A Phase I, safety and pharmacokinetic trial of BMS-275291, a matrix metalloproteinase inhibitor (MMPI), in patients with advanced or metastatic cancer. Rizvi, Naiyer A., Humphrey, Jeffrey S., Ness, Elizabeth A., Sonnichsen, Daryl, Daly, Diana J., Cooper, Michael, Conway, Delina, Marshall, John, Hurwitz, Herbert. Developmental Therapeutics, Lombardi Cancer Center, Georgetown University, Washington, DC; Duke University Medical Center, Durham, NC; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT. This is an open-label, single arm, multicenter phase I trial in which cohorts of patients with advanced or metastatic cancer will receive escalation doses of BMS-275291 daily by mouth on an outpatient basis. Individual patients will receive BMS-275291 daiy until unacceptable study drug-related toxicity or disease progression, whichever occurs first. BMS-275291 is an orally bioavailable, peptidomimetic small molecule inhibitor of matrix metalloproteinases (MMPs) which contains a novel mercaptoacyl zinc-binding group. The molecule was rationally designed to inhibit a broad spectrum of MMPs (including MMP-1, MMP-2, and MMP-9) while not inhibiting closely related metalloproteinases known as sheddases. Sheddases, such as TNF a converting enzyme, regulate cytokine and cytokine receptor release from the cell surface, and sheddase inhibition is hypothesized to play a role in the dose limiting arthralgia/myalgia reported for some hydroxamate-based MMPIs. BMS-275291 was selected by combinatorial chemistry and high throughput screening to inhibit MMPs selectively while sparing sheddases. A phase I trial of BMS-275291 in patients with solid tumor malignancies was initiated in 2/99. At the first three dose levels (600, 900, and 1200 mg/d), 25 patients with metastatic solid tumors have been enrolled and received study drug: 18 men and 7 women; median age = 56.5 years; 20/25 with Karnofsky PS > 90; 10 colorectal, 5 NSCLC, 2 breast cancer, 2 melanoma, 6 other. 22/25 had prior cytotoxic chemotherapy (11/25 had 2 or more prior regimens); 10/25 prior radiation; 2/25 no prior systemic treatment. Patients received once-daily oral administration of BMS-275291 in 4 week courses continuously until unmanageable toxicity or progressive disease. Overall, BMS-275291 was well tolerated. Grade 1 and 2 myalgia/arthralgia judged to be possibly drug-related was observed in 7/25 (28%) and 1/25 (4%) patients, respectively. These adverse events were not dose-related and no grade 3 or 4 arthralgia/myalgia has been observed to date. A reversible skin rash was observed in 5/25 (20%) of patients. At the 600 mg/d dose level, 1/8 patients experienced a dose limiting asymptomatic reversible grade 3 AST elevation. At the 1200 mg/d dose level, 1/8 patients experienced a reversible dose limiting exacerbation of baseline grade 2 dyspnea to grade 4 with associated rash, however the dyspnea was in the setting of progressing NSCLC. At a dose of 600 mg/day, the mean steady-state trough plasma concentration of BMS-275291 (367 ng/mL) exceeded in vitro IC50s for MMP-2 (20.5 ng/mL) and MMP-9 (12.5 ng/mL) by more than 10-fold. At a dose of 1200 mg/day, the mean steady-state trough plasma BMS-275291 concentration (605 ng/mL) exceeded the IC90s for MMP-2 (547 ng/mL) and MMP-9 (482 ng/mL). Preliminary analysis by ELISA assay do not show BMS-275291 inhibition of TNF a release and TNF RII shedding consistent with the design of this agent to spare sheddase. Additionally, 6 pts have been accrued to each of the final two dose levels to be explored, 1800 mg/d and 2400 mg/d.
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