DOSE-ESCALATION STUDY OF CARBOPLATIN AND CYCLOPHOSPHAMIDE WITH FILGRASTIM SUPPORT - A PHASE-I STUDY

This clinical trial was designed to explore dose escalation of carbopl atin and cyclophosphamide when supported with filgrastim. Twenty-seven patients who had advanced solid tumors received up to six cycles of t reatment; a total of 92 cycles of chemotherapy were delivered. Two con trol groups received standard-dose carboplatin (300 mg/m(2)) and cyclo phosphamide (600 mg/m(2)), with and without filgrastim. Subsequently, the doses of both carboplatin and cyclophospha mide were increased si multaneously by 50% of the standard dose in sequential cohorts. Doses of up to 2.5 times the standard dose were explored. A final dose of ca rboplatin, 600 mg/m(2), and cyclophosphamide, 1,500 mg/m(2), was teste d in 4 patients. The duration of neutropenia was brief, even at the hi ghest dose levels. The mean duration of grade 3 or 4 neutropenia was 5 .8 days at standard dose without filgrastim and 5.4 days at 2.5 times standard dose with filgrastim. More severe neutropenia was more prolon ged at higher doses but remained brief in duration. The mean duration of neutropenia of less than 100 x 10(6)/l was 0.4 days at standard dos e without filgrastim and 1.3 days at 2.5 times standard dose. There wa s no evidence of cumulative neutropenia over repeated cycles of treatm ent. In contrast, thrombocytopenia was both dose limiting, and cumulat ive. The mean duration of grade 3 or 4 thrombocytopenia was 1.6 days a t standard dose and 9.6 days at 2.5 times standard dose. An average of 2.3 platelet transfusions per cycle of treatment was required at the highest dose. Thrombocytopenia was worse with repetitive cycles of the rapy. The mean duration of grade 3 or 4 thrombocytopenia was 2.2 days after the first cycle of chemotherapy and 7.8 days after cycle four. T he maximum tolerated dose, as defined prospectively, was not reached b ut further dose escalation was not thought to be warranted because of the severity of thrombocytopenia. When supported with filgrastim, carb oplatin and cyclophosphamide can be administered safely with substanti ally increased dose and acceptable toxicity.