461P - Safety, pharmacokinetics (PK) and efficacy of cyclin-dependent kinase (CDK) 4 and 6 inhibitor, palbociclib (PD-0332991): Results from a phase 1 stu...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Clinical Research
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Hirofumi Mukai
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors H. Mukai1, T. Yoshino2, S. Osera3, M. Sasaki1, C. Shimizu4, K. Yonemori5, M. Koudaira5, Y. Tanabe6, N. Matsuda7, N. Mizutani7, Y. Mori7, S. Hashigaki7, T. Nagasawa7, Y. Umeyama8, S. Randolph9, K. Tamura10
  • 1Breast And Medical Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 2Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 3Gastroenterology Endoscopy, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 4Department Of Breast And Medical Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 5Breast And Medical Oncology Division, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 6Exploratory Oncology Research And Clinical Trial Center, National Cancer Center, 104-0045 - Tokyo/JP
  • 7Clinical Research, Pfizer Japan Inc., Tokyo/JP
  • 8Clinical Research, Pfizer Japan Inc., 151-8589 - Tokyo/JP
  • 9Clinical Research, Pfizer Oncolgy, San Diego/US
  • 10Breast And Medical Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP



Palbociclib is a potent and highly selective reversible oral inhibitor of CDK 4/6. This ongoing phase 1 study evaluates the safety, PK and preliminary efficacy of palbociclib as a single agent in Japanese pts with solid tumors (part 1) and in combination with letrozole (LET) in 1st-line treatment of Japanese postmenopausal pts with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer (part 2).


Two dose levels (100 and 125 mg; n=6 each) of palbociclib monotherapy once daily were studied in a 3-wk-on/1-wk-off treatment schedule (schedule 3/1) to evaluate the maximum tolerated dose (MTD) in part 1. The MTD of palbociclib (decided in part 1) was then used in combination with LET 2.5 mg in part 2 (n=6).


Dose-limiting toxicity was noted in 1 pt at each dose level: <75% of planned palbociclib dose received due to neutropenia (100 mg) and grade 4 thrombocytopenia (125 mg). MTD in Japanese pts was determined as 125 mg. The most common treatment-related adverse events (AEs) were hematologic toxicities; neutropenia (all grade/grade 3): 83%/67% (100 mg), 67%/33% (125 mg) and 100%/67% (in combination with LET). No ≥grade 3 treatment-related nonhematologic AE was noted. In PK assessment of 100 and 125 mg (part 1), higher exposure was observed at 125 mg: mean area under the concentration-time curve was 547.5 and 1322 ng•h/mL after single dose and 1276 and 2838 ng•h/mL after multiple doses (MD); mean maximum concentration was 41.4 and 104.1 ng/mL after single dose and 77.4 and 185.5 ng/mL after MD. Half-life was 24–26 h. Drug-drug interaction between palbociclib and LET was not indicated in part 2. Four pts had stable disease (SD) in part 1 (>24 wks in 1 esophageal cancer pt at 125 mg); 2 pts had unconfirmed partial response and 2 had SD in part 2.


Hematologic toxicities were common with palbociclib monotherapy and combination therapy. Although a higher than dose-proportional increase in exposure was observed at 125 mg, the 125-mg dose (schedule 3/1) was tolerated and considered a recommended dose for monotherapy and LET combination therapy in Japanese pts.


H. Mukai, T. Yoshino, S. Osera, M. Sasaki, C. Shimizu, K. Yonemori, M. Koudaira, Y. Tanabe and K. Tamura: corporate(Pfizer)-sponsored research; N. Matsuda, N. Mizutani,Y. Mori, S. Hashigaki,T. Nagasawa and Y. Umeyama: Employee of Pfizer Japan; S. Randolph: Employee of Pfizer Oncology.