ALBERT

Description: Abstract 3535 Background: AYAs with ALL are increasingly recognized as a distinct population with unique biomedical and psychosocial characteristics. However, little is known about factors that may influence participation in, and compliance with, the challenging treatment regimens that are currently being tested in this patient population. U.S. Intergroup trial C10403 was designed to prospectively evaluate a successful pediatric treatment approach in AYAs with ALL, with an additional aim to assess demographics, social support, and potential barriers to care that may impact outcomes. We describe here for the first time the baseline characteristics of patients enrolled on C10403 in order to begin to understand the personal challenges they face during treatment. Methods: Self-administered surveys were conducted at specified time points over the course of treatment. Survey 1, which explored demographics, decision making, and social support, was administered to patients following completion of induction chemotherapy. Survey 2, which evaluated treatment delays and barriers to care, was administered after remission consolidation at about 6 months. Descriptive statistics were used to summarize patient demographics and responses to survey questions. Results: Between November, 2007 and July, 2012, 296 patients across the United States aged16–39 were enrolled on C10403; 269 signed consent to participate in the survey study. 183 (68%), 129 (48%), and 193 (72%) completed survey 1, survey 2, or either survey. Of the survey respondents, 61% were male, 73% white, 11% African American, and 11% Hispanic. Median age was 24 years (yrs) (range 17–39); 17%, 62%, and 22% were

Description: Abstract 306 Introduction: Histone deacetylase inhibitors potentiate the efficacy of anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore conducted a phase I clinical trial to evaluate the safety of the histone deacetylase inhibitor, vorinostat, in combination with pegylated liposomal doxorubicin (PLD) and bortezomib for patients with relapsed/refractory MM. Patients and Methods: Patients received bortezomib at 1.3mg/m2 on days 1, 4, 8, and 11; PLD at 30mg/m2 on day 4, and escalating doses of vorinostat (200 to 400mg once daily) on days 4 through 11 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients remained on therapy until disease progression or unacceptable toxicity. Eligibility criteria included an ANC of ≥1.0×109/L, platelets of ≥100×109/L, a CrCl of ≥30 mL/min., and adequate hepatic and cardiac function. The primary objectives of the study were to establish dose limiting toxicities (DLTs) in cycle 1 and the maximum tolerated dose (MTD) for future phase II testing. Results: Nine patients have enrolled thus far at vorinostat dose levels of 200mg (n=3), 300mg (n=4), and 400mg (n=2). Six patients had relapsed disease, while 3 had relapsed disease that was refractory to their last prior therapy. The median age was 56 (range 44–73), median time from diagnosis was 66 months (range 28 to 117), and median prior number of lines of therapy was 2 (1 to 7). Six of 9 patients received prior bortezomib, 3 of whom were refractory, 7 of 9 had received anthracyclines, 9 of 9 were treated with corticosteroids, 8 of 9 were treated with immunomodulatory agents, and 7 of 9 had undergone autologous stem cell transplantation. One patient was removed from the study at the 300mg vorinostat dose level due to a grade 3 infusion reaction with the first dose of PLD and was not evaluable for DLT or response. Otherwise, there have been no DLTs, serious adverse events, or deaths to date. Common non-hematologic toxicities of all grades have included fatigue (44%), constipation (67%), diarrhea (67%), nausea (56%), vomiting (33%), and peripheral neuropathy (56%), the majority of which were grade 1 and 2 in severity. Grade 3 sensory neuropathy was seen in 2 patients. Common hematologic toxicities of all grades have included neutropenia (44%), lymphopenia (44%), and thrombocytopenia (67%). Grade 3/4 neutropenia, lymphopenia and thrombocytopenia were seen in 2, 3, and 2 patients, respectively. Dose reductions for non-hematologic toxicities have been necessary for 3 patients thus far. Using International Myeloma Working Group criteria, 6 out of 7 evaluable patients have responded to treatment, including 1 complete remission (CR), 1 very good partial remission, and 4 partial remissions (PRs). The only non-responder was assigned to the 200mg vorinostat dose level. PRs were seen in 2 of 3 patients with bortezomib-refractory disease. Conclusions: At the dose levels tested thus far, the addition of vorinostat to the PLD/bortezomib backbone is safe and efficacious in relapsed/refractory MM patients, including those with bortezomib-refractory disease. Cumulative constitutional, gastrointestinal, and neurologic toxicities are common but manageable, and will need to be considered when determining the optimal phase II dose moving forward. Enrollment into the 400mg dose cohort continues. Disclosures: Voorhees: Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Off Label Use: Vorinostat for the treatment of multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Foster:Genzyme: Consultancy, Research Funding. Shea:Otsuka: Research Funding; Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Research Funding; Genzyme: Consultancy, Research Funding; Genetech: Consultancy. Rizvi:Merck: Employment.

