Abstract LB081: Carboxyamidotriazole orotate (CTO) with temozolomide (TMZ) for recurrent high-grade gliomas (rHGG) and in combination with TMZ/RT->TMZ in newly diagnosed glioblastoma (ndGBM): Long term follow-up of phase IB trial

Abstract Background: CTO, an oral brain penetrant inhibitor of calcium signaling pathways was evaluated in rHGG and ndGBM. Intracellular Ca2+ homeostasis is altered in cancer cells and results in abnormal gene expression and immune evasion.Primary objectives of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose were reported [Omuro et al. JCO 2018]. This analysis presents secondary outcome of overall survival (OS) and comparison with historical controls. Methods: In a 3+3 design, CTO was given daily p.o. in: i) rHGG: CTO (219-812.5mg/m2/d and in 6 pts 600mg/day) and TMZ (150 mg/m2 x 5 every 28 d). OS was compared to phase III in rHGG treated with lomustine . (N=259)ii) ndGBM: CTO (219-481 mg/m2) and standard of care TMZ/RT [Stupp et al. NEJM 2005] OS was compared to phase III in ndGBM treated with SOC (N=1,339). Results: i) rHGG (N=26 pts): CTO was well tolerated (no DLT) and median OS (mOS) was 10.5 mo with 95% CI (8.0, 14.8) and 1-year OS of 47.4%, compared to lomustine treated pts with mOS 7.0 months (6.1, 7.7) and 1-year OS of 25.4%, p=0.0126.ii) ndGBM: All pts (N=15) had GBM (methylated MGMT gene in 33%; EGFR in 27%). In SOC+CTO pts, treatment was well tolerated, mOS was 37.8 mo (95% CI 20.9, 51.9) and a 2-yr survival of 69%, compared to historical control mOS of 15.8 mo 95% CI (15.1, 16.5) and 2-yr OS of 28.4%, p=0.006. Conclusion: Addition of CTO to TMZ or TMZ/RT respectively was safe with no DLT. Survival in both recurrent HGG and newly diagnosed GBM patients compares favorably with historical controls. Phase 2 randomized trials are planned. Citation Format: Thomas Kaley, Elena Pentsova, Cameron Brennan, Debyani Chakravarty, Lindsey Myers, Nancy Keith, Adam Newton, Kathryn Beal, Robert Aiken, Antonio Omuro, Priya Kumthekar, Rashida A. Karmali. Carboxyamidotriazole orotate (CTO) with temozolomide (TMZ) for recurrent high-grade gliomas (rHGG) and in combination with TMZ/RT->TMZ in newly diagnosed glioblastoma (ndGBM): Long term follow-up of phase IB trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB081.