FDA Place Clinical Hold on Phase 1 Trial Examining FHD-286 in Relapsed/Refractory AML and MDS

The FDA has placed a full clinical hold on a phase 1 dose escalation trial investigating the BRG1/BRM inhibitor FHD-286 in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

The FDA has placed a full clinical hold on a phase 1 dose escalation trial (NCT04891757) investigating the BRG1/BRM inhibitor FHD-286 in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), according to an announcement from Foghorn Therapeutics.1

The move comes after the observation of additional suspected cases of fatal differentiation syndrome believed to be associated with FHD-286. Differentiation syndrome is linked to AML/MDS therapeutics that induce differentiation, an effect that is believed to be on-target for the proposed mechanism of action for FHD-286.

The observations about additional suspected cases of differentiation syndrome were submitted in a response to the FDA after the regulatory agency placed a partial clinical hold on the trial in May 2022 due to the report of a death potentially due to differentiation syndrome.2

The agency will conduct further analyses before the full clinical hold may be lifted. Notably, a phase 1 dose escalation trial (NCT04879017) evaluating FHD-286 in patients with metastatic uveal melanoma continues to enroll per protocol.

“We are committed to patient safety and will work with the FDA to address the agency’s questions and provide further analyses to resolve the clinical hold as soon as possible,” Adrian Gottschalk, chief executive officer of Foghorn Therapeutics, stated in a press release.

FHD-286 is a highly potent, selective, allosteric, and orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM. Preclinical studies demonstrated that FHD-286 elicited antitumor activity across a broad range of malignancies, including both hematologic and solid tumors.

Investigators are evaluating the agent in the phase 1 trial involving patients who are at least 18 years old with hematologic malignancies, specifically relapsed/refractory AML and MDS. Eligible patients include those with AML who relapsed after transplantation; who relapsed in the second line or later; were refractory to initial induction or reinduction treatment; or who relapsed within 1 year of initial treatment. All patients with AML were required to have failed all prior therapies known to be active for their disease, and patients with MDS were required to have failed treatment with at least 4 cycles of a hypomethylating agent.3

Enrolled patients with AML or MDS needed to have a life expectancy of at least 3 months, an ECOG performance status of 2 or less, an adequate platelet count, and adequate renal, cardiovascular, respiratory, and immune system function.

Patients were excluded from the trial if they underwent a hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of FHD-286, required the use of immunosuppressive therapy following HSCT at the time of screening, had graft-vs-host disease, had clinical symptoms suggesting active central nervous system leukemia, had immediate, life-threatening complications of leukemia, or had another malignancy that could interfere with the diagnosis or treatment of advanced hematologic malignancies.

The dose-escalation portion of the trial is evaluating varying doses of FHD-286 in approximately 25 to 50 patients to determine the recommended phase 2 dose.

The primary objectives of the trial include the incidence of treatment-emergent adverse effects (AEs) for up to 18 months; the incidence of AEs, serious AEs, and AEs leading to discontinuation for up to 18 months; and incidence of dose-limiting toxicities during cycle 1 of treatment.

In the cohort of patients with AML, secondary end points consisted of complete remission (CR) rate, duration of CR, CR plus CR with partial hematologic recovery (CRh) rate, duration of CR plus CRh, transfusion independence rate, event-free survival (EFS), and overall survival (OS). In the MDS cohort, CR rate, duration of CR, partial remission (PR) rate, duration of PR, CR plus PR rate, duration of CR plus PR, hematologic improvement rate, EFS, and OS serve as secondary end points.


  1. Foghorn Therapeutics provides further update on FHD-286 phase I study in relapsed/refractory AML/MDS. News release. Foghorn Therapeutics. August 23, 2022. Accessed August 23, 2022. https://bit.ly/3QJtlNf
  2. Foghorn Therapeutics provides update on phase 1 study of FHD-286 in relapsed and/or refractory AML and MDS. News release. Foghorn Therapeutics. May 19, 2022. Accessed August 23, 2022. https://bit.ly/3MGKhlO
  3. FHD-286 in subjects with advanced hematologic malignancies. ClinicalTrials.gov. Updated May 24, 2022. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04891757