Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma

Abstract

This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6–specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1–12 of a 21-day cycle with bortezomib 1.0 mg/m² (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade ≤ 3. At a bortezomib dose lower than that in other combination therapy studies, antitumor activity was observed (phase 1). In phase 2, objective responses were achieved in 5 (20%) patients; 11 (44%) achieved stable disease. Biomarker and pharmacodynamic assessments demonstrated that palbociclib inhibited CDK4/6 and the cell cycle initially in most patients.

Keywords::

• Cell cycle
• CDK 4/6
• cyclin-dependent kinase 4/6
• multiple myeloma
• palbociclib

Acknowledgements

This study was sponsored by Pfizer Inc. The authors would like to thank Colin P. Mitchell, PhD, and Tiffany Brake, PhD, from Complete Healthcare Communications, Inc., who provided medical writing assistance, which was funded by Pfizer Inc.

Pfizer Inc. provided funding to the investigators for study design, study conduct, treatment administration, and collection of data. All authors had unrestricted access to the data, were responsible for data interpretation and manuscript preparation, and approved submission of the final manuscript for publication.

Potential conflicts of interest: Ruben Niesvizky has received research funding, honoraria, and has served as a consultant/advisor and member of speakers’ bureaus for Celgene, Millennium, and Onyx; Luciano J. Costa has received research funding from Pfizer; Seema B. Singhal has served on speakers bureaus for Celgene and Millennium; Edward A. Stadtmauer has received research funding from Pfizer; Abdulraheem Yacoub serves as a consultant/advisor to Seattle genetics, Alexion Pharmaceuticals, Incyte, and Sanofi; Georg Hess has received research funding and has served as a consultant/advisor to Pfizer; Suzanne Lentzsch has received research funding and has served as a consultant/advisor to Celgene and has received honoraria from Celgene, Bristol-Myers Squibb, and Bayer; Ivan Spicka has received research funding from Celgene, has been a consultant/advisor for Celgene and Janssen-Cilag, and has received honoraria and served on speakers bureaus for Celgene, Janssen-Cilag, and Novartis; Marc S. Raab has received research funding from Eli Lilly and Novartis and honoraria from Celgene; Ravi Vij has received research funding from Onyx and Celgene, has been a consultant/advisor for Celgene, Onyx, Array, and Bristol-Myers Squibb, and has received honoraria and served on speakers bureaus for Celgene, Onyx, and Millennium; Jeffrey A. Zonder has received research funding from Amgen and Celgene, has been a consultant/advisor for Bristol-Myers Squibb and Celgene, and has received honoraria from Prothena; Xin Huang, Yuqiu Jiang, Sindy T. Kim, and Sophia Randolph are Pfizer employees and own Pfizer stock; Ashraf Z. Badros, Scott A. Ely, Nisreen A. Haideri, Asher A. Chanan-Khan, Stefano Tarantolo, Xiangao Huang, David Jayabalan, Maurizio Di Liberto, and Selina Chen-Kiang have no disclosures to report. Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal

Supplementary material available online

Supplementary material Table I.