinostatin stimalamer, n  = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse. Content Type Journal Article Category PHASE II STUDIES Pages 1-11 DOI 10.1007/s10637-011-9776-4 Authors Takuji Okusaka, Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Hiroshi Kasugai, Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Hiroshi Ishii, Hepatobiliary and Pancreatic Section, Gastroenterological Division, Cancer Institute Hospital, Tokyo, Japan Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kinki University, Osaka, Japan Michio Sata, Division of Gastroenterology, Kurume University, Fukuoka, Japan Katsuaki Tanaka, Gastroenterological Center, Yokohama City University Hospital Medical Center, Kanagawa, Japan Yasukazu Shioyama, Department of Radiology, Dokkyo Medical University, Tochigi, Japan Kazuaki Chayama, Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan Hiromitsu Kumada, Department of Hepatology, Toranomon Hospital, Tokyo, Japan Masaharu Yoshikawa, Department of Medicine and Clinical Oncology, Chiba University, Chiba, Japan Toshihito Seki, Department of Gastroenterology and Hepatology, Kansai Medical University Takii Hospital, Osaka, Japan Hidetugu Saito, Department of Internal Medicine, School of Medicine, Keio University Hospital, Tokyo, Japan Naoaki Hayashi, Department of Gastroenterology, Tokyo Women’s Medical University Hospital, Tokyo, Japan Keiko Shiratori, Department of Gastroenterology, Tokyo Women’s Medical University Hospital, Tokyo, Japan Kiwamu Okita, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan Isao Sakaida, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan Masao Honda, Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan Yukio Kusumoto, Department of Internal Medicine, Nagasaki Municipal Hospital, Nagasaki, Japan Takuya Tsutsumi, Department of Internal Medicine, Nagasaki Municipal Hospital, Nagasaki, Japan Kenji Sakata, Department of Gastroenterology, Omuta General Hospital, Omuta, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Erratum to: Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma Content Type Journal Article Category Erratum Pages 1-1 DOI 10.1007/s10637-011-9780-8 Authors Jason Konner, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Rachel N. Grisham, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Jae Park, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Owen A. O’Connor, New York University Cancer Institute, New York, NY, USA Gillian Cropp, Nereus Pharmaceuticals, Inc, San Diego, CA, USA Robert Johnson, Aeolian Biomed, Lafayette, CA, USA Alison L. Hannah, Nereus Pharmaceuticals, Inc, San Diego, CA, USA Martee L. Hensley, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Paul Sabbatini, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Svetlana Mironov, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Samuel Danishefsky, Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA David Hyman, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA David R. Spriggs, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Jakob Dupont, Genentech, Inc, 1 DNA Way, South San Francisco, CA, USA Carol Aghajanian, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    As an alternative to directly targeting of necrotic tissue using hypericin, we synthesized a conjugate of hypericin to biotin for use in a pretargeting approach. With this conjugate, we explored the possibility of a two-step pretargeting strategy using 123 I-labeled avidin as effector molecule directed against necrotic RIF-1 tumors. Hypericin was conjugated to biotin-ethylenediamine in a straightforward coupling method using n-hydroxysuccinimide and dicyclohexylcarbodiimide. The necrosis avidity of the conjugate was first confirmed in necrotic liver tissue by means of fluorescence microscopy. Using autoradiography imaging and whole body-biodistribution, the accumulation of 123 I-avidin in necrotic tumor tissue was evaluated 24 h after administration and 48 h after pretargeting with hypericin-biotin. Analysis of autoradiography images show a higher accumulation of 123 I-avidin in pretargeted compared to nontargeted tissue. However, absolute accumulation of 123 I-avidin in necrotic tumors was low as shown by biodistribution experiments. Direct injection of hypericin-biotin or biotin-fluorescein did not substantially improve 123 I-avidin accumulation after pretargeting, pointing towards a poor penetration of avidin in necrotic tissue. Our results show the feasibility of a pretargeting technique using a small molecule as targeting agent. However, for a more efficient accumulation of the effector molecule in necrotic tissue, other pretargeting strategies need to be investigated. