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4263 Phase I/II Study of Quizartinib, Venetoclax, and Decitabine Triple Combination in FLT3-ITD Mutated AML

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, Research, Clinical trials, AML, Drug development, Clinical Research, Diseases, Treatment Considerations, Myeloid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Musa Yilmaz, MD1*, Muharrem Muftuoglu, MD2, Nicholas J. Short, MD1, Sanam Loghavi, MD3, Tapan M. Kadia, MD1, Courtney D. DiNardo, MD, MSc4, Gautam Borthakur, MD2, Naveen Pemmaraju, MD5, Yesid Alvarado Valero, MD1, Abhishek Maiti, MBBS6, Marina Konopleva7, Lucia Masarova, MD1, Guillermo Montalban-Bravo, MD1, Carissa Jurisprudencia8*, Allison Pike, RN1*, Keyur P. Patel, MBBS, PhD3, Guilin Tang, MD, PhD3*, Jairo Matthews, BA9*, Steven M. Kornblau, MD1, Elias Jabbour, MD10, Guillermo Garcia-Manero, MD1, Koichi Takahashi, MD, PhD11, Michael Andreeff, MD, PhD2, Farhad Ravandi, MBBS12, Hagop M. Kantarjian, MD8 and Naval Daver, MD13

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Bellaire, TX
6Department of Leukemia, The University of Texas Health Science Center At Houston, Houston, TX
7Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY
8The University of Texas MD Anderson Cancer Center, Houston, TX
9The University of Texas at MD Anderson Cancer center, Houston, TX
10Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
11Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
12Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
13MD Anderson Cancer Center, Houston, TX

Background: Patients (pts) newly diagnosed with FLT3-ITD mutated (m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC) experience poor outcomes with a median overall survival (OS) of 9.9 months with azacitidine+venetoclax (VEN) (Konopleva et al. 2022, Clinical Cancer Research).We aimed to evaluate the safety and efficacy of the triple combination of Quizartinib (Quiz), VEN, and decitabine (DAC) in pts with relapsed/refractory (R/R) or newly diagnosed FLT3-ITD m AML.

Aims: The primary objectives were to determine the recommended phase 2 dose (RP2D) and optimal schedule of DAC + VEN + Quiz in R/R or newly diagnosed FLT3m AML.

Methods: The study included newly diagnosed pts ineligible for IC and R/R pts who had received ≤ 6 prior treatments for AML. On cycle 1 Day 14, all pts underwent bone marrow (BM) evaluation, and VEN (400 mg/day or equivalent with azole) was discontinued on cycle 1 Day 14 for pts with BM blasts ≤ 5% (or marrow aplasia/hypocellularity). Pts with cycle 1 Day 14 BM blast >5% continued VEN for 21 days. Pts received 10 days of DAC (20 mg/m2) for induction, followed by 5-day DAC in subsequent cycles. Quiz (30 or 40 mg/day) was continuously administered daily.

Results: A total of 66 pts were enrolled, including 47 R/R and 19 newly FLT3-ITD mutated AML pts. A detailed demographic data will be reported at the time of presentation. The 47 R/R AML pts were heavily pretreated (median 3 [range 1-5] prior AML therapies), 85% (40/47) had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib, and 38% having undergone prior allogeneic stem cell transplantation (ASCT). The rates of CRc, CR+CRi, measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC, sensitivity 10-4), and FLT3-PCR (sensitivity 10-2 - 10-3) negativity among the R/R pts were 60%, 28%, 29% (8/28), and 32% (9/28), respectively). The 60-day mortality in R/R cohort was 13%. With a median follow-up of 29 months, the median OS was 6.3 months, the 1-year OS rate was 20%, and 34% (16 out of 47) underwent ASCT in R/R cohort. Among 40 prior FLT3 inhibitor exposed pts the CRc, CR+CRi, median OS and 1-year OS were 58%, 22%, 6.3 month, and 19%. Among the seven prior FLT3 inhibitor naïve pts the CRc, CR+CRi, median OS and 1-year OS were 71%, 57%, 10.3 months and 28%.

We enrolled 19 newly diagnosed AML (median age 70 years, 26% >/= 75 years), 12 with diploid cytogenetics, and 11 ELN adverse. Overall 95% (18/19) achieved CRc (12 CR, 6CRi), with 14/17 (82%) and 11/16 (69%) evaluable responders being FLT3-PCR and MFC negative, respectively. All 18 responders had achieved BM <5% or aplasia/hypocellularity on cycle 1 Day 14. The 60-day mortality was 5%. The median time to ANC>0.5, ANC>1.0, and PLT>50K after cycle 1 were 40 [range 28-56], 40 [range 28-58], and 36 [range 22-56] days. A total of 4 pts have relapsed (all 4 had secondary / therapy related AML, 2 of 4 had RAS/MAPK emergent/expanded mutations at relapse, no TKD emergence detected) and 4 pts died (2 deaths in CR, 2 deaths due to progressive leukemia). 26% (5 out of 19) frontline patients underwent ASCT. With a median follow-up of 17 months, the median OS was not reached with 1-year OS of 78%.

