A partial clinical hold has been placed by the FDA on a phase 1 trial examining the use of FHD-286 as treatment for patients with relapsed and/or refractory acute myeloid leukemia and myelodysplastic syndrome.
The FDA has placed a partial clinical hold on a phase 1 trial (NCT04891757) examining the use of FHD-286 as treatment for patients with relapsed and/or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).1
The basis of the partial hold follows the recent report regarding the death of a patient with potential differentiation syndrome, which is linked to AML/MDS therapies that induce differentiation. Differentiation is an effect believed to be on-target for the proposed mechanism of action for FHD-286.
The FDA has requested that they review the safety database, risk mitigation strategies, and a breakdown of clinical activity across dose levels observed in the trial. Due to the partial hold, Foghorn Therapeutics has suspended guidance on the timing of the release of data from the phase 1 trial.
Additionally, patients who are currently enrolled and who have demonstrated a benefit from FHD-286 are permitted to continue treatment. 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,” stated Adrian Gottschalk, chief executive officer of Foghorn Therapeutics, in the press release.
In preclinical studies, FHD-286, a highly potent, selective, allosteric and orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM, has demonstrated antitumor activity across a broad range of malignancies. Activity has been seen in both hematologic and solid tumors.
The multicenter, open-label, dose-escalation, phase 1 study aims to evaluate FHD-286 in approximately 25 to 50 patients aged 18 years or older with hematologic malignancies, specifically R/R AML and MDS.2 Patients would then be enrolled into the dose-escalation arm of the trial and receive varying doses of oral FHD-286 with the goal of establishing the recommended phase 2 dose.
Enrollment was open to patients with AML 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, and all patients with AML must have previously failed prior therapies known to be active for treatment of their diagnosed hematologic disease. Individuals with MDS must have previously failed treatment with at least 4 cycles of a hypomethylating agent.
Other requirements needed for inclusion consisted of 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.
Primary end points of the trial include the incidence of treatment-emergent adverse events (AEs), the incidence of AEs, serious AEs and AEs leading to discontinuation for up to 18 months, and the incidence of dose-limiting toxicities within cycle 1 of treatment.
In regard to secondary end points, pharmacokinetics and plasma concentrations of FHD-286 are being examined for all patients.
For the AML cohort, secondary end points consist 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). The secondary end points for the MDS cohort include 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.
Currently, FHD-286 is being evaluated in another phase 1 trial (NCT04879017) for patients with metastatic uveal melanoma. As the partial clinical hold does not apply to that trial, it will continue to enroll patients, per protocol.