Cancer Therapy: Clinical Phase I Study of Flavopiridol with Oxaliplatin and Fluorouracil/ Leucovorin in Advanced Solid Tumors

Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatinand fluorouracil (5FU)–induced apoptosis in a sequence-dependent manner. Experimental Design: We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. Results: Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m) and 5FU (2,400 mg/m), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m flavopiridol, 85 mg/m oxaliplatin, and 1,800 mg/m 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders. Conclusions: Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinumrefractory germ cell tumor population has prompted a phase II trial that is currently open for accrual. (Clin Cancer Res 2009;15(23):7405–11) Flavopiridol is a pan-cyclin–dependent kinase inhibitor that promotes cell cycle arrest at nanomolar concentrations and has been associated with the selective induction of apoptosis in DNA-damaged tumor cells (1, 2). In the laboratory, flavopiridol has been shown to potently enhance the effects of a wide range of chemotherapeutic agents, including SN38 and taxane derivatives, in a timeand sequence-dependent manner (3–5). This has been translated into a series of phase I trials in advanced solid tumors with encouraging clinical results, a reasonable safety profile, and pharmacologic levels of the drug that are sufficient to potentiate the effect of chemotherapy in vivo (6–8). Oxaliplatin, a platinum-based agent, has shown antiproliferative activity equivalent to or higher than that of cisplatin in a wide range of experimental tumor models. In vitro and in vivo, oxaliplatin has exhibited enhanced cytotoxic properties when combined with fluoropyrimidines [fluorouracil (5FU) and gemcitabine], thymidylate synthase inhibitors (AG337), topoisomerase I inhibitors (CPT-11 and SN38), microtubule inhibitors (paclitaxel), and DNA-modifying agents (cisplatin and cyclophosphamide; 9, 10). In the clinic, oxaliplatin has shown antitumor activity as a single agent in a variety of solid tumors, and also in combination with leucovorin [folinic acid (FOL)] and 5FU as part of the FOLFOX regimen for the treatment of metastatic colon cancer (11). Similar to preclinical data on the effects of flavopiridol with mitomycin C, paclitaxel, and SN38, flavopiridol enhances the Authors' Affiliations: Genitourinary Oncology Service, Melanoma and Sarcoma Service, and Gastrointestinal Oncology Service, Department of Medicine; Molecular Pharmacology and Chemistry Program, SloanKettering Institute; Department of Radiology and Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York Received 6/11/09; revised 7/30/09; accepted 9/3/09; published OnlineFirst 11/24/09. Grant support: National Cancer Institute grant R01CA67819. 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 with 18 U.S.C. Section 1734 solely to indicate this fact. Note: The material in this work has previously been presented in abstract format at the 2008 American Society of Clinical Oncology Annual symposium. Requests for reprints: Gary K. Schwartz, Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 212-639-8624; Fax: 212-7173340; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1502 7405 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on April 11, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-09-1502