KS03.5.A EVALUATION OF VAL-083 IN GBM AGILE, A PHASE 3 REGISTRATION PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract BACKGROUND GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies efficiently against a common control (C) with a primary endpoint of overall survival (OS). VAL-083 (VAL) is a DNA targeting agent that, independent of O6-methylguanine DNA methyltransferase promoter methylation status, targets the N7 position of guanine residues and facilitates inter-strand DNA crosslinks, leading to DNA double-strand breaks and cell death. It entered the trial in January 2021, and it is the 2nd arm (of 6) to complete its evaluation. MATERIAL AND METHODS Patient subtypes considered in GBM AGILE are newly diagnosed methylated (NDM), ND unmethylated (NDU), & recurrent disease (RD). C is temozolomide (in ND) & lomustine (in RD). Arms open to all 3 subtypes are evaluated in 5 prospectively defined signatures (sig): NDU, NDM, RD, all ND and All. Randomization (rand.) to C is 20% in each subtype. Exp arms in GBM AGILE have 1 or 2 stages. Efficacy is based on OS hazard ratio (HR) of arm/C. Efficacy goal is a final Bayesian probability ≥ 98% for HR <1.00 in combined Stages 1 & 2. Arms stop accruing in Stage 1 if they reach max sample size (N) or drop for futility or safety. Exp arms in Stage 1 are adaptively rand. with allocation being proportional to an arm’s current probability of having ≥ 30% benefit in OS, P(HR <0.70). In stage 1, exp arms are evaluated monthly, and arms showing Bayesian predictive power (PP) ≥ 0.8, graduate into Stage 2 with fixed rand. in one sig. For all exp arms, follow up continues for 12 mos after accrual stops. Arms are declared futile at any monthly analysis when PP is <0.25 for all sigs. Open to all 3 subtypes, VAL entered as the 1st arm in NDM and was rand. 1:1 to C in this subtype until additional arms entered. The target max N for VAL in its Stages 1 & 2 were 150 and 50, resp. RESULTS At the interim after VAL reached max sample size in Stage 1, the PP for all sigs was <0.8 and >0.25 for at least one sig. Thus, VAL did not graduate nor drop for futility, but accrual stopped for max N in Stage 1 VAL/C sample sizes were 39/92, 28/30, 87/225, 67/122, 154/347 for sigs NDU, NDM, RD, ND, and all. Resp. PPs: 0.086, 0.286, 0.005, 0.148, and 0.014. Resp. mean HRs: 1.36, 1.07, 1.69, 1.18, 1.4. At the interim after which VAL stopped for max N, mean HRs were 1.36, 1.07, 1.69, 1.18, and 1.40 with final probabilities of benefit (HR< 1.00) equal to 0.794, 0.564, 0.345, 0.708, and 0.564. Final results will be presented at the meeting. CONCLUSION GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms. © 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2024 ASCO Annual Meeting. All rights reserved.

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