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

• Published in: Clinical cancer research Vol. 15; no. 13; pp. 4475 - 4483
• Main Authors: BOSS, David S, SIEGEL- LAKHAI, Wandena S, VAN EGMOND-SCHOEMAKER, Nadja E, PLUIM, Dick, ROSING, Hilde, TEN BOKKEL HUININK, Wim W, BEIJNEN, Jos H, SCHELLENS, Jan H. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-2009
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Carboplatin; Carboplatin - administration & dosage; Carboplatin - adverse effects; Carboplatin - pharmacokinetics; DNA Adducts - analysis; DNA Adducts - blood; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; phase I; Topotecan; Topotecan - administration & dosage; Topotecan - adverse effects; Topotecan - pharmacokinetics; Treatment Outcome; Tumors; Camptothecin derivatives; Antineoplastic agent; Human; Pharmacokinetic pharmacodynamic relationship; Solid tumor; Intravenous administration; Enzyme; DNA topoisomerase; Enzyme inhibitor; Patient; Topotecan; Malignant tumor; Isomerases; Carboplatin; Topoisomerase I inhibitor; Cancer; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-3144

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/m 2 /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/m 2 /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.