Phase I trial of bortezomib (PS-341) in combination with docetaxel in patients with advanced solid tumors

Abstract

3052 Background: Bortezomib (PS-341), a first-in-class dipeptidyl boronic acid, is an inhibitor of the 26S proteasome, an ATP-dependent multicatalytic protease central to the ubiquitin-proteasome degradation pathway. The principal mode of bortezomib detoxification is via deboronization involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. A phase I study combining bortezomib and docetaxel is being performed to determine the MTD/toxicities and pharmacokinetics (PK) of this combination in refractory solid tumor pts. Methods: Pts received escalating doses of weekly docetaxel (d1 and d8) and twice-weekly bortezomib (d2, d5, d9, and d12) in 3-wk cycles. Two pts were enrolled at each dose level, with cohort expansion to 6pts for DLT (occurring in cycles 1 or 2). Dose level 1 (DL1), 2 (DL2), and 3 (DL3) consisted of docetaxel/bortezomib 25/0.8 mg/m2, 25/1.0 mg/m2, and 30/1.0 mg/m2, respectively. CYP3A activity, determined using the erythromycin breath test (ERMBT), and docetaxel PK were evaluated during weeks 1 (docetaxel alone) and 5 (docetaxel + bortezomib). Results: Thirteen pts (10 M/3 F; mean (range) age, 62 (40–76) years; ECOG PS, 0–1) received a total of 31 cycles. DL2 was expanded for DLT which occurred in 2 of 6 pts (febrile neutropenia [1 pt] and thrombocytopenia [1pt]), thus exceeding the MTD. DL1 was then expanded to 6 pts where no DLTs occurred; one additional patient will be enrolled to replace a pt not evaluable for toxicity to define the MTD at DL1. One pt received 2 cycles at DL3 with dose-reduction to DL2; gr 3 thrombocytopenia occurred at cycle 3. Both episodes of gr3 thrombocytopenia were transient (<7d) without clinical sequelae. The ERMBT parameter, 14C-exhaled/h (%), and docetaxel clearance did not change between weeks 1 and 5; mean (SD) values were 1.99 (0.84)% vs 2.31 (0.81)% (P=.44) and 29.2 (13.5) L/h vs 27.0 (14.6) (P = .49), respectively. Conclusions: The MTD of docetaxel given weekly for 2 of 3 weeks with bortezomib twice-weekly (4 doses) has been defined. Bortezomib treatment did not alter CYP3A activity and docetaxel CL demonstrating lack of a drug interaction with this drug combination. Supported by U01 CA70095 and Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis (Speaker's Bureau) Aventis