Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer Journal Article
| Authors: | Flaherty, K. T.; LoRusso, P. M.; DeMichele, A.; Abramson, V. G.; Courtney, R.; Randolph, S. S.; Shaik, M. N.; Wilner, K. D.; O'Dwyer, P. J.; Schwartz, G. K. |
| Article Title: | Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer |
| Abstract: | Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic- pharmacodynamic relationships relative to drug effects. Experimental Design: This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design. Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most commonnon-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median T max, 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration - time curve increased linearly with dose. Using an E max model, neutropenia was shown to be proportional to exposure. Conclusions: PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. ©2011 AACR. |
| Keywords: | adult; clinical article; controlled study; treatment outcome; aged; middle aged; young adult; constipation; drug tolerability; fatigue; neutropenia; advanced cancer; area under the curve; diarrhea; dose response; drug efficacy; drug safety; gastrointestinal hemorrhage; recommended drug dose; side effect; solid tumor; antineoplastic agents; pyridines; neoplasms; pharmacodynamics; sensory neuropathy; anemia; leukopenia; nausea; thrombocytopenia; vomiting; cohort analysis; antineoplastic activity; drug effect; dose-response relationship, drug; abdominal pain; arthralgia; drug dose escalation; dyspnea; hyponatremia; drug distribution; dosage schedule comparison; pleura effusion; area under curve; time to maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; piperazines; drug half life; administration, oral; cyclin-dependent kinases; 6 acetyl 8 cyclopentyl 5 methyl 2 [5 (1 piperazinyl) 2 pyridinylamino] 8h pyrido[2,3 d]pyrimidin 7 one; retinoblastoma protein; uric acid blood level; heart arrest; drug elimination; neck pain; failure to thrive; hip arthroplasty; dysphasia |
| Journal Title: | Clinical Cancer Research |
| Volume: | 18 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2012-01-15 |
| Start Page: | 568 |
| End Page: | 576 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-11-0509 |
| PROVIDER: | scopus |
| PUBMED: | 22090362 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2012" - "CODEN: CCREF" - "Source: Scopus" |
