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.