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Leuk Lymphoma. 2015;56(12):3320-8. doi: 10.3109/10428194.2015.1030641. Epub 2015 May 15.

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

Author information

  • 1a Medicine and Hematology/Oncology, Weill Cornell Medical College , New York , NY , USA.
  • 2b Department of Medicine , University of Maryland Greenebaum Cancer Center , Baltimore , MD , USA.
  • 3c Department of Medicine and UAB-CCC , Bone Marrow Transplantation and Cell Therapy Program, University of Alabama , Birmingham , AL , USA.
  • 4d Pathology and Laboratory Medicine, Weill Cornell Medical College , New York , NY , USA.
  • 5e Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine , Chicago , IL , USA.
  • 6f Division of Hematology/Oncology, University of Pennsylvania Abramson Cancer Center , Philadelphia , PA , USA.
  • 7g Oncology/Hematology and Internal Medicine, Saint Luke's Health System , Kansas City , MO , USA.
  • 8h Hematology and Oncology, University of Kansas Medical Center , Kansas City , KS , USA.
  • 9i Department of Hematology , Oncology and Pneumology, University Medical School of the Johannes Gutenberg-University , Mainz , Germany.
  • 10j Division of Hematology/Oncology, Columbia University Medical Center , New York , NY , USA.
  • 11k 1st Department of Internal Medicine , Charles University , Praha , Czech Republic.
  • 12l Department of Hematology/Oncology , Mayo Clinic , Jacksonville , FL , USA.
  • 13m Department of Internal Medicine V , University of Heidelberg, and German Cancer Research Center (DFKZ) , Heidelberg , Germany.
  • 14n Methodist Hospital and Nebraska Cancer Specialists , Omaha , NE , USA.
  • 15o Section of BMT and Leukemia, Washington University School of Medicine , St. Louis , MO , USA.
  • 16p Oncology and Internal Medicine, Karmanos Cancer Institute/Wayne State University , Detroit , MI , USA.
  • 17q Pfizer Oncology , San Diego , CA , USA.

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 gradeā‰¤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:

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

PMID:
25813205
[PubMed - in process]
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