Abstract LB-B16: The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia (T-ALL); a Pediatric Preclinical Testing Consortium Study
Authors: Lock Richard B. , Evans Kathryn , Yung Raymond , Pritchard Tara , Teicher Beverly A. , Duan JianXin , Guo Yuelong , Erickson Stephen W. , Smith Malcolm A. 
Published: August 2018

Abstract
Introduction: Aldo-keto reductase family 1 member C3 (AKR1C3) belongs to a superfamily of oxidoreductases that are broadly expressed in human tissues. AKR1C3 catalyzes the reduction of a diverse group of substrates, and is expressed at high levels in several human cancers including T-ALL. We previously showed that AKR1C3 is a biomarker of T-ALL sensitivity to the hypoxia-activated pre-prodrug PR-104, which is also activated under aerobic conditions by AKR1C3 (Manesh et al, Blood, 2015;126:1193-202). Therefore, it was of interest to test the in vivo efficacy of OBI-3424 against preclinical models of T-ALL, since OBI-3424 is a highly selective prodrug that is converted by AKR1C3 to a DNA alkylating agent. Methods: ALL patient-derived xenografts (PDXs) grew in an orthotopic manner following intravenous inoculation into NSG mice. Engraftment and response to treatment were assessed by enumeration of the % human leukemic blasts in the murine peripheral blood (%huCD45+). Treatment commenced when the %huCD45+ exceeded a median of 1%, and mice received OBI-3424 (2.5 mg/kg by the intraperitoneal route once weekly x 3) or vehicle. An event was defined as the %huCD45+ exceeding 25% or leukemia-related morbidity. The Kaplan-Meier method was used to compare event-free survival (EFS) between treated (T) and control (C) groups. Stringent objective response measures were assigned to each mouse and reported as group medians (Houghton et al, PBC, 2007;49:928-40). Leukemia infiltration into the femoral bone marrow was also assessed at Day 28 following treatment initiation. OBI-3424 was provided by Threshold Pharmaceutical and is being developed by OBI Pharma, Inc. (ex-Asia) and Ascenta Pharma (Asia). Results: OBI-3424 was well tolerated, with only a 2.8% toxicity rate in the drug-treated groups. OBI-3424 induced significant differences in EFS distribution compared to control in 9 of 9 (100%) of the evaluable PDXs. T-C values ranged from 17.1 to 65.2 days (T/C 2.3-14.0), and objective responses were observed in 8 of 9 PDXs (2 complete responses, CRs; 6 maintained CRs, MCRs). A significant reduction (P&lt;0.0001) in bone marrow infiltration at Day 28 was observed in 4 of 6 evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo responses of ALL PDXs to OBI-3424 was verified using a B-cell precursor ALL PDX (ALL-11) that had been lentivirally transduced to stably overexpress AKR1C3 (ALL-11/1C3) compared with empty vector control (ALL-11/EV). Mice engrafted with ALL-11/1C3 exhibited an MCR (T-C &gt;37.3 days, T/C &gt;3) compared with a CR for ALL-11/EV (T-C 21.1 days, T/C 2.5). Infiltration of ALL-11/1C3 cells into the murine bone marrow was significantly reduced at Day 28 in OBI-3424-treated compared with vehicle-treated mice (P&lt;0.0001) but not in mice engrafted with ALL-11/EV. Conclusions: At a dose of 2.5 mg/kg, which is estimated to achieve exposure levels in mice that will be readily attainable in humans, OBI-3424 exerted profound in vivo efficacy against a broad range of T-ALL PDXs and significantly reduced leukemia infiltration in the bone marrow. Since these PDXs were derived predominantly from aggressive and fatal disease, OBI-3424 may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial. (Supported by NCI Grants CA199222 & CA199000)
Citation Format: Richard B. Lock, Kathryn Evans, Raymond Yung, Tara Pritchard, Beverly A. Teicher, JianXin Duan, Yuelong Guo, Stephen W. Erickson, Malcolm A. Smith. The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia (T-ALL); a Pediatric Preclinical Testing Consortium Study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B16.