FDA Places Partial Clinical Hold on Phase 1 Trial Evaluating FHD-286 in Relapsed/Refractory AML and MDS

US FDA

The FDA has placed a partial clinical hold on a phase 1 trial (NCT04891757) investigating FHD-286 as a treatment for patients with relapsed and/or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).¹

The partial hold was initiated following the report of a recent death of a patient who had potential differentiation syndrome. Differentiation syndrome is linked to AML/MDS therapeutics that induce differentiation, which is an effect that is believed to be on-target for the proposed mechanism of action for FHD-286.

The FDA will review the safety database, risk mitigation strategies and a breakdown of clinical activity across dose levels observed in the trial.

Currently enrolled patients who have demonstrated a benefit from FHD-286 will be permitted to continue treatment, although no new patients will be enrolled until the partial hold is lifted.

“Patient safety remains our top priority. We appreciate the dialogue with the FDA and will work diligently with the agency to resolve the partial clinical hold in AML/MDS 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.

The phase 1, multicenter, open-label, dose-escalation study is evaluating FHD-286 in patients at least 18 years of age with hematologic malignancies, specifically relapsed or refractory AML and MDS. Patients with AML included those who relapsed after transplantation; relapsed 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 previously failed all prior therapies known to be active for treatment of their diagnosed hematologic disease. Patients with MDS must have previously failed treatment with at least 4 cycles of a hypomethylating agent.2

Other key inclusion criteria for all patients included an ECOG performance status of 2 or lower, a life expectancy of at least 3 months, an adequate platelet level, and adequate hepatic, renal, cardiovascular, respiratory, and immune system function. Key exclusion criteria included hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of FHD-286, the use of immunosuppressive therapy following HSCT at the time of screening, the presence of graft-vs-host disease, clinical symptoms suggesting active central nervous system leukemia, the presence of immediate, life-threatening complications of leukemia, and the presence of another malignancy that could interfere with the diagnosis or treatment of advanced hematologic malignancies.

Between approximately 25 and 50 patients were expected to be enrolled in the dose-escalation arm of the trial to receive varying doses of oral FHD-286 to establish the recommended phase 2 dose.

The co-primary end points of the trial are 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.

Secondary end points for the AML cohort include 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). Secondary end points for the MDS cohort are 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. Additionally, pharmacokinetics and plasma concentrations of FHD-286 are secondary end points for all patients.

Due to the partial hold, Foghorn Therapeutics has suspended guidance on the timing of the release of data from the phase 1 trial.

FHD-286 is also being evaluated in another phase 1 trial (NCT04879017) in patients with metastatic uveal melanoma. The partial clinical hold does not apply to that trial, which will continue to enroll patients, per protocol.

References

1. 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 May 20, 2022. https://bit.ly/3MGKhlO
2. FHD-286 in subjects with advanced hematologic malignancies. ClinicalTrials.gov. Updated February 23, 2022. Accessed May 20, 2022. https://clinicaltrials.gov/ct2/show/NCT04891757