ALBERT

Description: Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

Description: Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody. Superiority of Obinutuzumab could be demonstrated in xenograft models of mantle cell lymphoma and DLBCL. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclins from higher treatment lines. With Pixantrone, a drug structurally related to anthracyclines and especially anthracenediones, a re-exposition against this drug class has been shown to be feasible. In 70 heavily pre-treated patients, a best ORR of 40% (20% CR/CRu) was observed (Pettengell et al). Experiences from further antibody drug combinations lead to the assumption that the effects of Pixantrone will be augmented by a monoclonal antibody without increasing toxicity. We thus initiated a trial combining both agents for the first time. The trial has opened in Q4/2015 and recruitment is ongoing. Overall, a total of up 70 patients will be enrolled for a number of 64 evaluable patients. Primary endpoint will be the objective overall response rate, with secondary endpoints being safety, PFS and OS. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven DLBCL, FL grade IIIb or transformed indolent lymphoma, CD20 positive disease, no curative option available, relapsed disease, measurable disease, ECOG 〈 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. There was no upper limit or prior treatment lines. Treatment consisted of Pixantrone 50mg/m² day 1, 8 and 15 of each cycle, Obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. A total of 6 cycles was planned with interim staging after 3 cycles. Results: 24 patients (pts) have been included until now. Concerning clinical characteristics, all were caucasian, 12 were female and the other 12 male and median age was 75 years. Most of the patients suffered from DLBCL (18 pts, 82%). Median number of prior therapies was 2 (1 to 6). Until now 55 evaluable cycles of chemotherapy (median 2 cycles (0 to 6)) have been performed. At this time, the treatment seems to be well tolerated, with no unforeseen side effects. Observed toxicity was predominantly hematologic. The following hematologic adverse events of grade 3/4 were noted: leukopenia (4 pts, 17%), neutropenia (6 pts, 25%), granulocytopenia (1 pts, 4%), as well as thrombocytopenia (2 pts). Non-hematologic grade 3/4 adverse events were observed in at least two patients: hypertension (2 pts) and pelvic pain (2 pts). Response: currently, best responses were 4 PR, 1 SD, and 8 PD in 13 patients evaluable so far. Four patients died, all after progression of lymphoma. Summary: the combination of Obinutuzumab and Pixantrone seems to be feasible and safe with early signs of efficacy. Updated results of this trial in progress with a focus on safety will be presented. Disclosures Hess: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria. Marks:Pfizer: Honoraria. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Viardot:Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Description: Key Points The results of this retrospective analysis do not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission.

