FDA Places Full Clinical Hold on Study of FHD-286 in R/R AML and MDS

Due to suspected cases of fatal differentiation syndrome in a clinical trial, the FDA has placed a full clinical hold on the study of FHD-286 in acute myeloid leukemia and myelodysplastic syndrome.

The FDA has placed a full clinical hold on the phase 1 study of FHD-286, an inhibitor of BRG1/BRM, in relapsed and/or refractory acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).1

The full clinical hold was placed as result of additional suspected cases of fatal differentiation syndrome which were believed to be associated with FHD-286. Additional questions as well as further analyses are needed by the FDA before the clinical hold may be lifted.

However, the dose-escalation, phase 1 study of FHD-286 (NCT04891757), in patients with metastatic uveal melanoma (mUM) continues per protocol (NCT04879017). As the full clinical hold does not apply to this trial, it may continue to enroll patients and data are expected in the first half of 2023.

“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,” said Adrian Gottschalk, chief executive officer of Foghorn Therapeutics Inc, in the press release.

FHD-286 is a highly potent, selective, allosteric, orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM. Preclinical studies have shown FHD-286 to demonstrate anti-tumor activity across various malignancies, including hematologic and solid tumors.2

The multicenter, open-label, dose-escalation, phase 1 study looked to examine the safety and tolerability of FHD-286 in patients with relapsed/refractory AML and MDS.2 Patients enrolled in the dose-escalation arm of the trial received varying doses of FHD-286 orally in order to determine the recommended phase 2 dose.

Enrollment was open to approximately 25 to 50 patients who were aged 18 years or older with hematologic malignancies. Inclusion was open to those with AML who relapsed after transplantation or in the second-line or later, were refractory to initial induction or reinduction treatment, or relapsed within 1 year of initial treatment. All patients with AML must have failed prior therapies that were active for treatment of their diagnosis.

Additionally, enrolled patients with MDS must have previously failed treatment with at least 4 cycles of a hypomethylating agent. Patients must also have had an ECOG performance status of 2 or lower, a life expectancy of 3 months or more, and adequate platelet level, hepatic, renal, cardiovascular, respiratory, and immune system function.

Primary end points of the trial were the incidence of treatment-emergent adverse events (AEs), the incidence of AEs, serious AEs, AEs leading to discontinuation for up to 18 months, and the incidence of dose-limiting toxicities within cycle 1 of treatment. Secondary end points included pharmacokinetics and plasma concentrations of FHD-286 for both the AML and MDS cohorts.

Secondary end points for the AML cohort also 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).

For the MDS cohort, secondary end points were 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.

Foghorn Therapeutics provides further update on FHD-286 phase I study in relapsed/refractory AML/MDS. News release. Foghorn Therapeutics, Inc. August 23, 2022. Accessed August 24, 2022.
FHD-286 in subjects with advanced hematologic malignancies. ClinicalTrials.gov. Updated May 24, 2022. Accessed August 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04891757

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