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-011-9778-2 Authors Thierry Marysael, Laboratorium voor Farmaceutische Biologie, Faculteit Farmaceutische Wetenschappen, KU Leuven, Herestraat 49-bus 824, B-3000 Leuven, Belgium Matthias Bauwens, Laboratorium voor Radiofarmacie, Faculteit Farmaceutische Wetenschappen, K.U.Leuven, Leuven, Belgium Yicheng Ni, Departement Radiology, Faculteit Geneeskunde, K.U.Leuven, Leuven, Belgium Guy Bormans, Laboratorium voor Radiofarmacie, Faculteit Farmaceutische Wetenschappen, K.U.Leuven, Leuven, Belgium Jef Rozenski, Laboratorium voor Medicinale Chemie, K.U.Leuven, Leuven, Belgium Peter de Witte, Laboratorium voor Farmaceutische Biologie, Faculteit Farmaceutische Wetenschappen, KU Leuven, Herestraat 49-bus 824, B-3000 Leuven, Belgium Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung: Erratum to: Reappraisal of treatment-induced renal dysfunction in patients receiving antiangiogenic agents in phase I trials Content Type Journal Article Category Erratum Pages 1-1 DOI 10.1007/s10637-011-9783-5 Authors Antonin Levy, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Laurence Albiges-Sauvin, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Christophe Massard, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Hassan Izzedine, Department of Nephrology, AP-HP, Hôpital Pitié Salpetrière, Paris, France Stéphane Ederhy, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Ratio Bahleda, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Carlos Gomez-Roca, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Cyrus Chargari, Inserm 1030, Institut Gustave Roussy, Paris XI University, Villejuif, France Isabelle Brocheriou-Spelle, Department of Pathology, AP-HP, Hôpital Pitié Salpetrière, Paris, France Jean-Charles Soria, SITEP (Service des Innovations Therapeutiques Precoces), Department of Medicine, Institut Gustave Roussy, Paris XI University, 114 rue Edouard Vaillant, 94805 Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. Methods A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3 weeks (one course) with an initial dose of 12.4 mg/m 2 up to 22.0 mg/m 2 for a maximum of 6 courses. Results The maximum tolerated dose (MTD) was determined to be 16.5 mg/m 2 . The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12 weeks. Conclusions Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-011-9773-7 Authors Kazuhiro Araki, Department of Clinical Oncology, Saitama Medical University, Saitama, Japan Koichi Kitagawa, Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan Hirofumi Mukai, Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan Toru Mukohara, Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan Keiji Kodama, Department of Clinical Oncology, Saitama Medical University, Saitama, Japan Yuichi Ando, Department of Clinical Oncology, Saitama Medical University, Saitama, Japan Masaru Narabayashi, Department of Clinical Oncology, Saitama Medical University, Saitama, Japan Hironobu Minami, Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan Kiyomi Mera, Bayer Yakuhin Ltd., Osaka, Japan Yasutsuna Sasaki, Department of Clinical Oncology, Saitama Medical University, Saitama, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16–120 mg/m 2 ). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m 2 . Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m 2 . PK data were linear from 16 to 100 mg/m 2 , with proportional increases in mean C max and AUC tot as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m 2 revealed the following: half-life (t ½ ) = 9.1 ± 2.2 h; volume of distribution (V z ) = 119 ± 41 L/m 2 ; clearance (CL) = 9.3 ± 3.2 L/h/m 2 . MTBF ( n  = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m 2 . Tumor shrinkage ( n  = 2, lymphoma), stable disease 〉3 months ( n  = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions ( n  = 1, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m 2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-011-9765-7 Authors Jason Konner, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Rachel N. Grisham, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Jae Park, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Owen A. O’Connor, New York University Cancer Institute, New York, NY, USA Gillian Cropp, Nereus Pharmaceuticals, Inc, San Diego, CA, USA Robert Johnson, Aeolian Biomed, Lafayette, CA, USA Alison L. Hannah, Nereus Pharmaceuticals, Inc, San Diego, CA, USA Martee L. Hensley, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Paul Sabbatini, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Svetlana Miranov, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Samuel Danishefsky, Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA David Hyman, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA David R. Spriggs, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Jakob Dupont, Genentech, Inc, 1 DNA Way, South San Francisco, CA, USA Carol Aghajanian, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. Experimental design This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40–195 mg/m 2 ) were combined with 500 mg/m 2 of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. Results A total of 31 patients were enrolled into six cohorts (three at 40 mg/m 2 over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m 2 , 70 mg/m 2 , and 195 mg/m 2 ; 13 at 105 mg/m 2 ; six at 150 mg/m 2 ). