FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies

A Phase 1, Multicenter, Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered FHD-286, as Monotherapy or Combination Therapy, in Subjects With Advanced Hematologic Malignancies

This Phase 1, multicenter, open-label, dose escalation study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FHD-286 administered orally as monotherapy or combination therapy, in subjects with advanced hematologic malignancies.

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Relapsed Acute Myeloid Leukemia; Relapsed Myelodysplastic Syndromes; Refractory Myelodysplastic Syndromes; Advanced Hematologic Malignancy; Relapsed Chronic Myelomonocytic Leukemia
• Intervention / Treatment: Drug: FHD-286; Drug: Low Dose Cytarabine; Drug: Decitabine

Detailed Description

This study is primarily intended to evaluate the safety and tolerability of FHD-286 when administered orally as monotherapy or in combination with either LDAC or decitabine to subjects with R/R AML, R/R MDS, and R/R CMML not in blast crisis. In each arm of the study, successive cohorts of participants will receive increasing oral doses of FHD-286 as a single agent or in combination with LDAC or decitabine to determine the RP2D(s) in this population.

The data from this study in subjects with advanced hematologic malignancies, including safety, tolerability, PK/PD findings, and antitumor activity, will form the basis for subsequent clinical development of FHD-286.

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City Of Hope National Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Subject must be ≥16 years of age.

2. Subject must:

   • Have a confirmed diagnosis of R/R AML, R/R MDS, or R/R CMML not in blast crisis AND
   • Have received ≤4 prior lines of systemic anticancer therapy for their disease under study; subjects who have received >4 prior lines of systemic anticancer therapy for their disease under study must receive Sponsor approval. AND
   • Be an appropriate candidate for treatment with LDAC (Arm A) or decitabine (Arm B)
3. Subject or their parent or legal guardian (when applicable) must be able to understand and be willing to sign an informed consent and, when applicable, subject must sign an assent form.
4. Subject must be willing and able to comply with scheduled study visits and treatment plans.
5. Subject must be willing to undergo all study procedures unless contraindicated due to medical risk.
6. Subject must have an ECOG PS of ≤2.
7. Subject must have a life expectancy of ≥3 months.
8. Subject must have adequate hepatic function.
9. Subject must have adequate renal function.
10. Subject must have a WBC count ≤20×109/L; treatment with a stable dose of hydroxyurea or other cytoreductive agent (eg, cytarabine) to achieve this count is allowed.
11. Subject must have adequate cardiovascular, respiratory, and immune system function.
12. Subject must agree to abide by dietary and other considerations required during the study.
13. Subject must meet timing requirements with respect to prior therapy and surgery
14. Toxicity related to prior therapy must have returned to Grade ≤2 by CTCAE by approximately 14 days before the start of study treatment or be deemed irreversible and stable by the Investigator. Exceptions include alopecia, neuropathy, appropriately controlled endocrine toxicities, and other well-controlled stable toxicities with discussion with the Sponsor.

15. Female subjects must be:

    • postmenopausal; or
    • permanently sterile, or, if sexually active with male partners, these partners must be azoospermic; or
    • nonpregnant, nonlactating, and, if sexually active with fertile male partners, having agreed to use a highly effective method of contraception
16. Male subjects must have documented azoospermia or, if fertile and sexually active, must agree to use a highly effective method of contraception with their partners of childbearing potential

Key Exclusion Criteria:

1. Subject is unable to provide informed consent and/or to follow protocol requirements.

2. Subject:

   • Has undergone chimeric antigen receptor T cell therapy or HSCT within 60 days of the first dose of study treatment OR
   • Has clinically significant GVHD
3. Subject has evidence (or suspicion) of extramedullary involvement, unless approved by Sponsor.
4. Subject has an immediately life-threatening, severe complication(s) of advanced myeloid malignancy, such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
5. Subject has other malignancy that may interfere with the diagnosis and/or treatment of advanced hematologic malignancies.
6. Subject has active HBV or HCV infections; Subject has known positive HIV antibody results, or AIDS-related illness.
7. Subject has an active severe infection that requires anti-infective therapy or has an unexplained temperature of >38.5°C during screening visits or on their first day of study treatment.
8. Subject has an uncontrolled intercurrent illness.
9. Subject has QTcF >470 msec or other factors that increase the risk of QTc prolongation or arrhythmic events.
10. Subject has any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent/assent, cooperate, or participate in the study.

