FDA Lifts Partial Clinical Hold on Study of FHD-286 in R/R AML, MDS

The FDA has lifted the clinical hold on the phase 1 study of FHD-286 (NCT04891757), an inhibitor of BRG1/BRM, for the treatment of patients with relapsed/refractory (R/R) acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).¹

A phase 1 study evaluating FHD-286 in combination with decitabine or low-dose cytarabine in patients with R/R AML is expected to begin in the third quarter of 2023.

“I’m delighted that the FDA has lifted the hold on the phase 1 study of FHD-286. Relapsed and refractory AML remains an area of unmet clinical need where patient outcomes remain unacceptably poor. The early experience with FHD-286 as monotherapy justifies the next steps, which are combinations with decitabine or low-dose cytarabine. I’m excited to start enrolling patients again,” Eytan Stein, MD, chief of the Leukemia Service, clinical investigator, and director of the Program for Drug Development in Leukemia on the Leukemia Service at Memorial Sloan Kettering Cancer Center, told Targeted Oncology^TM.

FHD-286 is a highly potent, selective, allosteric, orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM. In preclinical studies, FHD-286 has demonstrated anti-tumor activity across various malignancies, including hematologic and solid tumors.²

Previously in August 2022, the FDA placed a full clinical hold on FHD-286 as a result of additional suspected cases of fatal differentiation syndrome believed to be associated with the agent.

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In the phase 1 dose-escalation study evaluating FHD-286 in 36 patients with R/R AML and 4 with MDS who had exhausted all other treatment options, findings showed that FHD-286 had an adverse event (AE) profile that was generally consistent with a high-risk R/R AML patient population.¹

The study was designed to assess safety and tolerability and tested FHD-286 at doses of 2.5 mg, 5.0 mg, 7.5 mg, and 10.0 mg taken orally once daily.³ Among those included, most patients had an abnormal karyotype (82.5%), poor genetic risk factors (65% with adverse genetic status), and had received 3 or more prior lines of therapy (67.5%).¹

The most common treatment-related AEs observed in the study were dry mouth, increased blood bilirubin, increased alanine transaminase (ALT), and rash. The most common grade 3 or higher treatment-related AEs consisted of increased blood bilirubin, hypocalcemia, differentiation syndrome, stomatitis, and increased ALT.

Findings also showed that there were reductions in both peripheral and bone marrow blast counts, as well as recoveries in absolute neutrophil count among a subset of heavily pre-treated R/R patients, irrespective of mutational status. Differentiation was observed across a broad range of patients, both morphologically and/or through biomarkers.

“Clinical data from the phase 1 dose-escalation study showed a robust differentiation effect in heavily pre-treated patients across a range of mutational backgrounds, and pre-clinical data support the development of FHD-286 as a combination therapy in AML. With its broad-based mechanism of action, FHD-286, in combination with 1 of the standard agents, has the potential to address a significant unmet need in relapsed/refractory AML patients,” said Stein, in the press release.

Now lifted, the company has amended the protocol and there are plans to start a phase 1 study of FHD-286. Clinical data have shown FHD-286’s effect as a broad-based differentiation agent. This, as well as its safety profile and supportive pre-clinical combination data, including robust efficacy data, support the company's decision to advance to the phase 1 combination study.

In the phase 1 combination study, FHD-286 will be dose escalated and combined with combination fixed dose decitabine or fixed dose cytarabine using a standard 3+3 dose-escalation design. Patients are eligible for enrollment in the study if they have R/R AML, and investigators aim to assess safety, tolerability, and efficacy of the combination regimens.

Investigators believe that the combination of FHD-286 with decitabine or cytarabine may mitigate the risk for differentiation syndrome given the cytoreductive properties of these agents.

“With a focus on patient safety, we have worked with the FDA to resolve the clinical hold on FHD-286 in AML and MDS,” said Adrian Gottschalk, president and chief executive officer of Foghorn, in the press release. “Clinical data suggest FHD-286 is a potent, broad-based differentiation therapeutic, and we believe it has significant combination potential as a treatment in AML. We anticipate commencing a phase 1 combination study focusing on first-line relapsed and/or refractory AML patients in the third quarter of 2023.””

REFERENCES:

1. Foghorn Therapeutics announces FDA has lifted clinical hold on phase 1 study of FHD-286 in relapsed and/or refractory AML/MDS patients. News release. Foghorn Therapeutics, Inc. June 5, 2023. Accessed June 8, 2023. https://tinyurl.com/242kuctr

2. 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 June 8, 2023.

3. FHD-286 in subjects with advanced hematologic malignancies. ClinicalTrials.gov. Updated September 8, 2022. Accessed June 8, 2023. https://clinicaltrials.gov/ct2/show/NCT04891757