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m 2 ); reversible infusion-related reaction (150 mg/m 2 ); thrombocytopenia (195 mg/m 2 ); and fatigue (195 mg/m 2 ). The maximum tolerated dose was defined as 150 mg/m 2 . The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m 2 . Conclusion LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9815-9 Authors Glen J. Weiss, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Ross C. Donehower, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA Tara Iyengar, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Ramesh K. Ramanathan, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Karen Lewandowski, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Eric Westin, Eli Lilly and Company, Indianapolis, Indiana Karla Hurt, Eli Lilly and Company, Indianapolis, Indiana Scott M. Hynes, Eli Lilly and Company, Indianapolis, Indiana Stephen P. Anthony, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Scott McKane, PharmaNet/i3, Eden Prairie, MN, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. Experimental design We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results A total of 56 doses were administered to 21 patients over 8 dose levels (15–164 mg/m 2 ). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m 2 and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K trans in some patients. Conclusions CYT997 is orally bioavailable. The 118 mg/m 2 dose level should be used to guide dosing in future studies. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-012-9813-y Authors Matthew Burge, Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia Alessandra B. Francesconi, Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia Dusan Kotasek, Adelaide Cancer Centre, Kurralta Park, South Australia 5037, Australia Rosa Fida, Cytopia Research Pty Ltd, Richmond, Victoria 3121, Australia Gregg Smith, Cytopia Research Pty Ltd, Richmond, Victoria 3121, Australia Andrew Wilks, Cytopia Research Pty Ltd, Richmond, Victoria 3121, Australia Paul A. Vasey, Haematology and Oncology Clinics of Australia, Wesley Medical Centre, Auchenflower, Queensland 4066, Australia Jason D. Lickliter, Phase I Cancer Trials Program, Monash Medical Centre and Monash Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. Methods In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. Results Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n  = 3; epistaxis, n  = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease ( n  = 5; 83.3%) and stable disease ( n  = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. Conclusions The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors. Content Type Journal Article Category PHASE I STUDIES Pages 1-8 DOI 10.1007/s10637-012-9801-2 Authors Christina M. Annunziata, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 12 N226, Bethesda, MD 20892-1906, USA Elise C. Kohn, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 12 N226, Bethesda, MD 20892-1906, USA Patricia LoRusso, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA Nicole D. Houston, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 12 N226, Bethesda, MD 20892-1906, USA Robert L. Coleman, Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Manuela Buzoianu, MedImmune, LLC, Gaithersburg, MD 20878, USA Gabriel Robbie, MedImmune, LLC, Gaithersburg, MD 20878, USA Robert Lechleider, Human Genome Sciences, Inc, Rockville, MD 20850, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies—VEGF and mTOR inhibitors—are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib. Content Type Journal Article Category REVIEW Pages 1-14 DOI 10.1007/s10637-012-9796-8 Authors Roger B. Cohen, Division of Hematology/Oncology, University of Pennsylvania, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104, USA Stéphane Oudard, Medical Oncology Department, Georges Pompidou European Hospital, 20 Rue Leblanc, Paris, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    L-Glutamate (Glu) plays a crucial role in the growth of malignant gliomas. We have established the feasibility of accelerating a naturally occurring brain to-blood Glu efflux by decreasing blood Glu levels with intravenous oxaloacetate, the respective Glu co-substrate of the blood resident enzyme humane glutamate–oxaloacetate transaminase (hGOT). We wished to demonstrate that blood Glu scavenging provides neuroprotection in the case of glioma. We now describe the neuroprotective effects of blood Glu scavenging in a fatal condition such as brain-implanted C6 glioma in rats and brain-implanted human U87 MG glioma in nude mice. Rat (C-6) or human (U87) glioma cells were grafted stereotactically in the brain of rats or mice. After development of tumors, the animals were drinking oxaloacetate with or without injections of hGOT. In addition, mice were treated with combination treatment, which included drinking oxaloacetate with intracutaneous injections of hGOT and intraperitoneal injection of Temozolomide. Animals drinking oxaloacetate with or without injections of hGOT displayed a smaller tumor volume, reduced invasiveness and prolonged survival than control animals drinking saline. These effects were significantly enhanced by Temozolomide in mice, which increased survival by 237%. This is the first demonstration of blood Glu scavenging in brain cancer, and because of its safety, is likely to be of clinical significance for the future treatment of human gliomas. As we demonstrated, the blood glutamate scavenging treatment in combination with TMZ could be a good candidate or as an alternative treatment to the patients that do not respond to TMZ. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9794-x Authors Angela Ruban, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100 Israel Tamara Berkutzki, Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, 76100 Israel Itzik Cooper, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100 Israel Boaz Mohar, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100 Israel Vivian I. Teichberg, Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100 Israel Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. Experimental Design Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. Results Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was 〉80%. Four patients achieved partial response (response rate 13%, 95% CI 1–25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19–52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib ( P  = .0085) and with primary genotypes other than KIT exon 11 mutation ( P  = .0341) was significantly shorter than that of patients without. Conclusions Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks. Content Type Journal Article Category PHASE II STUDIES Pages 1-7 DOI 10.1007/s10637-012-9795-9 Authors S. H. Park, Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University Samsung Medical Center, Seoul, South Korea M. H. Ryu, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea B. Y. Ryoo, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea S. A. Im, Department of Internal Medicine, Seoul National University Hospital, Soeul, South Korea H. C. Kwon, Department of Internal Medicine, Dong-A University College of Medicine, Dong-A University Hospital, Busan, South Korea S. S. Lee, Division of Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea S. R. Park, Research Institute and Hospital, National Cancer Center, Gyeonggi, South Korea B. Y. Kang, Department of Oncology/Hematology, Kyungpook National University Hospital, Daegu, South Korea Y. K. Kang, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n  = 3; 30 mg cohort: n  = 3; 45 mg cohort: n  = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors. Content Type Journal Article Category PHASE I STUDIES Pages 1-12 DOI 10.1007/s10637-011-9789-z Authors Toshiaki Takahashi, Shizuoka Cancer Center, Shizuoka, Japan Narikazu Boku, Shizuoka Cancer Center, Shizuoka, Japan Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka, Japan Tateaki Naito, Shizuoka Cancer Center, Shizuoka, Japan Asuka Tsuya, Shizuoka Cancer Center, Shizuoka, Japan Yukiko Nakamura, Shizuoka Cancer Center, Shizuoka, Japan Akira Ono, Shizuoka Cancer Center, Shizuoka, Japan Nozomu Machida, Shizuoka Cancer Center, Shizuoka, Japan Kentaro Yamazaki, Shizuoka Cancer Center, Shizuoka, Japan Junichiro Watanabe, Shizuoka Cancer Center, Shizuoka, Japan Ana Ruiz-Garcia, Pfizer Oncology, La Jolla, CA, USA Keiji Imai, Pfizer Japan Inc., Tokyo, Japan Emiko Ohki, Pfizer Japan Inc., Tokyo, Japan Nobuyuki Yamamoto, Shizuoka Cancer Center, Shizuoka, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The basal SOCS1 mRNA levels were significantly lower in p53 mutated BJAB and MAVER leukemic cell lines with respect to p53 wild-type SKW6.4 and JVM-2 leukemic cell lines, p53 wild-type primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53 wild-type B-CLL cells as well as in p53 wild-type B leukemic cell lines, but not in p53 mutated B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important therapeutic target of Nutlin-3 in B-CLL. Content Type Journal Article Category SHORT REPORT Pages 1-4 DOI 10.1007/s10637-011-9786-2 Authors Maria Grazia di Iasio, Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy Alessia Norcio, Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy Elisabetta Melloni, Department of Morphology and Embryology and LTTA Centre, University of Ferrara, Ferrara, Italy Giorgio Zauli, Institute for Maternal and Child Health, IRCCS Burlo Garofolo of Trieste, Via dell’Istria 65/1, 34100 Trieste, Italy Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Purpose Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In phase III trials, ipilimumab was shown to be the first agent to improve survival in advanced melanoma patients, regardless of previous treatment. We report a case of severe neurologic disease after ipilimumab treatment. Patient and methods Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed with time a few days after the fourth monthly ipilimumab infusion. Analysis of the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic meningitis. Despite high doses of steroids and symptomatic treatment, the symptoms worsened. Results Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later. Conclusion The adverse event profile associated with ipilimumab was primarily immune-related. This is the first case in which such a severe event has been reported. Content Type Journal Article Category SHORT REPORT Pages 1-4 DOI 10.1007/s10637-011-9787-1 Authors Flavie