ABSTRACT
BACKGROUND: The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors. METHODS: Patients who had received >/=1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m(2), 1.3 mg/m(2), or 1.5 mg/m(2)) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m(2) to 125 mg/m(2)) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS: Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received >/=1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m(2) bortezomib and 125 mg/m(2) irinotecan. The most common grade >/=3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes). grade >/=3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration. CONCLUSIONS: The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m(2) on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m(2) on Days 1 and 8 every 21 days were the recommended Phase II doses.
