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.

• Authors: Ruben Niesvizky, Ashraf Z Badros, Luciano J Costa, Scott A Ely, Seema B Singhal, Edward A Stadtmauer, Nisreen A Haideri, Abdulraheem Yacoub, Georg Hess, Suzanne Lentzsch, Ivan Spicka, Asher A Chanan-Khan, Marc S Raab, Stefano Tarantolo, Ravi Vij, Jeffrey A Zonder, Xiangao Huang, David Jayabalan, Maurizio Di Liberto, Xin Huang, Yuqiu Jiang, Sindy T Kim, Sophia Randolph, Selina Chen-Kiang
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 56 Issue 12 Pg. 3320-8 ( 2015) ISSN: 1029-2403 [Electronic] United States
• PMID: 25813205 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Piperazines
• Pyridines
• Bortezomib
• Dexamethasone
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Bortezomib
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Dexamethasone (administration & dosage)
• Drug Administration Schedule
• Drug Monitoring
• Drug Resistance, Neoplasm
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Multiple Myeloma (drug therapy, metabolism, mortality, pathology)
• Neoplasm Staging
• Piperazines (administration & dosage)
• Pyridines (administration & dosage)
• Recurrence
• Retreatment
• Treatment Outcome