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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Hematologic Malignancy, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Relapsed Myelodysplastic Syndromes, Refractory Myelodysplastic Syndromes, Relapsed Chronic Myelomonocytic Leukemia, Refractory Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: FHD-286
* Drug: Low Dose Cytarabine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject must be ≥16 years of age. Subject must: • Have a confirmed diagnosis of R/R AML, R/R MDS, or R/R CMML not in blast crisis AND • Be an appropriate candidate for treatment with LDAC (Arm A) or decitabine (Arm B) 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. Subject must be willing and able to comply with scheduled study visits and treatment plans. Subject must be willing to undergo all study procedures unless contraindicated due to medical risk. Subject must have an ECOG PS of ≤2. Subject must have a life expectancy of ≥3 months. Subject must have adequate hepatic function Subject must have adequate renal function Subject must have a WBC count ≤20×109/L Subject must have adequate cardiovascular, respiratory, and immune system function Subject must agree to abide by dietary and other considerations required during the study Subject must meet timing requirements with respect to prior therapy and surgery Toxicity related to prior therapy must have returned to Grade ≤2 by CTCAE by approximately 14 days before the start of study treatment 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 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: Subject is unable to provide informed consent and/or to follow protocol requirements. 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 Subject has clinical symptoms suggesting active CNS leukemia or known CNS leukemia. 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. Subject has other malignancy that may interfere with the diagnosis and/or treatment of advanced hematologic malignancies. Subject has active HBV or HCV infections; Subject has known positive HIV antibody results, or AIDS-related illness; 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 Subject has an uncontrolled intercurrent illness. Subject has QTcF >470 msec or other factors that increase the risk of QTc prolongation or arrhythmic events 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. 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 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. Subject is receiving any other investigational agents. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since last administration of a prior investigational drug at the start of study treatment. Exceptions include participation in any observational or nontherapeutic clinical trials. Subject is on medications classified as: Strong CYP3A inhibitors - Triazole antifungal agents, including those classified as strong CYP3A inhibitors , are permitted. Strong CYP3A inducers Sensitive CYP3A substrates with narrow TIs 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. Administration of PPIs should be stopped or switched to another ARA 7 days before administration of FHD-286. 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. Subject has undergone any prior treatment with a BRG1/BRM inhibitor. Subject is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, MDS, Relapsed Myelodysplastic Syndromes, Refractory Myelodysplastic Syndromes, Phase 1, FHD-286, Foghorn, CMML, Refractory Chronic Myelomonocytic Leukemia, Relapsed Chronic Myelomonocytic Leukemia