A PHASE-I CLINICAL AND PHARMACOLOGICAL 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

BACKGROUND. This Phase I study was designed to determine the toxicity and efficacy of a carboplatin and irinotecan (CPT-11) regimen with rec ombinant human granulocyte colony-stimulating factor (rhG-CSF) support for patients with advanced nonsmall cell lung carcinoma. METHODS. Tre atment consisted of carboplatin administered intravenously (i.v.) on D ay 1 plus CPT-11 i.v. on Days 1, 8, and 15. The carboplatin dose was c alculated using Calvert's formula, where the target area under the pla sma concentration versus the time curve (AUC) was 5 or 6 mg . min/mL. rhG-CSF (2 mu g/kg) was administered daily, except on Days 1, 8, and 1 5, until the leukocyte count exceeded 20,000/mm(3) (10,000/mm(3) after Day 16). Cycles were repeated every 4 weeks. Groups entered the trial at escalating CPT-11 and carboplatin dose levels of 60 mg/m(2) and 5 mg . min/mL, 70/5 and 60/6. RESULTS. Twenty-one patients were enrolled in this study, of whom 20 were assessable for toxicity and therapeuti c 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 ve ry mild at the 60/5 dose level. At the 60/6 dose level, 1 of 6 patient s experienced severe, life-threatening toxicity. Therefore, subsequent dose escalation was stopped and the study terminated. There were 7 re sponses (35%) among the 20 patients. At the 60/6 dose level (n = 5), t he observed carboplatin AUC after aiming for a target AUC of 6 was 5.9 +/- 0.9 mg min/mL, as expected, although the AUCs of both CPT-11 and its active metabolite, SN-38, were lower than expected. CONCLUSIONS. T he recommended doses for Phase II studies are 60 mg/m(2) of CPT-11 and a target AUC of 5 mg . min/mL for carboplatin, plus rhG-CSF. The comb ination of AUG-based carboplatin and CPT-11 with rhG-CSF support appea rs to be an active regimen in the treatment of patients with NSCLC. (C ) 1998 American Cancer Society.