Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients.

Abstract

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half-life was 23-26 h. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.

• Authors: Kenji Tamura, Hirofumi Mukai, Yoichi Naito, Kan Yonemori, Makoto Kodaira, Yuko Tanabe, Noboru Yamamoto, Shozo Osera, Masaoki Sasaki, Yuko Mori, Satoshi Hashigaki, Takashi Nagasawa, Yoshiko Umeyama, Takayuki Yoshino
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 6 Pg. 755-63 (Jun 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 26991823 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Piperazines
• Pyridines
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Female
• Humans
• Japan
• Male
• Middle Aged
• Neoplasms (drug therapy, enzymology, pathology)
• Neutrophils (cytology)
• Piperazines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Survival Analysis
• Young Adult