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 FHD-286

What's the purpose of this trial?

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.

This trial is currently open and accepting patients.


What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

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.

Additional Trial Information

Phase 1

Enrollment: 144 patients (estimated)

View More

Published Results

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

November 28, 2023

As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations.

85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each).

2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD.

Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients).

16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A.

Trial Locations

All Trial Locations

View all clinical trial locations sorted by state.

California

City of Hope Comprehensive Cancer Center Beckman Research Institute

Duarte, CA

Open and Accepting

Colorado

Massachusetts

Dana-Farber Cancer Institute (Main)

Boston, MA

Open and Accepting

New York

Memorial Sloan Kettering Cancer Center

New York, NY

Open and Accepting

Memorial Sloan Kettering Cancer Center

West Harrison, NY

Open and Accepting

Tennessee

Vanderbilt-Ingram Cancer Center Henry-Joyce Cancer Clinic

Nashville, TN

Open and Accepting

Texas

MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting
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