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Randomized Phase III Study of Matrix Metalloproteinase Inhibitor BMS-275291 in Combination With Paclitaxel and Carboplatin in Advanced Non-Small-Cell Lung Cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18

From the National Cancer Institute of Canada–Clinical Trials Group, Kingston; University Health Network/Princess Margaret Hospital, Toronto; The Margaret & Charles Juravinski Cancer Centre (formerly known as Hamilton Regional Cancer Centre), Hamilton, Ontario; Hospital Universitario Doce de Octubre, Madrid, Spain; Centre Rene Gauducheau, Nantes, France; Klinikum Rechts Der III Medizinische Klinik, Munich; Krankenhaus Grobhansdorf der LVA, Grobhansdorf, Germany; Hôpital Jean Minjoz, Besançon, France; Istituto Clinico Humanitas, Rozzano, Italy; University of Bern, Inselspital, Institute of Medical Oncology, Bern, Switzerland; Medical University of Gdansk, Gdansk, Poland; Duke University Medical Center, Durham, NC; Bristol-Myers Squibb, Wallingford, CT

Address reprint requests to Natasha Leighl, MD, 5-222 610 University Avenue, Toronto, ON M5G 2M9, Canada; e-mail: Natasha.Leighl{at}uhn.on.ca

PURPOSE: 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.

PATIENTS AND METHODS: 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.

RESULTS: 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%).

CONCLUSION: BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.

Supported in part by a grant from Bristol-Myers Squibb, Wallingford, CT.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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