A Phase 3 Study to Evaluate the Efficacy and Safety of Dinaciclib Compared to Ofatumumab in Patients with Refractory Chronic Lymphocytic Leukemia

Introduction: Abnormalities of cell cycle regulation have an important role in the pathogenesis of cancers. Cyclin dependent kinase (CDK) inhibitors have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. Dinaciclib (MK-7965/SCH 727965) is a novel, selective inhibitor of CDK1, CDK2, CDK5, and CDK9. Prior studies show that dinaciclib has anti-leukemic activity against CLL. The present study compared the efficacy and safety of dinaciclib with ofatumumab in patients with refractory CLL.

Methods: This Phase 3 randomized, open-label, active-controlled, balanced, multi-site, group sequential confirmatory trial evaluated the progression-free survival (PFS; primary objective), overall response rate and overall survival (secondary objectives), and safety of dinaciclib vs. ofatumumab in patients with refractory CLL. Patients with a confirmed diagnosis of CLL (based on 2008 International Workshop on CLL criteria) and fludarabine or chemoimmunotherapy refractory disease were enrolled if they had no central nervous system involvement, prior allogenic bone marrow transplant or uncontrolled autoimmune anemia or thrombocytopenia. Patients previously treated with dinaciclib, ofatumumab, or other CDK inhibitors were excluded. In Cycle 1, dinaciclib was administered intravenously (IV) over 2 hours at doses of 7 mg/m² on Day 1, 10 mg/m² on Day 8 and 14 mg/m² on Day 15. In Cycle 2 and thereafter, dinaciclib was dosed at 14 mg/m²on Days 1, 8, and 15 of each 28-day cycle for a total of 12 cycles. Ofatumumab was administered IV once-weekly for 8 weeks starting in Cycle 1 on Day 1, followed by 9 monthly doses as follows: 300 mg in Cycle 1 on Day 1; 2000 mg in Cycle 1 on Days 8, 15, and 22, Cycle 2 Days 1, 8, 15, and 22, and 5 weeks later on Day 1 of Cycles 4-12.   Efficacy results are from the intent to treat (ITT) population, and safety results are from the all-subjects-as-treated population.

Results: In total, 44 patients were randomized (ITT) and 42 were treated (20 dinaciclib and 22 ofatumumab) due to early study termination not attributed to safety. At study entry, the median age was 62 years (range, 43-77), 32/42 (76.2%) patients were male, 26/42 (62.0%) were RAI stage III-IV, 24/42 (57.1%) had bulky disease, 40/42 (95.2%) were ECOG ≤ 1, the median number of prior therapies was 3 (range, 1-20), and 39/42 (92.9%) patients received prior fludarabine. Deletion 17p (del 17p) was present in 17/42 (38.6%) patients, 7 dinaciclib and 10 ofatumumab.

Median follow-up (range) was 16.7 (0.4-26.1) months. In the dinaciclib and ofatumumab groups, respectively, 11 (55.0%) and 17 (70.8%) patients had PFS events, and median (95% CI) PFS was 59.7 (45.0, 92.1) and 25.7 (9.3, 40.7) weeks. Overall response (all partial responses) was recorded for 8 (40.0%) dinaciclib and 2 (8.3%) ofatumumab patients. Stable disease was achieved by 7 (35.0%) dinaciclib and 11 (45.8%) ofatumumab patients. Median survival (95% CI) was 21.2 (16.6, NR) months with dinaciclib and 16.7 (2.3, 20.2) months with ofatumumab; 6 (30.0%) and 11 (45.8%) patients have died in each group, respectively. There were 2 treatment-related deaths in the dinaciclib arm (pneumonia and febrile neutropenia) and none in the ofatumumab arm. Median survival (95% CI) in the del 17p population was 21.2 (1.4, 21.2) months with dinaciclib and 5.4 (0.4, NR) months with ofatumumab.

Overall, 17 (85.0%) dinaciclib and 13 (59.0%) ofatumumab patients had a grade 3-5 adverse event (AE). The most common grade ≥ 3 AEs with dinaciclib and ofatumumab, respectively, were neutropenia, 7 (35.0%) vs. 2 (9.1%); thrombocytopenia, 4 (20.0%) vs. 2 (9.1%); decreased neutrophil count, 4 (20.0%) vs. 1 (4.5%); pneumonia, 1 (5.0%) vs. 3 (13.6%); sepsis, 1 (5.0%) vs. 3 (13.6%); and febrile neutropenia, 2 (10.0%) vs. 1 (4.5%). One dinaciclib patient developed tumor lysis syndrome that was deemed not treatment-related. Ten (50.0%) dinaciclib and 13 (54.2%) ofatumumab patients discontinued from the study for the following reasons: AE, 3 (15.0%) vs. 1 (4.2%); disease progression, 4 (20.0%) vs. 4 (16.7%); death, 1 (5.0%) vs. 5 (20.8%); and other/unknown, 2 (10.0%) vs. 4 (16.7%).

Conclusion: The limited data from this study demonstrate potential anti-cancer activity and tolerability of dinaciclib compared with ofatumumab in patients with refractory CLL. Based on these results and given the distinct mechanism of action, combinations of dinaciclib with other novel therapies should be explored.