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Inefficiencies in phase II to phase III transition impeding successful drug development in glioblastoma
Adithya Balasubramanian1, Ashray Gunjur1, Umbreen Hafeez1,2
1Medical Oncology Department, Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Heidelberg, Victoria, Australia.
Background:
Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon.
Methods:
Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was "optimally matched," where same drug was used in similar schedule and similar population; "suboptimally matched" if dis-similar schedule and/or treatment setting; or "lacking." Phase II/III transition data were compared by Pearson Correlation, Fisher's exact or chi-square testing.
Results:
Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 "optimally matched" dyads showed strong concordance for mPFS (r 2 = 0.95, P < .01) and mOS (r 2 = 0.84, P < .01), while 7 "suboptimally matched" dyads did not (P > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. "Newly diagnosed" P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. "Recurrent" P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts.
Conclusion:
Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.
Insights
Optimally designed phase II trials are crucial for glioblastoma (GBM) drug development. Well-matched phase II data strongly predict phase III outcomes, improving GBM treatment strategies.
Area of Science:
- Neuro-oncology
- Clinical trial design
- Drug development
Background:
- Glioblastoma (GBM) treatment outcomes remain a significant challenge in neuro-oncology.
- Optimizing clinical trial design is essential for advancing GBM therapies.
Purpose of the Study:
- To systematically review phase II and III trial parameters in GBM.
- To quantify the impact of trial design on glioblastoma treatment outcomes.
Main Methods:
- Systematic review of phase II (P2T) and phase III (P3T) GBM trials (2005-2019).
- P2T data were "optimally matched," "suboptimally matched," or "lacking" relative to P3T.
- Statistical comparison of phase II/III transition data using correlation and chi-square tests.
Main Results:
- 30% of P3Ts lacked corresponding P2T data.
- 13 "optimally matched" dyads showed strong concordance for median progression-free survival (mPFS) and overall survival (mOS) (P < .01).
- "Suboptimally matched" dyads and specific P2T outcome thresholds (e.g., mPFS < 14 months for newly diagnosed) predicted negative P3T results.
Conclusions:
- Optimally designed phase II trials are critical for successful glioblastoma drug development.
- Phase II trial design significantly impacts the success of subsequent phase III trials in GBM.
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