Clinical trial NCT04891757: FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: 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
Keywords: 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
Lead sponsor: Foghorn Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2021-05-18
Enrollment: 144
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of AEs, dose-limiting toxicities (DLTs), serious AEs (SAEs), AEs leading to discontinuation, and adverse events of special interest (AESIs); safety laboratory assessments
timeFrame: Up to 18 months
Secondary outcomes:
measure: AML: Complete remission (CR) rate
timeFrame: Up to 18 months
measure: AML: Duration of CR
timeFrame: Up 18 months
measure: AML: CR + CR with partial hematologic recovery (CRh) rate
timeFrame: Up 18 months
measure: AML: Duration of CR + CRh
timeFrame: Up 18 months
measure: AML: Transfusion independence rate
timeFrame: Up 18 months
measure: AML: Event free survival (EFS)
timeFrame: Up 42 months
measure: AML: Overall survival (OS)
timeFrame: Up to 42 months
measure: MDS: CR rate
timeFrame: Up to 18 months
measure: MDS & CMML: Duration of CR
timeFrame: Up to 18 months
measure: MDS & CMML: Partial remission (PR) rate
timeFrame: Up to 18 months
measure: MDS & CMML: Duration of PR
timeFrame: Up to 18 months
measure: MDS & CMML: CR + PR
timeFrame: Up to 18 months
measure: MDS & CMML: Duration of CR + PR
timeFrame: Up to 18 months
measure: MDS & CMML: Hematologic Improvement rate
timeFrame: Up to 18 months
measure: MDS & CMML: EFS
timeFrame: Up to 42 months
measure: MDS: OS
timeFrame: Up to 42 months
measure: PK parameter: Area under the plasma concentration time curve (AUC)
timeFrame: Day 1 and day 8 of cycle 1 (each cycle is 28 days)
measure: Plasma concentration vs. time profiles
timeFrame: Day 1 and day 8 of cycle 1 (each cycle is 28 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Foghorn Therapeutics
name: Sarah Reilly, MD
role: STUDY_DIRECTOR
References: