Abstract
Abstract INTRODUCTION We undertook a literature review testing the hypothesis that inefficiencies in the Phase 2/3 transition contributes to most GBM Phase 3 trials (P3T’s) being negative. METHODS Studies between 2005–2019 inclusive were identified though MEDLINE(R) using keywords and MeSH terms, and manual bibliography searches. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, Phase 2 trial (P2T) data was “optimally matched” where same drug was used in similar schedule and GBM population; “partially matched” where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. Data were compared by Pearson Correlation, t-test or chi-square as appropriate. RESULTS 18 relevant P3T’s and 15 P2T’s were identified. Median values for median progression free survival (mPFS) and median overall survival (mOS) in P3T’s were 7.9 and 17.9 mths respectively for first line studies; 2.2 and 7.9 mths for recurrent studies. These were 11.8 and 20.4 mths for 1st line P2T’s, suggesting selection bias, and 3.3 and 7.5 mths for recurrent studies. 50% of P3T had optimally matched P2D, with high concordance for mPFS (r2= 0.90, p< 0.01) and mOS (r2= 0.84, p< 0.01) between corresponding P3T and P2T. The remain 50% of P3T had ‘partially matched’ (22.2%) or lacked P2T data (27.8%). ‘Partially matched’ trials also had a high concordance for mPFS (r2= 0.92, p< 0.01) and mOS (r2= 0.83, p< 0.01). However, 80% of P3T planned for HR didn’t meet expected benefit. All first-line P2T with mPFS< 15 months and/or OS< 22 months had negative P3T. All recurrent P2T with mPFS< 5 months and mOS< 12 months had negative P3T. Impact of sponsors and molecular subtypes will be presented. CONCLUSIONS This review identified issues (selection bias, lack of appropriate P2T and possible underpowered P3T’s) at the Phase 2/3 interface and provides data for future trial design.
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