Phase 2 Study Results for Tivantinib in Combination with Cetuximab and Irinotecan for Colorectal Cancer Presented at ASCO 2013
ArQule, Inc. (Nasdaq: ARQL) today announced final data from a randomized, placebo-controlled, double-blind, Phase 2 clinical trial with tivantinib in combination with cetuximab and irinotecan in patients with relapsed or refractory KRAS wild-type metastatic colorectal cancer (CRC). These data were presented today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO) (abstract number 3508) by Dr. Cathy Eng, M.D., F.A.C.P., M.D. Anderson Cancer Center, Associate Director, Colorectal Center.
?The multiple encouraging signals of clinical benefit observed in this trial include consistent trends in improved progression free survival (PFS), overall response rate (ORR) and overall survival (OS) in patients who received tivantinib in combination with cetuximab and irinotecan,? said Dr. Eng. ?Trends toward improvements in all of these outcomes were also seen in a small MET high sub-group, but a larger sample size is required to validate conclusively the treatment impact in this population. The results also underscore the need to ensure standardized pretreatment regimens among enrolled patients and uniform tissue collection procedures at enrollment to allow for more robust correlative outcome assessments related to the MET pathway.?
The primary endpoint of this trial was PFS in the intent to treat (ITT) population. Other study endpoints were OS, ORR and safety for the ITT population. Patient recruitment in the trial was discontinued prior to meeting the original goal of 150 patients. As a result, the number of PFS events available for statistical analysis was decreased from 110 to 80.
As previously announced, the trial did not meet its primary endpoint, but data analyses showed that the median PFS in the treatment arm (patients treated with tivantinib plus irinotecan and cetuximab) was 8.3 months, compared with 7.3 months in the control arm (patients treated with placebo plus irinotecan and cetuximab) (hazard ratio = 0.85, 95% CI: 0.55, 1.33, stratified log-rank p = 0.38).
Median OS in the treatment arm was 19.8 months, compared with 16.9 months in the control arm (hazard ratio = 0.70, 95% CI: 0.42, 1.17, stratified log-rank p = 0.25). ORR in the treatment arm was 45 percent versus 33 percent in the control arm. The PFS and ORR results obtained in both the treatment and control arms were substantially greater than expected compared to previously published historical norms.
Patients pre-treated with oxaliplatin in the treatment arm experienced favorable PFS and OS results. Among these patients, median PFS was 8.3 months compared with 7.2 months in the oxaliplatin-treated control arm (hazard ratio = 0.66 CI: 0.41, 1.09, stratified log-rank p=0.10), and median OS was 22.3 months compared with 14.1 months (hazard ratio = 0.58, 95% CI: 0.33, 1.02, stratified log-rank p = 0.06). ORR in oxaliplatin pre-treated patients who received tivantinib was 42.6 percent, compared with 27.1 percent in the placebo arm. Efficacy observations in a small MET-high sub-group were inconclusive and would require further assessment with a larger sample size.
Adverse events were reported at similar rates in the treatment and control arms of the trial, except for increased neutropenia observed in the treatment arm, with no discontinuations of treatment for this reason. No treatment-emergent adverse events leading to death were assessed as related to study treatment. Tivantinib was generally well tolerated in combination with the approved doses of irinotecan and cetuximab studied in this trial.
The 122 patients in the trial (US n=67; Russia n=39; Western Europe n=16) had unresectable CRC and disease progression after first-line therapy. Patients were randomized to receive tivantinib at 360 milligrams (mg) twice daily in combination with cetuximab at 500 mg/square meter every 14 days and irinotecan at 500 mg/square meter every 14 days or placebo twice daily with the same regimen of cetuximab and irinotecan.
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