FDA Places Partial Clinical Hold on Trial of FHD-609 in Synovial Sarcoma and SMARCB1-Deleted Tumors

FDA

The FDA has placed a partial clinical hold on the phase 1 trial (NCT04965753) evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and early clinical activity of FHD-609 in patients with advanced synovial sarcoma and SMARCB1-deleted tumors.¹

Foghorn Therapeutics, Inc. paused enrollment to the trial after a grade 4 QTc prolongation event observed in a patient with synovial sarcoma who received FHD-609 at the second highest dose examined.

To date, the dose-escalation portion of the research has concluded, and the maximum tolerated dose of the investigative drug has been determined. The dose has been reduced in the affected cohort. The clinical-stage biotechnology company communicated the decision to pause enrollment and the actions taken to mitigate risks to authorities in the United States and Europe. Subsequently, the FDA placed the partial hold on the trial. However, participants who are deriving benefit can continue the treatment.

The drug is a protein degrader of BRD9, which is a component of one form of the BAF complex.² FHD-609 comprises two domains: one that blinds to BRD9 and the other that binds to a complex that directs proteins for elimination. Targeting BRD9 for degradation allows for the depletion of SS18, a subunit of the BAF complex, which is needed for cancer cells to survive.

“The Company is not at this time planning to pursue a dose-expansion study independently,” according to the press release.

The multicenter, open-label, dose-escalation and -expansion trial enrolled patients who had a diagnosis of synovial sarcoma or a SMARCB1-loss tumor.³ Those with sarcoma needed to have evidence of a SS18-SSX rearrangement and/or a confirmed pathologic diagnosis of sarcoma. Those with a solid tumor primarily characterized by SMARCB1 loss, such as malignant rhabdoid tumors, epithelioid sarcoma, and poorly differentiated chordoma, needed to have documentation of biallelic SMARCB1 alterations and/or corresponding protein loss.

Patients were also required to have measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 to 2, a life expectancy of at least 3 months, and acceptable cardiac, hepatic, renal, hematologic, and coagulation function.

Patients received the agent intravenously, twice weekly.

The primary outcome measures of the trial included incidence of treatment-emergent toxicities; incidence of adverse effects (AEs) and serious AEs, including changes in safety laboratory parameters and toxicities resulting in discontinuation; and incidence of dose-limiting toxicities.

Other outcome measures of interest included objective response rate, duration of response, progression-free survival, time to response, overall survival, and plasma concentration of the drug to characterize its PK parameters.

References

1. Foghorn Therapeutics provides an update on FHD-609. News release. Foghorn Therapeutics, Inc. April 24, 2023. Accessed April 24, 2023. https://ir.foghorntx.com/news-releases/news-release-details/foghorn-therapeutics-provides-update-fhd-609
2. FHD-609. Foghorn Therapeutics, Inc. website. Accessed April 24, 2023. https://foghorntx.com/pipeline/
3. FHD-609 in subjects with advanced synovial sarcoma or advanced SMARCB1-loss tumors. ClinicalTrials.gov. Updated March 31, 2023. Accessed April 24, 2023. https://clinicaltrials.gov/ct2/show/NCT04965753