Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background: To determine the dose-limiting toxicity of CPT-11 in combination with oxaliplatin, and the maximal tolerated dose (MTD) and the recommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods: The study was designed to evaluate escalated doses of CPT-11 starting at 100 mg/m(2) with a fixed clinically-relevant dose of 85 mg/m(2) oxaliplatin given every two weeks. Results: Twenty-three patients and 186 cycles were evaluable for toxicity (median per patient: 7, range: 1-13). Grade 3 oxaliplatin-induced neurotoxicity was cumulative and limiting in 39% (9 of 23) of patients. The MTD of CPT-11 was 200 mg/m(2), with incomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175 mg/m(2) of CPT-11): no grade 4 neutropenia was seen in the two first cycles; 30% of patients experienced grade 3-4 diarrhea. Febrile neutropenia (3.2% of all cycles) was 3-fold more frequent in performance status (PS) 2 than in PS 0-1 patients. Among eleven colorectal cancer (CRC) patients, three complete and four partial responses were documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion: To combine CPT-11 175 mg/m(2) and oxaliplatin 85 mg/m(2) every two weeks is feasible in an outpatient setting, and very active in 5-FU resistant CRC patients. A dose of 150 mg/m(2) CPT-11 is recommended in PS 2 patients.