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Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors

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{at}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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