Phase I trial of carboplatin and paclitaxel with escalating doses of oral topotecan in patients with solid tumors

Carboplatin, paclitaxel, and topotecan have activity against a variety of cancers. This phase I study was designed to determine the maximum tolerated dose of oral topotecan when given in combination with carboplatin and paclitaxel. Eligibility criteria were as follows: Karnofsky Performance score greater than or equal to 80; and adequate hepatic, renal, and bone marrow function. Patients received paclitaxel 175 mg/m(2) intravenously followed by carboplatin AUC(5) iv on day 1 every 3 weeks for up to 6 cycles. Cohorts of 3 to 5 were treated with escalating doses of oral topotecan on days I to 5, initially at 0.75 mg/m(2) then 1 mg/m(2) and 1.25 mg/m(2) in subsequent cohorts. Thirteen patients were treated. Three of three patients in cohort I had grade IV neutropenia, with one neutropenic fever and one patient requiring a platelet transfusion. In cohort 2, three of five patients had grade III/IV neutropenia including two with neutropenic fever. Four patients required blood transfusions and one required platelet transfusions. In cohort 3, three of five had grade III/IV neutropenia, one of five had grade IV thrombocytopenia, and one patient required blood transfusions. In conclusion, this three-drug regimen resulted in significant cumulative myelosuppression in the doses and schedule tested in this phase I trial. Subsequent combinations of these drugs should focus on alternate doses or schedules.