Interim Results for the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia (CC-5013-CLL-009 Study)

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.

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.

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.

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.

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.