Clinical Trials /

FHD-286 in Subjects With Advanced Hematologic Malignancies

NCT04891757

Description:

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 oral monotherapy in subjects with advanced hematologic malignancies, specifically relapsed or refractory (R/R) acute myeloid leukemia (AML) or R/R myelodysplastic syndromes (MDS).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: FHD-286 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 in Subjects With Advanced Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: FHD-286-C-002
  • NCT ID: NCT04891757

Conditions

  • Advanced Hematologic Malignancy
  • Relapsed Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Relapsed Myelodysplastic Syndromes
  • Refractory Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
FHD-286FHD-286 dose escalation

Purpose

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 oral monotherapy in subjects with advanced hematologic malignancies, specifically relapsed or refractory (R/R) acute myeloid leukemia (AML) or R/R myelodysplastic syndromes (MDS).

Detailed Description

      This study is an ascending multiple dose escalation clinical trial. It is primarily intended
      to evaluate the safety and tolerability of FHD-286 when administered orally to subjects with
      advanced hematologic malignancies, specifically R/R AML and R/R MDS. This dose escalation
      study will allow for the determination of the maximum tolerated dose (MTD) and/or the
      recommended phase 2 dose (RP2D) of FHD-286 in patients with advanced hematologic
      malignancies. This study will also evaluate the PK/PD profiles of multiple dose
      administration of FHD-286 and provide a preliminary assessment of antitumor activity in
      subjects with R/R AML and R/R MDS as well as other associated hematologic malignancies.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
FHD-286 dose escalationExperimentalApproximately 25-50 patients will be enrolled in the dose escalation arm
  • FHD-286

Eligibility Criteria

        Inclusion Criteria:

          1. Subject must be ≥ 18 years of age.

          2. Subject must have a confirmed diagnosis of an advanced hematologic malignancy,
             specified as follows:

               -  R/R AML (subjects who relapse after transplantation; subjects in second or later
                  relapse; subjects who are refractory to initial induction or reinduction
                  treatment; subjects who relapse within 1 year of initial treatment). Subjects
                  with AML must have previously failed all prior therapies known to be active for
                  treatment of their diagnosed hematologic disease.

               -  R/R MDS. Subjects with MDS must have previously failed treatment with at least 4
                  cycles of a hypomethylating agent, known to be active for treatment of their
                  diagnosed hematologic disease.

          3. Subject must be able to understand and be willing to sign an informed consent.

          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 (fresh bone marrow biopsy
             and/or aspirate at baseline within 28 days of first dose plus bone marrow evaluations
             every 4 weeks for the first 24 weeks, then every 8 weeks for the next 48 weeks of
             treatment, as clinically indicated thereafter, and 1 EOT bone marrow evaluation
             (unless contraindicated due to medical risk; other exceptions to this are at the
             discretion of the Sponsor's Medical Monitor), peripheral blood and tissue sampling,
             and urine sampling during the study.

          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 as evidenced by:

               -  Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless considered due
                  to leukemic involvement following approval by the study Sponsor Aspartate
                  aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase
                  (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following
                  approval by the study Sponsor

               -  Prothrombin time (PT) ≤ 1.5 × ULN or international normalized ratio (INR) ≤ 1.4

               -  Activated partial thromboplastin time (aPTT) ≤ ULN

               -  No known portal vein thrombosis

          9. Subject must have adequate renal function as evidenced by:

             • Creatinine clearance > 60 mL/min based on the Cockcroft-Gault glomerular filtration
             rate (GFR) estimation

         10. Subject must have an adequate platelet level, defined as:

             • Platelets > 50 × 109/L (transfusions to achieve this level are allowed.) Subjects
             with a baseline platelet count of ≤ 50 × 109/L due to underlying malignancy are
             eligible with Medical Monitor approval.

         11. Subject must have adequate cardiovascular, respiratory, and immune system function as
             evidenced by the below criteria and in the opinion of the Investigator:

             • LVEF of ≥ 40% by ECHO

         12. Subjects must agree to discontinue intake of beverages, herbal supplements, or food
             known to inhibit or induce cytochrome P450 (CYP) 3A such as grapefruit juice, St
             John's wort, echinacea, and goldenseal from 72 hours before admission until 72 hours
             following final dose of study drug.

         13. Timing requirements with respect to prior therapy and surgery are as follows:

               -  2 weeks and/or at least 5 half-lives, whichever is shorter, must have elapsed
                  since administration of the last dose of any prior systemic anticancer therapy.
                  Hydroxyurea is allowed prior to enrollment and after the start of FHD-286 for the
                  control of peripheral leukemic blasts in subjects with leukocytosis (eg, white
                  blood cell [WBC] counts > 30 × 109/L) with approval of the Medical Monitor.
                  (Patients must either be intolerant to and/or have experienced disease
                  progression on their prior therapy in the opinion of the treating physician.)

               -  4 weeks must have elapsed since the last dose of post-transplant calcineurin
                  inhibitors.

               -  4 weeks must have elapsed since the last major surgery, 2 weeks for minor surgery
                  (eg, port placement).