No pts experienced dose-limiting toxicity (DLT) with Quiz 30 mg/day; however, with Quiz 40 mg/day, the first 2 pts treated developed hematologic DLT (grade 4 neutropenia with a <5% cellular bone marrow with no residual AML lasting ≥42 days). Consequently, Quiz 30 mg/day was declared the RP2D for this combination. In the R/R cohort, grade ≥3 non-hematologic toxicities regardless of attribution, in >10% of pts, included pneumonia (73%), neutropenic fever (53%), sepsis (18%), other infections involving the skin (18%)bacteremia (15%), and gastrointestinal tract (13%), with 8% experiencing grade 3 QTcF prolongations. Grade ≥3 non-hematologic toxicities was less common in the frontline cohort, with pneumonia (40%), neutropenic fever (50%), sepsis (10%), bacteremia (20%), and no grade 3 QTcF prolongations observed.

Conclusion: The combination of DAC + VEN + Quiz demonstrated activity in heavily pretreated and prior FLT3i-exposed (including 78% with prior gilteritinib exposure) R/R FLT3-ITDm pts, with a CRc rate of 60% and a median OS of 6.3 months. In the frontline setting, 95% of pts achieved CRc with a median platelet and ANC recovery of 36 and 40 days, and a median OS not reached. The study continues to accrue, and updated results will be reported at the meeting.

Disclosures: Yilmaz: daiichi sankyo: Honoraria, Research Funding. Short: Xencor: Research Funding; Takeda Oncology: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria; Adaptive Biotechnologies: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; NextCure: Research Funding; Autolus: Honoraria; Novartis: Honoraria; Pfizer Inc.: Honoraria; GSK: Consultancy, Research Funding; Amgen: Honoraria. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Kadia: Novartis: Honoraria; Sellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; JAZZ: Research Funding; Servier: Consultancy; Incyte: Research Funding; BMS: Consultancy, Research Funding; ASTEX: Research Funding; Cellenkos: Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Pfizer: Research Funding; Rigel: Honoraria; DrenBio: Consultancy, Research Funding; Amgen: Research Funding; Regeneron: Research Funding. DiNardo: AstraZeneca: Honoraria; Riegel: Honoraria; Immunogen: Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Astex: Research Funding; Cleave: Research Funding; Foghorn: Research Funding; Jazz: Consultancy, Honoraria; Schrodinger: Consultancy, Honoraria; Gilead: Consultancy; Loxo: Research Funding; Astellas: Consultancy, Honoraria; GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Rigel: Research Funding; Amgen: Consultancy; ImmuneOnc: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Borthakur: Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Pemmaraju: Novartis: Honoraria, Research Funding; Protagonist Therapeutics: Consultancy; DAVA Oncology: Honoraria, Other: Travel Expenses; Incyte: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Other: Travel Expenses; Cellectis: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; ClearView Healthcare Partners: Consultancy; Aptitude Health: Honoraria; Plexxikon: Research Funding; Bristol-Myers Squibb: Consultancy; Pacylex: Consultancy; Samus Therapeutics: Research Funding; Triptych Health Partners: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Neopharm: Honoraria; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; LFB Biotechnologies: Honoraria; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; Immunogen: Consultancy; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Maiti: Lin Biosciences: Research Funding; CytoMed Therapeutics: Research Funding; Inspirna: Research Funding; Indapta Therapeutics: Research Funding; Chimeric Therapeutics: Research Funding; Hibercell Inc.: Research Funding. Konopleva: Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Other: clinical trials; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; Vincerx: Consultancy; Intellisphere: Speakers Bureau; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy; Curis: Consultancy; Servier: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Klondike Biopharma: Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees. Masarova: GSK: Consultancy, Other: Travel support; MorphoSys: Other: Advisory Board Participant; Cogent: Other: Advisory Board Participant; PharmaEssentia: Other: Advisory Board Participant. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Garcia-Manero: Janssen: Research Funding; Helsinn: Research Funding; Aprea: Research Funding; Forty Seven: Research Funding; Curis: Research Funding; Astex: Other: Personal fees; Genentech: Research Funding; Amphivena: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Onconova: Research Funding; Astex: Research Funding; Helsinn: Other: Personal fees; Genentech: Other: Personal fees; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Novartis: Research Funding. Andreeff: Boehringer-Ingelheim: Honoraria; Sellas: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Syndax: Honoraria, Research Funding; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Oxford Biomedical: Research Funding; Chimerix: Current holder of stock options in a privately-held company; Oncolyze: Current holder of stock options in a privately-held company; Ellipses: Research Funding; Glycomimetics: Honoraria; Aptose: Honoraria; Ona: Honoraria; Kintor Pharmaceutical: Research Funding; Paraza: Honoraria; Roivant: Honoraria. Ravandi: Amgen: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Syndax: Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Daver: Syndax: Consultancy; Celgene: Consultancy; Jazz: Consultancy; Agios: Consultancy; KITE: Research Funding; Astellas: Consultancy, Research Funding; Shattuck Labs: Consultancy; Pfizer: Consultancy, Research Funding; Arog: Consultancy; Gilead: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Menarini Group: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding.

*signifies non-member of ASH