Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer.
BACKGROUND
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Douillard
Jean-Yves
JY
Centre Rene Gauducheau, Nantes, France.
Peschel
Christian
C
Shepherd
Frances
F
Paz-Ares
Luis
L
Arnold
Andrew
A
Davis
Mary
M
Tonato
Maurizio
M
Smylie
Michael
M
Tu
Dongsheng
D
Voi
Maurizio
M
Humphrey
Jeffrey
J
Ottaway
Jon
J
Young
Katherine
K
Vreckem
Anne Van
AV
Seymour
Lesley
L
D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles; D007262:Infusions, Intravenous; 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
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