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

• Published in: Leukemia & lymphoma 2015-12, Vol.56 (12), p.3320-3328
• Main Authors: Niesvizky, Ruben, Badros, Ashraf Z, Costa, Luciano J, Ely, Scott A, Singhal, Seema B, Stadtmauer, Edward A, Haideri, Nisreen A, Yacoub, Abdulraheem, Hess, Georg, Lentzsch, Suzanne, Spicka, Ivan, Chanan-Khan, Asher A, Raab, Marc S, Tarantolo, Stefano, Vij, Ravi, Zonder, Jeffrey A, Huang, Xiangao, Jayabalan, David, Di Liberto, Maurizio, Huang, Xin, Jiang, Yuqiu, Kim, Sindy T, Randolph, Sophia, Chen-Kiang, Selina
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - 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; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Neoplasm Staging; Piperazines - administration & dosage; Pyridines - administration & dosage; Recurrence; Retreatment; Treatment Outcome
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2015.1030641

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.