Treatment with the investigational drug FHD-286 exhibits positive results in patients with metastatic uveal melanoma and will be explored further in acute myeloid leukemia and myelodysplastic syndrome.
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The safety and tolerability of FHD-286 in metastatic uveal melanoma (mUM) have been emphasized in a phase 1 dose-escalation study (NCT04879017).1
FHD-286 is a small molecule, enzymatic inhibitor of BRG1 and BRM. Preclinically, the agent has shown antitumor activity in multiple solid and hematologic malignancies.
Data announced in a press release by Foghorn Therapeutics, Inc came from 73 patients with mUM treated with 1 of 4 continuous daily doses of FHD-286. Overall, 2 patients in the study received the 2.5-mg dose, 12 were administered the 5.0-mg dose, 12 received FHD-286 7.5 mg, 9 were given 15.0 mg, 3 received 17.5 mg, 5 were given 20.0 mg, and 6 received 22.5 mg.
Trial Name: A Phase 1, Multicenter, Open-Label, Dose Escalation and Expansion Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered FHD-286 in Subjects With Metastatic Uveal Melanoma
ClinicalTrials.gov Identifier: NCT04879017
Sponsor: Foghorn Therapeutics Inc.
Recruitment Contact: 1-888-615-1298, clinicaltrials@foghorntx.com
Completion Date: August 29, 2025
A durable partial response was reported for 1 patient who remained on FHD-286 for more than 16 months. Stable disease was observed in 9 patients, and 8 showed reduction in target lesions. Moreover, reductions in circulating tumor DNA were demonstrated with the agent.
In terms of safety, FHD-286 was safe and tolerable. Of the treatment-related adverse events (TRAEs) observed during the study, the most common were dysgeusia, fatigue, aspartate aminotransferase increase, nausea, vomiting, dry mouth, and rash. The most common grade 3 or higher TRAEs were anemia, asthenia, alkaline phosphatase increase, hypokalemia, muscular weakness, and rash.
Full results from the study will be presented at an upcoming scientific meeting, according to Foghorn Therapeutics. In addition, the first patient with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) will be dose in another phase 1 study of FHD-286 in combination with decitabine or cytarabine within the next 3 months (NCT04891757).
“The clinical data further support the safety and tolerability of FHD-286 and build on the previously disclosed AML/MDS data. In the study, nine patients had stable disease and one patient had a durable partial response,” said Adrian Gottschalk, the president and chief executive officer of Foghorn, in a press release. “However, Foghorn does not plan to pursue this indication on its own. We plan to initiate dosing the FHD-286 combination study in relapsed/refractory AML during the third quarter of 2023 and continue to invest in our promising pre-clinical programs such as Selective-BRM, CBP, EP300, and ARID1B.”
In the phase 1, multicenter, open-label, dose-escalation and dose-expansion study aiming to evaluate the safety, tolerability, pharmacokinetics (PK), and early activity of single-agent FHD-286 in patients with mUM. Patients in the study are given ascending doses of the drug orally, during the dose-escalation portion of the study. Dose-escalation is designed to determine the recommended phase 2 dose and maximum-tolerated dose of FHD-286 in this patient population. During the dose-expansion portion of the study, investigators will conduct an in-depth safety evaluation and look at PK, pharmacodynamics, and efficacy.2
The primary end points being assessed during the study include the incidence of treatment-emergent adverse events (TEAEs), the incidence of AEs, serious AEs, and the incidence of dose-limiting toxicities. The study will also investigate the secondary end points of objective response rate, duration of response, time to progression, progression-free survival, overall survival, PK parameters, and plasma concentration compared with time profiles.
Investigators estimated an enrollment of 100 patients with mUM who will be treated at sites in the United States, France, and the Netherlands. As of June 29, 2023, 125 patients have been enrolled and more are being recruited.
To be eligible for the study, patients must be 18 years of age or older with metastatic histologically or cytologically confirmed mUM. All patients are required to have measurable disease per RECIST v1.1, and an ECOG performance status of 2 or lower. Patients must be willing to provide new tumor tissue for biopsy at baseline and while on treatment.
Patients are excluded from the study if they present with another malignancy or have thrombocytopenia, or another serious bleeding disorder. Patients are also ineligible if they have active hepatitis B or C, active infection, uncontrolled intercurrent illness, QT prolongation, or are receiving certain medications like CYP3A inhibitors, digoxin, systemic steroid therapy, or other systemic immunosuppressive therapy. Patients previously treated with a BRG1 or BRM inhibitor are also ineligible for the study.
REFERENCES:
1. Foghorn Therapeutics announces clinical data from phase 1 study of FHD-286 in metastatic uveal melanoma. News release. Foghorn Therapeutics, Inc, June 28, 2023. Accessed June 29, 2023.https://tinyurl.com/mrxrcpjj
2. FHD-286 in subjects with metastatic uveal melanoma. ClinicalTrials.gov. Updated March 16, 2023. Accessed June 29, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04879017?term=FHD-286&draw=2&rank=1
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