TY - JOUR
T1 - Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy
T2 - A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization
AU - Rahman, Rifaquat
AU - Trippa, Lorenzo
AU - Lee, Eudocia Q.
AU - Arrillaga-Romany, Isabel
AU - Fell, Geoffrey
AU - Touat, Mehdi
AU - McCluskey, Christine
AU - Wiley, Jennifer
AU - Gaffey, Sarah
AU - Drappatz, Jan
AU - Welch, Mary R.
AU - Galanis, Evanthia
AU - Ahluwalia, Manmeet S.
AU - Colman, Howard
AU - Nabors, L. Burt
AU - Hepel, Jaroslaw
AU - Elinzano, Heinrich
AU - Schiff, David
AU - Chukwueke, Ugonma N.
AU - Beroukhim, Rameen
AU - Nayak, Lakshmi
AU - McFaline-Figueroa, J. Ricardo
AU - Batchelor, Tracy T.
AU - Rinne, Mikael L.
AU - Kaley, Thomas J.
AU - Lu-Emerson, Christine
AU - Mellinghoff, Ingo K.
AU - Bi, Wenya Linda
AU - Arnaout, Omar
AU - Peruzzi, Pier Paolo
AU - Haas-Kogan, Daphne
AU - Tanguturi, Shyam
AU - Cagney, Daniel
AU - Aizer, Ayal
AU - Doherty, Lisa
AU - Lavallee, Maria
AU - Fisher-Longden, Brittany
AU - Dowling, Shanna
AU - Geduldig, Jack
AU - Watkinson, Fiona
AU - Pisano, William
AU - Malinowski, Seth
AU - Ramkissoon, Shakti
AU - Santagata, Sandro
AU - Meredith, David M.
AU - Chiocca, E. Antonio
AU - Reardon, David A.
AU - Alexander, Brian M.
AU - Ligon, Keith L.
AU - Wen, Patrick Y.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/12/20
Y1 - 2023/12/20
N2 - PURPOSEThe 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 METHODSPatients 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).RESULTSTwo 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).CONCLUSIONThe 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.
AB - PURPOSEThe 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 METHODSPatients 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).RESULTSTwo 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).CONCLUSIONThe 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.
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U2 - 10.1200/JCO.23.00493
DO - 10.1200/JCO.23.00493
M3 - Article
C2 - 37722087
AN - SCOPUS:85173938464
SN - 0732-183X
VL - 41
SP - 5524
EP - 5535
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 36
ER -