A Phase 1, Multicenter, Open-Label, Dose Escalation and Expansion Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered FHD-286 in Subjects with Metastatic Uveal Melanoma

1. Subject must be >= 18 years of age.
2. Subject must have a diagnosis of metastatic histologically or cytologically
confirmed UM. If histologic or cytologic confirmation of the tumor is not
available, clinical confirmation of a diagnosis of metastatic UM, as per
standard practice for UM, by the treating investigator can be obtained, and
fall into any of the following categories:
• Newly diagnosed subject who has not yet received liver-directed or systemic
treatment
• Subject ineligible for any available therapy likely to convey clinical benefit
• Subject who has disease progression after treatment with available therapies
and/or who is intolerant to those treatments.
Note: Inclusion criterion 15 provides timing requirements for prior therapy.
3. Subject must have measurable disease by RECIST v1.1, defined as at least 1
lesion that can be accurately measured in at least 1 dimension (longest
diameter to be recorded) as >= 10 mm with calipers and/or CT scan. Measurable
lesions cannot have undergone any local treatment (including liver-directed
radio- or immune- therapies) or radiation, unless there has been interim
progression of that lesion, nor can any local treatment or radiation involving
measurable lesions be anticipated.
Note: A malignant lymph node must be >= 15 mm on the short axis when assessed by
CT scan to be considered pathologically enlarged and measurable.
4. Subject must be able to understand and be willing to sign an informed
consent.
5. Subject must be willing and able to comply with scheduled study visits and
treatment plans.
6. Subject must be willing to undergo all study procedures (fresh biopsies at
baseline, at least 1 additional biopsy on-treatment, and 1 EOT biopsy [unless
contraindicated due to medical risk]; archival biopsies of sufficient sample
size collected within 6 months of first dose and subsequent to other prior
therapies will be accepted as a substitute for a fresh baseline biopsy; other
exceptions to this are at the discretion of the Sponsor), laboratory testing,
and imaging every 8 weeks for 48 weeks and 12 weeks thereafter until
relapse/progression, start of alternate anticancer therapy, or withdrawal from
the study, independent of dose delays, interruptions, or reductions.
7. Subject must have adequate venous access for blood collection.
8. Subject must have an ECOG PS of <= 2.
• Arm 2 (Dose Expansion Phase): Subjects enrolling in Arm 2 must have an ECOG
PS of <= 3.
9. Subject must have a life expectancy of >= 3 months.
• Arm 2 (Dose Expansion Phase): Subjects enrolling in Arm 2 must have a life
expectancy of >= 2 months.
10. Subject must have adequate hepatic function as evidenced by:
• Serum total bilirubin <= 1.5 × upper limit of normal (ULN) (<= 3.0 × ULN for
subjects with Gilbert*s syndrome)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) <= 3.0 × ULN
(<= 5.0 × ULN if liver metastases are present)
• Prothrombin time (PT) <= 1.5 × ULN or international normalized ratio (INR) <=
1.4
• Activated partial thromboplastin time (aPTT) <= 1.5 x ULN
Note: Anticoagulation therapy is permitted as long as coagulation parameters
are within therapeutic range.
• No known portal vein thrombosis
Note: Subjects with organ function outside the parameters outlined in the above
inclusion criterion may be permitted to enroll only in Arm 2 of the Dose
Expansion Phase at the discretion of the Investigator and the Sponsor.
11. Subject must have adequate renal function as evidenced by:
• Glomerular filtration rate (GFR) >= 50 mL/min (based on a contemporary, widely
accepted, and clinically applicable equation that estimates glomerular
filtration rate or a measure of glomerular filtration rate)
Note: Subjects with organ function outside the parameters outlined in the above
inclusion criterion may be permitted to enroll only in Arm 2 of the Dose
Expansion Phase at the discretion of the Investigator and the Sponsor.
12. Subject must have adequate bone marrow function as evidenced by:
• Hemoglobin >= 9 g/dL (Transfusions to achieve this level are allowed.)
• White blood cells (WBCs) >= 2.0 × 109/L
• Absolute neutrophil count (ANC) > 1.0 × 109/L
• Platelets >= 50 × 109/L (Transfusions to achieve this level are allowed.)
Note: Subjects with organ function outside the parameters outlined in the above
inclusion criterion may be permitted to enroll only in Arm 2 of the Dose
Expansion Phase at the discretion of the Investigator and the Sponsor.
13. 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 (or other means)
14. Subject must agree to abide by dietary and other considerations required
during the study.
15. Timing requirements with respect to prior therapy and surgery are as
follows:
• At least 2 weeks or at least 5 half-lives, whichever is shorter, must have
elapsed since administration of the last dose of any prior systemic anticancer
therapy, including investigational agents. At least 4 weeks must have elapsed
if the last regimen included an anti-PD-1/PD-L1 antibody or an anti-CTLA4
antibody. At least 6 weeks must have elapsed
if the last regimen included BCNU or mitomycin C. (Subjects must be intolerant
to and/or have experienced disease progression on their prior therapy in the
opinion of the treating physician.)
