PHASE-I STUDY OF TOPOTECAN AND CISPLATIN IN PATIENTS WITH ADVANCED SOLID TUMORS - A CANCER AND LEUKEMIA GROUP-B STUDY

Purpose: The objectives of this phase I trial were to determine the do se-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor t opotecan combined with cisplatin, to define the maximum-tolerated dose s (MTDs) of the combination without and with the use of filgrastim, an d to define recommended doses for phase II trials. Patients and Method s: Patients with advanced solid tumors were eligible if they had norma l bone marrow, renal, and hepatic function and held not previously bee n treated with platinum compounds. Topotecan was administered intraven ously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m( 2)/d on the first four dose levels, and cisplatin was escalated in 25- mg/m(2) increments from 25 to 100 mg/m(2) without filgrastim. After en countering DLT, the dose of cisplatin was decreased by one level and t opotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 mu g/kg subcutaneously (SC) daily st arting on day 6 of treatment. Priming with filgrastim 5 mu g/kg SC on days -6 to -2 before the first course was explored last. Results: Of 3 8 patients entered, 37 were eligible, 35 assessable for toxicity in th e first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be con sidered dose-limiting. No DLT was observed at the starting cisplatin d ose of 25 mg/m(2) (dose level 1). On level2 (cisplatin 50 mg/m(2)), on e patient had dose-limiting neutropenia and one patient had grade 3 re nal toxicity. On level 3 (cisplatin 75 mg/m(2)), two patients had dose -limiting neutropenia., Therefore, cisplatin dose escalation was stopp ed. On dose level 5 (cisplatin 50 mg/m(2) and topotecan 1.25 mg/m(2)/d ), one patient had grade 4 neutropenia that lasted more than 7 days an d one patient died of neutropenic sepsis. The remaining dose levels us ed topotecan 1.0 mg/m(2)/d plus cisplatin 75 mg/m(2) (level 6) and 100 mg/m(2) (levels 7 and 8) with filgrastim. No DLT was observed on leve l 6. On level 7, two patients had dose-limiting neutropenia and one pa tient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one p atient with breast cancer had a complete response. Conclusion: Topotec an and cisplatin in combination cause more neutropenia than expected f rom either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m(2)/d for 5 days in combination with ci splatin 50 mg/m(2) on day 1 without filgrastim or cisplatin 75 mg/m(2) on day 1 with filgrastim support.