Mei, Jay

Abstract Abstract 2859 Introduction: Patients with chronic lymphocytic leukemia who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These patients have limited therapeutic options and novel agents with alternative mechanisms of action are needed. In phase 1 and 2 trials, escalating dose regimens of the immunomodulatory agent lenalidomide demonstrated promising activity with relapsed/refractory CLL. Of interest, the data indicate that superior efficacy might be achieved by a starting dose above 2.5 mg daily lenalidomide. A phase 2 trial (CLL-009 study) was developed to investigate the safety of different starting doses of lenalidomide followed by a step-wise dose escalation as tolerated in relapsed/refractory CLL. Methods: In this ongoing trial, eligible subjects with relapsed/refractory CLL who have received at least 1 prior treatment regimen are being enrolled. Subjects are randomized 1 :1 :1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral lenalidomide on days 1–28 of each 28-day cycle. The primary objectives are to determine the safety and efficacy of the different lenalidomide starting doses of 5 mg, 10 mg or 15 mg daily, followed by an intra-patient escalation up to a maximum of 25 mg daily using a Bayesian approach. Based on individual patient tolerability, the daily lenalidomide dose can be escalated every 28 days by 5 mg increments. Dose reductions also occur in 5 mg increments; however, dose levels below 5 mg sequentially include 2.5 mg and 1.25 mg daily. Tumor lysis syndrome (TLS) prophylaxis, comprised of oral hydration and allopurinol 300 mg/day is initiated at least 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. This adaptive design trial is considering joint efficacy and toxicity outcomes to stop randomization of less promising arms. Accrual to a starting dose arm will be stopped if unacceptable toxicities and/or high progression rate are observed in that arm. A total of 90 subjects will be enrolled in the study. Results: To date, 51 subjects with a median age of 63 years (range 39–78) have been enrolled. Subjects to date are primarily male (65%) and Caucasian (84%), and slightly more than half (53%) are ≥ 65 years old. Cytogenetic data is available for 42 subjects; 10 have del(11q), 8 have del(17p), and 24 have del(13q). Overall, 31 subjects had at least one cytogenetic deletion. Based on the Binet and Rai staging systems: 3 (6%), 10 (20%) and 15 (29%) of subjects are stage A, B and C, respectively; and, 6 (12%), 7 (14%) and 7 (14%) subjects are low, intermediate or high-risk disease, respectively. For 3 (6%) subjects the Binet/Rai staging is currently unknown. The most common hematological grade 3/4 adverse events (AEs) thus far include neutropenia (41% of patients) and thrombocytopenia (24%). The most common non-hematological grade 3/4 AEs include fatigue (12%) and tumor flare (12%). Only 1 subject (2%) experienced tumor lysis syndrome of grade 1. Over half of the subjects (53%) remain on therapy; 24 (47%) subjects have discontinued treatment. The longest subject has completed 17 cycles, and remains on study medication. The most common reasons for study discontinuation include disease progression (n = 8) and AEs (n = 10). To date, 20 subjects (54% of eligible patients) have successfully dose escalated above their respective starting double blinded dose level, including 3, 3, 2 and 12 subjects undergoing 4, 3, 2, and 1 dose escalations, respectively. As 14 patients are still in the first cycle of the study, a total of 20 subjects have had no dose level reduction or escalations. The average duration of treatment is 4.34 cycles, and the median number of cycles is 3. Efficacy evaluations are completed monthly after 3 months of study drug treatment. By investigator assessment, 34 subjects have been evaluated to date, including 1 (3%) complete response, 12 (35%) partial response, 7 (21%) stable disease, 10 (29%) progressive disease and 4 (12%) not evaluable. Conclusion: The independent Data Monitoring Committee, as of March 24, 2011 (N=41), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were tolerated. To date, the ORR is 38% (13/34 evaluable subjects), and 54% of subjects (20/37) have dose escalated at least once. In this relapsed/refractory CLL population lenalidomide appears active, and completion of accrual will hopefully demonstrate the appropriate starting dose. Disclosures: Wendtner: Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: lenalidomide in cll. Goldberg:Celgene: Honoraria, Research Funding, Speakers Bureau. Bloor:Celgene: Honoraria, Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Research Funding. Cymbalista:Roche: Research Funding; Mundipharma: Honoraria; Genzyme: Honoraria. Kipps:Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Genentech: Research Funding; Gilead Sciences: Consultancy, Research Funding; Igenica: Membership on an entity's Board of Directors or advisory committees. Purse:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment.

Abstract Introduction CC-292, an oral, highly selective, small-molecule irreversible-inhibitor of Btk is under investigation for the treatment of CLL and other B-cell malignancies. This phase 1 trial investigated the safety, dose limiting toxicities (DLT), and clinical activity of CC-292 monotherapy in subjects with relapsed or refractory (R/R) CLL or non-Hodgkin's lymphoma. This interim analysis focused on the safety and clinical activity in subjects with CLL and small cell lymphocytic leukemia (SLL). Methods Eligible subjects with R/R (≥ 1 prior therapy) CLL/SLL were treated with monotherapy CC-292 in a dose-escalation study with doses ranging from 125 mg to 1000 mg QD and BID dose levels of 375 mg and 500 mg. As a maximum tolerated dose was not established, CLL patients have been enrolled in an early dose expansion cohort of 750 mg QD and preliminary recommended phase 2 dose expansion cohort at 500 mg BID. All subjects received continuous dosing in 28-day cycles until progressive disease or intolerable toxicity. Clinical activity was investigator assessed per the 2008 iwCLL criteria. Results 83 subjects with R/R CLL/SLL have been enrolled as of June 30, 2013. Baseline characteristics include median age of 67 years (34-89), 52% Rai stage 3/4 disease, median 3 prior therapies (1-12), and 34% refractory to last treatment. Poor-risk factors were present in 67% of subjects, including del11q (22%), del17p (24%), and unmutated IgVH (54%). 67% of subjects remain on study. Subjects have received a median of 6 treatment cycles (0.2-21.6). The most frequent grade 3/4 adverse events (AEs) included neutropenia (21%), thrombocytopenia (15%), pneumonia (10%), and anemia (8%). Rates of febrile neutropenia were low (4%). The most common treatment-emergent AEs (≥ 10% of subjects) were diarrhea (59.7%), fatigue (37.5%), neutropenia (26.4%), thrombocytopenia (26.4%), nausea (26.4%), pyrexia (22.2%), headache (19.4%), cough (19.4%), upper respiratory infection (16.7%), peripheral edema (15.3%), abdominal pain (15.3%), dizziness (13.9%), muscle spasms (13.9%), contusion (13.9%), anemia (12.5%), pneumonia (12.5%), sinusitis (12.5%), and urinary tract infection (11.1%). One CLL patient at the 500 mg BID dose level has experienced a drug-related adverse event of grade 4 thrombocytopenia during Cycle 1 that was assessed as a DLT. The number of patients discontinuing study treatment due to AEs was low (2.4%). Results are summarized for efficacy-evaluable patients treated at the 4 dose levels where at least a partial response (PR) was achieved (750 mg, 1000 mg, 375 mg bid and 500 mg bid) (n = 55). During cycle 1, 89% experienced a ≥ 25% increase in absolute lymphocyte count (ALC), which usually resolved with continued treatment. The table below details the best responses achieved to date. In subjects with del11q, del17p, unmutated IgVH, and no high-risk genomic factors, the PR rate was 42% (5/12), 25% (3/12), 44% (7/16), and 47% (7/15), respectively. Importantly, nodal responses were induced in the majority of subjects receiving BID dosing (375 mg: 67%; 500 mg: 62%) with an overall PR rate of 40%. When achieved, nodal responses were typically observed by cycle 2 and were sustained with continued treatment. Although the sample size is small, subjects treated at 375 mg or 500 mg BID showed continued lymph node size reduction over time from cycle 2 (mean reduction of 42% and 45%, respectively) to cycle 7 (mean reduction of 60% and 71%, respectively). Conclusion CC-292 is well tolerated as an oral daily therapy. Single-agent therapy with CC-292 is sufficient to achieve high nodal and partial response rates in relapsed/refractory CLL subjects, including those with high-risk genomic features. These results support continued development of CC-292 for the treatment of patients with CLL/SLL. Disclosures: Brown: Pharmacyclics: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on CC292 which is an investigational product developed by Celgene. This investigational product is not approved by any health authority for any indication. Harb:Celgene: Research Funding. Hill:Celgene: Honoraria, Research Funding. Sharman:Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Cylene Pharmaceuticals: Consultancy, Research Funding; Avila Pharmaceuticals: Consultancy, Research Funding. Barr:Celgene: Consultancy. Foran:Celgene: Research Funding. Burger:Pharmalytics: Research Funding; Gilead: Research Funding. Mahadevan:Novartis: Speakers Bureau; Millennium: Speakers Bureau. Ma:Genentech: Consultancy; Abbvie: Consultancy. Barnett:Celgene: Employment, Equity Ownership. Marine:Celgene: Employment, Equity Ownership. Nava-Parada:Celgene: Employment, Equity Ownership. Azaryan:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.