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2910 A Phase I/II Study of Combination of ASTX727, Gilteritinib and Venetoclax in Patients with Relapsed/Refractory FLT3­ Mutated Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, adult, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Robert Briski, MD*, Nicholas J. Short, MD, Naval Daver, MD, Tapan M. Kadia, MD, Courtney D. DiNardo, MD, MSc, Musa Yilmaz, MD*, Yesid Alvarado Valero, MD, Kenneth Vaughan*, Sherry Pierce, BSN, BA*, Kathryn Montalbano*, Jillian Mullin, BA, RN, MN*, Hagop M. Kantarjian, MD, Guillermo Garcia-Manero, MD and Farhad Ravandi, MD, MBBS

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX


Activating mutations in FLT3 occur in approximately 30% of patients (pts) with AML. Gilteritinib (GILT), a second-generation type I oral FLT3 inhibitor, has been approved in pts with relapsed/refractory (R/R) FLT3-mutated AML. We conducted a phase I/II study to evaluate the combination of decitabine/cedazuridine (ASTX727), venetoclax (VEN), and GILT in pts with FLT3-mutated R/R AML or intermediate-2/high risk MDS/CMML.


This phase I/II study included pts with 1) R/R FLT3­-mutated AML or R/R intermediate-2/high risk MDS/CMML or 2) newly diagnosed FLT3-mutated AML unfit for intensive chemotherapy (eligible for phase II only). Here we report the initial data from the R/R cohort. In the phase I portion there was no restriction to the number of prior therapies received; however, in the phase II portion pts who had received ≥3 prior therapies were excluded. Pts with FLT3-ITD and/or TKD mutations were eligible. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1 (C1), pts received decitabine/cedazuridine (35mg/100mg) orally on days 1-5, VEN (ramp-up to 400mg with adjustment for concomitant azole) orally on days 1-28, and GILT orally continuously. The GILT dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). A bone marrow biopsy was performed on day 14, and if blasts were <5% or the marrow was insufficient/aplastic, the VEN was held. For C2 and beyond, ASTX727 was given for 5 days, VEN was given for 14-21 days and GILT was given continuously. The primary endpoint for the phase I was the MTD; and for the phase II, the overall response (defined as CR, CRh, CRi, or MLFS within 2 cycles of therapy).


The phase I portion is complete with 12 pts enrolled (11 AML, and 1 high-risk CMML). Nine pts received GILT 80mg and 3 received 120mg. No DLTs at either dose level were observed. However, 80mg of GILT was selected for the phase II portion of this study based on the more favorable safety/efficacy profile and better count recovery observed in a parallel study of azacitidine combined with VEN and GILT in AML.

In the combined phase I/II cohort of pts with R/R AML or MDS/CMML, 15 pts have been treated. The median age was 65 years (range 38-83 years). Thirteen pts had a FLT3-ITD mutation (including 2 with a concomitant TKD mutation), and 1 pt had a FLT3-TKD mutation alone. Among pts with a FLT3-ITD, the median allelic ratio was 0.21 (range, 0.09 – 10.6). Among pts with a FLT3-TKD, the median allelic ratio was 0.05 (range, 0.02-0.09). Nine pts had diploid karyotype, 2 had adverse risk karyotype, and 4 had miscellaneous, intermediate-risk cytogenetic findings. The median number of prior therapies was 1 (range 1-9).

Among the 15 pts treated, 8 (53%) responded: 1 (6%) with CRh, 3 (20%) with CRi, and 4 (27%) with MLFS. The pt with an isolated FLT3-TKD mutation (along with del7q) did not respond. The pt with high-risk CMML achieved a CRi. Six of 12 pts who received prior HMA + VEN responded (2 CRi and 4 MLFS), and 2 of 3 pts without prior HMA + VEN responded (1 CRh and 1 CRi).

The median number of cycles received by pts was 2 (range 1-8). Best response was achieved by the end of C1 in 50% of responders, and by the end of C2 in the other 50% of responders. Of the 8 responders, 1 proceeded to alloSCT (with flow positive MRD at 0.3% but FLT3 negative by PCR), 1 is still receiving treatment on protocol with continued response, 5 relapsed without HSCT (median time to relapse 2 months [range, 0.5-7 months]), and 1 died in MLFS. The transplanted pt remains in MRD-negative remission 5 months after alloSCT and is receiving maintenance GILT off protocol. With a median follow-up of 3.8 months (range, 1-18 months), the median overall survival for the cohort was 6.1 months.

There were 3 pts with grade 1-2 toxicities (1 with elevated liver enzymes, 2 with skin rash), 9 pts with grade 3 toxicities (9 with neutropenic fever, 4 of which became septic), no pts with grade 4 toxicities, and 2 patients with grade 5 toxicities (both had neutropenia and died from sepsis while on trial).


In this poor-risk population of pts with R/R FLT3-mutated AML or MDS/CMML, many of whom received prior HMA + VEN, the combination of ASTX727, VEN, and GILT was active, with an ORR of 53%. The trial continues to enroll to the R/R cohort, and is now open for patients with newly diagnosed FLT3-mutated AML who are unsuitable for intensive chemotherapy.

Disclosures: Short: Amgen: Honoraria; Stemline therapeutics: Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy. Daver: Gilead: Consultancy, Research Funding; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; AROG: Consultancy; Trillium: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Trovagene: Research Funding; Jazz: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Hanmi: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; FATE: Research Funding; Glycomimetics: Research Funding; Kronos Bio: Research Funding. Kadia: Janssen Research and Development: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Novartis: Consultancy; Hikma Pharmaceuticals: Speakers Bureau; Cellenkos Inc.: Research Funding; Genzyme: Honoraria; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Liberum: Consultancy; Astex: Honoraria; Iterion: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Agios: Consultancy; Astellas Pharma Global Development: Research Funding; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Glycomimetics: Research Funding; Amgen, Inc.: Research Funding; Ascentage Pharma Group: Research Funding; Cure: Speakers Bureau; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Cyclacel: Research Funding; Genentech: Consultancy, Research Funding; GenFleet Therapeutics: Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding. DiNardo: AbbVie/Genentech: Honoraria; Servier: Honoraria; Novartis: Honoraria; ImmuniOnc: Honoraria; Takeda: Honoraria; Fogham: Honoraria; Notable Labs: Honoraria; Schrödinger: Consultancy; BMS: Honoraria; Astellas: Honoraria. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Alvarado Valero: CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; Jazz: Research Funding. Kantarjian: Shenzhen Target Rx: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Labcorp: Honoraria, Research Funding; KAHR medical: Honoraria, Research Funding; Ipsen Biopharmaceuticals: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biologix: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Ascentage: Honoraria, Research Funding; Amphista: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Stemline: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Ravandi: Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Xencor: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH