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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  NCT 01684215.

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