A phase I dose finding study of weekly, sequential docetaxel (Doc) followed by flavopiridol (F) in patients with advanced solid tumors

Abstract

3072 Background: Flavopiridol is a cyclin dependent kinase inhibitor which enhances chemotherapy induced apoptosis. In vitro F enhances Doc-induced apoptosis in a sequence specific manner such that Doc must come before F (Motwani et al. Mol. Cancer Ther. 2:549–555, 2003). In vivoDoc must precede F by at least 4 hours in order to induce this effect. Methods: In view of this finding, we designed a phase I trial of weekly, sequential Doc followed by F in patients with advanced solid tumors. Docetaxel 35 mg/m2 was administered over 30 minutes, followed 4 hours later by escalating doses of F (20, 30, 40, 50, 60, and 70 mg/m2) administered weekly over one hour. This schedule was repeated for 3 weeks out of each 4 week cycle. We used standard eligibility criteria for this phase I trial including normal hepatic, renal, and bone marrow function, and Karnofsky Performance Status (KPS) ≥ 70%. Prior taxane therapy was allowed. Results: Eighteen evaluable patients have been enrolled: median age 56 (range 39–77), median KPS 80%, (range 70–90%), 7 males/11 females, median 3 prior regimens (range 0–10). We have observed no dose limiting toxicity up to a weekly F dose of 60 mg/m2. We observed 2 partial responses in breast (17 weeks) and ovarian cancer (12+ weeks) patients, both of whom had received a prior taxane. Stable disease has been seen in 3 patients with taxane refractory breast cancer (62+, 33, and 18 weeks), 2 patients with pancreas cancer (15 and 17 weeks), and 1 patient with gastric cancer (21 weeks). Conclusion: Our data show that treatment with weekly, sequential Doc followed by F is an effective and safe regimen in patients with advanced solid tumors. Clinical activity is encouraging, even in patients who have received prior taxane therapy. Dose escalation of F continues to the targeted dose of 70 mg/m2. Further dose escalations of F may be possible with a reduced dose of weekly Doc. Phase II trials of weekly, sequential Doc followed by F are planned as second line therapies in patients with metastatic pancreas and gastric cancers. Pharmacokinetic data will be presented. (Sponsored by Aventis Pharmaceuticals) . . Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals Aventis Pharmaceuticals