Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease

Inclusion Criteria:

• Male and female patients at least 18 years old

• Patients with confirmed pituitary origin Cushing syndrome defined as 1, 2& 3 or 4 & 5 below:

1. Persistent hypercortisolism defined as a mean of 3 consecutive 24h UFC atbaseline assessment ≥ 1.3x ULN

2. Normal or elevated plasma ACTH levels

3. Pituitary adenoma > 4mm visible on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and/or >2 after DDAVPstimulation.

4. Recurrent or persistent CD defined as pathologically confirmed previouslyresected pituitary ACTH-secreting tumor, and 24 hour UFC >ULN at least 4 weeksafter pituitary surgery.

5. Patients on medical treatment for CD. Washout periods will be completed asbelow before screening: Inhibitors of steroidogenesis (metyrapone,ketoconazole, osilodristat,

• Levo-ketoconazole): 2 weeks
• SRLs (pasireotide): 2 weeks
• Progesterone receptor antagonist (mifepristone): 2 weeks
• Dopamine agonists (cabergoline): 4 weeks
• CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6times the half-life of drug

Exclusion Criteria:

• Patients with compromised visual fields, or evidence of visual changes within past 6months

• Patients with sellar tumor abutting or compressing the optic chiasm on MRI andnormal visual fields

• Patients with Cushing's syndrome not due to an ACTH-secreting pituitary tumor

• Patients who have undergone major surgery including pituitary surgery within 1 monthof screening or who have any major surgical procedures planned across the studyperiod

• Patients with serum potassium < 3.5 mEq/L unless stably controlled on potassiumsupplementation

• Patients with poorly-controlled Diabetes mellitus evidenced by HbA1c levels >8

• Patients with poorly controlled hypertension (i.e. blood pressure ≥ 160/100 mm Hg)

• Patients who have clinically significant cardiovascular impairment, as evidenced bythe presence of bradycardia, ventricular tachycardia, history of myocardialinfarction within past year, or any other cardiovascular impairment that may posesignificant health risk in view of the investigator.

• Patients with liver disease or history of liver disease such as cirrhosis, chronicactive hepatitis B and C, or chronic persistent hepatitis, or patients with ALT orAST >1.5 x ULN, serum total bilirubin >ULN, serum albumin <0.67 x LLN at screening

• Patients with renal disease or history of renal disease with creatinine clearance of 30 cm3/min or less and/or creatinine > 1.5 mg/dl at screening

• Patients not biochemically euthyroid. Patients receiving thyroid-replacement therapymust be on a stable dose for at least 3 months.

• Patients who are known to be positive for HIV, or any other condition thatsignificantly compromises subject's immune system.

• History of alcohol abuse or illicit substance use within past year.

• Female patients who are pregnant or lactating or are of childbearing potentialunless willing to practice acceptable method of birth control. Women participatingin the trial must employ double barrier method through oral contraceptive ordiaphragm with partner utilizing a condom. Abstinence is an acceptable form of birthcontrol if routinely practiced. Male participants must utilize a condom withspermicidal cap/jelly and agree to not donate sperm for up to 3 months beyond mainstudy period.

• Patients who have participated in any clinical investigation with an investigationaldrug within 1 month prior to screening or within 5 half-lives of the investigationaltreatment whichever is longer.

• Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors.

• Patients who have received pituitary irradiation within the last 5 years prior tothe baseline visit

• Patients with known hepatitis B surface antigen (HbsAg) positivity

• Patients with known hepatitis C antibody (anti-HCV) positivity