o-(chloroacetylcarbamoyl)fumagillol and Sarcoma--Kaposi

The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack.

Topics: Administration, Oral; Alitretinoin; Anthracyclines; Antineoplastic Agents; Cyclohexanes; Humans; Immunosuppressive Agents; Liposomes; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sarcoma, Kaposi; Sesquiterpenes; Thalidomide; Tretinoin

The pharmacokinetics of TNP-470 and its major metabolites were investigated in AIDS patients enrolled in a phase I dose escalation trial for the treatment of Kaposi's sarcoma. The patients received TNP-470 by 1-h intravenous infusion in dose cohorts of 10, 20, 30, 40, 50 and 70 mg/m2. The parent drug and metabolites, MII and MIV, were measured by high-performance liquid chromatography/mass spectrometry (HPLC/MS) in plasma samples collected during and out to 168 h after the beginning of the infusion. Both metabolites were detected in all patients' plasma, while the parent drug was undetectable at time-points as early as 5 min after the end of infusion for some patients. A large interpatient variability of pharmacokinetic parameters among the dosing cohorts was observed for TNP-470, with a mean (+/- SD) plasma elimination half-life (t1/2) of 0.06 +/- 0.04 h, plasma clearance (CL) of 1487 +/- 1216 l/h and an area under the concentration versus time curve (AUC) of 49.9 +/- 35.8 ng/ml x h. Time to maximum plasma concentration (Tmax) typically occurred before the end of the infusion. The predominant plasma metabolite was MII with a t1/2 of 1.21 +/- 0.43 h, AUC of 1226 +/- 2303 l/h and a Tmax occurring between 5 and 15 min after infusion. The reported active metabolite MIV had a t1/2 of 0.24 +/- 0.13 h, AUC of 24.9 +/- 32.6 ng/ml x h and a Tmax occurring between the midpoint of the infusion and 15 min after infusion. The parent drug was undetectable by HPLC/MS/MS in urine samples collected and pooled between 0-6 and 6-24 h from the beginning of drug administration. Metabolite MIV was present in the 0-6-h urine pool of two patients enrolled in the highest dosing cohorts, equivalent to 0.4% of the administered dose. Metabolite MII was present in all 0-6-h samples analyzed and represented 1.12 +/- 0.9% of the administered dose. Renal clearance (CLR) for MII was 140 +/- 70 ml/h.

Topics: Acquired Immunodeficiency Syndrome; Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Chromatography, High Pressure Liquid; Cyclohexanes; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Mass Spectrometry; O-(Chloroacetylcarbamoyl)fumagillol; Sarcoma, Kaposi; Sensitivity and Specificity; Sesquiterpenes

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 with AIDS-related KS were required to have cutaneous disease with > or = 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.. The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 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 11 weeks (range, 3 to 26+).. 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.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antineoplastic; Area Under Curve; Cyclohexanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Half-Life; Humans; Male; Middle Aged; O-(Chloroacetylcarbamoyl)fumagillol; Sarcoma, Kaposi; Sesquiterpenes; Skin Neoplasms