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213 Phase 1 Results: First-in-Human Phase 1/2 Study of the Menin-MLL Inhibitor Enzomenib (DSP-5336) in Patients with Relapsed or Refractory Acute Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Menin Inhibitors in AML
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Saturday, December 7, 2024: 2:30 PM

Joshua F. Zeidner, MD1, Junichiro Yuda, MD, PhD2, Justin M. Watts, MD3, Mark J. Levis4, Harry P. Erba, MD, PhD5, Kentaro Fukushima, MD, PhD6*, Takahiro Shima, MD, PhD7, Neil D. Palmisiano, MD, MS8, Eunice S. Wang, MD9, Uma Borate, MD10, Joseph Brandwein, MD11, Cristina Papayannidis, MD, PhD12, Pau Montesinos, PhD, MD13*, Gina Keiffer, MD14, Yasushi Miyazaki, MD, PhD15, Naoko Hosono, MD, PhD16, Takayuki Ikezoe, MD, PhD17, Yoshiaki Ogawa, MD, PhD18*, Timothy S Pardee, MD, PhD19, Stephen Anthony Strickland, MD20, Koichi Onodera, MD21*, Shang-Ju Wu, MD, PhD22*, Melissa G Ooi, MB BCh, BAO, MRCP(I), FRCPath, PhD23*, Emmanuel Raffoux, MD24*, Susana Vives, MD25*, Alireza Eghtedar, MD26, Hongliang Cai, PhD27*, Curtis Allred, PhD28*, Bo Xu, PhD27*, Priya Robson27*, Akinobu Watanabe27*, Matthew Hitron, MD27*, Jatin Shah, MD27, Hagop M. Kantarjian, MD29 and Naval Daver, MD29

1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
2National Cancer Center Hospital East, Kashiwa, Japan
3Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL
4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
5Duke University Cancer Institute, Durham, NC
6Osaka University Graduate School of Medicine, Suita, Japan
7Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan
8Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
9Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
10The Ohio State University, Columbus, OH
11Department of Medicine, University of Alberta, Edmonton, AB, Canada
12IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
13Hematology, Hospital Universitari I Politécnic La Fe and Programa Español de Tratamientos en Hematología (PETHEMA) Group, Valencia, Spain
14Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA
15Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
16Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
17Fukushima Medical University, Fukushima, Japan
18Tokai University School of Medicine, Kanagawa, Japan
19Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC
20Sarah Cannon Research Institute, Nashville, TN
21Department of Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan
22National Taiwan University Hospital, Taipei, Taiwan
23Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
24Hematology Department, Saint Louis Hospital, Paris, France
25Hematology Department, Institut Catala d'Oncologia - Hospital Germans Trias i Pujol, Badalona, Spain
26Colorado Blood Cancer Institute, Denver, CO
27Sumitomo Pharma America, Inc., Marlborough, MA
28Sumitomo Pharma America, Inc., Marlborough
29Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: Menin inhibitors are an important new class of agents in development for acute leukemia. Over expression of HOXA9 and MEIS1 driven by the menin and KMT2A/MLL interaction occurs in leukemias with KMT2A rearrangement (KMT2Ar), NPM1 mutations (NPM1m), as well as other abnormalities. Enzomenib (DSP-5336) is an investigational, oral small molecule designed to inhibit the menin and KMT2A protein interaction. Herein, we report updated results of a Phase1/2 study of enzomenib in patients (pts) with relapsed/refractory (R/R) acute leukemia.

Methods: We conducted a Phase 1/2 study of enzomenib monotherapy in adult pts with R/R acute leukemia characterized by KMT2Ar, NPM1m, and other HOXA9/MEIS1 driven leukemia subsets. Other eligibility criteria included ECOG PS ≤ 2, QTcF interval ≤ 450 and 470 msec for male and female, adequate hepatic and renal function, & no active CNS leukemia. Dose escalation and optimization occurs in two parallel arms: Arm A (without strong CYP3A4 inhibitor azole antifungals) and Arm B (with strong CYP3A4 inhibitor azoles). The primary endpoints of this study were safety and tolerability (Phase 1) and preliminary efficacy (Phase 2) defined as CR+CRh rate. This study was IRB approved at 55 medical centers around the globe as of June 24, 2024 and registered at NIH ClinicalTrials.gov (NCT04988555).

