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Introduction: Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR)-signaling pathway has been the focus in many types of B-cell related hematological malignancies including mantle cell lymphoma (MCL). Methods: This reports the MCL cohort in a phase 2 trial that more broadly evaluated the efficacy and safety of entospletinib (800 mg BID) in patients with relapsed and refractory hematological malignancies (NCT01799889). Tumor response was assessed per Cheson 2007 criteria with imaging planned at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 16. All efficacy data were assessed by an Independent Review Committee. Results: A cohort of 39 patients with MCL was enrolled. The median age was 72 years (range: 49-92), 64% were male, and a median number of prior regimens were 2 (range: 1-6). Prior therapy included anti-CD20 antibodies (95%), alkylating agents (95%; bendamustine 44%), and anthracyclines (77%). Three patients (8%) have received ibrutinib either as investigational drug (n = 1) or as an approved drug (n = 2), and 1 patient (3%) received idelalisib. Median duration of treatment was 21 weeks (range: 1-87), with 1 patient continuing on treatment. Thirty-five (90%) patients were evaluable for tumor response. Four patients (10%) discontinued prior to initial tumor assessment: death (n = 1), disease progression (n = 2) and investigator's discretion (n = 1). The most common TEAEs (any grade/≥gr 3, independent of causality) and common lab abnormalities are summarized in Table 1. There were 4 TEAEs that led to study drug discontinuation (all n = 1): cardiac arrest, pruritus, pyrexia, and maculopapular rash. Six deaths were reported, none of which were related to study drug. The ORR was 15% (90% CI: 6.9%, 28.1%), with 6 (15%) patients achieving a PR and 23 (59%) patients maintaining a stable disease. The PFS rate at week 16 was 66% (95% CI: 46%, 79%). Median PFS was 5.6 months (95% CI: 3.6 months, 8.9 months). These results are based on data analysis of June 28, 2016. Conclusion: Entospletinib was well tolerated and demonstrated modest activity in patients with relapsed or refractory MCL. Further development of entospletinib in MCL will focus on the development of combination therapy. Figure 1 Waterfall Plot of Best % Change from Baseline in SPD. Figure 1. Waterfall Plot of Best % Change from Baseline in SPD. Figure 2 Kaplan-Meier Curve of Progression-Free Survival. Figure 2. Kaplan-Meier Curve of Progression-Free Survival. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Kolibaba:Amgen: Research Funding; Celgene: Research Funding; Cell Therapeutics: Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Novartis: Research Funding. Nay:Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria, Other: Advisory board; Celgene: Honoraria, Other: Advisory board; Amgen: Other: Advisory board; Lyndbeck: Honoraria; BMS: Honoraria. Zhang:Gilead Sciences: Employment, Equity Ownership. Shi:Gilead Sciences, Inc.: Employment, Equity Ownership. Forero:University of Alabama at Birmingham: Research Funding. Assouline:BMS: Speakers Bureau; Lundbeck: Consultancy; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau.

Purpose The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with follicular lymphoma whose disease was relapsed or refractory to prior treatment. Patients and Methods Patients received five 35-day cycles of bortezomib, bendamustine, and rituximab: bortezomib administered intravenously (IV) at a dose of 1.6 mg/m2 on days 1, 8, 15, and 22, cycles one to five; bendamustine 50, 70, or 90 mg/m2 IV over a 60-minute infusion on days 1 and 2, cycles one to five; and rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle one and day 1 of subsequent cycles. Patients were assessed using the International Workshop Response Criteria, with the primary end point of 60% complete response rate. Results Seventy-three patients were enrolled. During the dose-escalation phase, the maximum-tolerated dose for bendamustine was not reached; the 90 mg/m2 dose level was expanded for the efficacy assessment, and a total of 63 patients received bendamustine 90 mg/m2. In these 63 patients, the overall response rate was 88% (including 53% complete response). Median duration of response was 11.7 months (95% CI, 9.2 to 13.3). Median progression-free survival was 14.9 months (95% CI, 11.1 to 23.7). Toxicities were manageable; myelosuppression was the main toxicity (25% and 14% of patients experienced grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4 neuropathy occurred in 11% of patients. Conclusion The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment.

Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

Background: This study was designed to investigate the activity, safety, and pharmacokinetics of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in previously untreated patients with aggressive NHL. The initial results of R-CHOP induction therapy are reported here. Methods: 105 patients with aggressive NHL (diffuse large B-cell or follicle center/follicular grade III by REAL; Type D, F, G or H by IWF) were enrolled into this open-label, multi-center, community based, single-arm, Phase II trial. Patients received 6 or 8 cycles (per standard practice at each site) of R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 IV on Day 1, prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle, except for cycle 1, when it was given 2–3 days before CHOP administration. Subjects with documented responses (CR/CRu or PR) to induction receive maintenance R (4 weekly infusions) beginning 28 days after the completion of induction and repeated every 6 months for 2 years. The primary endpoints were CR/CRu after the completion of induction and the incidence of R infusion-related toxicity in induction and maintenance. Overall response rate (ORR), infusion times, serious adverse events (SAE), and the partial rituximab pharmacokinetic profile were also measured. Results: Baseline characteristics of patients enrolled were: median age 59 y (49.5% ≥60 y), IPI ≥3 in 31.4 % patients, Ann Arbor Stage II,III, IV in 21.9%, 39.0%, and 39.0% of patients, respectively. CR/CRu at the end of induction in 105 patients was 51.4% (80.0% ORR). 1.9% of patients had progressive disease (PD) during induction. SAE occurred in 33% of subjects during induction with the most common event being febrile neutropenia (14.3%). 5 subjects died during induction (pulmonary embolus, ruptured abdominal aortic aneurysm, pneumonia x2, unknown cause). Grade 3–4 rituximab infusion-related toxicity occurred in 3.9% of subjects during Cycle 1 which decreased to 0% by Cycle 5. 64.3% of patients received their R infusion within 3 hours on Cycle 2; this increased to 74.7% patients at cycle 6. The partial pharmacokinetic profile (peak and trough concentration) of R was measured in 10 patients and will be presented at the meeting. Conclusion: Rituximab + CHOP chemotherapy is well tolerated and has an excellent response rate when given in the community setting. The outcomes of maintenance therapy in this study await further follow-up.