n-((2s)-2-mercapto-1-oxo-4-(3-4-4--trimethyl-2-5-dioxo-1-imidazolidinyl)butyl)-l-leucyl-n-3--dimethyl-l-valinamide and Carcinoma--Non-Small-Cell-Lung

To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non-small-cell lung cancer (NSCLC). In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs.. Chemotherapy-naive patients with stage IIIB/IV NSCLC, performance status (PS) 0 to 2, and adequate organ function were eligible. All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression. The primary study end point was survival (OS); secondary end points included progression-free survival (PFS), response rates (RR), toxicity, and quality of life.. From 2000 to 2002, 774 patients were randomly assigned. Pretreatment characteristics were well balanced between arms: median age, 61 years; male sex, 73%; stage IV, 79%; PS 0 to 1, 88%. Interim safety analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS, PFS and RR in the final analysis in the BMS-275291 arm were 8.6 months, 4.9 months, and 25.8% respectively, and in the control arm 9.2 months, 5.3 months, 33.7%. Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%).. BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Humans; Imidazoles; Lung Neoplasms; Male; Matrix Metalloproteinases; Middle Aged; Organic Chemicals; Paclitaxel; Placebos; Treatment Outcome

This randomized, double-blind, placebo-controlled study was designed to assess whether the addition of the matrix metalloproteinase (MMP) inhibitor BMS-275291 to combined paclitaxel and carboplatin chemotherapy had an adverse impact on expected tumor response or had significant toxicity, especially arthrotoxicity, in patients with advanced non-small cell lung cancer (NSCLC).. Seventy-five chemotherapy-naive patients with stage IIIB-IV NSCLC were randomly assigned to BMS-275291 or placebo. All patients received paclitaxel 200mg/m(2) as a continuous 3-hour infusion followed by carboplatin calculated using the Calvert formula for a target AUC of 6 mg / (ml min), every 21 days for a maximum of eight cycles. BMS-275291 or placebo was administered on an outpatient basis at a daily oral dosage of 1200 mg.. All 75 patients were evaluable for toxicity and 65 (86.7%) for response. Drug-related arthrotoxicity > or =grade 2 occurred in 12 patients (31.6%) in the BMS-275291 group (lower limit of one-sided 95% CI: 19.3) and in 11 patients (29.7%) in the placebo treatment arm. The incidence of rash was higher in patients receiving BMS-275291 (28.9% versus 18.9%). An objective response rate of 21.9% was observed in the BMS-275291 treatment arm and 36.4% in the placebo arm.. BMS-275291 plus paclitaxel/carboplatin was well tolerated and active in advanced non-small cell lung cancer. Treatment with BMS-275291 was not limited by drug-related arthrotoxicity and tumor response was as expected. As planned, patient accrual continued to further investigate the effect of BMS-275291 on overall and progression-free survival in a phase III setting.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Double-Blind Method; Female; Humans; Imidazoles; Infusions, Intravenous; Lung Neoplasms; Male; Matrix Metalloproteinases; Middle Aged; Organic Chemicals; Paclitaxel; Placebos