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Background: Mantle cell lymphoma (MCL) is characterized by a recurrent chromosomal translocation t(11;14) that leads to aberrant expression of Cyclin D1 which, together with cyclin dependent kinases 4 and 6 (CDK4/6), inhibits the retinoblastoma (Rb) tumor suppressor protein and thereby induces malignant proliferation. Abemaciclib, a cell cycle inhibitor selective for CDK4/6 (Gelbert et al, 2014), has shown single agent clinical activity against multiple human tumors including lung cancer and breast cancer (Shapiro et al, ASCO 2013; Goldman et al, ASCO 2014; Patnaik et al, ASCO 2014). Based on molecular pathogenesis and single agent activity in preclinical models of human MCL, abemaciclib was evaluated in a single arm Phase II study for patients with relapsed or refractory MCL. Methods: The primary objective of this study was to estimate the disease control rate, which includes response (complete + unconfirmed complete + partial) plus stable disease, for patients who received abemaciclib for relapsed or refractory mantle cell lymphoma (MCL). Patients were scheduled to receive abemaciclib (200 mg) orally every 12 hours on Days 1 through 28 of each 28-day cycle. Eligibility criteria permitted an unlimited number of prior systemic therapies including high dose chemotherapy with stem cell transplantation, Eastern Cooperative Oncology Group (ECOG) performance status = 1.5 x 109/L, and platelets >= 75 x 109/L. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 were used to grade adverse events. Response Criteria for Non-Hodgkin’s Lymphomas (Cheson et al, 1999) were used to assess clinical activity. Plasma samples for pharmacokinetics were performed both after a single oral dose and after multiple doses at steady state. Flow cytometry was used to isolate circulating MCL cells for evaluation of pharmacodynamic effect on Rb phosphorylation. Results: In this Phase II study, 22 patients with relapsed or refractory MCL received single agent oral treatment with abemaciclib. Among these patients, 91% presented at initial diagnosis with Stage III or IV disease. At the time of study entry, these patients (9 female and 13 male) had a median age of 66 years (range: 53-83), 59% had ECOG performance status of 1 or 2, and all patients had constitutional B symptoms. Eighteen patients received >= 2 prior systemic therapies, and previous treatments for the overall study population included not only high dose chemotherapy with stem cell transplantation but also rituximab (96%), cyclophosphamide-based therapy (86%), cytarabine-based therapy (64%), temsirolimus (55%), and bendamustine (41%). Patients received 1-16 cycles of treatment with abemaciclib and 8 of 22 patients (36%) completed >= 6 cycles. The most common possibly related treatment-emergent adverse events across all grades included diarrhea (55%, including 9% G3/4), nausea (23%, with no G3/4), vomiting (32%, with no G3/4), fatigue (18%, with no G3/4), thrombocytopenia (55%, including 32% G3/4), neutropenia (36%, including 32% G3/4), and anemia (18%, with no G3/4). Plasma concentrations of abemaciclib were comparable to those previously observed and associated with clinical activity in patients with advanced non-hematologic malignancies. For patients with at least one post-treatment radiographic evaluation, preliminary investigator assessment indicates that single agent therapy with abemaciclib was associated with stable disease for 9 patients and partial response for 5 patients, including durable disease control (>= 6 cycles) in 8 of these 14 patients with relapsed or refractory MCL. Conclusions: Abemaciclib, a cell cycle inhibitor, demonstrates evidence of durable disease control as a single agent for patients with relapsed or refractory MCL. Disclosures Hahka-Kemppinen: Eli Lilly and Company: Employment, Equity Ownership. Xiaohui Wang:Eli Lilly and Company: Employment. Brueck:Eli Lilly and Company: Employment. Caldwell:Eli Lilly and Company: Employment. Beckmann:Eli Lilly and Company: Employment, Equity Ownership. Gelbert:Eli Lilly and Company : Consultancy. Cronier:Eli Lilly and Company: Employment. Lin:Eli Lilly and Company: Employment. Li:Eli Lilly and Company: Employment. Chan:Eli Lilly and Company: Employment, Equity Ownership. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boerhinger Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding.

Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Abstract 3942 Background: Pts with FL in whom position 158 on the FcγRIIIa (CD16) gene is heterozygous for valine/phenylalanine (V/F) or homozygous for phenylalanine (F/F) (F-carriers) have natural killer cells with lower binding affinity to IgG than valine homozygote (V/V) pts. These pts showed a lower response rate and shorter time to progression compared with V/V genotype pts after initial rituximab treatment. A humanized IgG1 anti-CD20 monoclonal antibody, LY2469298, was optimized through protein engineering in the Fc region to increase affinity with FcγIIIa and is expected to increase effector function in F-carriers. This phase I study was conducted to evaluate the safety, clinical activity, and pharmacokinetics (PK) of LY2469298 in Japanese pts with relapsed or refractory FL. Methods: Japanese pts with FL who relapsed or progressed after prior treatment, but not within 120 days of prior rituximab, received four infusions of LY2469298 at weekly intervals. The dose was assessed for safety, tolerability, and immunogenicity (HAHA) in 2 cohorts of 100 and 375 mg/m2. Dose-limiting toxicity (DLT) was evaluated from the day of the first infusion until two weeks after the last infusion. Response was evaluated according to the International Workshop Response Criteria (IWRC) at 9 and 21 weeks after the last dose. The PK of LY2469298 were assessed after the first and fourth dose by means of a non-compartmental analysis. Results: Ten pts (male/female: 5/5), median age 60.4 yrs (range: 39–75), were enrolled and treated in 2 cohorts: 3 pts at 100 mg/m2 and 7 pts at 375 mg/m2. The number of pts with stage I/II/III/IV at enrollment was 1/4/1/4, respectively. All pts received 1 or more treatment of prior rituximab alone or rituximab-containing regimen; 3/10 pts were refractory to the regimen. The median number of prior regimens was 2 (range: 1–9). Follicular Lymphoma International Prognostic Index (FLIPI) identified 4 pts at low risk, 2 at intermediate risk, and 4 at high risk. There was one V/V patient in the 375 mg/m2 cohort; all other pts were F-carriers. No DLT was observed in either cohort; therefore, the recommended phase II dose was determined to be 375 mg/m2. The most common adverse events (≥40% of pts) included hematological toxicities and infusion-related reactions: lymphopenia (n=10), pyrexia (8), leukopenia (7), chills (7), and neutropenia (5). Grade 3 or 4 hematological toxicities were lymphopenia (n=7) and neutropenia (2; no G-CSF required). There were no grade 3 or 4 infusion-related reactions; most reactions were limited to the first infusion. B-cell (CD19+) depletion in peripheral blood was rapid and sustained in all pts. B-cell recovery began in the 21-week observation period. LY2469298 was eliminated in a biphasic manner from pts' blood with a elimination half-life of 10 to 14 days. Clearance, elimination half-life, and volume of distribution were similar between the 2 doses. AUC and Cmax increased with dose. Of 10 evaluable pts, responses were observed in 5 pts (3 CR, 1 CRu, and 1 PR). Conclusions: Weekly doses of LY2469298 at 100 and 375 mg/m2 were well tolerated and resulted in evidence of clinical activity in pts with relapsed or refractory FL after prior rituximab alone or rituximab-containing regimens, although 9 of 10 pts were F-carriers. The PK characteristics of clearance, elimination half-life, and volume of distribution of the 2 LY2469298 doses were similar, both of which were eliminated in a biphasic manner. The promising results of this phase I study warrant further investigation of LY2469298 in pts with FL. Disclosures: Off Label Use: LY2469298 is an investigational agent. Matsue:Eli Lilly Japan KK: Employment. Cronier:Lilly UK: Employment. Wooldridge:Eli Lilly & Company: Employment. Koshiji:Eli Lilly Japan KK: Employment.