FHD-286 With Low-Dose Weekly Decitabine/Venetoclax in Patients With Acute Myeloid Leukemia

Summary

This is a Phase 1, uncontrolled, single-arm, open-label, nonrandomized, dose escalation, study of Decitabine (DAC)+Venetoclax (VEN)+FHD-286 in participants with newly diagnosed Acute Myeloid Leukemia (AML) classified as adverse risk per the 2022 European Leukemia Net (ELN) criteria or AML that has progressed after one prior line of therapy.

Timeline

Start

2026-02-03

Primary completion

2028-05

Completion

2030-02

Publications

• Background Dohner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Rollig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, Lowenberg B. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345-1377. doi: 10.1182/blood.2022016867.
• Background DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971.
• Background Aldoss I, Yang D, Aribi A, Ali H, Sandhu K, Al Malki MM, Mei M, Salhotra A, Khaled S, Nakamura R, Snyder D, O'Donnell M, Stein AS, Forman SJ, Marcucci G, Pullarkat V. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018 Sep;103(9):e404-e407. doi: 10.3324/haematol.2018.188094. Epub 2018 Mar 15. No abstract available.
• Background Pratz KW, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Dohner H, Recher C, Fiedler W, Yamamoto K, Wang J, Yoon SS, Wolach O, Yeh SP, Leber B, Esteve J, Mayer J, Porkka K, Illes A, Lemoli RM, Turgut M, Ku G, Miller C, Zhou Y, Zhang M, Chyla B, Potluri J, DiNardo CD. Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024 Apr;99(4):615-624. doi: 10.1002/ajh.27246. Epub 2024 Feb 11.
• Background Goldfinger M, Mantzaris I, Shastri A, Saunthararajah Y, Gritsman K, Sica RA, Kornblum N, Shah N, Levitz D, Rockwell B, Shapiro LC, Gupta R, Pradhan K, Xue X, Munoz A, Dhawan A, Fehn K, Comas M, Verceles JA, Jonas BA, Kambhampati S, Shi Y, Braunschweig I, Cooper DL, Konopleva M, Feldman EJ, Verma A. A weekly low-dose regimen of decitabine and venetoclax is efficacious and less myelotoxic in a racially diverse cohort. Blood. 2024 Nov 28;144(22):2360-2363. doi: 10.1182/blood.2024025834.
• Background Velcheti V, Schrump D, Saunthararajah Y. Ultimate Precision: Targeting Cancer but Not Normal Self-replication. Am Soc Clin Oncol Educ Book. 2018 May 23;38:950-963. doi: 10.1200/EDBK_199753.
• Background Saunthararajah Y, Sekeres M, Advani A, Mahfouz R, Durkin L, Radivoyevitch T, Englehaupt R, Juersivich J, Cooper K, Husseinzadeh H, Przychodzen B, Rump M, Hobson S, Earl M, Sobecks R, Dean R, Reu F, Tiu R, Hamilton B, Copelan E, Lichtin A, Hsi E, Kalaycio M, Maciejewski J. Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes. J Clin Invest. 2015 Mar 2;125(3):1043-55. doi: 10.1172/JCI78789. Epub 2015 Jan 26.
• Background Awada H, Mahfouz RZ, Kishtagari A, Kuzmanovic T, Durrani J, Kerr CM, Patel BJ, Visconte V, Radivoyevitch T, Lichtin A, Carraway HE, Maciejewski JP, Saunthararajah Y. Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies. Br J Haematol. 2020 Mar;188(6):924-929. doi: 10.1111/bjh.16281. Epub 2019 Nov 17.
