Phase 1/2, Open-Label, Dose Escalation, Dose Expansion Study of Menin Inhibitor DSP-5336 in Adult Patients (pts) with Acute Leukemia with and without Mixed-Lineage Leukemia (MLL)-Rearrangement or Nucleophosmin 1 (NPM1) Mutation
Authors: Daver Naval , Affinito John , Cai Hongliang , Dobrowolska Hanna , Dow Edward , Eguchi Ken , Song Gregory , Stoudemire Jay , Watanbe Akinobu , Komarnitsky Philip 
Published: November 2021

Abstract
Relapsed or refractory acute leukemia (AL) in adults, including acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL), still represents a significant unmet need. Once AML or ALL relapses after initial treatment, the prognosis is extremely limited, with median survival &lt;6 mo for AML and &lt;1 y for ALL. This is especially true of AML or ALL with MLL rearrangements (MLLr) or relapsed AML with NPM1 mutations. Translocations of the MLL gene, found in approximately 5% to 10% of adult patients with AL, result in an aggressive subtype of leukemia, with a median overall survival (OS) of approximately 9 months and a very high rate of relapse after standard induction therapy for AML or ALL. The NPM1 mutation (NPM1m) is seen in approximately 30-35% of adult AML cases, most commonly in de novo AML, and is associated with a more favorable prognosis in newly diagnosed AML. However, this favorable prognostic effect is lost in the presence of concomitant FLT3-internal tandem duplication (ITD) mutations, which are seen in 40% to 50% of AML with mutated NPM1.
These genomic alterations have been the focus for the development of DSP-5336, a novel small-molecule oral therapy that prevents binding of the menin protein to MLL fusion proteins that drive leukemogenesis.
In nonclinical studies, DSP-5336 showed selective cell growth inhibitory activity against human
AL cell lines with MLLr or NPM1m. In addition, evidence of antitumor activity and survival advantage was demonstrated in 3 AML xenograft models with MLLr and/or NPM1m. Treatment with DSP-5336 may result in the reduction of leukemic cells, offering therapeutic benefits that include achieving complete remission and prolonged survival in patients with relapsed or refractory AML with MLLr or NPM1m or pts with relapsed or refractory ALL with MLLr.
An open-label, single-arm, phase 1/2 study (NCT04988555) of DSP-5336 is being started to evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in adults aged ≥18 y with relapsed/refractory AML or ALL after at least one line of standard therapy, including hematopoietic stem cell transplant. Key inclusion criteria are ECOG performance status 0-2 and adequate cardiac, renal, and hepatic function. Patients on the strong CYP3A4 inhibitors ketoconazole, itraconazole, or isavuconazole, are excluded unless they can be safely taken off these medications or switched to another antifungal medication at least 7 days prior to start of study treatment.
Patients will be dosed twice daily for 28 days per cycle. The study design is depicted below in Figure 1. In phase 1, 21-30 pts will be enrolled into multiple ascending dose cohorts (1-6 pts per dose level), with dose escalation determined using a two-parameter Bayesian logistic regression model. Determination of the RP2D will be informed by the maximum biologic effect or maximum tolerated dose, whichever is lower. The phase 2 study will include arm A (relapsed or refractory AML with MLLr) and arm B (relapsed or refractory AML with NPM1m) (Figure 1). Patients will be treated at the RP2D to evaluate clinical activity and safety, which will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Study endpoints are summarized in Table 1.
Figure 1 Figure 1.

Disclosures
Daver: Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; ImmunoGen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novimmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Affinito: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Cai: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Dobrowolska: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Dow: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Eguchi: Sumitomo Dainippon Pharma: Current Employment. Song: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Stoudemire: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Watanbe: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Komarnitsky: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment.