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Supplementary Data from Phase I Pharmacokinetic and Pharmacodynamic Study of Carboplatin and Topotecan Administered Intravenously Every 28 Days to Patients with Malignant Solid Tumors

Purpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors.Experimental Design: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C→T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T→C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue.Results: Forty-one patients were included. Dose-limiting toxicities during the C→T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m2/d). Dose-limiting toxicities during the T→C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m2/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule.Conclusion: The T→C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.

Purpose: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. Methods: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. Results: The following single-point model was selected as optimal: AUC carboplatin (min mg−1 ml−1) = 418 · c2.5 h(mg/ml) + 0.43 (min mg−1 ml−1), where c2.5 h is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 ± 1.6%) and precise (root mean square error = 10.1 ± 1.5%). Conclusions: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualise treatment.

Purpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors. Experimental Design: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C→T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T→C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue. Results: Forty-one patients were included. Dose-limiting toxicities during the C→T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m2/d). Dose-limiting toxicities during the T→C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m2/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. Conclusion: The T→C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.

Spiroplatin was investigated in a multicentre phase I study. 67 patients with advanced solid tumours received 151 cycles either by short-term or prolonged infusion, repeated every 3 weeks, at 2.5–40 mg/m 2 . Myelosuppression and renal toxicity were dose-limiting. Proteinuria, which was dose- and schedule-dependent, indicated glomerular and tubular damage. The maximum tolerated doses (MTD) for poor-risk and good-risk patients were 35 and 40 mg/m 2 , respectively. The area under the curve (AUC) at the MTD did not correspond with the AUC at the LD 10 in mice with ratios of 0.3 for free platinum and 2.6 for total platinum; these were not suitable for predicting the MTD. 1 complete response was observed in a patient with breast cancer and lung metastases and 1 partial response in a patient with adenocarcinoma of the lung. The recommended dose for phase II studies was 30 mg/m 2 by 4 h infusion every 3 weeks.