Description: Abstract 3880 Background The HGF/c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Aberrant c-Met activation has been implicated in the pathogenesis of many human cancers. Furthermore, c-Met is of prognostic significance in several types of cancer such as diffuse large B cell lymphoma, bladder cancer, breast cancer, colorectal cancer and ovarian cancer. Expression of c-Met in Hodgkin lymphoma (HL) patients, as well as increased levels of HGF in the urine of HL patients has been reported, but no prognostic studies or functional data have been reported. Methods We studied the prognostic significance of c-Met expression by immunohistochemistry on paraffin sections of classical HL (cHL) patients from two independent patient cohorts. Functional studies were performed on HL cell line L428 that showed high c-Met levels, constitutive phosphorylated c-Met and no HGF expression. The effect of stimulation by HGF and inhibition by c-Met kinase inhibitor SU11274 was investigated by Western blot, cell proliferation and cell cycle progression analysis. Results Expression of c-Met was detected in Hodgkin Reed-Sternberg (HRS) cells in 52% (79/152) of primary cHL tissue samples and expression of its ligand, hepatocyte growth factor (HGF), was detected in HRS cells in 8% (10/120) of the cHL patients. Co-expression of HGF and c-Met in HRS cells was observed in only 3% (4/120) of cHL patients. A variable percentage of infiltrating cells stained positive for HGF, supporting a predominant paracrine activation route. In contrast to its adverse prognostic impact in other cancers, high c-Met expression significantly correlated with favorable 5 year progression free survival in both patient cohorts. To explain these unexpected findings we studied the c-Met/HGF signaling pathway in the L428 cHL cell line. The levels of phosphorylated c-Met, Akt, and Erk1/2 were upregulated upon HGF stimulation and this induction could be blocked by inhibiting c-Met activation with SU11274. Activation with HGF did not effect cell growth, while SU11274 alone suppressed cell growth. SU11274, as well as inhibitors of PI3K, MEK1/2 and Erk1/2 (downstream targets of the HGF/c-Met signaling pathway) induced G2/M cycle arrest. Conclusion Expression of c-Met in tumor cells was observed in 52% of cHL patients. In contrast to its prognostic value in other cancers, expression of c-Met in HRS cells of cHL patients correlated with favorable prognosis in two independent cohorts. Although triggering of c-Met in L428 cells with HGF induced activation of its downstream factors, no effect was observed on proliferation. Remarkably, the c-Met inhibitor did suppress cell growth of L428 cells. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Alkylating agent-rituximab combinations are a current standard of care for patients with iNHL. Most iNHL will eventually become refractory to current therapies. Particularly, once iNHL becomes “double-refractory” to rituximab + alkylating agents, there are few data available on beneficial therapeutic options and development of novel therapies is essential for this patient population. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated considerable activity in recurrent iNHL in a phase 1 trial (Kahl, ICML 2011). We thus evaluated idelalisib in a phase 2 trial for patients with double-refractory iNHL, an area of unmet medical need. We present mature response data and extended follow-up of this study. Methods Eligible iNHL patients (pts) included those with measurable disease who were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to, or progression of lymphoma within 6 months of completion of therapy, documented by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007). The new data cutoff date for this analysis was June 2013, 8 months after the last patient enrolled. Results Enrolled pts (N=125) had a median age of 64 years [range 33-87] and were 64% male. Indolent NHL subtypes included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], most common regimens included bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and 14 pts (11%) had a prior autologous transplant. 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. Median time since completion of last regimen was 3.9 months. At baseline, pts had elevated LDH (30%), bulky disease 〉7 cm (26%), anemia ≥grade 1 (51%), neutropenia ≥ grade 1 (24%), and thrombocytopenia ≥grade 1 (34%). With a median follow up 9.4 months, the overall response rate (ORR) was 57% (95% CI = 47.6, 65.6) with 71 responders, comprising 7 CRs (6%), 63 PRs (50%), and 1 minor response (MR) in a WM pt. There were 42 pts with stable disease (SD) (33%). 90% of pts experienced some decrease in tumor burden (Figure 1). Median time to response was 1.9 months (range 1.6-8.3), median time to CR was 3.7 months (range 1.9-12). ORR for iNHL subtypes was: FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). ORR for bendamustine refractory pts was 59%. ORR for pts with

