Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study.

Abstract

3030 Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, and potentially improves the safety profile and antitumor activity against chemo- and radio-resistant tumors. We conducted a first-in-human, phase 1, dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Methods: OBI-3424 was administered intravenously at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (Days 1 and 8 every 21 days, Schedule A) or 8, 10, 12, or 14 mg/m2 (Day 1 every 21 days, Schedule B). A “3+3” design was used for dose escalation. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 39 adult patients were treated. In patients receiving Schedule A, the maximum tolerated dose (MTD) of OBI-3424 was determined to be 8 mg/m2. Dose limiting toxicities (DLTs) were reported at the 12 mg/m2 dose level, including thrombocytopenia (Grade 3-4, 5 of 6 patients) and anemia (Grade 3-4, 5 of 6 patients). Platelet count nadirs were noted on Day 15 or Day 22. These cytopenias led to dose modification and resulted in protocol amendment (Schedule B). In Schedule B, the MTD was not reached at the maximum dose tested (14 mg/m2). Grade 3 or higher anemia was noted in 3 of 6 patients treated at 14 mg/m2; the recommended phase 2 dose (RP2D) is 12 mg/m2 (Day 1 every 21 days). Treatment-related AEs (TRAEs) were noted in 82% (32/39) of patients. The most common TRAEs were anemia (64%), thrombocytopenia (51%), nausea (26%), and fatigue (21%). No patient had a fatal TRAE, 49% had ≥Grade 3 TRAEs, including 3 patients who had serious TRAEs. OBI-3424 showed linear pharmacokinetics from 1 to 14 mg/m2, with minimal accumulation after repeated dosing. A retrospective validated automated immunohistochemistry assessment indicated that 27% of patients had high AKR1C3 staining (H-score ≥135). Best confirmed response was stable disease in 21 patients (54%). Conclusions: We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated. Dose-dependent, non-cumulative thrombocytopenia and anemia were dose limiting. We are currently enrolling patients with pancreatic cancer and other tumor types with overexpression of AKR1C3 (H-score ≥135) in the expansion phase of the study. Clinical trial information: NCT03592264.