A Phase II, Single-Arm, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of P276-00, a Cyclin-Dependent Kinase Inhibitor, in Patients With Relapsed or Refractory Mantle Cell Lymphoma

Inhibition of cyclin-dependent kinases (CDKs) is a promising strategy for mantle cell lymphoma (MCL). We conducted a phase II study of P276-00, a small molecule inhibitor of several CDK isoforms, in patients with relapsed or refractory MCL. Although relatively well-tolerated, no objective responses were seen. Future studies with this agent should consider it in new schedules or combined with other treatments. Introduction: Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin-dependent kinases (CDKs). P276-00 is a potent small molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T, with promising activity in preclinical models. In phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend toward single-agent efficacy. Patients and Methods: A phase IF study of P276-00 was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m(2)/day from days 1 to 5 of a 21-day cycle. Thirteen patients were enrolled in the present study. Results: Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE) and 1 patient died. Also, 11 patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Of the 13 patients, 9 (69.2%) received >= 2 cycles of treatment, which was the predefined threshold to be evaluable for efficacy. Treatment was discontinued early in 2 patients because of AEs (1 of which was attributed to P276-00 administration) and in 2 patients because of disease progression. Finally, 2 patients experienced stable disease for an estimated median duration of 60.5 days (range, 58-63 days). The estimated median time to progression for the predefined efficacy population was 43 days (range, 38-58 days). Conclusion: Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease. (C) 2015 Elsevier Inc. All rights reserved.