pci-32765 and palbociclib

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperazines; Piperidines; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Survival Rate

Topics: Adenine; Antineoplastic Agents; Drug Evaluation; Humans; Neoplasms; Patient Selection; Piperazines; Piperidines; Pragmatic Clinical Trials as Topic; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Design

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinases; Cysteine; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Mutation; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Serine