Phase I trial of the proteasome inhibitor bortezomib in combination with carboplatin in patients with platinum- and taxane-resistant ovarian cancer.
OBJECTIVE
This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the proteasome inhibitor bortezomib when combined with carboplatin in ovarian cancer patients with recurrent and platinum- and taxane-resistant disease.


METHODS
Patients with platinum- and taxane-resistant recurrent ovarian cancer, measurable disease, and a performance status of 0 to 2 were eligible. Bortezomib (0.8, 1.0, 1.3, or 1.5 mg/m2) was administered on days 1, 4, 8, and 11 by intravenous push with carboplatin (area under curve=5) on day 1; therapy was repeated every 28 days.


RESULTS
Twenty-one women (median age, 63 years; range, 43 to 83 years) were treated with carboplatin and bortezomib at 0.8 mg/m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2 (n=6). At these levels, there were 1, 0, 1, and 3 DLTs, respectively, attributable to bortezomib; all were grade 3. The DLTs were fatigue (n=3); nausea, vomiting, and dehydration (n=1); and anorexia, dehydration, and syncope (n=1). Common grade 2 toxicities included fatigue (n=12), nausea (n=10), and anorexia, anemia, and dyspnea (n=7 each). The 18 patients evaluable for response all had stable disease (SD; n=8) or progressive disease (n=10). The median duration of SD was 4 months (range, 3 to 7 months). At the MTD of 1.3 mg/m2, 3 of 6 patients had SD.


CONCLUSIONS
The recommended dose of bortezomib in combination with carboplatin is 1.3 mg/m2. Treatment was reasonably well tolerated at the MTD.
Ramirez
Pedro T
PT
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439, USA. peramire@mdanderson.org
Landen
Charles N
CN
Coleman
Robert L
RL
Milam
Michael R
MR
Levenback
Charles
C
Johnston
Taren A
TA
Gershenson
David M
DM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016190:Carboplatin