A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma
Peter Martin, Nancy L Bartlett, Kristie A Blum, Steven Park, Kami Maddocks, Jia Ruan, LeAnn Ridling, Christopher Dittus, Zhengming Chen, Xiangao Huang, Giorgio Inghirami, Maurizio DiLiberto, Selina Chen-Kiang, John P Leonard, Peter Martin, Nancy L Bartlett, Kristie A Blum, Steven Park, Kami Maddocks, Jia Ruan, LeAnn Ridling, Christopher Dittus, Zhengming Chen, Xiangao Huang, Giorgio Inghirami, Maurizio DiLiberto, Selina Chen-Kiang, John P Leonard
Abstract
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.
Conflict of interest statement
Conflict-of-interest disclosure: P.M. served as a consultant for Janssen, Gilead, AstraZeneca/Acerta, Celgene, Karyopharm, and Sandoz. S.P. received research funds from Takeda, Teva, Seattle Genetics, and BMS; served as a consultant for BMS, Rafael Pharma, G1 Therapeutics, Teva, and Bayer; and served on the speakers bureau for Gilead and Seattle Genetics K.A.B. received research funds from Pharmacyclics and Janssen. K.M. received research funds from Pharmacyclics, Merck, BMS, and Novartis and served as a consultant: for Pharmacyclics, AstraZeneca/Acerta, Bayer, Novartis, and Teva. S.C.-K. served as a consultant for Vigilant. J.P.L. served as a consultant for Sutro, Bayer, MEI Pharma, Gilead, AstraZeneca, Novartis, Celgene, Biotest, Merck, Morphosys, Beigene, Nordic Nanovector, Roche/Genentech, and ADC Therapeutics. The remaining authors declare no competing financial interests.
© 2019 by The American Society of Hematology.
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Source: PubMed