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

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, 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

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.

Keywords: Breast cancer; Japanese; cyclin-dependent kinase; letrozole; palbociclib.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Design of this phase I study of palbociclib in Japanese patients. 1In principle, two dosages (100 mg once daily [QD] and 125 mg QD) were examined; where necessary, additional/lower dose levels (75 mg QD, dose level −1) were explored. 2If two or more patients of three to six patients at dose level 1 experienced a dose‐limiting toxicity (DLT) during cycle 1, the dose was considered intolerable and a lower dose (75 mg QD, dose level −1) was used. 3If no further DLTs occurred in the three additional patients such that only one of six patients at dose level 1 experienced DLT(s) during the first cycle, then the dose was escalated to dose level 2 (125 mg QD) in a subsequent cohort of patients. 4If two or more patients of three to six patients at dose level 2 experienced a DLT during the first cycle, the dose was de‐escalated to dose level 1 (100 mg QD) unless six patients were enrolled and evaluated at dose level 1 at that time. ER+, estrogen receptor‐positive; HER2−, human epidermal growth factor receptor‐negative; MTD, maximum tolerated dose; pts, patients.
Figure 2
Figure 2
Time course change in absolute neutrophil count in a phase I study of palbociclib in Japanese patients. LET, letrozole.
Figure 3
Figure 3
Mean ± SD plasma palbociclib concentration–time profiles on pharmacokinetic lead‐in phase day −7 following single oral dosing (a) and day 8 of cycle 1 following multiple oral dosing (b) in Japanese patients.
Figure 4
Figure 4
Relationship between change in absolute neutrophil count and pharmacokinetic parameters area under the plasma concentration–time curve over dosing interval (AUC τ) (a) and maximum plasma concentration (Cmax) (b).
Figure 5
Figure 5
Maximum shrinkage of solid tumors and estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer tumors treated with palbociclib 100 or 125 mg once daily and palbociclib 125 mg combined with letrozole (LET). Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1. †Palbociclib 125 mg + LET. ‡Palbociclib 100 mg.

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