Phase 1/2 Trial of Bms-275291 in Patients With Human Immunodeficiency Virus-Related Kaposi Sarcoma: A Multicenter Trial of the Aids Malignancy Consortium

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Abstract

BACKGROUND.

Matrix metalloproteinases (MMPs) are overexpressed in Kaposi sarcoma (KS). The safety and efficacy of a novel, orally bioavailable MMP inhibitor, BMS-275291, was evaluated in patients with human immunodeficiency virus-associated KS and the correlation between changes in the percentage of apoptotic cells in tumor biopsies and response was explored.

METHODS.

Cohorts of 6 patients were to be treated with BMS-275291. The initial cohort received 1200 mg once a day; subsequent doses were to be escalated to 600 mg twice daily and 1200 mg twice daily, or decreased to 600 mg/day. Tumor biopsies for apoptosis assays were collected pretreatment and on Day 29. Prospectively defined dose level adjustments were to be based on dose-limiting toxicity (DLT), tolerability, changes in the percentage of apoptotic cells, and treatment response.

RESULTS.

Sixteen patients were enrolled; 15 received the study drug and could be evaluated. The median duration of treatment was 20 weeks (range, 3–54 weeks). A dose of 1200 mg once a day was well tolerated but induced only 1 response. A DLT occurred in 3 patients treated with 600 mg twice daily, and included grade 3 fatigue, grade 3 allergic reaction, and grade 3 arthralgias; 2 responses were noted at this dose level (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Based on predetermined endpoints, the trial was closed after accrual of 15 treated patients. Assessment of biologic response for dose escalation/de-escalation decisions utilizing the apoptosis assay was not feasible.

CONCLUSIONS.

BMS-275291 given at a dose of 600 mg twice daily induced unacceptable toxicity. The better-tolerated schedule of 1200 mg once a day demonstrated inadequate efficacy in patients with human immunodeficiency virus-associated KS. The apoptosis assay was not helpful in predicting response. Cancer 2008. © 2008 American Cancer Society.

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