Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization

by Selleckchem | Nov 13 2023

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.

Comments:

The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial designed to efficiently identify novel therapies for the treatment of glioblastoma, a highly aggressive and difficult-to-treat form of brain cancer. Here's an overview of the key aspects and findings of the INSIGhT trial:

1. **Purpose and Design**:
   - INSIGhT is a phase II platform trial that uses an innovative approach to identify potential therapies for further testing in phase III trials.
   - The trial employs response adaptive randomization and genomic profiling to tailor treatments to specific biomarker subpopulations within glioblastoma patients.
   - The trial initially evaluated three experimental arms (abemaciclib, neratinib, and CC-115) concurrently alongside a common control arm.

2. **Eligibility Criteria**:
- Patients eligible for the trial had newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma.
- Tumor genotyping was performed to identify specific biomarker subpopulations related to dominant glioblastoma signaling pathways, including EGFR, phosphatidylinositol 3-kinase, and CDK.

3. **Randomization**:
- Initially, patients were randomly assigned in a 1:1:1:1 ratio between the control arm (receiving radiation therapy and temozolomide) and the three experimental arms.
- Bayesian adaptive randomization was implemented based on biomarker-specific progression-free survival (PFS) data, allowing for adjustments to treatment allocation during the trial.

4. **Primary Endpoint**:
- The primary endpoint of the trial was overall survival (OS), which is a critical measure of a treatment's effectiveness in extending the lives of glioblastoma patients.

5. **Results**:
   - The trial enrolled a total of 237 patients over the years 2017-2021, with varying numbers of patients in each treatment arm (control: 71; abemaciclib: 73; neratinib: 81; CC-115: 12).
   - Abemaciclib and neratinib were well-tolerated, but CC-115 was associated with high-grade (≥ grade 3) treatment-related toxicity in 58% of patients.
   - Progression-free survival (PFS) was significantly longer in the abemaciclib and neratinib arms compared to the control arm, as indicated by hazard ratios (HRs).
   - None of the experimental therapies demonstrated a significant OS benefit compared to the control arm.

6. **Conclusion**:
   - The INSIGhT trial's innovative design allowed for the efficient simultaneous testing of three experimental therapies alongside a shared control arm.
   - Abemaciclib and neratinib showed improved PFS compared to the control arm, but none of the therapies demonstrated a statistically significant improvement in overall survival.
   - The INSIGhT trial design may hold promise for improving and streamlining therapeutic discovery in glioblastoma, and new arms have been added to the trial for further investigation.

In summary, the INSIGhT trial represents an adaptive platform trial design that seeks to identify promising therapies for glioblastoma treatment by tailoring treatments to specific genetic subgroups of patients. While some experimental arms showed improvements in PFS, no significant OS benefit was observed in this phase II trial. Further research and testing are ongoing to refine and expand treatment options for glioblastoma patients.