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.

Abstract

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 II 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Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died.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.

• Authors: Ryan D Cassaday, Andre Goy, Suresh Advani, Purvi Chawla, Rajesh Nachankar, Mansi Gandhi, Ajay K Gopal
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 15 Issue 7 Pg. 392-7 (Jul 2015) ISSN: 2152-2669 [Electronic] United States
• PMID: 25816934 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin-Dependent Kinase Inhibitor Proteins
• Flavones
• P276-00
• Cyclin D1

Topics

• Aged
• Aged, 80 and over
• Cyclin D1 (drug effects)
• Cyclin-Dependent Kinase Inhibitor Proteins (adverse effects, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Flavones (adverse effects, therapeutic use)
• Humans
• Lymphoma, Mantle-Cell (drug therapy)
• Male
• Neoplasm Recurrence, Local (drug therapy)
• Treatment Outcome