Abstract CT199: An open-label phase 1 study to investigate JBZ001 in adults with advanced solid tumors and non-Hodjkin lymphoma (JBZ001, trial in progress)
Authors: Asrar Alahmadi, Chad Bennett, Sebastian Biglione, Zuzana Jirakova, Carly JR Pilcher, Ridge Archer, Tamara Jovonovich, Dwight Owen, Christian Rolfo, Robert Wesolowski, Claire Verschraegen, David Carbone
Journal: Cancer Research (2025)

Abstract Background: Pyrimidine biosynthesis, as a precursor of RNA and DNA, is essential for cell proliferation. Targeting pyrimidine metabolism with chemotherapy has been a treatment backbone for many cancers. Dihydroorotate dehydrogenase (DHODH) is an enzyme that is critical for de novo pyrimidine biosynthesis. Our team designed and synthesized an orally bioavailable small-molecule DHODH inhibitor, JBZ-001 (HOSU-53), as a candidate with good drug-like properties and oral bioavailability in mice and rats. In vivo testing of JBZ-001 established efficacy in multiple mouse xenograft models: small-cell lung cancer (NCI-H82 xenograft, tumor growth inhibition, TGI = 84%), colorectal cancer (HCT-15 xenograft, TGI = 91%), lymphoma (Z-138 xenograft, TGI = 102%), gastric cancer (SNU-16 xenograft, TGI = 88%), and melanoma (A375 xenograft, TGI = 64%) (Bennett C, ACS 2024). It showed superior preclinical efficacy when compared with other clinical candidates. It also showed a favorable toxicity profile with no observed adverse effects levels identified in the preclinical toxicity studies in rats and dogs. JBZ-001 has been moved to phase 1 testing in humans. Methods: The JBZ-001- phase 1 study will characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of JBZ-001 as a single agent in patients with advanced solid tumors and non-Hodgkin lymphoma (NHL). Dose escalation will identify the optimal biological dose (Part 1), and the dose expansion (Part 2). We will test preliminary activity in cohorts of up to 10 patients with the same tumor type. A Bayesian safety monitoring rule will be used to evaluate the rate of dose-limiting toxicities (DLTs). Eligible patients are adults ≥18 years of age with confirmed relapsed or refractory advanced solid tumors and NHL, for which no standard approved treatment is available; have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and an ECOG performance status of 0-2. The primary endpoint is determination of the optimal dose by assessment of specific DLTs and adverse events per Common Terminology Criteria for Adverse Events (CTCAE) v.5. Secondary endpoints include PK and PD parameters, objective response rate per RECIST v1.1, and duration of response. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Recruitment is ongoing for Part 1 at The Ohio State University Comprehensive Cancer Center (WCG IRB 20245148). Citation Format: Asrar Alahmadi, Chad Bennett, Sebastian Biglione, Zuzana, Jirakova, Carly JR Pilcher, Ridge Archer, Tamara Jovonovich, Dwight Owen, Christian Rolfo, Robert Wesolowski, Claire Verschraegen, David Carbone. An open-label phase 1 study to investigate JBZ001 in adults with advanced solid tumors and non-Hodjkin lymphoma (JBZ001, trial in progress) [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 CT199.