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

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.