PHASE-I CLINICAL-TRIAL OF IRINOTECAN (CPT-11), PIPERIDINO)-1-PIPERIDINO]CARBONYLOXY-CAMPTOTHECIN, AND CISPLATIN IN COMBINATION WITH FIXED-DOSE OF VINDESINE IN ADVANCED NONSMALL CELL LUNG-CANCER

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of campt othecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination p hase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32-73 years ) entered into these trials had a good performance status (Eastern Coo perative Oncology Group score, 0-1) and had received no prior chemothe rapy or radiotherapy. In the first trial, 14 stage IV and 2 stage III patients were studied; in the second trial 30 patients with stage IV d isease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisp latin (100 mg/m(2), i.v., on day 1) and vindesine (3 mg/m(2), i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m (2), and the dose was increased in increments of 25 mg/m(2). In the se cond trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (da y 1) were escalated with a fixed dose of vindesine (same dose as the f irst study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m(2), respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m(2). At lea st 3 patients were entered at each dose level in both trials. Use of g ranulocyte colony-stimulating factor or granulocyte-macrophage colony- stimulating factor was not permitted in this trial. In the first trial , grade 4 granulocytopenia and grade greater than or equal to 3 diarrh ea were dose limiting at 50 mg/m(2) CPT-11, which represented the maxi mum tolerated dose. At the subsequent dose of CPT-11, 7 new patients w ere requited at the 50% reduced dose level of 37.5 mg/m(2) on days 1 a nd 8. Nine patients were evaluable for response, and 4 of them achieve d a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/m(2 ), the maximum concentration in plasma of CPT-11 (>0.4 mu g/ml) reache d >10-fold the in vitro concentration of CPT-11 required for 50% inhib ition of growth. In the second trial, the dose-limiting toxicities wer e grade 4 granulocytopenia lasting for greater than or equal to 7 days and grade greater than or equal to 3 diarrhea. The maximum tolerated dose was 100 mg/m(2) of CPT-11 and 60 mg/m(2) of cisplatin in this reg imen. The other severe toxicity was to the liver. Ten of 30 patients e ntered (10 of 22 patients assessable for response) achieved a partial response. Intractable diarrhea induced by CPT-11 was associated with t he dose of cisplatin used in our trials and occurred coincidentally wi th granulocytopenia of grade 4. For future phase II trials, we recomme nd doses of CPT-11 of 37.5 and 80 mg/m(2) on days 1 and 8 combined wit h vindesine and either high-dose cisplatin (100 mg/m(2)) or low-dose c isplatin (60 mg/m(2)), respectively.