title: 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.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.|Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.|Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodaira
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.|Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology Endoscopy, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Osera
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Masaoki
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Pfizer Japan Inc., Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Pfizer Japan Inc., Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hashigaki
authors.affiliation: Pfizer Japan Inc., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: Pfizer Japan Inc., Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Umeyama
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000166:cytology; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: Breast cancer; Japanese; cyclin-dependent kinase; letrozole; palbociclib