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

• Published in: Clinical cancer research Vol. 12; no. 4; pp. 1270 - 1275
• Main Authors: Messersmith, Wells A, Baker, Sharyn D, Lassiter, Lance, Sullivan, Rana A, Dinh, Kimberly, Almuete, Virna I, Wright, John J, Donehower, Ross C, Carducci, Michael A, Armstrong, Deborah K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2006
• Subjects: Adult; Aged; Anemia - chemically induced; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacokinetics; Bortezomib; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Fatigue - chemically induced; Female; Humans; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Taxoids - administration & dosage; Taxoids - adverse effects; Taxoids - pharmacokinetics; Treatment Outcome; Antineoplastic agent; Human; Solid tumor; Bortezomib; Taxane derivatives; Docetaxel; Phase I trial; Advanced stage; Malignant tumor; Antimitotic
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1942

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/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.