• Background Gu X, Tohme R, Tomlinson B, Sakre N, Hasipek M, Durkin L, Schuerger C, Grabowski D, Zidan AM, Radivoyevitch T, Hong C, Carraway H, Hamilton B, Sobecks R, Patel B, Jha BK, Hsi ED, Maciejewski J, Saunthararajah Y. Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network. Leukemia. 2021 Apr;35(4):1023-1036. doi: 10.1038/s41375-020-1003-x. Epub 2020 Aug 7.
• Background Zavras PD, Shastri A, Goldfinger M, Verma AK, Saunthararajah Y. Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions. Clin Cancer Res. 2021 Dec 15;27(24):6653-6661. doi: 10.1158/1078-0432.CCR-21-2139. Epub 2021 Sep 22.
• Background DiNardo CD, Fathi AT, Kishtagari A, Bhalla KN, Quintas-Cardama A, Reilly SA, Almon C, Patriquin C, Nabhan S, Healy K, Hickman D, Collins MP, Khalil A, Corrigan D, Zhao T, Piel J, Lyons K, Horrigan K, Schuck V, Martin P, Elliott G, Lahr DL, Bosinger M, D'Aco K, Smolen GA, Hentemann M, Loghavi S, Agresta S, Savona MR, Stein EM. A Phase I Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients with Advanced Myeloid Malignancies. Clin Cancer Res. 2025 Jun 13;31(12):2327-2338. doi: 10.1158/1078-0432.CCR-24-3790.
• Background Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019 Dec;33(12):2795-2804. doi: 10.1038/s41375-019-0612-8. Epub 2019 Oct 18.
• Background Winters AC, Gutman JA, Purev E, Nakic M, Tobin J, Chase S, Kaiser J, Lyle L, Boggs C, Halsema K, Schowinsky JT, Rosser J, Ewalt MD, Siegele B, Rana V, Schuster S, Abbott D, Stevens BM, Jordan CT, Smith C, Pollyea DA. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019 Oct 22;3(20):2911-2919. doi: 10.1182/bloodadvances.2019000243.
• Background Abaza Y, Winer ES, Murthy GSG, Shallis RM, Matthews AH, Badar T, Geramita EM, Kota VK, Swaroop A, Doukas P, Bradshaw D, Helenowski IB, Liu Y, Zhang H, Im A, Litzow MR, Perl AE, Atallah E, Altman JK. Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers. Am J Hematol. 2024 Apr;99(4):606-614. doi: 10.1002/ajh.27231. Epub 2024 Feb 11.
• Background Brandwein J, Page D, Liew E, Hnatiuk M, Bolster L, Hamilton M, Sawler D, Wang P. A Real-World Evaluation of Frontline Treatment for Acute Myeloid Leukemia With Azacitidine Plus Venetoclax. Clin Lymphoma Myeloma Leuk. 2025 Jul;25(7):e435-e442. doi: 10.1016/j.clml.2025.01.024. Epub 2025 Feb 1.
• Background Short NJ, Daver N, Dinardo CD, Kadia T, Nasr LF, Macaron W, Yilmaz M, Borthakur G, Montalban-Bravo G, Garcia-Manero G, Issa GC, Chien KS, Jabbour E, Nasnas C, Huang X, Qiao W, Matthews J, Stojanik CJ, Patel KP, Abramova R, Thankachan J, Konopleva M, Kantarjian H, Ravandi F. Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML. J Clin Oncol. 2024 May 1;42(13):1499-1508. doi: 10.1200/JCO.23.01911. Epub 2024 Jan 26.
• Background DiNardo CD, Marvin-Peek J, Loghavi S, Takahashi K, Issa GC, Jen WY, Daver NG, Reville PK, Short NJ, Sasaki K, Mullin JK, Bradley CA, Borthakur G, Maiti A, Alvarado Y, Pemmaraju N, Abbas HA, Hammond DE, Haddad F, Bravo GM, Chien KS, Yilmaz M, Kornblau SM, Jabbour E, Ravandi F, Kadia T, Garcia-Manero G, Konopleva MY, Kantarjian HM. Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML. J Clin Oncol. 2025 Aug 20;43(24):2692-2699. doi: 10.1200/JCO-25-00640. Epub 2025 Jun 13.
