TY - JOUR
T1 - Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors
AU - Messersmith, Wells A.
AU - Baker, Sharyn D.
AU - Lassiter, Lance
AU - Sullivan, Rana A.
AU - Dinh, Kimberly
AU - Almuete, Virna I.
AU - Wright, John J.
AU - Donehower, Ross C.
AU - Carducci, Michael A.
AU - Armstrong, Deborah K.
PY - 2006/2/15
Y1 - 2006/2/15
N2 - 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/m 2 (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.
AB - 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/m 2 (days 2, 5, 9, and 12) given every 21 days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.
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U2 - 10.1158/1078-0432.CCR-05-1942
DO - 10.1158/1078-0432.CCR-05-1942
M3 - Article
C2 - 16489083
AN - SCOPUS:33644785935
SN - 1078-0432
VL - 12
SP - 1270
EP - 1275
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -