Abstract 3187: Pediatric Preclinical Testing Consortium evaluation of the menin inhibitor, VTP-50469, against xenograft models of MLL-rearranged infant acute lymphoblastic leukemia (2018)

Abstract Introduction: Rearrangements involving the MLL (mixed lineage leukemia, KMT2A) gene (MLLr) occur broadly in acute leukemia, in ~80% of infant acute lymphoblastic leukemia (ALL) cases, and are associated with poor outcome. Menin is a ubiquitously expressed nuclear protein, and the MLLr-menin interaction is the key impetus for transformation of MLLr-expressing cells. VTP-50469 is a potent, orally available, small molecule inhibitor of the MLL-menin interaction with pM binding affinity for menin. Therefore, it was of interest to test the in vivo efficacy of VTP-50469 against preclinical models of infant MLLr-ALL. Methods: Infant MLLr-ALL patient-derived xenografts (PDXs) grew in an orthotopic manner in 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 median %huCD45+ exceeded 1%, and mice received VTP-50469 (120 mg/kg by oral gavage twice daily x 28) or vehicle. An event was defined as the %huCD45+ &amp;gt;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, Pediatr. Blood Cancer, 2007;49:928-40). Leukemia infiltration into the femoral bone marrow was also assessed at Day 28 following treatment initiation. VTP-50469 was provided by Vitae Pharmaceuticals. Results: VTP-50469 was well tolerated, with maximum average weight losses of 1.6-6.4% across treatment groups compared to 0-2.0% in vehicle control treated groups. VTP-50469 induced significant differences in EFS distribution compared to control in 6 of 6 (100%) of the evaluable MLLr-ALL PDXs. VTP-50469 T-C values in MLLr-ALL PDXs ranged from 1.2 to 100 days (T/C 1.3-21.1), and Maintained Complete Responses (MCRs) were observed in 5 of 6 PDXs. Two of 8 mice engrafted with an MLLr-ALL harboring the MLL-AFF1 (t4;11) translocation had not reached event &amp;gt;230 days following treatment initiation. A significant reduction (P&amp;lt;0.001) in bone marrow infiltration at Day 28 was observed in 2 of 4 evaluable MLLr-ALL PDXs. VTP-50469 at 30 mg/kg (4-fold lower than its maximum tolerated dose) also elicited MCRs in 8 of 8 mice engrafted with an MLL-AFF1 PDX. The on-target activity of VTP-50469 was verified by its lack of efficacy against an ALL PDX harboring the BCR-ABL1 translocation. Conclusions: VTP-50469 exerted profound in vivo efficacy against ALL PDXs derived from infants harboring MLL-AFF1, MLL-GAS7, and MLL-ENL translocations, and significantly reduced leukemia infiltration in the bone marrow. VTP-50469 was also effective across a broad dose range, indicating that it may represent a novel treatment for MLLr leukemia. (Supported by NCI Grants CA199222 &amp; CA199000) Citation Format: Richard B. Lock, Kathryn Evans, Tara Pritchard, Stephen W. Erickson, Yuelong Guo, David A. Claremon, Gerard M. McGeehan, Beverly A. Teicher, Malcolm A. Smith. Pediatric Preclinical Testing Consortium evaluation of the menin inhibitor, VTP-50469, against xenograft models of MLL-rearranged infant acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3187.