• Background Fiskus W, Piel J, Collins M, Hentemann M, Cuglievan B, Mill CP, Birdwell CE, Das K, Davis JA, Hou H, Jain A, Malovannaya A, Kadia TM, Daver N, Sasaki K, Takahashi K, Hammond D, Reville PK, Wang J, Loghavi S, Sen R, Ruan X, Su X, Flores LB, DiNardo CD, Bhalla KN. BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor. Blood. 2024 May 16;143(20):2059-2072. doi: 10.1182/blood.2023022832.
• Background DiNardo CD, Roboz GJ, Watts JM, Madanat YF, Prince GT, Baratam P, de Botton S, Stein A, Foran JM, Arellano ML, Sallman DA, Hossain M, Marchione DM, Bai X, Patel PA, Kapsalis SM, Garcia-Manero G, Fathi AT. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024 Aug 13;8(15):4209-4220. doi: 10.1182/bloodadvances.2023012302.
• Background Lee SH, Erber WN, Porwit A, Tomonaga M, Peterson LC; International Council for Standardization In Hematology. ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol. 2008 Oct;30(5):349-64. doi: 10.1111/j.1751-553X.2008.01100.x.
• Background Norsworthy KJ, Mulkey F, Scott EC, Ward AF, Przepiorka D, Charlab R, Dorff SE, Deisseroth A, Kazandjian D, Sridhara R, Beaver JA, Farrell AT, de Claro RA, Pazdur R. Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration Systematic Analysis. Clin Cancer Res. 2020 Aug 15;26(16):4280-4288. doi: 10.1158/1078-0432.CCR-20-0834. Epub 2020 May 11.
• Background Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J, Leon A, Esteve J, Milone G, Deben G, Rivas C, Gonzalez M, Tormo M, Diaz-Mediavilla J, Gonzalez JD, Negri S, Amutio E, Brunet S, Lowenberg B, Sanz MA. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009 Jan 22;113(4):775-83. doi: 10.1182/blood-2008-07-168617. Epub 2008 Oct 22.
• Background Stahl M, Tallman MS. Differentiation syndrome in acute promyelocytic leukaemia. Br J Haematol. 2019 Oct;187(2):157-162. doi: 10.1111/bjh.16151. Epub 2019 Aug 13.
• Background Gu X, Tohme R, Goldfinger M, et al: Venetoclax inhibition of pyrimidine synthesis guides methods for integration with decitabine or 5-azacytidine that are non-myelosuppressive. Presented at the 62nd ASH Annual Meeting and Exposition, Virtual, 05-08 Dec, 2020
• Background Dinardo CD, Kishtagari A, Ball B, et al: Preliminary safety, pharmacokinetic, and clinical activity results with FHD-286, a BRG1/BRM inhibitor, plus decitabine in a Phase 1 study in patients with relapsed or refractory myeloid malignancies. Presented at the EHA2025 Congress, Milan, Italy, 12-15 Jun, 2025
• Background Fiskus W, Piel J, Hentemann M, et al: Pre-clinical efficacy of targeting BAF complexes through inhibition of the dual ATPases BRG1 and BRM by FHD-286 in cellular models of AML of diverse genetic background. Presented at the American Society of Hematology (ASH) Annual Meeting & Exposition, New Orleans, Louisiana, 10-13 December, 2022
• Background Ueda M, El-Jurdi N, Cooper B, Caimi P, Baer L, Kolk M, Brister L, Wald DN, Otegbeye F, Lazarus HM, Sandmaier BM, William B, Saunthararajah Y, Woost P, Jacobberger JW, de Lima M. Low-Dose Azacitidine with DNMT1 Level Monitoring to Treat Post-Transplantation Acute Myelogenous Leukemia or Myelodysplastic Syndrome Relapse. Biol Blood Marrow Transplant. 2019 Jun;25(6):1122-1127. doi: 10.1016/j.bbmt.2018.12.764. Epub 2018 Dec 30.

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