Description: Abstract 1039 Poster Board I-61 Background: The inhibitor of apoptosis protein (IAP) survivin is central in integrating proliferative and cell cycle regulatory networks. In leukemic cells, survivin mediates survival as well as resistance to chemotherapeutics and Flt-3 inhibitors. Experimentally targeting survivin has shown anti-leukemic activity and is a postulated therapeutic approach. Herein we report a clinical trial with the novel survivin and cdc2 (CDK1) inhibitor Terameprocol (EM-1421) in patients (pts) with advanced hematological malignancies. As little is known about in-vivo up- and downstream regulatory pathways of survivin and it's inhibition, specimens from pts were collected for correlative pharmacodynamic (PD) marker analysis. Methods: Open-label, single agent, phase I dose escalation study of Terameprocol (T) in pts with advanced, relapsed or refractory hematological malignancies (AML, ALL, MDS, advanced CLL or CML). Pts age 〉 18 years with adequate organ function and performance status (ECOG) ≤ 1were treated with 1000, 1500 and 2200 mg of intravenous Terameprocol 3x/week (wk) for 2 of 3 wks in cohorts of 3 pts to establish the safety, maximum tolerated dose (MTD) and to assess pharmacokinetics at the studied dose schedule (primary objectives). Secondary objectives were to select the recommended phase 2 dose (RP2D) and to assess anti-leukemic activity and PD marker regulation (baseline, cycle 1 day 5 and 12, end of study). Results: Between 8/2007 and 3/2009, sixteen pts (4 female, 12 male) with a median age of 68.5 years (range 42-78) and median of 2 prior regimens (range 0-5) were enrolled. Most pts had AML (n=13), 7 pts primary and 6 pts secondary or treatment related AML; one pt each had CML-BP, T-ALL and MDS. Ten pts had unfavorable or complex cytogenetics including 6 pts with 5q/7q and 2 pts with 11q23 aberrations. Four, 5 and 6 pts were treated at the 1000, 1500 and 2200 mg dose cohorts respectively. One pt did not start treatment on study. 15 pts received ≥ 1 dose/cycle, 6 of whom (38%) received ≥ 2 cycles of T (range 1-5). Common possible or probable treatment related adverse events (AE) were grade 1 or 2 headache (n=3, 20%), transaminitis (grade 2 n=2, grade 3 n=2) and pruritus (n=2). Treatment related serious AE's (SAE) was a grade 4 pneumonia in 1 pt. Non-drug related SAE's ≥ grade 3 or 4 included sepsis/febrile neutropenia (n=3), pneumonia (n=2), dyspnea (n=2), cerebral hemorrhage (n=1), confusion/mental status change (n=1), cardiac arrest (n=1) and AML progression (n=3) leading to death in 2 pts. No AE/SAE was felt to constitute a dose limiting toxicity (DLT) per protocol definition. However, due to grade 3 transaminitis observed in 2 pts together with concerns of compromised respiratory status of pts treated at the 2200 mg cohort, the investigators determined the maximum tolerated dose (MTD) to be 1500 mg 3x/week for 2 of 3 weeks, which is also the recommended RP2D. One heavily pretreated pt (3 prior regimens) with CML-BP myeloid, achieved a partial remission (1500 mg) and transfusion independence for 5 cycles prior to disease progression. Hematological improvement (HI-E, HI-P) was seen in 1 pt (1000 mg), and 5 pts had stable disease. Surprisingly, Cmax of T at 1500 mg was higher than at 2200 or 1000 mg. Overall concentrations of T were in the same range as measured in previous studies of T in solid tumors (daily x5), indicating adequate drug exposure at the schedule studied. PD samples at indicated time points were collected and are currently being analyzed to assess the effects of T on survivin, cdc2/CDK1 and survivin associated regulatory genes. Conclusion: The novel small molecule surivin inhibitor Terameprocol can be safely administered to pts with advanced leukemias. Sufficient drug exposure was seen in pts and the MTD and RP2D were established for future studies. Clinical activity was observed in a pt with myeloid CML-BP and potentially in pts with AML. Interestingly, previous work showed an association between progression to advanced stages of CML and survivin expression. Data on correlative PD marker experiments will be presented. Disclosures: Tibes: Erimos Pharmaceuticals : Research Funding. McDonagh:Erimos: Research Funding. Frazer:Erimos Pharmaceuticals: Employment. Mohrland:Erimos Pharmaceuticals: Employment. Von Hoff:Erimos Pharmaceuticals: Consultancy.

