Clinical Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention
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Clinical Cancer Research Vol. 7, 1198-1203, May 2001
© 2001 American Association for Cancer Research

Clinical Trials

Phase I Trial of the Angiogenesis Inhibitor TNP-470 for Progressive Androgen-independent Prostate Cancer1

Christopher J. Logothetis2, Kenneth K. Wu, Laury D. Finn, Danai Daliani, William Figg, Habib Ghaddar and Jordan U. Gutterman

Departments of Genitourinary Medical Oncology [C. J. L., D. D.], Blood and Marrow Transplantation [K. K. W.], Neuro-Oncology [H. G.], Protocol Research [L. D. F.], and Cellular Molecular Growth Regulation [J. U. G.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Department of Clinical Pharmacology, National Cancer Institute, Bethesda, Maryland 20892 [W. F.]

Clinical and laboratory observations support the view that angiogenesis is necessary for prostate cancer progression. The angiogenesis inhibitor TNP-470 has demonstrated in vivo antitumor activity in a series of clinical models. To evaluate a possible therapeutic clinical value, we conducted a Phase I dose escalation trial of alternate-day i.v. TNP-470 in 33 patients with metastatic and androgen-independent prostate cancer. The patients were evaluated during therapy for evidence of neurological toxic effects. An assay of endothelial and vascular proliferation "markers" and a sequential assay of serum prostate-specific antigen concentration were performed. The effects of TNP-470 could be evaluated in 32 of the 33 patients. The maximum tolerated dose was 70.88 mg/m2 of body surface area. The dose-limiting toxic effect was a characteristic neuropsychiatric symptom complex (anesthesia, gait disturbance, and agitation) that resolved upon cessation of therapy. The times to clinical recovery of neurological side effects were 6, 8, and 14 weeks. No definite antitumor activity of TNP-470 was observed; however, transient stimulation of the serum prostate-specific antigen concentration occurred in some of the patients treated. Additional studies of TNP-470 should be conducted using an alternate-day i.v. injection of 47.25 mg/m2 body surface area and should focus on understanding and overcoming the neurological toxic effects. In addition, valid intermediate end points that reflect the status of tumor-associated neovascularity are needed to facilitate effective development of treatment strategies.




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Copyright © 2001 by the American Association for Cancer Research.