Phase IDose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect.We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors. Experimental Design: Docetaxel at a fixed dose of 35 mg/m was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m in successive cohorts, administered weekly over 1h. This schedule was repeated for 3 weeks of each 4-week cycle. Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m (grade 4 neutropenia). We observed 1complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from1.49 F 0.69 Amol/L (flavopiridol 20 mg/m) to 4.54 F 0.08 Amol/L (flavopiridol 60 mg/m) in cycle1. Conclusions:Treatment withweekly, sequential docetaxel followedby flavopiridol is an effective and safe regimen at all flavopiridol dose levels.The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer. Progression through the different phases of the cell cycle is driven by the coordinated activation of cyclin-dependent kinases (CDK): CDKs are essential enzymes for the cell cycle, and when activated, they allow the transit of the cell between the different phases of the cell cycle, whether it is G1 to S or G2 to M. Deregulated CDK activity is frequently present in malignant cells. Inhibition of CDKs can lead to cell cycle arrest and subsequent apoptosis (1, 2). This rationale led to the development of CDK inhibitors as novel antitumor agents. Flavopiridol is among the first potent CDK inhibitors to enter clinical trials. Flavopiridol is prepared by total synthesis and is identical to a compound obtained by derivation from a natural product obtained by Dysoxylum binectariferum , a plant indigenous to India (3). Flavopiridol inhibits CDKs including CDK1, CDK2, CDK4, and CDK6, and it inhibits tumor cell growth in vitro through blockade of cell cycle progression at the G1-S or G2-M interfaces (4–7). Flavopiridol therefore causes cell cycle arrest, induces apoptosis, inhibits angiogenesis, and potentiates the effects of chemotherapy (5–7). Single-agent antitumor activity has been observed in a variety of preclinical models (8, 9). We have shown that flavopiridol enhances paclitaxel-mediated apoptosis of MKN-74 gastric cancer cells and MCF-7 breast cancer cells by activation of caspase-3 (10). For both docetaxel and paclitaxel, the enhancement of apoptosis by flavopiridol is highly sequence dependent such that the taxane must precede flavopiridol to induce this effect. Furthermore, in vivo, the effect is time dependent such that docetaxel must be administered at least 4 h before the flavopiridol (11). Flavopiridol has been evaluated in phase I clinical trials with chemotherapy with promising clinical activity (12, 13). Based on these preclinical and clinical observations, we conducted a phase I trial of weekly, sequential docetaxel followed by flavopiridol in patients with advanced solid tumors such that docetaxel was administered 4 h before the flavopiridol. Because prolonged infusions of flavopiridol had been associated with considerable clinical toxicity, and because prior phase I experience with weekly flavopiridol in combination Cancer Therapy: Clinical Authors’Affiliations: Breast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine; Genitourinary Oncology Service, Division of SolidTumor Oncology; Gastrointestinal Oncology Service, Division of SolidTumor Oncology; Department of Epidemiology and Biostatistics; Department of Radiology; and Department of Melanoma and Sarcoma Service, Memorial SloanKettering Cancer Center, NewYork, New York Received 5/16/07; revised 7/11/07; accepted 7/17/07. Grant support: Sanofi Aventis Pharmaceuticals. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Gary K. Schwartz, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 457, New York, NY 10021. Phone: 212-639-8324; Fax: 212-717-3340; E-mail: schwartg@ mskcc.org. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1218 www.aacrjournals. org Clin Cancer Res 2007;13(19) October1, 2007 5841 Research. on May 1, 2017. © 2007 American Association for Cancer clincancerres.aacrjournals. org Downloaded from with irinotecan showed tolerability and encouraging activity, we chose a weekly 1-h infusion of flavopiridol. This schedule would also allow us to achieve higher peak flavopiridol levels (13). The primary objective of this trial was to determine the maximum tolerated dose (MTD) of weekly flavopiridol when administered in combination with a fixed dose of weekly docetaxel to patients with advanced solid tumors. Secondary objectives were to investigate the clinical pharmacokinetics of weekly i.v. 1-h infusion of flavopiridol in combination with docetaxel, and to obtain preliminary data on the therapeutic activity of this regimen.