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4863 Azacitidine, Venetoclax and Allogeneic NK Cells in Newly Diagnosed Acute Myeloid Leukemia (ADVENT-AML): An Investigator-Initiated Multicenter Phase Ib Trial

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, Research, Biological therapies, AML, clinical trials, apoptosis, Non-Biological therapies, Translational Research, elderly, Chemotherapy, Clinical Research, Combination therapy, Diseases, Therapies, immunology, Myeloid Malignancies, Biological Processes, Natural Killer (NK) Cell Therapies, Study Population, Human, Minimal Residual Disease
Monday, December 11, 2023, 6:00 PM-8:00 PM

Abhishek Maiti, MD1, Muharrem Muftuoglu, MD2, James J. Ignatz-Hoover, MD, PhD3*, Courtney D. DiNardo, MD, MSc4, Farhad Ravandi, MD, MBBS4, Michael Andreeff, MD PhD4, Lianchun Xiao5*, Xuelin Huang, PhD6*, Keyur P. Patel, MBBS, PhD7, Jason B Litten, MD8*, Eliot Bourk8*, Stephanie Astrow8*, Hagop M. Kantarjian, MD4, Ben K. Tomlinson, MD9, Naval Daver, MD4 and David Wald10*

1Department of Leukemia, MD Anderson Cancer Center, Houston, TX
2Section of Molecular Hematology and Therapy, Department of Leukemia, Houston, TX
3Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH
4Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston
6Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
8Chimeric Therapeutics, Carlton, Australia
9University Hospitals Seidman Cancer Center, Cleveland, OH
10Case Western Reserve University, Cleveland, OH

BACKGROUND AND SIGNIFICANCE: Older/unfit patients with acute myeloid leukemia (AML) have limited treatment options. Outcomes in adverse-risk subgroups of AML are modest with CR/CRi rates of 45% to 60% and median overall survival (OS) of 5 to 12 months with current standard frontline therapy of hypomethylating agent with venetoclax (HMA-VEN). While allogeneic stem cell transplantation (allo-SCT) can significantly improve OS in AML, only 10 to 20% of older pts are able to undergo allo-SCT (Pratz et al. Blood 2019, Maiti et al. Blood 2022)

Natural killer (NK) cells bridge the innate and adaptive immune system and play a major role in graft-vs-leukemia (GVL) effect responsible for the clinical benefit noted with allo-SCT. NK cell-based adoptive cellular therapies have shown good safety profiles and promising activity in AML with responses noted in 25% to 88% of patients. Furthermore, NK cells are less likely to induce graft-versus-host disease (GVHD), severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

We hypothesize that the combination of azacitidine, venetoclax and allogeneic NK cells will be safe and improve cure rates in AML compared to either Aza/Ven or NK cells alone. Improved clinical activity may be mediated through multiple synergistic mechanisms including reduction of disease burden by Aza/Ven, upregulation of epigenetically silenced NKG2D ligands, dual activation of extrinsic and intrinsic apoptotic cascades, mitochondrial priming of leukemia cells by venetoclax, and bypassing significant morbidity and mortality associated allo-SCT.

Significance: This will be the first trial to evaluate 1) cellular therapy in the frontline setting in AML; 2) the synergy of venetoclax with adoptive NK cell therapy; and 3) Aza/Ven as a lymphodepletion strategy. The results will have significant impact on the development of cellular therapies for hematological and solid tumors.

STUDY DESIGN AND METHODS: This investigator-initiated, multicenter, open-label, phase Ib study will evaluate the combination of azacitidine, venetoclax and ex vivo-expanded, off-the-shelf cryopreserved allogeneic NK cells in patients with AML (NCT05834244).

Eligibility criteria: The dose escalation phase will enroll adults with relapsed or refractory AML or MDS/AML, and the dose expansion phase will enroll older/unfit pts with newly diagnosed adverse-risk AML. Eligible Pts will be ≥ 75 years, or ≥ 18 years with at least one protocol-defined comorbidity. Patients with favorable risk AML, poor end-organ function, needing immunosuppression, uncontrolled infection or CNS leukemia will be excluded.

Trial design: The dose escalation phase will enroll a maximum of 12 patients at 2 dose levels to establish a recommended phase 2 dose (RP2D) using a BOIN design. The dose expansion will enroll up to 20 patients at the RP2D (Fig. 1).

Study treatment: Patients will receive Aza/Ven as standard. Two dose levels of NK cells including 0.5 x109 and 1 x109 flat dose on day 8 and 15 of the first 4 cycles will be evaluated. Subsequently, pts will continue Aza/Ven indefinitely.

Objectives: The primary objective is to determine the safety of this novel triplet combination in terms of dose-limiting toxicities including acute GVHD, CRS or ICANS. Secondary objectives include overall response rate, CR/CRi by 4 cycles, rate of negative measurable residual disease, OS and relapse-free survival. Exploratory objectives include additional response and survival endpoints, the persistence of NK cells using SNP-NGS chimerism, kinetics of allorejection, remodeling of host immune microenvironment and impact on AML stem/progenitor cell hierarchies using single cell CyTOF to understand response/resistance mechanisms.

Status: Trial approved by the FDA and institutional IRB. Activation planned for 2H 2023.

Funding: Gateway for Cancer Research, MDACC PRIME Award, Chimeric Therapeutics, NCI Cancer Center Support Grant.

Disclosures: Maiti: Celgene: Research Funding; Lin BioScience: Research Funding. DiNardo: Schrödinger: Consultancy; Takeda: Honoraria; Fogham: Honoraria; Notable Labs: Honoraria; Astellas: Honoraria; Servier: Honoraria; Novartis: Honoraria; ImmuniOnc: Honoraria; AbbVie/Genentech: Honoraria; BMS: Honoraria. Ravandi: Prelude: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Xencor: Research Funding. Andreeff: PMV: Research Funding; Kintor Pharmaceutical: Research Funding. Litten: Chimeric Therapeutics: Current Employment. Bourk: Chimeric Therapeutics: Current Employment. Astrow: Chimeric Therapeutics: Current Employment. Kantarjian: Shenzhen Target Rx: Honoraria; AstraZeneca/MedImmune: Honoraria; Daiichih-Sankyo (Inst): Honoraria, Research Funding; KAHR Medical: Honoraria; Ascentage Pharma Group: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Abbvie: Consultancy, Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria; Taiho Pharmaceutical: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Amgen (Inst): Research Funding; Abbvie (Inst): Research Funding; Novartis (Inst): Research Funding. Daver: Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; FATE: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trovagene: Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; AROG: Consultancy; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Celgene: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kronos Bio: Research Funding. Wald: Chimeric Therapeutics: Research Funding.

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