• Subjects must be recovered from any clinically relevant effects of any prior
surgery.
• At least 2 weeks must have elapsed since the last radiotherapy. Palliative
radiation therapy is permitted so long as it does not involve the target
lesion(s) (see exclusion criterion 18).
• At least 2 weeks or at least 5 half-lives, whichever is shorter, must have
elapsed since the last liver-directed therapy.
16. Toxicity related to prior therapy must have returned to <= Grade 1 by CTCAE
by approximatelly 14 days prior to study start. Exceptions include Grade 2
alopecia, and appropriately controlled Grade 2 hypophysitis, thyroid
dysfunction, and adrenal insufficiency.
17. 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 if sexually active
with male partners, these partners must be azoospermic (vasectomized or due to
a medical cause) as affirmed by the subject; or
• Nonpregnant, nonlactating, and if sexually active with fertile male partner
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 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.
18. Male subjects must have azoospermia (vasectomized or due to a medical
cause) or if fertile and 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 final dose of
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.

1. Subject is unable to provide informed consent and/or to follow protocol
requirements.
2. Subject has thrombocytopenia (platelets < 50 × 109/L) or another major
bleeding disorder/diathesis.
Note: Subjects with platelets < 50 × 109/L may be permitted to enroll only in
Arm 2 of the Dose Expansion Phase at the discretion of the Investigator and the
Sponsor.
3. Subject has active brain metastases and/or leptomeningeal disease. Subjects
with known central nervous system (CNS) metastases are only permitted under the
following conditions; exceptions may be made on a case-by-case basis with
approval of the Sponsor: Brain metastases must have been stable for
approximately 2 months since completion of most recent CNS-directed
intervention. Subject may be on corticosteroids so long as the dose is stable
for approximately 14 days or decreasing at the time of study entry.
Anti-epileptic therapy is allowed so long as medications are not otherwise
excluded (see exclusion criteria 13 and 14) and seizures have been controlled
for approximately 4 weeks since last anti-epileptic medication adjustment.
• Dose Escalation Phase: Subjects with known CNS metastases that meet the above
conditions are permitted to enroll in dose escalation.
• Arm 1 (Dose Expansion Phase): Subjects with known or suspected CNS metastases
are excluded from Arm 1.
• Arm 2 (Dose Expansion Phase): Subjects with CNS metastases that meet the
above conditions are permitted to enroll in Arm 2.
4. Subject has other malignancy which may interfere with the diagnosis and/or
treatment of metastatic UM.
5. 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
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.
6. Subject has an active infection. Subject is permitted to enroll once any
required antibiotic and/or antifungal therapy has been completed and/or
infection is determined to be controlled.
7. Subject has an uncontrolled intercurrent illness.
8. Subject has 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 (see Appendix 15.2). Subjects
with bundle branch block and a prolonged QTc should be reviewed by the Sponsor
for potential inclusion.
9. 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.
10. Subject has known hypersensitivities to components of the FHD-286
formulation.
11. Subject is unable to tolerate the administration of oral medication or has
gastrointestinal (GI) dysfunction that would preclude adequate absorption,
distribution, metabolism, or excretion of study drug.
12. Subject is participating in any other clinical trials. Exceptions include
participation in any observational or nontherapeutic clinical trials.
13. Subject is on medications that are strong CYP3A inhibitors, are strong
CYP3A inducers, or are sensitive CYP3A substrates with narrow therapeutic
indices (TIs) (see Appendix 15.5).
14. Subject is on medications with narrow TIs that are sensitive P-glycoprotein
(P-gp) or breast cancer resistance protein (BCRP) substrates and are
administered orally, such as digoxin (see Appendix 15.6).
15. Administration of proton pump inhibitors (PPI) should be stopped or
switched to another acid-reducing agent (ARA; eg, antacids or histamine
H2-receptor antagonists [H2 blockers]) 7 days before administration of study
drug. In the event that it is medically necessary to dose PPIs concomitantly
with FHD-286, this may be permitted with Sponsor approval.
16. Subject is requiring clinically significant or increasing doses of systemic
steroid therapy or any other systemic immunosuppressive medication. The use of
a stable dose of systemic steroids and/or immunosuppressive medication is
permitted with Sponsor approval. Local or targeted steroid and
immunosuppressive therapies (eg, inhaled or topical steroids) are acceptable.
Appropriate steroid replacement to manage endocrine toxicities resulting from
prior systemic anticancer therapy is permitted. See exclusion criterion 3 for
exceptions regarding steroid therapy for subjects with CNS metastases. See
exclusion criterion13for exclusions regarding medications that are strong CYP3A
inhibitors, strong CYP3A inducers, or sensitive CYP3A substrates with narrow
TIs.
17. Subject has undergone any prior treatment with a BRG1/BRM inhibitor.
18. Palliative radiation or other intervention directed at or involving the
target lesion(s) is not allowed. Exceptions to this may be made at the
discretion of the Sponsor. See inclusion criterion 15.
19. Subject is pregnant or breastfeeding or is planning to become pregnant
within 1 year of study. Subject is a woman or man of childbearing capabilities
who is unwilling to use effective contraception.