BACKGROUND: To establish the recommended dose (RD) of the thymidylate-synthase inhibitor ZD9331 administered with irinotecan (CPT-11) in patients with pretreated metastatic colorectal cancer, and to assess toxicity profile, pharmacokinetics (PK), and anti-tumor activity in a phase I/II open, multicenter, intrapatient chemotherapy dose escalating trial. PATIENTS AND METHODS: Twenty-one patients who failed first-line therapy (5-fluorouracil/leucovorin +/- oxaliplatin) received every 2 weeks CPT-11 180 mg/m2 D1, followed by ZD9331 30-minute infusion D2 at three dose levels: 90, 120 and 150 mg/m2. RESULTS: RD of ZD9331 was established at 90 mg/m2 for the first two cycles, with possibility to escalate at 120 mg/m2 according to safety evaluation. Grade 3-4 toxicities were neutropenia (67% of patients), grade 3 vomiting (14%), grade 3 nausea (10%) and grade 3 diarrhea (5%). ZD9331 dose level does not affect the PK of CPT-11 or SN-38. Tumor growth control (PR + SD) was achieved for 14 (66.7%) patients. Median time to progression was 6 months, and median survival was 8.4 months. CONCLUSION: ZD9331 90 mg/m2 combined with CPT-11 180 mg/m2 may be a viable option for treatment of metastatic colorectal cancer, with possible escalation to 120 mg/m2 of ZD9331 according to safety evaluation.
BACKGROUND: To establish the recommended dose (RD) of the thymidylate-synthase inhibitor ZD9331 administered with irinotecan (CPT-11) in patients with pretreated metastatic colorectal cancer, and to assess toxicity profile, pharmacokinetics (PK), and anti-tumor activity in a phase I/II open, multicenter, intrapatient chemotherapy dose escalating trial. PATIENTS AND METHODS: Twenty-one patients who failed first-line therapy (5-fluorouracil/leucovorin +/- oxaliplatin) received every 2 weeks CPT-11 180 mg/m2 D1, followed by ZD9331 30-minute infusion D2 at three dose levels: 90, 120 and 150 mg/m2. RESULTS: RD of ZD9331 was established at 90 mg/m2 for the first two cycles, with possibility to escalate at 120 mg/m2 according to safety evaluation. Grade 3-4 toxicities were neutropenia (67% of patients), grade 3 vomiting (14%), grade 3 nausea (10%) and grade 3 diarrhea (5%). ZD9331 dose level does not affect the PK of CPT-11 or SN-38. Tumor growth control (PR + SD) was achieved for 14 (66.7%) patients. Median time to progression was 6 months, and median survival was 8.4 months. CONCLUSION:ZD9331 90 mg/m2 combined with CPT-11 180 mg/m2 may be a viable option for treatment of metastatic colorectal cancer, with possible escalation to 120 mg/m2 of ZD9331 according to safety evaluation.