A phase I clinical and pharmacologic study of a carboplatin and irinotecan regimen combined with recombinant human granulocyte-colony stimulating factor in the treatment of patients with advanced nonsmall cell lung carcinoma.

ABSTRACT

BACKGROUND: This Phase I study was designed to determine the toxicity and efficacy of a carboplatin and irinotecan (CPT-11) regimen with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support for patients with advanced nonsmall cell lung carcinoma. METHODS: Treatment consisted of carboplatin administered intravenously (i.v.) on Day 1 plus CPT-11 i.v. on Days 1, 8, and 15. The carboplatin dose was calculated using Calvert's formula, where the target area under the plasma concentration versus the time curve (AUC) was 5 or 6 mg x min/mL. rhG-CSF (2 microg/kg) was administered daily, except on Days 1, 8, and 15, until the leukocyte count exceeded 20,000/mm3 (10,000/mm3 after Day 16). Cycles were repeated every 4 weeks. Groups entered the trial at escalating CPT-11 and carboplatin dose levels of 60 mg/m2 and 5 mg x min/mL, 70/5 and 60/6. RESULTS: Twenty-one patients were enrolled in this study, of whom 20 were assessable for toxicity and therapeutic efficacy. Two of 6 patients experienced Grade 4 diarrhea at the 70/5 dose level, suggesting that this was the maximum tolerated dose (MTD). However, the 60/6 dose level was included because toxicities were very mild at the 60/5 dose level. At the 60/6 dose level, 1 of 6 patients experienced severe, life-threatening toxicity. Therefore, subsequent dose escalation was stopped and the study terminated. There were 7 responses (35%) among the 20 patients. At the 60/6 dose level (n=5), the observed carboplatin AUC after aiming for a target AUC of 6 was 5.9+/-0.9 mg x min/mL, as expected, although the AUCs of both CPT-11 and its active metabolite, SN-38, were lower than expected. CONCLUSIONS: The recommended doses for Phase II studies are 60 mg/m2 of CPT-11 and a target AUC of 5 mg x min/mL for carboplatin, plus rhG-CSF. The combination of AUC-based carboplatin and CPT-11 with rhG-CSF support appears to be an active regimen in the treatment of patients with NSCLC.