Description: Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Description: Abstract 3985 Introduction: Although the combination of PLD and B improved time to progression (TTP) compared with B alone in patients (pts) with R/R MM, the overall response rate (ORR) of the regimen was only 44%, while TTP was 9.3 months. As such, strategies that build upon the efficacy of this regimen are needed. Vorinostat (V) is a histone deacetylase inhibitor that has demonstrated additive to synergistic activity with proteasome inhibitors and anthracyclines in preclinical models of MM. We therefore conducted a phase I study evaluating the safety and preliminary efficacy of V when combined with the PLD/B backbone. Patients and Methods: Pts were treated with standard doses of B and PLD (B 1.3mg/m2 on D1, 4, 8, 11, and PLD 30mg/m2 on D4) and escalating doses of V from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard 3 + 3 design. Eligibility criteria included a diagnosis of relapsed or relapsed/refractory MM, absolute neutrophil count ≥1.0×109/L, platelets ≥100×109/L, creatinine clearance ≥30mL/min, and adequate hepatic and cardiac function. The primary objective was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen and the secondary objective was to assess preliminary efficacy. Results: 32 pts were enrolled at the following dose levels: The median age was 61 (39–75) and median β2-microglobulin 3.57 mcg/mL (1.26–10.6). 69% of the pts were male, 31% female. The median time from diagnosis was 46 months (13–155) and median number of prior lines of therapy 2 (1–9). 78% of pts had received prior B, 56% PLD or doxorubicin, 91% thalidomide and/or lenalidomide, and 66% autologous and/or allogeneic stem cell transplantation. 44% (11 of 25 pts) had disease refractory to prior B-based therapy. The median number of complete cycles administered was 6 (0–15). No patients on dose level 1 or 2 suffered DLTs. One of 6 pts on dose level 3 had a DLT consisting of grade 4 systolic dysfunction in the setting of atrial flutter, which subsequently resolved. Two of 6 pts at dose level 4 experienced grade 4 thrombocytopenia in cycle 1, establishing dose level 3 as the MTD. Nine pts experienced serious adverse events at least possibly attributable to protocol therapy, including the 1 case of systolic dysfunction/atrial flutter noted above, 2 cases of nausea and vomiting with dehydration, and diarrhea, diastolic dysfunction, upper respiratory infection, syncopal episode and hypertension in 1 pt each. Grade 3 neutropenia was seen in 34% of pts (3% grade 4). 4 pts had grade 3 infections (1 attributed to protocol therapy), but no grade 4 infections were seen regardless of attribution. Grade 3 and 4 thrombocytopenia was documented in 16% and 34%, but no serious hemorrhagic events were seen. Non-hematologic toxicity at least possibly attributable to therapy included fatigue in 63% (16% grade 3, 0% grade 4). GI toxicity was common with anorexia, constipation, diarrhea, nausea and vomiting occurring in 47% (3% grade 3), 50%, 81% (16% grade 3, 3% grade 4), 78% (9% grade 3) and 50% (9% grade 3) of pts, respectively. Peripheral neuropathy at least possibly attributable to therapy was seen in 38% of pts (6% grade 3), while hand-foot syndrome was seen in 25% (9% grade 3). There were no deaths on study. Among 31 evaluable pts, the ORR using International Uniform criteria was 65% (95% confidence interval (CI): 45–81%), and the ≥very good partial remission (VGPR) rate was 29% (95% CI: 14–48%). The ORR + minimal response (MR) rate was 74% (95% CI: 55–88%). Of 14 pts with B-sensitive disease, there was 1 MR, 5 PRs and 