Results: As of June 24, 2024, 81 pts were enrolled; 31 in Arm A and 50 in Arm B. The median age was 60.0 years (range 20 - 89) and 56.8% were female; 76 (93.8%) had AML. The median number of prior lines of therapy was 3 (range 1 to 9); 23 pts (28.4 %) had prior allogeneic stem cell transplant, 63 pts (77.8%) had prior venetoclax, and 6 pts (7.4%) had received a prior menin inhibitor. Documented KMT2Ar was reported in 41 pts (50.6%) and NPM1m in 20 (24.7%).

In the phase 1 portion, the enzomenib dose was escalated from 40 mg BID to 300 mg BID (n=81) with no dose limiting toxicities (DLTs) observed. Treatment emergent adverse events (TEAEs) assessed as related to enzomenib in ≥10% of pts was vomiting (14.8%), nausea (13.6%); grade 3 nausea and vomiting were reported in 1 pt. TEAE in ≥ 20% of pts regardless of relationship included nausea (39.5%), vomiting (29.6%), febrile neutropenia, diarrhea, hypokalaemia (22.2% each), decreased appetite, and headache (21.0% each). There were no reports of grade > 3 QTc prolongation related to enzomenib; grade 1 QTc prolongation was reported in 2 pts (2.5%) and grade 2 in 2 pts (2.5%). Possible differentiation syndrome (DS) was reported in 9 patients (11.1%) with no deaths from DS, and no treatment-related deaths.

A total of 35 pts with KMT2Ar or NPM1m had not received a prior menin inhibitor and were treated with active doses of enzomenib (≥ 140 mg BID in Arm A or Arm B). Among the 22 pts with KMT2Ar (20 AML, 2 ALL), the objective response rate (ORR) by ELN 2017 (CR+CRi+MLFS) was 59.1% (13/22) with CR + CRh achieved in 22.7% (5/22). Among the 13 pts with NPM1m AML, the ORR was 53.8% (7/13) and CR + CRh achieved in 23.1% (3/13). Among pts with other menin-sensitizing genetics, 1 pt (AML) with a CALM-AF10 fusion also achieved a CR. Overall, the median time to objective response and to CR+CRh was 1.0 and 1.0 months, respectively.

Dose-dependent increases in exposure were observed, particularly at doses > 140 mg BID. Little to no drug accumulation was observed with repeat dosing in both arms and data to date suggest that azoles do not have a significant impact on enzomenib exposure.

Pharmacodynamic changes potentially indicative of leukemic differentiation were noted in pts with KMT2Ar or NPM1m, including rapid decreases in stemness markers HOXA9, MEIS1, and PBX3 by qPCR and, conversely, increase in the differentiation marker CD11b by qPCR compared to baseline.

Conclusion: Enzomenib has been well tolerated with no DLT in 81 pts with R/R acute leukemia. No therapy-related discontinuations or deaths have been observed, and pharmacokinetic (PK) studies have not identified significant drug-drug interaction with strong CYP3A4 inhibitor azoles. Promising single agent activity has been observed in pts with R/R KMT2Ar and NPM1m acute leukemia across a wide therapeutic range of 140 mg to 300 mg BID. Dose optimization continues with the goal of identifying the RP2D for monotherapy. Updated clinical and translational data will be presented.

Disclosures: Yuda: BMS: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Sumitomo Pharma: Research Funding; Chugai: Research Funding; Genmab: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Daiichi Sankyo: Research Funding; BrightPath Biotherapeutics Co.,Ltd.: Research Funding; Mitsubishi Tanabe: Research Funding; MSD: Research Funding. Watts: Rafael Pharma: Consultancy; Immune Systems Key: Research Funding; Celgene/BMS: Consultancy; Reven Pharma: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Research Funding; Incyte: Research Funding; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Other: safety monitoring or advisory boards, Research Funding. Levis: Astellas: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy. Erba: Daiichi Sankyo: Honoraria. Fukushima: Pfizer Japan Inc.: Honoraria; Janssen Pharma: Honoraria. Palmisiano: Abbvie: Consultancy, Research Funding; BMS: Consultancy; Rigel: Consultancy. Wang: J&J: Membership on an entity's Board of Directors or advisory committees; Sellas: Membership on an entity's Board of Directors or advisory committees; UptoDate: Other: Section Editor; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Speakers Bureau; Rigel: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Schrodinger: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Award Committee, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Immunogen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kura: Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding, Speakers Bureau. Borate: Incyte: Consultancy; Astellas: Consultancy; BMS: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Rigel: Consultancy; Daiichi Sankyo: Consultancy; Sumitomo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: IDMC. Brandwein: Servier: Honoraria; Pfizer: Honoraria; Paladin: Honoraria; Jazz: Honoraria; BMS: Honoraria; Avir: Honoraria; Astellas: Honoraria; Amgen: Honoraria; AbbVie: Honoraria. Papayannidis: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Menarini/Stemline: Honoraria; BMS: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Delbert Laboratories: Membership on an entity's Board of Directors or advisory committees. Montesinos: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Syndax: Consultancy; Glycomimetics: Consultancy. Keiffer: Prelude: Research Funding; Sumitomo Pharma America: Research Funding; Astellas: Honoraria; Cyteir: Research Funding; Schrodinger: Research Funding; AbbVie: Research Funding. Miyazaki: AbbVie: Honoraria; Otsuka Pharmaceutical: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Janssen Pharmaceutical: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Eizai: Honoraria; Sumitomo Pharma: Honoraria; Kyowa-Kirin: Honoraria; Chugai: Honoraria. Hosono: AbbVie: Honoraria; Astellas Pharma: Honoraria. Ikezoe: Novartis: Honoraria; Otsuka: Honoraria; Ono: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; Chugai: Honoraria; Nippon Shinyaku: Honoraria; AsahiKasei Pharma: Honoraria, Research Funding; Alexion: Consultancy. Ogawa: Mochida Pharmaceutical: Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria; Alexion Pharmaceuticals: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; Sanofi: Honoraria; CSL Behring: Honoraria; Takeda: Honoraria; Chugai: Honoraria; Nippon Shinyaku: Honoraria; NIPRO: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; PharmaEssentia: Honoraria; Bristol: Honoraria; Meiji Seika Pharma: Honoraria. Pardee: Karyopharm: Research Funding; Gentech: Membership on an entity's Board of Directors or advisory committees; DeltaFly Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. Strickland: SentBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Onodera: Otsuka: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria; Janssen Pharmaceutical: Honoraria; Meiji Seika Pharma: Honoraria; Novartis pharma: Honoraria; Nippon Shinyaku: Honoraria; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; BMS: Honoraria; Astellas pharma: Honoraria; Asahi Kasei Pharma: Honoraria; Abbvie: Honoraria, Research Funding. Wu: MSD: Consultancy; Roche: Consultancy. Ooi: Pfizer: Other: Sponsorship for conference; Abbvie: Other: Sponsorship for conference; BMS: Honoraria; GSK: Honoraria; Antegene: Honoraria; Amgen: Honoraria, Other: Sponsorship for conference; Johnson and Johnson: Honoraria. Cai: Sumitomo Pharma America: Current Employment. Allred: Sumitomo Pharma America: Current Employment. Xu: Sumitomo Pharma America: Current Employment. Robson: Sumitomo Pharma America: Current Employment. Watanabe: Sumitomo Pharma America: Current Employment. Hitron: Sumitomo Pharma America: Current Employment. Shah: Sumitomo Pharma America: Current Employment. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Daver: Novartis: Consultancy; Jazz: Consultancy; Syndax: Consultancy; Servier: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; KITE: Research Funding; Shattuck Labs: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Arog: Consultancy; Genentech: Consultancy, Research Funding; Agios: Consultancy; Novimmune: Research Funding; Trovagene: Research Funding; Hanmi: Research Funding; Astellas: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Menarini Group: Consultancy; Gilead: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding.

*signifies non-member of ASH