Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors
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Published:1999-04
Issue:4
Volume:17
Page:1095-1095
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ISSN:0732-183X
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Container-title:Journal of Clinical Oncology
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language:en
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Short-container-title:JCO
Author:
Eckhardt S. Gail1, Rizzo Jinee1, Sweeney Kevin R.1, Cropp Gillian1, Baker Sharyn D.1, Kraynak,† Maura A.1, Kuhn John G.1, Villalona-Calero Miguel A.1, Hammond Lisa1, Weiss Geoffrey1, Thurman Allison1, Smith Lon1, Drengler Ronald1, Eckardt John R.1, Moczygemba Judy1, Hannah Alison L.1, Von Hoff Daniel D.1, Rowinsky Eric K.1
Affiliation:
1. From the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; South Texas Oncology and Hematology, PA, San Antonio, TX; Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX; School of Pharmacy, University of Connecticut, Farmington, CT; and Sugen, Inc, Redwood City, CA.
Abstract
PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m2 as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-α and -β receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m2 dose levels. Dose escalation of SU101 above 443 mg/m2/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 ± 12 days. At the 443 mg/m2/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 μmol/L. Immunohistochemical studies revealed PDGF-α and -β receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m2/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Reference21 articles.
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