A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients with Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1 Alterations

Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustai...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.57-57
Main Authors: Jabbour, Elias, Searle, Emma, Abdul-Hay, Maher, Abedin, Sameem, Aldoss, Ibrahim, Alfonso Piérola, Ana, Alonso-Dominguez, Juan Manuel, Chevallier, Patrice, Cost, Carrye, Daskalakis, Nikki, Dillon, Richard, Dunavin, Neil, Esteve, Jordi, Fathi, Amir T., Fedele, Pasquale L., Ferrante, Lucille, Garciaz, Sylvain, Guttke, Christina, Gyan, Emmanuel, Hiebert, Brett, Kwon, Min Chul, Miller, Jonathan, Ng, Teng Fong, Packman, Kathryn, Philippar, Ulrike, Pigneux, Arnaud, Recher, Christian, Salamero, Olga, Sanga, Madhu, Stone, Richard M, Tan, Peter, Thuring, Jan Willem, Tucker, Trevor, Vyas, Paresh
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Language:English
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Summary:Background: Relapsed/refractory (R/R)acute leukemia withalterations in KMT2A (also called MLL1; 9-15% of adult AML, 10% of ALL) or NPM1 (30% of adult AML) are often associated with poor outcomes. Pre-clinical studies demonstrated the relevance of the menin-KMT2A protein-protein interaction in sustaining leukemic cells with KMT2A and NPM1 alterations (Kuhn 2016). JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A with preclinical activity in KMT2A-rearranged or NPM1-mutated leukemic cell lines and primary leukemia patient samples in vitro and in vivo (Kwon 2022). We report initial data investigating JNJ-75276617 in adult participants (pts) with R/R acute leukemia harboring KMT2A alterations (rearrangements, amplifications, or partial tandem duplications) or NPM1 mutations. Methods: 75276617ALE1001 (NCT04811560) is an ongoing Phase 1, multicenter, open-label, dose-finding study. Pts in dose escalation receive JNJ-75276617 orally on a 28-day cycle. As of 8 April 2023, multiple dose levels ≥15 mg have been explored on either a daily or twice daily (BID) dosing schedule. AEs were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2017. Preliminary safety, efficacy and PD data are reported herein, with a focused review of the efficacy in higher dose levels with ≥3 pts dosed. Results: Fifty-eight pts received JNJ-75276617. The median age was 63 (range: 19-83) years; 56 pts (97%) had R/R AML and 2 (3%) had R/R ALL. The median number of prior lines of treatment was 2 (range: 1-7), including 10 (17%) pts with a prior allogeneic stem cell transplant. A KMT2A or NPM1 alteration was present in 33 (57%) and 25 (43%) pts, respectively. Thirty (52%) pts experienced ≥1 treatment-related AE (TRAE); most commonly differentiation syndrome (DS) (8 [14%]). Grade ≥3 TRAEs were observed in 17 (29%) pts; those reported in ≥2 pts were neutropenia (6 [10%]), anemia and thrombocytopenia (4 [7%] each), DS (3 [5%]), and ALT and AST increase (2 [3%] each). Dose limiting toxicities (DLTs) were observed in 5 (9%) pts, with DS (2 [3%]) as the only DLT reported in ≥2 pts. In 26 (63%) of the 41 pts with disease evaluation data, there was a reduction in bone marrow (BM) disease burden ( Figure 1). Of these, a ≥50% decrease in BM blasts was observed in 16 (39%) pts. In the highest dose level with ≥3 pts (90 mg BID; n=8), the ORR (≥PR) was 50% (n=4), with all responders ongoing ( Figure 2). The
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-172422