A first-in-man phase I/II study of OBI-3424, an AKR1C3-selective bis-alkylating agent prodrug, in subjects with advanced cancer, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC).

Abstract

TPS3658 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including HCC. In prostate cancer cells exposed to anti-androgen therapies, AKR1C3 is adaptively upregulated. CRPC is a potential indication for this targeted alkylating agent. AKR1C3 tumor expression is associated with poor patient survival and resistance to cancer therapies. OBI-3424 is a nitro-benzene prodrug of a nitrogen mustard that can be selectively cleaved in the presence of AKR1C3 enzyme into a bis-alkylating agent capable of forming intra- and inter-strand crosslinks with DNA, thereby resulting in cell death. The selectivity of OBI-3424 for AKR1C3 distinguishes it from traditional alkylating agents, which are nonselective. The primary objectives of the study are to evaluate the safety and tolerability of single-agent OBI-3424. The dose-escalation phase will determine the dose-limiting toxicities (DLT), maximum tolerable dose (MTD), and recommended Phase 2 dose (RP2D) of OBI-3424 through assessment of PK of OBI-3424 and OBI-2660 in plasma and urine. After determining the maximum tolerated dose (MTD), the study will enroll subjects with advanced HCC or CRPC, two tumor types with a high likelihood of overexpression of AKR1C3, into the dose expansion portion of the study according to a Simon two-stage phase 2 design. This phase is designed to assess the objective response rate, and progression-free survival in patients with HCC and CRPC. Immunohistochemistry assays are being developed to assess tumor expression of AKR1C3 for this study. The clinical safety and relationship of efficacy to AKR1C3 tumor expression will serve to guide further clinical development of OBI-3424 in these two unmet need settings. Methods: Based on the toxicology and PK results in cynomolgus monkeys, the starting dose is one sixth of the human equivalent dose of the highest non-severely toxic dose observed. Doses of 1, 2, 4, 6, 8, 12, and 14 mg/m2 will be used. OBI-3424 is administered intravenously (IV) over 30 minutes on days 1 and 8 of each 21-day cycle. Subjects without clinically significant disease progression may continue on treatment for up to 2 years, if they do not experience a DLT or other significant toxicity. Clinical trial information: NCT03592264 .