Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors

Background: Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the op timal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. Patients and methods: Patients with advanced cancer and performance status ECOG less than or equal to2. The starting dose was paclitaxel 175 mg/m(2) d ay 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m(2) daily day 1-5 (e arly sequence). The next course of paclitaxel and carboplatin administratio n was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granuloc yte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. Results: Fifty-one patients were entered; men : women ratio 30 : 21. Dose-l imiting toxicity (DLT) for the early sequence was neutropenia at doses pacl itaxel mg/m(2)/carboplatin AUC 5/topotecan mg/m(2) (PCT) 175/5/0.75 for fou r to five days. DLT for the late sequence was neutropenia at PCT doses of 1 75/5/1.0 for four days. G-CSF 5 mug/kg subcutaneously starting day 6 permit ted further topotecan dose escalation. After adding G-CSF, late sequence DL T was neutropenia at doses 175/5/1.25 for four days. Forty-six patients wer e evaluable for response and of those, there were thirteen partial response s. Conclusions: The late sequence resulted in less toxicity and was better tol erated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for f ive days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.