[Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors]
>>Clinical Cancer Research Vol. 12, 1270-1275, February 2006
Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors
Wells A. Messersmith1, Sharyn D. Baker1, Lance Lassiter1, Rana A. Sullivan1, Kimberly Dinh1, Virna I. Almuete1, John J. Wright2, Ross C. Donehower1, Michael A. Carducci1 and Deborah K. Armstrong1
Authors' Affiliations: 1 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and 2 Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Wells Messersmith, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, CRB 1M88, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-502-6873; Fax: 410-614-9006; E-mail: wmesser1@jhmi.edu.
Purpose: Bortezomib (PS-341), a first-in-class proteasome inhibitor, is metabolized by deboronation involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. Preclinical studies have shown synergy between bortezomib and taxanes. We conducted a phase I study combining bortezomib and docetaxel in refractory solid tumor patients.
Experimental Design: Patients received escalating doses of weekly docetaxel (days 1 and 8) and twice weekly bortezomib (days 2, 5, 9, and 12) in 3-week cycles. Two subjects were enrolled at each dose level, with cohort expansion to six for dose-limiting toxicity (DLT). Dose levels 1, 2, and 3 consisted of docetaxel/bortezomib 25/0.8, 25/1.0, and 30/1.0 mg/m2, respectively. CYP3A activity and docetaxel pharmacokinetic studies were conducted, and proteasome inhibition was assessed.
Results: Fourteen patients received a total of 34 cycles of treatment. Dose level 2 was expanded for DLT that occurred in two of six patients consisting of febrile neutropenia in one patient and grade 3 thrombocytopenia in one patient. One patient received two cycles at dose level 3 with dose reduction to dose level 2, where grade 3 thrombocytopenia occurred at cycle 3. Both episodes of grade 3 thrombocytopenia were transient (<7 days). Dose level 1 was then expanded to six patients where no DLTs occurred. CYP3A activity and docetaxel clearance did not change between weeks 1 and 5.
Conclusions: The maximum tolerated dose was docetaxel 25 mg/m2 (days 1 and 8) with bortezomib 0.8 mg/m2 (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance. <<
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