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
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.
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
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
- 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
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
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
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
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
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
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.