Safety and Efficacy of Menin Inhibition in Patients (Pts) with MLL-Rearranged and NPM1 Mutant Acute Leukemia: A Phase (Ph) 1, First-in-Human Study of SNDX-5613 (AUGMENT 101)
Authors: Stein Eytan M. , Aldoss Ibrahim , DiPersio John F. , Stone Richard M. , Arellano Martha L. , Rosen Galit , Meyers Michael L. , Huang Yifan , Smith Steve , Bagley Rebecca G. , Thirman Michael , Patel Manish R. , Issa Ghayas C. 
Published: November 2021

Abstract
Introduction: Translocations involving the MLL gene on chromosome 11q23 result in fusions with ≥10 partner genes that act as drivers in relatively chemotherapy resistant MLL-rearranged (MLLr) leukemias. These chimeric proteins form part of protein complexes that aberrantly upregulate transcription of the leukemogenic HOX and MEIS1 genes. Menin is a key member of the complex and localizes the complex to chromatin. Similarly, in NPM1 mutant (mNPM1) AML, the interaction between wild-type MLL and menin leads to a HOX and MEIS1-mediated leukemogenic transcriptional program. In preclinical models of MLLr and mNPM1 leukemias, inhibition of the interaction between MLL and menin downregulates HOX and MEIS1 transcription and reverses leukemogenesis (Uckelmann 2020; Krivstov 2019). SNDX-5613 (5613) is a potent, selective protein-protein interaction inhibitor of menin being evaluated in the AUGMENT-101 study, a first-in-human (FIH), Ph 1/2 study in pts with R/R acute leukemia. Here, we report the results of the completed, Ph 1 component.
Methods: The study includes 2 parallel dose-escalation cohorts: pts not taking (Arm A) or taking (Arm B) strong CYP3A4 inhibitors. An early amendment restricted enrollment to MLLr or mNPM1 leukemias. Dose escalation used a "rolling 6" design with expansion at efficacious doses. 5613 is dosed orally q12h in continuous 28-day cycles. Dose levels evaluated in Arm A were 113 (n=1), 226 (n=6), 276 (n=10), and 339 mg (n=8), and in Arm B 113 (n=16), 163 (n=6), and 226 mg (n=7). Primary objectives of Ph 1 were to determine the safety, MTD, recommended Ph 2 dose (RP2D), and PK profile of 5613. Exploratory endpoints included antileukemic activity and pharmacodynamics of 5613.
Results: As of 29Jun2021, 54 pts had received at least 1 dose of 5613; 13 pts remained on treatment. Baseline characteristics are detailed in Table 1. The median age was 49 years; 82% (n=44) of pts had AML; 65% (n=35) had MLLr leukemia, and 19% (n=10) had mNPM1 leukemia. Pts had a median of 3 prior therapies (range, 1-12); 57% and 44% had prior venetoclax or transplant, respectively; 59% of pts had not responded to their most recent line of therapy.
5613 exhibited dose-proportional PK, and exposure increased ~2-3-fold when given with a strong CYP3A4 inhibitor. Measurement of target occupancy and gene expression showed that 5613 disrupted menin binding to chromatin and decreased leukemogenic gene expression consistent with the established mechanism of action.
The only DLTs were Grade 3 prolonged QTc; all events were clinically asymptomatic. The MTD was 276 mg q12h in Arm A and 163 mg q12h in Arm B; 2 doses in each arm met the protocol-defined criteria (safety, percentage of planned dose intensity, and pharmacokinetic exposure) for a RP2D. The frequency of Grade 3 prolonged QTc at these doses was 8% (3/38). No ventricular arrhythmias were reported, and no pts discontinued 5613 due to a treatment-related event. Other common (&gt;10%) treatment-related AE (TRAE) were nausea (n=12; 22%), vomiting (n=9; 17%), differentiation syndrome (n=8; 15%), and diarrhea (n=6;11%). Grade ≥3 TRAE are shown in Table 2.
In the 45 pts with MLLr or mNPM1 leukemias, responses were seen in both Arms A and B and at multiple dose levels. The composite CR (CRc: CR+CRh+CRp+CRi/MLFS) rate was 44% (20/45 pts) (Table 3). Among pts with MLLr leukemia, the CRc rate was 49% (17/35 pts) and in pts with mNPM1 leukemia, the CRc rate was 30% (3/10 pts); 14/20 (70%) pts with CRc achieved MRD negativity assessed locally by flow cytometry or PCR. Of 22 pts who received prior transplant, 10 (45%) achieved CRc. The CR/CRh rate was 22% (10/45) in pts with MLLr or mNPM1 leukemia. Median time to CR/CRh was 2 months (mo). With a median follow-up of 3.2 mo, the median duration of response (DoR) for patients achieving a CR/CRh was 5.2 mo. Responding patients were censored at the time they discontinued the study to proceed to an allogeneic stem cell transplant (n=6). Consistent with the proposed preclinical mechanism of menin inhibition, the 9 patients with wild-type MLL and NPM1 did not respond to 5613.
Conclusion: In this FIH Ph 1 study, SNDX-5613 demonstrates an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R MLLr and mNPM1 acute leukemia. Two dose levels in each arm met the prespecified criteria for RP2D. Ph 2 expansion includes cohorts of pts with MLLr AML, MLLr ALL, and mNPM1 AML.
Figure 1 Figure 1.

Disclosures
Stein: Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Syndax Pharmaceuticals: Consultancy. Stone: Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Innate: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Jazz: Consultancy; Onconova: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Rosen: Syndax: Current Employment. Meyers: Syndax Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Patents & Royalties; Nuvalent: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huang: Syndax: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Serapta: Ended employment in the past 24 months. Smith: Syndax: Consultancy; Tempest: Current holder of stock options in a privately-held company; Athira: Current holder of stock options in a privately-held company. Bagley: Syndax: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Radius Health: Ended employment in the past 24 months. Thirman: AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pharmacyclics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Merck: Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding. Patel: Ignyta: Research Funding; Incyte: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Hutchinson MediPharma: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; Gilead: Research Funding; GlaxoSmithKline: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Evelo Biosciences: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Effector Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Curis: Research Funding; Clovis: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding.