Evaluation of phase 2 single-arm two-stage trials in glioblastoma and brain tumor.

Abstract

e14033 Background: Oncology clinical trials have shown the lowest success rate on Phase 2 and the highest median expense in a new drug to market. We aimed to assess the appropriate implementation of single-arm two-stage Phase 2 trials with other critical design issues of phase 2 single-arm trials such as selection of primary endpoint and historical control rates, and challenges of the blood-brain barrier, and to suggest guidelines to handle design issues related to single-arm Phase 2 trials in Neuro-Oncology. Methods: Two researchers searched with the key words of “phase 2 single arm two-stage design in glioblastoma” through PubMed.gov, clinicaltrials.gov, and Google Scholar to examine study designs of (i) study information, (ii) two-stage design parameters, (iii) rejection numbers and sample size for each stage. Design issues in primary endpoints, historical controls, and challenges on brain tumor trials were discussed with the effect of adaptive design on two-stage designs, and several guidelines on these issues were suggested for investigators in Phase 2 single-arm Neuro-Oncology trials. Results: Almost 50% of single-arm two-stage studies failed to provide key information related to study designs and sample size calculation, even wrong power analysis and interpretation. Response rate and progression-free survival are used as popular surrogate endpoints for overall survival. It is time to evaluate other potential endpoints like post-progress survival and hazard ratio, and usefulness of co-primary endpoint. Investigators should keep transparency of the trials by fully providing and citing historical data source. If there exist large variabilities among existing historical data, meta-analysis can be a good option to accurately estimate the historical control. Conclusions: The appropriate selection on primary endpoint(s) and historical control data, incorporation of adaptive designs if necessary, and right application of two-stage design might help overcoming the challenges on low success rates in new therapeutic oncology trials. Furthermore, the new paradigm of Phase 0 trial might be one potential tool to overcome the challenges with insufficient penetration of therapeutic agents across the blood-brain barrier and limitations in the applicability of animal models to the human condition in glioblastoma and Neuro-Oncology.