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Phase 1/2 trial of BMS‐275291 in patients with human immunodeficiency virus‐related Kaposi sarcoma
Author(s) -
Brinker Brett T.,
Krown Susan E.,
Lee Jeannette Y.,
Cesarman Ethel,
Chadburn Amy,
Kaplan Lawrence D.,
Henry David H.,
Von Roenn Jamie H.
Publication year - 2008
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.23108
Subject(s) - medicine , tolerability , toxicity , sarcoma , cancer , gastroenterology , chemotherapy , surgery , adverse effect , pharmacology , pathology
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.