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61 Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Relapsed/Refractory AML
Hematology Disease Topics & Pathways:
Biological therapies, Antibody Therapy, clinical trials, Research, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, drug development, Diseases, Immunotherapy, Therapies, Monoclonal Antibody Therapy, Myeloid Malignancies
Saturday, December 10, 2022: 9:30 AM

Naval Daver, MD1, Jayastu Senapati, MD, MBBS, DM1*, Abhishek Maiti, MBBS2, Sanam Loghavi, MD3, Tapan M. Kadia, MD4, Courtney D. DiNardo, MD, MSCE1, Naveen Pemmaraju, MD1, Elias Jabbour, MD1, Guillermo Montalban-Bravo, MD1, Guilin Tang, MD, PhD3*, Koji Sasaki, MD1, Gautam Borthakur, MD1, Musa Yilmaz, MD4, Joie Alvarez, BSN1*, Sherry A. Pierce, BSN, BA1*, Graciela M. Nogueras González, MPH5*, Jing Ning6*, Ghayas C. Issa, MD7,8, Michael Andreeff, MD, PhD1, Hussein A Abbas, MD, PhD1, Farhad Ravandi, MD1, Guillermo Garcia-Manero, MD9 and Hagop Kantarjian, MD10

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas Health Science Center At Houston, Houston, TX
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
6department of biostatics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX
7Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
8Department of Leukemia, Universit Y of Texas At Houston, Houston, TX
9Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
10Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction:

Despite frontline response rates of 65-70% with AZA-VEN a majority of pts relapse, with only 35-40% alive at 3+ years and pts with TP53 mutation (TP53mut) have continued poor outcomes with median overall survival (mOS) of 5-6 months (m) (Kim K et al, Cancer 2021, Pollyea D et al ASH 2021). R/R AML have mOS of around 6 m with HMA-VEN. Magro, an anti-CD47 antibody that blocks the “don’t eat me signal” on leukemia cells, demonstrated efficacy with AZA in ND TP53wt (ORR: 63%, mOS 18.9 m) and TP53mut AML (ORR 49%, CR 33%, mOS 10.8m) (Daver N, EHA 2022). Magro with AZA-VEN increased phagocytosis in AML cell lines in vitro, and prolonged survival in vivo in AML PDXs regardless of TP53 mut status (Jia Y et al, ASH 2021). We designed a phase Ib/II clinical trial to evaluate this triplet combination therapy (NCT04435691).

Methods: Pts ³18 years with ECOG PS ≤2, WBC <15x109/L and adequate organ function were eligible. The initial phase Ib enrolled R/R AML pts only. Once the RP2D was established the Phase II allowed both frontline and R/R pts. The frontline cohort enrolled pts ≥75yrs, or pts with documented comorbidities conferring ineligibility for intensive therapy; or pts with adverse risk karyotype (defined by ELN 2017 criteria) and/or TP53mut regardless of age/fitness.

Pts received AZA 75 mg/m2 on D1-7, VEN 400 mg (or equivalent per VEN label) on D1-28. The Magro RP2D dose was established as 1 mg/kg on C1D1 and C1D4, 15 mg/kg on C1D8, and 30 mg/kg on C1D11, C1D15, C1D22, weekly in cycle 2, and every 2 weeks in cycle 3+..

Primary study objectives were safety and RP2D of the triplet. Secondary objectives included CR/CRi rate, DOR and OS. Responses were per ELN2017 criteria.

Results:

From Aug 2020 to data cut off on June 1 2022, 74 pts were enrolled of whom 41 pts had ND AML (32 de novo or therapy related, 9 untreated secondary). An additional 4 pts had prior HMA treated, secondary ND AML. 29 pts had R/R disease (12 prior VEN naïve and 17 prior VEN exposed). Table 1 shows the baseline characteristics and responses in the ND AML pts based on their TP53 mutation status. Majority of the ND pts had high risk disease: 38/41 (93%) pts had adverse risk per ELN 2017, including adverse cytogenetics in 29/41 (71%) pts and therapy related AML in 15/41 (37%) pts. All pts who received at least one dose of any study drug were included for response and adverse events (AEs).