Bompaire, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Christine Mateus, Service de dermatologie, département d’oncologie médicale, Institut Gustave Roussy, Villejuif, France Hervé Taillia, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Thierry De Greslan, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Marion Lahutte, Service de radiologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Magali Sallansonnet-Froment, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Madani Ouologuem, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Jean-Luc Renard, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Guy Gorochov, Laboratoire d’Immunologie, Hôpital de la Pitié Salpêtrière, Paris, France Caroline Robert, Service de dermatologie, département d’oncologie médicale, Institut Gustave Roussy, Villejuif, France Damien Ricard, Service de neurologie, Hôpital d’instruction des armées du Val de Grâce, Service de santé des Armées, Paris, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Ent-11-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) isolated from Pteris Semipinnata L is known to inhibit certain tumor cells in vitro. The information on the in vivo effect of 5F is limited and its effect on hepatocellular carcinoma (HCC) is unknown. In this study, the anti-tumor effect of 5F was investigated in a diethylnitrosamine (DEN)-induced mouse HCC model. In addition to therapeutic effect, the potential side effect was monitored. A panel of cultured HCC cells was used to confirm the in vivo data and explore the responsible molecular pathway. The result showed that 5F significantly inhibited the DEN-induced HCC tumors by reducing the number of tumor foci and the volume of tumors. Furthermore, 5F induced the death of cultured HCC cells in dose- and time-dependent manners. The cell death was confirmed to be apoptotic by in vivo and in vitro TUNEL assays. 5F inhibited NF-kB by stabilizing its inhibitor IkBα, reducing the nuclear p65 and inhibiting NF-kB activity. Subsequently it affected the NF-kB downstream molecules with a decrease in anti-apoptotic Bcl-2 and increase in pro-apoptotic Bax and Bak. During the whole period of the experiment, mice receiving 5F appeared to be healthy, though they suffered from a mild degree of hair loss. 5F did not damage liver and renal functions. In conclusion, 5F is effective against HCC with minimal side effects. It induces apoptosis in HCC cells via inhibiting NF-kB, leading to the decrease of Bcl-2 but the increase of Bax and Bak. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-011-9791-5 Authors George G. Chen, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Jackie Leung, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Nian Ci Liang, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Li Li, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Kefeng Wu, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Ursula P. F. Chan, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Billy C. S. Leung, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Mingyue Li, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Jing Du, Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China Yi Feng Deng, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Xianling Gong, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Yingnian Lv, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, Guangdong, China Ernest C. W. Chak, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Paul B. S. Lai, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The epidermal growth factor receptor (EGFR) pathway is aberrantly activated in tumors and plays a key role in promoting tumor growth. Small molecule inhibitors which bind reversibly to EGFR have demonstrated limited clinical activity. Thus, there is a continued need to develop novel EGFR inhibitors with improved anti-tumor activity. Bay846 is a newly developed small molecule inhibitor that binds irreversibly to the tyrosine kinase domains of EGFR and Her2. The in vitro and in vivo efficacy of Bay846 was tested using a panel of nine human malignant brain tumor (glioma) models. Lapatinib, a reversible inhibitor of EGFR and Her2, was included for comparison. Six glioma cell lines were sensitive to Bay846 treatment. Bay846 strongly suppressed tumor cell growth in vitro by inducing cell lysis/death rather than cell cycle arrest. Consistent with this, Bay846 had potent anti-tumor activity which led to regressions in tumor size. The active, phosphorylated form of EGFR was reduced by Bay846 treatment in vitro and in tumors. Importantly, the efficacy of Bay846 was significantly greater than lapatinib in all assays. Bay846-sensitivity was associated with expression of a wild-type PTEN in conjunction with high levels of an oncogenic EGFR variant (A289V or EGFRvIII). These studies demonstrate that targeting the EGFR pathway with the irreversible inhibitor Bay846 has great potential to increase the efficacy of this cancer therapy. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-12 DOI 10.1007/s10637-011-9784-4 Authors Sharon L. Longo, Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, 750 East Adams St., Rm 4117 IHP, Syracuse, NY 13210, USA David J. Padalino, Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, 750 East Adams St., Rm 4117 IHP, Syracuse, NY 13210, USA Sandra McGillis, Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, 750 East Adams St., Rm 4117 IHP, Syracuse, NY 13210, USA Kirstin Petersen, Bayer Healthcare, Berlin, Germany Hartmut Schirok, Bayer Healthcare, Berlin, Germany Oliver Politz, Bayer Healthcare, Berlin, Germany Gregory W. Canute, Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, 750 East Adams St., Rm 4117 IHP, Syracuse, NY 13210, USA Dawn E. Post, Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, 750 East Adams St., Rm 4117 IHP, Syracuse, NY 13210, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Biliary tract cancer (BTC) is associated with poor survival and unresponsiveness to chemotherapy. Targeted therapies for BTC have been studied, and HER family members are promising therapeutic targets in BTC. In this study, we evaluated the efficacy of PF00299804, an irreversible pan-HER inhibitor, in eight BTC cell lines alone or combined with gemcitabine. PF00299804 potently inhibited the growth of two cell lines (SNU308 and SNU478) out of the eight BTC cell lines as a single agent. PF00299804 blocked HER family and downstream signaling pathways, inducing G1 arrest or apoptosis. Moreover, PF00299804 exerted synergistic effects with gemcitabine in seven of the eight BTC cell lines, possibly through the regulation of the genes involved in the response to gemcitabine, such as TS (thymidylate synthase), RRM1 (ribonucleotide reductase), and MAGEH1, which is negatively correlated with gemcitabine sensitivity. Our results support the need for further study of PF00299804 alone or combined with gemcitabine for the treatment of BTC. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-13 DOI 10.1007/s10637-011-9782-6 Authors Hyun-Jin Nam, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Hwang-Phill Kim, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Young-Kwang Yoon, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Sang-Hyun Song, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Ah-Rum Min, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Sae-Won Han, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Seock-Ah Im, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Tae-You Kim, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Do-Youn Oh, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Yung-Jue Bang, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    The bisecting GlcNAc is transferred to the core mannose residue of complex or hybrid N-glycans on glycoproteins by the β1,4- N -acetylglucosaminyltransferase III (GlcNAcT-III) or MGAT3. The addition of the bisecting GlcNAc confers unique lectin recognition properties to N-glycans. Thus, LEC10 gain-of-function Chinese hamster ovary (CHO) cells selected for the acquisition of ricin resistance, carry N-glycans with a bisecting GlcNAc, which enhances the binding of the erythroagglutinin E-PHA, but reduces the binding of ricin and galectins-1, -3 and -8. The altered interaction with galactose-binding lectins suggests that the bisecting GlcNAc affects N-glycan conformation. LEC10 mutants expressing polyoma middle T antigen (PyMT) exhibit reduced growth factor signaling. Furthermore, PyMT-induced mammary tumors lacking MGAT3, progress more rapidly than tumors with the bisecting GlcNAc on N-glycans of cell surface glycoproteins. In recent years, evidence for a new paradigm of cell growth control has emerged involving regulation of cell surface residency of growth factor and cytokine receptors via interactions and cross-linking of their branched N-glycans with a lattice of galectin(s). Specific cross-linking of glycoprotein receptors in the lattice regulates their endocytosis, leading to effects on growth factor-induced signaling. This review will describe evidence that the bisecting GlcNAc of N-glycans regulates cellular signaling and tumor progression, apparently through modulating N-glycan/galectin interactions. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9373-6 Authors Hazuki E. Miwa, Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA Yinghui Song, Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA Richard Alvarez, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Richard D. Cummings, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Pamela Stanley, Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    The past 25 years have seen significant advances in understanding the diversity and functions of glycoprotein glycans in Drosophila melanogaster . Genetic screens have captured mutations that reveal important biological activities modulated by glycans, including protein folding and trafficking, as well as cell signaling, tissue morphogenesis, fertility, and viability. Many of these glycan functions have parallels in vertebrate development and disease, providing increasing opportunities to dissect pathologic mechanisms using Drosophila genetics. Advances in the sensitivity of structural analytic techniques have allowed the glycan profiles of wild-type and mutant tissues to be assessed, revealing novel glycan structures that may be functionally analogous to vertebrate glycans. This review describes a selected set of recent advances in understanding the functions of N-linked and O-linked (non-glycosaminoglycan) glycoprotein glycans in Drosophila with emphasis on their relatedness to vertebrate organisms. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9442-x Authors Toshihiko Katoh, The Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA Michael Tiemeyer, The Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    In this study, we purified and characterized the β-xylosidase involved in the turnover of plant complex type N -glycans to homogeneity from mature red tomatoes. Purified β-xylosidase (β-Xyl’ase Le-1) gave a single band with molecular masses of 67 kDa on SDS-PAGE under a reducing condition and 60 kDa on gelfiltration, indicating that β-Xyl’ase Le-1 has a monomeric structure in plant cells. The N- terminal amino acid could not be identified owing to a chemical modification. When pyridylaminated (PA-) N- glycans were used as substrates, β-Xyl’ase Le-1 showed optimum activity at about pH 5 at 40 °C, suggesting that the enzyme functions in a rather acidic circumstance such as in the vacuole or cell wall. β-Xyl’ase Le-1 hydrolyzed the β1-2 xylosyl residue from Man 1 Xyl 1 GlcNAc 2 -PA, Man 1 Xyl 1 Fuc 1 GlcNAc 2 -PA, and Man 2 Xyl 1 Fuc 1 GlcNAc 2 -PA, but not that from Man 3 Xyl 1 GlcNAc 2 -PA or Man 3 Xyl 1 Fuc 1 GlcNAc 2 -PA, indicating that the α1-3 arm mannosyl residue exerts significant steric hindrance for the access of β-Xyl’ase Le-1 to the xylosyl residue, whereas the α1-3 fucosyl residue exerts little effect. These results suggest that the release of the β1-2 xylosyl residue by β-Xyl’ase Le-1 occurs at least after the removal the α-1,3-mannosyl residue in the core trimannosyl unit. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9441-y Authors Daisuke Yokouchi, Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima-Naka 1-1-1, Okayama, 700-8530 Japan Natsuko Ono, Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima-Naka 1-1-1, Okayama, 700-8530 Japan Kosuke Nakamura, Kagome Research Institute, Kagome Co., Ltd., 17 Nishitomiyama, Nasushiobara, Tochigi 329-2762, Japan Megumi Maeda, Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima-Naka 1-1-1, Okayama, 700-8530 Japan Yoshinobu Kimura, Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima-Naka 1-1-1, Okayama, 700-8530 Japan Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Many post-translational modifications, including glycosylation, are pivotal for the structural integrity, location and functional activity of glycoproteins. Sub-populations of proteins that are relocated or functionally changed by such modifications can change resting proteins into active ones, mediating specific effector functions, as in the case of monoclonal antibodies. To ensure safe and efficacious drugs it is essential to employ appropriate robust, quantitative analytical strategies that can (i) perform detailed glycan structural analysis, (ii) characterise specific subsets of glycans to assess known critical features of therapeutic activities (iii) rapidly profile glycan pools for at-line monitoring or high level batch to batch screening. Here we focus on these aspects of glycan analysis, showing how state-of-the-art technologies are required at all stages during the production of recombinant glycotherapeutics. These data can provide insights into processing pathways and suggest markers for intervention at critical control points in bioprocessing and also critical decision points in disease and drug monitoring in patients. Importantly, these tools are now enabling the first glycome/genome studies in large populations, allowing the integration of glycomics into other ‘omics platforms in a systems biology context. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9443-9 Authors Tharmala Tharmalingam, NIBRT Glycobiology Laboratory, NIBRT - The National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland Barbara Adamczyk, NIBRT Glycobiology Laboratory, NIBRT - The National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland Margaret A. Doherty, NIBRT Glycobiology Laboratory, NIBRT - The National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland Louise Royle, Ludger Ltd., Culham Science Centre, Oxfordshire, OX14 3EB UK Pauline M. Rudd, NIBRT Glycobiology Laboratory, NIBRT - The National Institute for Bioprocessing Research and Training, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Beschreibung:    Background Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. Results Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43 % of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for ≥13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. Conclusion Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN. Content Type Journal Article Category PHASE II STUDIES Pages 1-8 DOI 10.1007/s10637-012-9861-3 Authors Tanguy Seiwert, The University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637, USA John Sarantopoulos, University of Texas