Background: Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. We report on the feasibility and conduct of this approach. Methods: Tumor genotyping was performed prior to treatment assignment on eligible participants with newly diagnosed MGMT-unmethylated glioblastoma to identify biomarker signatures. Initial randomization was 1:1:1:1 between control (temozolomide) and 3 experimental arms (abemaciclib, CC-115, and neratinib). Subsequent randomization was adapted based on Bayesian estimation of biomarker-naïve and biomarker-specific probabilities of treatment impact on progression-free survival (PFS). Ineffective or toxic arms were discontinued by protocol amendment. The primary endpoint was overall survival (OS). Results: INSIGhT randomized 71 patients to the control arm, 73 patients to the abemaciclib arm, 12 patients to the CC-115 arm, and 81 patients to the neratinib arm between 2/9/2017 and 5/14/2021. Following the initial equal randomization period, early data were repeatedly analyzed during the study to capture early signals of treatment effects across the enrolled population or in specific biomarker subgroups. The results of these interim analyses influenced the randomization probability for future enrolled patients. In total, 77% of the participants were randomized before assessing their biomarker profile and 23% were biomarker randomized. The CC-115 arm opened and closed three times during the safety lead-in. The randomization probability to the CC-115 arm decreased based on poor early PFS results and the arm eventually closed after 12 patients due to toxicity. The randomization probability to the abemacicilb arm increased based on promising early PFS results. After the completion of accrual into the abemaciclib arm, the trial switched to block randomization to finish enrolling into the remaining neratinib and control arms. A total of 28 interim analyses and 32 randomization tables were created throughout the course of the trial with 4 adjustments (3 due to CC-115 closures and 1 due to completion of the abemaciclib arm). Biomarker association trends for neratinib and abemaciclib were similar to those seen in preclinical modeling of the trial. Conclusions: Relative to a standard randomization design, the adaptive platform design facilitated more efficient and economical testing of experimental arms by sharing a control arm, decreasing the probability of enrollment to potentially ineffective arms, and increasing the probability of enrollment to potentially effective arms. Additional future arms are planned on INSIGhT. Clinical trial information: NCT02977780.