In the ND cohort, 33/41 pts (80%) had an overall response, including in 27 TP53mut (ORR 74%, CR/CRi 63%, CR 41%) and 14 TP53wt pts (ORR 93%, CR/CRi 86%, CR 57%).With a median (med) follow up (F/U) of 9.2 m for the frontline non-secondary ND group (n=32), the mOS was not reached (NR) for both TP53mut and TP53wt pts (1 year OS: 53% and 83%, resp, Fig. 1) with med DOR 7.4 m and NR, resp. In the ND untreated secondary AML pts, with a med F/U of 17.5 mo, the med DOR and OS were 6.5 and 7.2 m respectively. 8/27 (30%) TP53mut and 4/14 (29%) TP53wt proceeded to allogeneic stem cell transplantation (ASCT) in remission.

In the R/R cohort, only 2/17 (12%) pts with prior VEN exposure had a response (both CRi) with DOR 3.6 and 2.5m and mOS of 3.1 m. This cohort has been closed for futility. 8/12 (75%) VEN-naïve pts responded (6 CR, 1 CRi and MLFS each) with a med DOR and med OS of 5.1 and 7.4 m respectively with med F/U 14 mo. 4/12 (33%) VEN-naïve R/R pts could proceed directly to a ASCT, with a mOS of 10 m in transplanted pts.

The 4- and 8-weeks mortality across the whole cohort was 0% and 7% respectively (all in the R/R pts with no 8-wk mortality in ND pts). Eighteen pts (24%) had a ≥ grade 3 anemia while on study. With pre-Magro dosing Hb cut-off at 8.5 g/dL there were no anemia related life-threatening events or deaths. The med drop in Hb post first infusion of Magro in the N/D cohort (n=41) was 1.2 g/dl (range, 0 - 3.9 g/dl). Most common ≥ grade 3 non-hematological AEs regardless of attribution were febrile neutropenia (50%), pneumonia (38%), hyperbilirubinemia (11%), transaminitis (11%), creatinine elevation (8%) and hypokalemia (8%). No immune related AEs were documented.

Conclusion:

The triplet combination of AZA VEN Magro appears safe with encouraging CR rates in a cohort of ND pts with 93% adverse risk ELN and 71% with adverse cytogenetic features. Responses in R/R AML were modest with prior VEN exposed pts faring poorly. Further trial enrollment and correlative analysis is underway and a phase III placebo controlled, randomized, international study to evaluate this triplet in ND AML has been initiated (ENHANCE-3, NCT05079230).

Disclosures: Daver: Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Loghavi: Astellas: Research Funding; PeerView: Honoraria; Amgen: Research Funding; QualWorld: Consultancy; GLG: Consultancy; Abbvie: Consultancy, Current equity holder in publicly-traded company; Guidepoint: Consultancy; Caris: Consultancy; BluePrint Medicine: Consultancy; Daiichi Sankyo: Consultancy. Kadia: Iterion: Research Funding; cyclacel: Research Funding; Delta-Fly: Research Funding; Astellas: Research Funding; AstraZeneca: Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Amgen: Research Funding; Genfleet: Research Funding; Servier: Consultancy; cellenkos: Research Funding; Ascentage: Research Funding; Astex: Honoraria; Glycomimetics: Research Funding; PinotBio: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Novartis: Consultancy; JAZZ: Consultancy, Research Funding; Regeneron: Research Funding. DiNardo: Jazz: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Forma: Research Funding; Cleave: Research Funding; Astex: Research Funding; Takeda: Honoraria; Novartis: Honoraria; LOXO: Research Funding; ImmuneOnc: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Roche Diagnostics: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Jabbour: Pfizer: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Amgen: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding. Sasaki: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Borthakur: Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Issa: Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Andreeff: AstraZeneca: Research Funding; German Research Council: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Current holder of stock options in a privately-held company; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Chimerix: Current holder of stock options in a privately-held company; Glycomimetics: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; NCI: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical UK: Research Funding; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Pinot Bio: Research Funding; Brooklyn ITX: Research Funding; Senti Bio: Consultancy, Research Funding; Kintor Pharmaceutical: Research Funding; Reata: Current holder of stock options in a privately-held company; Syndax: Consultancy, Research Funding. Ravandi: Amgen: Honoraria, Research Funding; AstraZeneca: Consultancy; Xencor: Research Funding; Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding. Garcia-Manero: Curis: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Aprea: Honoraria; Gilead Sciences: Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy. Kantarjian: AbbVie: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; ImmunoGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria.

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*signifies non-member of ASH