Case Study: Application of Adaptive Enrichment Design with Co-Primary Endpoints in the Command Clinical Trial for Treatment of Mesothelioma

• Activity Number: 605
• Type: Contributed
• Date/Time: Thursday, August 7, 2014 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Robin Bliss*+ and John Balser and Joanna Horobin and Mitchell Keegan
• Companies: Veristat and Veristat and Verastem and Verastem
• Keywords: Adaptive design ; Enrichment ; Sample size re-estimation ; Time to event ; Randomized clinical trial

Abstract

Malignant pleural mesothelioma is a rare, aggressive tumor, usually diagnosed at an advanced stage of disease. Verastem, Inc. hypothesized that subjects with a particular biomarker are more sensitive to their novel treatment than subjects without the biomarker. An adaptive enrichment design was selected for the registration-directed COMMAND study to investigate the effect in the full sample(FS) with an opportunity at a planned interim analysis to enrich with biomarker positive subjects(BPS). Co-primary endpoints are progression free survival(PFS) and overall survival(OS). The interim analysis will occur after 50%PFS events. Using the pre-specified criteria, the study may be stopped for futility if the conditional power(CP) of the FS is low; may continue as planned if the CP of the FS is high or if the CP is moderate but the BPS do not outperform the FS; or enriched if the BPS outperforms the FS. The final PFS analysis will be performed when sufficient events are observed. If a significant result is observed, a sample size re-estimation for OS will occur. OS analysis will follow after sufficient survival events. Simulations illustrate control of the type I error rate and power.