               -  2 weeks must have elapsed since the last radiotherapy. Exceptions may be made in
                  the case of palliative radiotherapy at the discretion of the Medical Monitor.

         14. Toxicity related to prior therapy must have returned to ≤ Grade 2 by CTCAE at least 14
             days prior to study start or be deemed irreversible by the Investigator. Exceptions
             include alopecia, neuropathy, appropriately controlled endocrine toxicities, and other
             toxicities similar to these with discussion with the Medical Monitor.

         15. Female subjects must be:

               -  postmenopausal, defined as at least 12 months post cessation of menses (without
                  an alternative medical cause), or

               -  permanently sterile following documented hysterectomy, bilateral salpingectomy,
                  bilateral oophorectomy, or tubal ligation or having a male partner with vasectomy
                  as affirmed by the subject, or

               -  nonpregnant, nonlactating, and if sexually active having agreed to use a highly
                  effective method of contraception (ie, hormonal contraceptives associated with
                  inhibition of ovulation or intrauterine device [IUD], or intrauterine
                  hormone-releasing system [IUS], or sexual abstinence) from Screening Visit until
                  90 days after the final dose of the study drug.

             Note: The potential risk to female fertility posed by FHD-286 is unknown; it is
             recommended that subjects discuss options for fertility preservation with their doctor
             prior to study start.

         16. Male subjects must have documented vasectomy or if sexually active must agree to use a
             highly effective method of contraception with their partners of childbearing potential
             (ie, hormonal contraceptives associated with the inhibition of ovulation or IUD, or
             IUS, or sexual abstinence) from Screening until 90 days after the final dose of the
             study drug. Male subjects must agree to refrain from donating sperm during this time
             period.

        Note: The potential risk to male fertility posed by FHD-286 is unknown; it is recommended
        that subjects discuss options for fertility preservation with their doctor prior to study
        start.

        Exclusion Criteria:

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

          2. Subject has undergone HSCT within 60 days of the first dose of FHD-286, or subject is
             on immunosuppressive therapy post-HSCT at the time of screening, or subject has
             clinically significant graft-versus-host disease (GVHD). The use of a stable dose of
             oral steroids post-HSCT is permitted with Medical Monitor approval.

          3. Subject has clinical symptoms suggesting active central nervous system (CNS) leukemia
             or known CNS leukemia. Evaluation of the cerebrospinal fluid is only required if there
             is a clinical suspicion of CNS involvement by leukemia during screening.

          4. Subject has an immediately life-threatening, severe complications of leukemia, such as
             uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
             intravascular coagulation.

          5. Subject has other malignancy which may interfere with the diagnosis and/or treatment
             of advanced hematologic malignancies.

          6. Subject has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections;
             subjects with a sustained viral response to HCV treatment or immunity to prior HBV
             infection will be permitted. Subject has known positive human immunodeficiency virus
             (HIV)antibody results, or acquired immunodeficiency syndrome (AIDS)-related illness;
             subjects with CD4+ T-cell counts ≥ 350 cells/μL will be permitted as will subjects who
             have not had an AIDS-related illness within the past 12 months.

          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 drug administration (at the discretion of the Investigator, subjects with tumor
             fever may be enrolled).

          8. Subject has an uncontrolled intercurrent illness.

          9. Subjects with corrected QT interval (QTc) using Fridericia's formula (QTcF) > 470
             msecs or other factors that increase the risk of QTc prolongation or arrhythmic events
             (eg, heart failure, hypokalemia, family history of long QT interval syndrome)
             including heart failure that meets New York Heart Association (NYHA) class III and IV
             definitions are excluded.

         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,
             cooperate, or participate in the study.

         11. Subject has known allergies or hypersensitivities to components of the FHD-286
             formulation.

         12. Subject is unable to tolerate the administration of oral medication or has GI
             dysfunction that could interfere with absorption of FHD-286 (eg, ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, partial bowel
             resections).

         13. Subject is receiving any other investigational agents.

         14. Subject has participated in any other clinical trials within 2 weeks or at least 5
             half-lives of a prior investigational drug at the start of study treatment. Exceptions
             include participation in any observational or nontherapeutic clinical trials.

         15. Subject is on medications that are strong CYP3A inhibitors, are strong CYP3A inducers,
             or are sensitive CYP3A substrates with narrow TIs. Exceptions may be made for therapy
             in the case of life-threatening infections, for example a triazole anti-fungal agent
             to reduce the risk of invasive fungal infections, at the discretion of the Medical
             Monitor.

         16. Subject is on medications with narrow TIs that are sensitive P-gp or breast cancer
             BCRP substrates and are administered orally, such as digoxin or on medications that
             are strong inhibitors of P-gp or BCRP.

         17. Subject on medications that are acid-reducing agents (ARA) such as histamine
             H2-receptor antagonists (H2 blockers), and proton pump inhibitors (PPIs). The last
             dose of PPIs must be administered 7 days prior to administration of study drug.
             Antacids are acceptable when administered in a staggered dosing manner with FHD-286.