5 VGPRs. Two PRs, 2 VGPRs and 1 complete remission (CR) were documented in 6 pts with B-naïve disease. Notably, there were 2 MRs, 4 PRs and 1 CR out of the 11 pts with B-refractory disease. Conclusions: The MTD of vorinostat when added to the PLD/bortezomib backbone is 400 mg administered daily on days 4–11. The ORR is highly promising, with responses seen in pts with bortezomib-naïve, -sensitive and -refractory disease. Although serious toxicities were infrequent, constitutional and GI side effects were highly prevalent. All together, our data support further development of this combination in pts with MM, with special attention to developing strategies and guidelines to better ameliorate toxicity. Disclosures: Voorhees: Merck: Research Funding; Celgene: Research Funding; Centocor Ortho Biotech: Research Funding; MedImmune: Consultancy; Pfizer: Research Funding. Off Label Use: Vorinostat for the treatment of relapsed and relapsed and refractory multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Richards:Merck: Consultancy. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Sigma-Tau: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Orlowski:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria; Johnson and Johnson: Research Funding.

Description: Abstract 1955 Introduction: The histone deacetylase inhibitor vorinostat has additive to synergistic activity in combination with anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore sought to evaluate the safety of vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in patients with relapsed and/or refractory MM. Patients and Methods: Treatment consisted of PLD 30mg/m2 on D4, bortezomib 1.3mg/m2 on D1,4,8,11 and escalating doses of vorinostat from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients could remain on therapy until disease progression or unacceptable toxicity. Key eligibility criteria: relapsed and/or refractory MM, ANC≥1.0×109/L. plts≥100×109/L, CrCl≥30mL/min, adequate hepatic and cardiac function. The primary objective of the study was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen. Results: 20 patients have enrolled at the following dose levels: The median age was 60 (range 44–73), median time from diagnosis 42.5 months (9 to 117), and median number of prior lines of therapy 2 (1 to 7). 90% of patients received prior immunomodulatory drugs, 65% bortezomib, 65% autologous stem cell transplantation, and 50% anthracyclines. 55% of patients were relapsed; 45% relapsed and refractory. 9 of 13 patients had disease resistant to prior bortezomib-based therapy. Grade 3 and 4 neutropenia was seen in 35% and 5% of patients, respectively, while grade 3/4 lymphopenia and thrombocytopenia were seen in 30%/5% and 10%/20%, respectively. Two grade 3 infections were seen, 1 of which was attributable to study treatment, but no ≥grade 4 infections were encountered. Common non-hematologic toxicities of all grades regardless of attribution included fatigue (70%), anorexia (55%), nausea (80%), vomiting (60%), diarrhea (85%), constipation (70%) and peripheral neuropathy (75%), most of which was grade 1 or 2 in severity. Grade 3 fatigue, peripheral neuropathy and hand foot syndrome were seen in 10% of patients each, while grade 3 diarrhea was seen in 20%. 1 DLT of transient atrial flutter with grade 4 systolic dysfunction was seen at dose level 3. Two of six patients suffered DLTs at dose level 4 consisting of grade 4 thrombocytopenia without bleeding sequelae, thus establishing dose level 3 as the MTD. Serious adverse events included the above mentioned systolic dysfunction and a limited episode of diastolic dysfunction in one patient. No deaths have occurred on study. Using International Myeloma Working Group criteria, 38% of patients have had ≥VGPR and 61% ≥PR. Only 2 of 18 evaluable patients have had progressive disease on treatment. 7 of 10 patients with relapsed disease had ≥PRs, 6 of which were VGPRs, whereas 4 of 8 patients with relapsed and refractory disease responded. 