Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.
OBJECTIVE
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.


METHODS
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/m(2), 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/m(2) (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.
Messersmith
Wells A
WA
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA. wmesser1@jhmi.edu
Baker
Sharyn D
SD
Lassiter
Lance
L
Sullivan
Rana A
RA
Dinh
Kimberly
K
Almuete
Virna I
VI
Wright
John J
JJ
Donehower
Ross C
RC
Carducci
Michael A
MA
Armstrong
Deborah K
DK
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D043823:Taxoids; D000077143:Docetaxel; D000069286:Bortezomib; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D046988:Proteasome Endopeptidase Complex