Description: MT103 (MEDI-538), a bispecific, single chain construct specific for CD19 and CD3, is a member of a novel class of highly active antibody derivatives that direct T-cells to target cells. The primary objective of this study is to evaluate the safety and tolerability of a 4- to 8-week continuous intravenous infusion at increasing dose levels in patients with relapsed NHL, starting at dose level 1 (DL1) of 0.5μg/m2/24h. Dose-limiting toxicities (DLTs) were assessed during the first 2 weeks of infusion. To date, 31 patients have been included up to a dose level of 30μg/m2/24h. No DLTs were observed from DL1 to DL3 (5μg/m2/24h. At DL4 (5μg/m2/24h on day 1, followed by 15 μg/m2/24h maintenance dose), 7 patients (pts) were treated. One of the 7 pts had elevated liver enzymes up to CTC grade 3 after 2 weeks, and another patient showed reversible confusion, assessed as a DLT on the 2nd treatment day. For further optimization of safety and convenience of the initiation phase, the stepwise increase was modified to a constant infusion rate. This regimen was well tolerated and showed a favorable safety profile. Due to these modifications a total of 13 pts were treated at 15μg/m2/24h. At 30μg/m2/24h, 6 pts were treated; one DLT (metabolic acidosis, grade 4) was recorded. Confounding factors for this event were pre-existing renal insufficiency, fever and increasing anemia. The adverse events (AEs) were transient and the most common ones observed so far in all cohorts, regardless of causality, were (overall/grade 3 or 4) leucopenia (63%/37%), lymphopenia (59%/59%), pyrexia (55%/7%) elevated liver enzymes (44%/4%). At the dose level of 15μg/ m2/24h, MT103 induced 1 complete (CR) and 2 partial responses (PRs) in indolent lymphoma, which had not been observed at the previous dose levels. A total of 5 pts including the responders at this dose level had bone marrow involvement by indolent lymphoma. MT103 induced complete disappearance of lymphoma cells from the bone marrow in 3 and partial reduction in 2 of the 5 cases. One of these 5 patients had lymphoplasmocytoid lymphoma pre-treated with fludarabine. MT103 induced a 60% reduction of paraprotein. At the dose level of 30μg/m2/24h, clinical benefit was observed in mantle cell lymphoma (MCL), which had not been noted at the previous dose levels. One out of 3 evaluable pts with MCL enrolled at this dose level experienced a CR and one showed complete disappearance of lymphoma cells from the bone marrow. Best responses in the 26 evaluable pts overall were 2 CRs, 2 PRs, 2 minimal responses (MRs) and 13 SDs. Best responses in 14 evaluable patients starting at the dose level of 15μg/m2/24h were 2 CRs, 2 PRs, 2 MRs and 5 SDs.Conclusions: The current data suggest a favorable safety profile of MT103 administered as continuous 4 to 8 week infusion. MT103 induces CRs and PRs in relapsed indolent lymphoma and MCL in an apparently dose dependent fashion. Pronounced effects on lymphoma bone marrow infiltration have further demonstrated the clinical activity of MT103. Determination of the optimal biological dose is ongoing.

Description: Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the mTOR inhibitor Temsirolimus from 25, 50, 75 and 100 mg were predefined. Results. Here we report on the preliminary results of part I of this clinical trial. 15 patients were included - 8 patients in the 25 mg cohort and 7 patients in the 50 mg cohort. Median age was 70 (range 49-76) years and median number of prior regimen was 1. Two DLTs (one venous thrombosis in the 25 mg cohort, one esophagus infection in the 50 mg cohort) were observed. The most frequent non-hematologic side effects were nausea (9 pts, 60%), epistaxis (7 pts, 47%), fatigue (6 pts, 40%), increased ALT (6 pts, 40%) and increased creatinine (6 pts, 40%). Frequent grade 3/4 events (n〉2) in both cohorts (25mg|50mg) included leukopenia (11 pts, 73% - with a mean duration of 4.4 days | 6.7 days ), thrombocytopenia (11 pts, 73% - with a mean duration of 4.6 days | 11.9 days), lymphopenia (6pts, 40%), anemia (5 pts, 33%), neutropenia (3 pts, 20%), renal failure (3 pts, 20%) and infections (4 pts, 27%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. All but one evaluable patient responded (10/11 pts, 91%), with two CRs and one CRu (27%). Four patients could not be evaluated for response at the time of this report. After a median follow up of 12 (range 5-22) months, no relapse has been documented so far (1 pt lost to follow up). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Recruitment into part II is ongoing and updated results will be presented. Disclosures Witzens-Harig: Pfizer: Honoraria, Research Funding; Roche: Honoraria. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Viardot:Roche: Honoraria; CTI: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Ho:Sanofi: Research Funding. Hess:Janssen, Roche, Celgene, Novartis: Consultancy; Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding.

Description: Abstract 4715 Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome. We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation. To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated. Disclosures: Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria.