Fumagillin analog in the treatment of Kaposi's sarcoma: A phase I AIDS Clinical Trial Group Study

Purpose: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth, The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. Patients and Methods: Patients with AIDS-related KS were required to have cutaneous disease with greater than or equal to 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. Results: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m(2), Median CD4 count was 24 cells/mu l (range, 0 to 460). Fourteen patients (36%) had greater than or equal to 50 cutaneous lesions and 19(49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability, Elimination half-life values were short (range, 0.01 to 0.61 hours), Seven patients (18%) achieved a partial response, The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 1 1 weeks (range, 3 to 26+), Conclusion: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested, Tumor responses were observed in a substantial number of cases and occurred at various dose levels, TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy. (C) 1998 by American Society of Clinical Oncology.