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Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial
Rifaquat Rahman1,2, Lorenzo Trippa1, Eudocia Q Lee1,2
1Dana-Farber Cancer Institute, Boston, MA.
Purpose:
The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design.
Patients And Methods:
Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780).
Results:
Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05).
Conclusion:
The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.
Insights
The INSIGhT trial efficiently tested new glioblastoma therapies using adaptive randomization. Abemaciclib and neratinib improved progression-free survival, but no drug significantly extended overall survival in this phase II study.
Area of Science:
- Oncology
- Clinical Trials
- Genomics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Novel therapies are needed to improve patient outcomes.
- Genomic profiling and adaptive trial designs can accelerate drug discovery.
Purpose of the Study:
- To evaluate the efficacy and safety of abemaciclib, neratinib, and CC-115 in newly diagnosed, O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma.
- To assess the feasibility of a phase II platform trial design using response-adaptive randomization.
- To identify promising agents for further phase III investigation.
Main Methods:
- The INSIGhT trial employed a phase II platform design with Bayesian adaptive randomization.
- Patients received standard care (radiation therapy and temozolomide) or experimental agents (abemaciclib, neratinib, CC-115).
- Randomization adapted based on progression-free survival (PFS) data within biomarker-defined subpopulations.
Main Results:
- Abemaciclib and neratinib demonstrated significantly longer PFS compared to the control arm (one-sided P = .046 and P = .033, respectively).
- CC-115 was associated with high toxicity and showed no PFS benefit.
- No significant overall survival (OS) benefit was observed for any experimental arm.
Conclusions:
- The INSIGhT adaptive platform design efficiently evaluated multiple glioblastoma therapies.
- Abemaciclib and neratinib showed potential by improving PFS, warranting further study.
- The trial design facilitates accelerated therapeutic discovery for glioblastoma.
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