Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization
Authors: Rahman Rifaquat , Trippa Lorenzo , Lee Eudocia Q. , Arrillaga-Romany Isabel , Fell Geoffrey , Touat Mehdi , McCluskey Christine , Wiley Jennifer , Gaffey Sarah , Drappatz Jan , Welch Mary R. , Galanis Evanthia , Ahluwalia Manmeet S. , Colman Howard , Nabors L. Burt , Hepel Jaroslaw , Elinzano Heinrich , Schiff David , Chukwueke Ugonma N. , Beroukhim Rameen , Nayak Lakshmi , McFaline-Figueroa J. Ricardo , Batchelor Tracy T. , Rinne Mikael L. , Kaley Thomas J. , Lu-Emerson Christine , Mellinghoff Ingo K. , Bi Wenya Linda , Arnaout Omar , Peruzzi Pier Paolo , Haas-Kogan Daphne , Tanguturi Shyam , Cagney Daniel , Aizer Ayal , Doherty Lisa , Lavallee Maria , Fisher-Longden Brittany , Dowling Shanna , Geduldig Jack , Watkinson Fiona , Pisano William , Malinowski Seth , Ramkissoon Shakti , Santagata Sandro , Meredith David M. , Chiocca E. Antonio , Reardon David A. , Alexander Brian M. , Ligon Keith L. , Wen Patrick Y. 
Published: September 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.