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

• Published in: Clinical cancer research 2001-05, Vol.7 (5), p.1198-1203
• Main Authors: LOGOTHETIS, Christopher J, WU, Kenneth K, FINN, Laury D, DALIANI, Danai, FIGG, William, GHADDAR, Habib, GUTTERMAN, Jordan U
• Format: Article
• Language: English
• Subjects: Aged; Androgens - metabolism; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - therapeutic use; Antineoplastic agents; Biological and medical sciences; Blood Glucose - drug effects; Bone and Bones - drug effects; Chemotherapy; Communicable Diseases - etiology; Cyclohexanes; Digestive System - drug effects; Fibroblast Growth Factors - urine; Humans; Kinetics; Liver - drug effects; Male; Medical sciences; Middle Aged; Pain - etiology; Pharmacology. Drug treatments; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - complications; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Sesquiterpenes - adverse effects; Sesquiterpenes - therapeutic use; Thrombomodulin - blood
• ISSN: 1078-0432; 1557-3265

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/m 2 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/m 2 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.