Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer

Clinical and laboratory observations support the view that angiogenesis is necessary for prostate cancer progression. The angiogenesis inhibitor TNP-4 70 has demonstrated irt vivo antitumor activity in a series of clinical mod els. To evaluate a possible therapeutic clinical value, we conducted a Phas e I dose escalation trial of alternate-day i.v. TNP-470 in 33 patients with metastatic and androgen-independent prostate cancer. The patients were eva luated 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 effec ts of TNP-470 could be evaluated in 32 of the 33 patients. The maximum tole rated dose was 70.88 mg/m(2) of body surface area. The dose-limiting toxic effect was a characteristic neuropsychiatric symptom complex (anesthesia, g ait disturbance, and agitation) that resolved upon cessation of therapy. Th e times to clinical recovery of neurological side effects were 6, 8, and 14 weeks, No definite antitumor activity of TNP-470 was observed; however, tr ansient stimulation of the serum prostate-specific antigen concentration oc curred in some of the patients treated. Additional studies of TNP-470 shoul d 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 neurologi cal toxic effects. In addition, valid intermediate end points that reflect the status of tumor-associtated neovascularity are needed to facilitate eff ective development of treatment strategies.