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.

Abstract

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.

• Authors: Natasha B Leighl, Luis Paz-Ares, Jean-Yves Douillard, Christian Peschel, Andrew Arnold, Alain Depierre, Armando Santoro, Daniel C Betticher, Ulrich Gatzemeier, Jacek Jassem, Jeffrey Crawford, Dongsheng Tu, Andrea Bezjak, Jeffrey S Humphrey, Maurizio Voi, Susan Galbraith, Katherine Hann, Lesley Seymour, Frances A Shepherd
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 12 Pg. 2831-9 (Apr 20 2005) ISSN: 0732-183X [Print] United States
• PMID: 15837997 (Publication Type: Clinical Trial, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Organic Chemicals
• Placebos
• N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide
• Carboplatin
• Matrix Metalloproteinases
• Paclitaxel

Topics

• Administration, Oral
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Disease-Free Survival
• Female
• Humans
• Imidazoles
• Lung Neoplasms (drug therapy, pathology)
• Male
• Matrix Metalloproteinases
• Middle Aged
• Organic Chemicals (administration & dosage, adverse effects, therapeutic use)
• Paclitaxel (administration & dosage)
• Placebos
• Treatment Outcome