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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 and John P. Leonard

Key Points

  • Ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle could be safely administered to patients with previously treated MCL.

  • Complete responses and duration of response (median, >2 years) were high relative to studies of single-agent ibrutinib.

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.

  • Submitted November 15, 2018.
  • Accepted January 14, 2019.
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