4 of 5 bortezomib-naïve patients responded to treatment and 4 of 4 patients with bortezomib-pretreated but sensitive disease had PRs or better. 3 of 9 patients with bortezomib-refractory disease had ≥PRs but MRs were seen in an additional 3. Conclusions: The MTD of vorinostat in combination with PLD and bortezomib was 400mg on D4-11. Constitutional, gastrointestinal, and neurologic toxicities were common, but predominantly grade 1 and 2 in severity, and largely manageable. Responses were seen in patients with bortezomib-resistant and -sensitive disease. Dose level 3 has been expanded to include an additional 12 patients. Our results support further clinical testing of this combination in patients with MM. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: Vorinostat for the treatment of myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Richards:Cephalon: Speakers Bureau; Merck/Shering-Plough: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hurd:Celgene: Research Funding.

Description: RAS oncogene family members are molecular switches of signaling pathways that control cell growth, proliferation, differentiation, and survival. In colorectal cancer, Kirsten-RAS (KRAS) and neuroblastoma-RAS (NRAS) are the commonly mutated isoforms. Activating mutations in RAS result in cellular transformation independent of upregulated epidermal growth factor receptor (EGFR)-initiated signaling. The present study characterized the functional consequences of non-canonical/novel KRAS and NRAS mutants identified in a targeted next-generation sequencing study of colorectal cancer specimens from Filipino patients. In vitro assays in NIH3T3 cells showed that similar to the canonical KRAS G12D mutant, overexpression of KRAS G12S, A59T, and Y137C, but not NRAS G12D and NRAS A11V, confer higher proliferation and migration rates. HCT116 cells transfected with the novel NRAS A11V and the canonical NRAS G12D, but not the KRAS mutants, display enhanced resistance to apoptosis. All four non-canonical/novel KRAS and NRAS mutants induce gross changes in F-actin cytoskeletal organization and cellular morphology of NIH3T3 cells. Only KRAS G12S and KRAS A59T appear to deregulate extracellular signal-regulated kinase (ERK) and its downstream target ETS transcription factor ELK1 (ELK1). Elucidation of differential effector engagement responsible for the variable phenotypic readouts of the mutants is warranted. If validated by mouse studies and clinical correlates, these can have wider implications in choosing treatment options.

Description: Phosphatidylinositol 3-kinase, catalytic subunit alpha (PIK3CA) is an oncogene often mutated in colorectal cancer (CRC). The contribution of PIK3CA mutations in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy is well documented, but their prognostic and predictive value remain unclear. Domain- and exon-specific mutations are implicated in either favorable or poor prognoses, but there is paucity in the number of mutations characterized outside of the mutational hotspots. Here, two novel non-hotspot mutants—Q661K in exon 13 and C901R in exon 19—were characterized alongside the canonical exon 9 E545K and exon 20 H1047R mutants in NIH3T3 and HCT116 cells. Q661K and E545K both map to the helical domain, whereas C901R and H1047R map to the kinase domain. Results showed variable effects of Q661K and C901R on morphology, cellular proliferation, apoptosis resistance, and cytoskeletal reorganization, with both not having any effect on cellular migration. In comparison, E545K markedly promoted proliferation, survival, cytoskeletal reorganization, migration, and spheroid formation, whereas H1047R only enhanced the first three. In silico docking suggested these mutations negatively affect binding of the p85 alpha regulatory subunit to PIK3CA, thereby relieving PIK3CA inhibition. Altogether, these findings support intra-domain and mutation-specific variability in oncogenic readouts, with implications in degree of aggressiveness.