         18. Subject is receiving systemic steroid therapy or any other systemic immunosuppressive
             medication. The use of a stable dose of oral steroids post-HSCT is permitted with
             Medical Monitor approval. Local steroid therapies (inhaled or topical steroids) 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 study start. Subject is a woman or man of childbearing capabilities who is
             unwilling to use effective contraception.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:Up to 18 months
Safety Issue:
Description:Dose escalation

Secondary Outcome Measures

Measure:AML: Complete remission (CR) rate
Time Frame:Up to 18 months
Safety Issue:
Description:Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 × 109/L (1000/μL); platelet count > 100 × 109/L (100,000/μL); independence of red cell transfusions
Measure:AML: Duration of CR
Time Frame:Up 18 months
Safety Issue:
Description:Time from first documented evidence of CR until the earliest date of documented progression or death due to any cause
Measure:AML: CR + CR with partial hematologic recovery (CRh) rate
Time Frame:Up 18 months
Safety Issue:
Description:CR as described above For documentation of CRh, FDA has used the following definition: Marrow blasts < 5% by morphological examination ANC > 0.5 Gi/L (>0.5 × 109/L (500/μL); and platelet count > 50 Gi/L ( >50 × 109/L (50,000/μL), but the count recovery criteria for CR are not met Absence of leukemic blasts in the peripheral blood by morphological examination No evidence of extramedullary disease
Measure:AML: Duration of CR + CRh
Time Frame:Up 18 months
Safety Issue:
Description:Time from first documented evidence of CR + CRh until the earliest date of documented progression or death due to any cause
Measure:AML: Transfusion independence rate
Time Frame:Up 18 months
Safety Issue:
Description:The absence of red blood cell and platelet transfusions for 28 days during continued treatment. For patients with active AML, transfusion dependence at baseline is based on the receipt of any red blood cell or platelet transfusions within at least 28 days prior to the start of study treatment
Measure:AML: Event free survival (EFS)
Time Frame:Up 42 months
Safety Issue:
Description:Time from first dose of study treatment until the first date of documented relapse (excluding relapse after partial response), treatment failure or death, whichever comes first
Measure:AML: Overall survival (OS)
Time Frame:Up to 42 months
Safety Issue:
Description:Time from first dose of study treatment to the date of death due to any cause
Measure:MDS: CR rate
Time Frame:Up to 18 months
Safety Issue:
Description:Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines Persistent dysplasia will be noted Hgb ≥ 11 g/dL Platelets ≥ 100 × 109/L Neutrophils ≥ 1.0 × 109/L Blasts = 0%
Measure:MDS: Duration of CR
Time Frame:Up to 18 months
Safety Issue:
Description:Time from first documented evidence of CR until the earliest date of documented progression or death due to any cause
Measure:MDS: Partial remission (PR) rate
Time Frame:Up to 18 months
Safety Issue:
Description:All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by ≥50% over pretreatment but still > 5% Cellularity and morphology not relevant
Measure:MDS: Duration of PR
Time Frame:Up to 18 months
Safety Issue:
Description:Time from first documented evidence of PR until the earliest date of documented progression or death due to any cause
Measure:MDS: CR + PR
Time Frame:Up to 18 months
Safety Issue:
Description:CR as described above; PR as described above
Measure:MDS: Duration of CR + PR
Time Frame:Up to 18 months
Safety Issue:
Description:Time from first documented evidence of CR + PR until the earliest date of documented progression or death due to any cause
Measure:MDS: Hematologic Improvement (HI) rate
Time Frame:Up to 18 months
Safety Issue:
Description:Erythroid response (pretreatment, < 11 g/dL): Hgb increase by ≥ 1.5 g/dL Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation Platelet response (pretreatment, < 100 × 109/L): Absolute increase of ≥ 30 × 109/L for subjects starting with > 20 × 109/L platelets Increase from < 20 × 109/L to > 20 × 109/L and by at least 100% Neutrophil response (pretreatment, < 1.0 × 109/L): At least 100% increase and an absolute increase > 0.5 × 109/L Response must last up to 8 weeks
Measure:MDS: EFS
Time Frame:Up to 42 months
Safety Issue:
Description:Time from first dose of study treatment until the first date of documented relapse (excluding relapse after partial response), treatment failure or death, whichever comes first
Measure:MDS: OS
Time Frame:Up to 42 months
Safety Issue:
Description:Time from first dose of study treatment to the date of death due to any cause
Measure:PK parameter: Area under the plasma concentration time curve (AUC)
Time Frame:Day 1 and day 8 of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Characterization of the PK profile of FHD-286
Measure:Plasma concentration vs. time profiles
Time Frame:Day 1 and day 8 of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Plasma concentrations of FHD-286 at the scheduled timepoints

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Foghorn Therapeutics Inc.

Trial Keywords

  • AML
  • Relapsed Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • MDS
  • Relapsed Myelodysplastic Syndromes
  • Refractory Myelodysplastic Syndromes
  • Phase 1
  • FHD-286
  • Foghorn

Last Updated

May 18, 2021