Abstract 7050: Preclinical evaluation of the AKR1C3-activated alkylator OBI-3424 in hepatoblastoma: A report from the Pediatric Preclinical In Vivo Testing Consortium (PIVOT)

Abstract Introduction: OBI-3424 is a DNA alkylating prodrug activated by aldo-keto reductase family 1 member C3 (AKR1C3). Elevated AKR1C3 expression is observed in a variety of tumors including prostate cancer, T-cell acute lymphoblastic leukemia (T-ALL), hepatocellular carcinoma (HCC) and hepatoblastoma. Interim Phase 2 data of OBI-3424 in advanced HCC patients showed encouraging survival benefit and a good safety profile. Evaluation of AKR1C3 expression across a spectrum of pediatric tumors showed highest expression in T-ALL and hepatoblastoma. Prior preclinical testing of OBI-3424 in T-ALL patient-derived xenograft (PDX) models showed significant activity with prolonged complete remissions. Hence, we evaluated the anti-tumor activity of OBI-3424 across a panel of hepatoblastoma PDXs and examined AKR1C3 expression as a response biomarker. Methods: Tumors from 8 hepatoblastoma PDXs were evaluated for AKR1C3 expression by immunohistochemistry and H-scores assigned following pathology review. OBI-3424 was provided by OBI Pharma and administered intravenously at 2.5 mg/kg weekly for 3 weeks. Tolerability testing was performed in 3 non-tumor bearing immunodeficient mice at 100%, 75% and 50% of the recommended dose (2.5 mg/kg). In efficacy studies, 3-6 mice were treated per treatment group (vehicle, OBI-3424) across the 8 hepatoblastoma PDXs profiled for AKR1C3 expression. Previously described measures assessing event-free survival (EFS T/C = ratio of median EFS for treated versus control animals) and overall objective response measures (ORMs) modeled after the clinical setting were used to evaluate activity (Houghton et al., Pediatr Blood Cancer, 2007). Results: H-scores for AKR1C3 expression ranged from 50 - 255 (median: 158) with 5 of 8 models having H-scores ≥100. AKR1C3 transcript expression was well correlated with protein expression. OBI-3424 was well tolerated at all dose levels tested with no significant weight loss in 2 different immunodeficient mouse strains. Among 8 models tested, partial responses (PRs) were observed in 3 models and 1 model showed stable disease (SD). Three models were categorized as progressive disease with tumor growth delay (PD2), and 1 model continues to undergo testing. EFS T/C values ranged from 2.34-5.62. Preliminary assessments of response do not appear to consistently correlate with AKR1C3 expression level (e.g., PR and PD2 observed in models with H-scores of 250 and 255, respectively). Conclusions: OBI-3424 shows promising preclinical activity in hepatoblastoma PDX models inducing objective responses. The role of AKR1C3 expression as a response biomarker for hepatoblastoma requires further investigation. Results from this study along with encouraging interim Phase 2 clinical data for advanced HCC patients may provide rationale for future clinical development of OBI-3424 in hepatoblastoma. Citation Format: Filemon Dela Cruz, Andrew Kung, Raushan Kurmasheva, Peter Houghton, Daoqi You, Glorife Ibanez Sanchez, Steven Neuhauser, Tim Stearns, Jeff Chuang, Jee Young Kwon, Emily L. Jocoy, Yu-Jung Chen, Ming-Chen Yang, Beverly Teicher, Carol J. Bult, Malcolm A. Smith. Preclinical evaluation of the AKR1C3-activated alkylator OBI-3424 in hepatoblastoma: A report from the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7050.