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.
OBJECTIVE
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.


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%).


CONCLUSIONS
BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.
Leighl
Natasha B
NB
National Cancer Institute of Canada--Clinical Trials Group, Kingston, Canada. Natasha.Leighl@uhn.on.ca
Paz-Ares
Luis
L
Douillard
Jean-Yves
JY
Peschel
Christian
C
Arnold
Andrew
A
Depierre
Alain
A
Santoro
Armando
A
Betticher
Daniel C
DC
Gatzemeier
Ulrich
U
Jassem
Jacek
J
Crawford
Jeffrey
J
Tu
Dongsheng
D
Bezjak
Andrea
A
Humphrey
Jeffrey S
JS
Voi
Maurizio
M
Galbraith
Susan
S
Hann
Katherine
K
Seymour
Lesley
L
Shepherd
Frances A
FA
D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases; D008875:Middle Aged; D009930:Organic Chemicals / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage; D010919:Placebos; D016896:Treatment Outcome
D007093:Imidazoles; D009930:Organic Chemicals; D010919:Placebos; C422302:N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide; D016190:Carboplatin; D020782:Matrix Metalloproteinases; D017239:Paclitaxel