11. Subject has known allergies or hypersensitivities to:

    • All subjects: components of the FHD-286 formulation
    • Arm A: cytarabine or any of the excipients
    • Arm B: decitabine or any of the excipients
12. Subject is unable to tolerate the administration of oral medication or has GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of FHD-286.
13. Subject is receiving any other anticancer investigational agents. Investigational agents to treat non-cancer indications may be permitted with Sponsor approval.
14. Exclusion Criteria #14 was removed.

15. Subject is on medications classified as:

    • Strong CYP3A inhibitors [Exception: Triazole antifungal agents, including those classified as strong CYP3A inhibitors, are permitted.]
    • Strong CYP3A inducers
    • Sensitive CYP3A substrates with narrow TIs [Stable doses of immunosuppressant medications that are sensitive CYP3A4 substrates may be permitted with Sponsor approval.]
16. Subject is on medications with narrow TIs that are sensitive P-gp or BCRP substrates and are administered orally or on medications classified as strong inhibitors of P-gp or BCRP.
17. Administration of PPIs should be stopped or switched to another ARA 7 days before administration of FHD-286.
18. Subject is requiring clinically significant or increasing doses of systemic steroid therapy or any other systemic immunosuppressive medication. Local or targeted steroid and immunosuppressive therapies are acceptable. Appropriate steroid replacement to manage endocrine toxicities resulting from prior anticancer systemic therapy is permitted.
19. Subject has undergone any prior treatment with a BRG1/BRM inhibitor.
20. Subject is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FHD-286 Monotherapy; Closed to Enrollment	Drug: FHD-286; FHD-286 administered orally
Experimental: FHD-286 in Combination with LDAC; FHD-286 administered orally + LDAC administered subcutaneously	Drug: FHD-286; FHD-286 administered orally; Drug: Low Dose Cytarabine; LDAC administered subcutaneously (SC); Other Names: LDAC
Experimental: FHD-286 in Combination with Decitabine; FHD-286 administered orally + decitabine administered intravenously (IV)	Drug: FHD-286; FHD-286 administered orally; Drug: Decitabine; Decitabine administered intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of AEs, dose-limiting toxicities (DLTs), serious AEs (SAEs), AEs leading to discontinuation, and adverse events of special interest (AESIs); safety laboratory assessments	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
AML: Complete remission (CR) rate	Up to 18 months
AML: Duration of CR	Up 18 months
AML: CR + CR with partial hematologic recovery (CRh) rate	Up 18 months
AML: Duration of CR + CRh	Up 18 months
AML: Transfusion independence rate	Up 18 months
AML: Event free survival (EFS)	Up 42 months
AML: Overall survival (OS)	Up to 42 months
MDS: CR rate	Up to 18 months
MDS & CMML: Duration of CR	Up to 18 months
MDS & CMML: Partial remission (PR) rate	Up to 18 months
MDS & CMML: Duration of PR	Up to 18 months
MDS & CMML: CR + PR	Up to 18 months
MDS & CMML: Duration of CR + PR	Up to 18 months
MDS & CMML: Hematologic Improvement rate	Up to 18 months
MDS & CMML: EFS	Up to 42 months
MDS: OS	Up to 42 months
PK parameter: Area under the plasma concentration time curve (AUC)	Day 1 and day 8 of cycle 1 (each cycle is 28 days)
Plasma concentration vs. time profiles	Day 1 and day 8 of cycle 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Foghorn Therapeutics Inc.
• Investigators: Study Director: Sarah Reilly, MD, Foghorn Therapeutics

Publications and helpful links

General Publications

• DiNardo CD, Fathi AT, Kishtagari A, Bhalla KN, Quintas-Cardama A, Reilly SA, Almon C, Patriquin C, Nabhan S, Healy K, Hickman D, Collins MP, Khalil A, Corrigan D, Zhao T, Piel J, Lyons K, Horrigan K, Schuck V, Martin P, Elliott G, Lahr DL, Bosinger M, D'Aco K, Smolen GA, Hentemann M, Loghavi S, Agresta S, Savona MR, Stein EM. A Phase I Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients with Advanced Myeloid Malignancies. Clin Cancer Res. 2025 Jun 13;31(12):2327-2338. doi: 10.1158/1078-0432.CCR-24-3790.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2021
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: May 13, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 18, 2021

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: July 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: AML; Phase 1; MDS; Relapsed Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; CMML; FHD-286; Foghorn; Relapsed Myelodysplastic Syndromes; Refractory Myelodysplastic Syndromes; Refractory Chronic Myelomonocytic Leukemia; Relapsed Chronic Myelomonocytic Leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Neoplasms; Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Preleukemia; Myelodysplastic Syndromes; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Decitabine; Cytarabine
• Other Study ID Numbers: FHD-286-C-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No