title: 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: BACKGROUND
  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.
  
  
  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  Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died.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).
  
  
  CONCLUSIONS
  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: Department of Medicine, University of Washington School of Medicine, and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Ryan D
authors: RD
authors: Cassaday
authors: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
authors: Andre
authors: A
authors: Goy
authors: Jaslok Hospital and Research Centre, Mumbai, India.
authors: Suresh
authors: S
authors: Advani
authors: Piramal Enterprises Limited, Mumbai, India.
authors: Purvi
authors: P
authors: Chawla
authors: Piramal Enterprises Limited, Mumbai, India.
authors: Rajesh
authors: R
authors: Nachankar
authors: Piramal Enterprises Limited, Mumbai, India.
authors: Mansi
authors: M
authors: Gandhi
authors: Department of Medicine, University of Washington School of Medicine, and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: agopal@uw.edu.
authors: Ajay K
authors: AK
authors: Gopal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000187:drug effects; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D047309:Flavones / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D047309:Flavones; C520467:P276-00; D019938:Cyclin D1
keywords: CDK inhibitor; Non-Hodgkin lymphoma; Targeted therapy