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Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients.
- Source :
-
Cancer science [Cancer Sci] 2016 Jun; Vol. 107 (6), pp. 755-63. Date of Electronic Publication: 2016 May 11. - Publication Year :
- 2016
-
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.<br /> (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
- Subjects :
- Adult
Aged
Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Female
Humans
Japan
Male
Middle Aged
Neoplasms enzymology
Neoplasms pathology
Neutrophils cytology
Piperazines administration & dosage
Piperazines adverse effects
Piperazines pharmacokinetics
Pyridines administration & dosage
Pyridines adverse effects
Pyridines pharmacokinetics
Survival Analysis
Young Adult
Antineoplastic Agents therapeutic use
Cyclin-Dependent Kinase 4 antagonists & inhibitors
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Neoplasms drug therapy
Piperazines therapeutic use
Pyridines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 107
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 26991823
- Full Text :
- https://doi.org/10.1111/cas.12932