Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors

Gary K. Schwartz, Eileen O'Reilly, David Ilson, Leonard Saltz, Sunil Sharma, William Tong, Peter Maslak, Maxine Stoltz, Larry Eden, Pam Perkins, Sandra Endres, John Barazzoul, David Spriggs, David Kelsen

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

Abstract

Purpose: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. Patients and Methods: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. Results: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m2 and flavopiridol doses of 10 and 20 mg/m2, respectively. With 3-hour paclitaxel at 100 mg/m2, flavopiridol could be escalated to 70 mg/m2 without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m2, dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m2. This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m2, dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m2. Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. Conclusion: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m2 on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m2 on day 2. Flavopiridol dose escalations to 80 mg/m2 are possible. At these doses, toxicities are manageable and clinical activity is promising.

Original languageEnglish
Pages (from-to)2157-2170
Number of pages14
JournalJournal of Clinical Oncology
Volume20
Issue number8
DOIs
StatePublished - 15 Apr 2002
Externally publishedYes

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