Health Science Center, San Antonio, TX, USA Howard Kallender, GlaxoSmithKline, Collegeville, PA, USA Stewart McCallum, GlaxoSmithKline, Collegeville, PA, USA Harold N. Keer, Exelixis, South San Francisco, CA, USA George Blumenschein Jr., The University of Texas MD Anderson Cancer Center, Houston, TX, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Background CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG 1 κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. Methods In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. Results Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD 〉6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥3 AEs. Common grade ≥3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-μg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. Conclusion Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC. Content Type Journal Article Category PHASE II STUDIES Pages 1-9 DOI 10.1007/s10637-012-9869-8 Authors Kenneth J. Pienta, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Room 7308, Ann Arbor, MI 48109, USA Jean-Pascal Machiels, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Dirk Schrijvers, Ziekenhuisnetwerk Antwerpen-Middelheim, Antwerp, Belgium Boris Alekseev, FGU Hertzen Oncology Research Institute of Rosmedtechnology, Moscow, Russia Mikhail Shkolnik, Russian Scientific Center of Radiology and Surgical Technologies, Federal Agency for High Technology Medical Care, St. Petersburg, Russia Simon J. Crabb, University of Southampton Faculty of Medicine, Southampton, UK Susan Li, Janssen Research & Development, Spring House, PA, USA Shobha Seetharam, Janssen Research & Development, Radnor, PA, USA Thomas A. Puchalski, Janssen Research & Development, Spring House, PA, USA Chris Takimoto, Janssen Research & Development, Radnor, PA, USA Yusri Elsayed, Janssen Research & Development, Raritan, NJ, USA Fitzroy Dawkins, Janssen Research & Development, Raritan, NJ, USA Johann S. de Bono, Royal Marsden, NHS Foundation Trust and the Institute of Cancer Research, Sutton, UK Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m 2 (1.1 MBq) of 14  C–radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (V ss : 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2–3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9838-2 Authors Kevin R. Kelly, Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX, USA Markus Zollinger, Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland Frédéric Lozac’h, Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland Eugene Tan, Department of Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA Alain Mita, Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX, USA Felix Waldmeier, Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland Patrick Urban, Department of Oncology Clinical Research, Novartis Pharmaceuticals Corporation, Basel, Switzerland Suraj Anand, Department of Biostatistics and Data Management, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA Yanfeng Wang, Department of Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA Piet Swart, Department of Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland Chris Takimoto, Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX, USA Monica Mita, Institute For Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents. Content Type Journal Article Category REVIEW Pages 1-17 DOI 10.1007/s10637-012-9873-z Authors Henry C. Lai, Departments of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195, USA Narendra P. Singh, Departments of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195, USA Tomikazu Sasaki, Departments of Chemistry, University of Washington, Seattle, WA 98195, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Beschreibung:    Topoisomerase II α enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II α (hTopo II α) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II α enzyme. Five out of nine andrographolide analogues potently reduced hTopo II α activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC 50 values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 μM. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II α activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 μM concentration inhibited hTopo II α, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II α functions. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-13 DOI 10.1007/s10637-012-9868-9 Authors Jintapat Nateewattana, Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Rungnapha Saeeng, Department of Chemistry, Faculty of Science, Burapha University, Chonburi, 20131 Thailand Sakkasem Kasemsook, Department of Chemistry, Faculty of Science, Burapha University, Chonburi, 20131 Thailand Kanoknetr Suksen, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Suman Dutta, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Surawat Jariyawat, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Arthit Chairoungdua, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Apichart Suksamrarn, Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, 10240 Thailand Pawinee Piyachaturawat, Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997