Cushing's Syndrome - Baltimore MD

Summary:

Purpose:
To evaluate the efficacy of ascending doses of COR-003 (2S,4R-ketoconazole) in subjects with elevated levels of cortisol due to endogenous CS by assessment of reduction in UFC levels (based on adequately collected 24-hour urine collections)

To identify the range of effective and safe doses of COR-003 that reduce mean UFC levels to ≤ the upper limit of the normal range (ULN) of the assay at month 6 of the maintenance phase of dosing without a prior dose increase in that phase

Inclusion Criteria

Subjects eligible for enrollment in the study must meet all the following criteria:

1. Male or female ≥18 years of age
2. Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if they are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008). Previous medical records will be collected and used to support the diagnosis. The diagnostic criteria for appropriateness of inclusion of each subject into the study will be reviewed by the Medical Monitor.
• Subjects MUST have elevated 24-hour UFC levels ≥1.5X ULN of assay based on a minimum of 4 measurements from adequately collected urine. Urine may be collected on sequential days.
• Diagnosis of the disease will also need to be based on the association of clinical features of endogenous CS, review of past medication history, excluding exogenous sources of glucocorticoids, and abnormal values from one of the following tests:
1. Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 g/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 2 months; previous test results and details of conduct will need to be available)
2. Elevated late night salivary cortisol concentrations (at least 2 measurements) >ULN at screening

NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by Modified Diet in Renal Disease MDRD equation) >40 and <60 mL/min/1.73 m2 in addition to meeting the UFC criteria, late night salivary cortisol test results (≥2 measurements) MUST also demonstrate evidence of CS.

• For subjects with Cushing’s disease who have already undergone surgery, a minimum of 3 months should have elapsed before the subject can be deemed a surgical failure.
3. Previously irradiated subjects will be allowed as long as the radiation treatment occurred > 4 years ago and they have not exhibited evidence for improvement in their underlying Cushing’s disease for 6 months. The total number of previously irradiated subjects enrolled in this study will not exceed 10.
• In the vast majority of subjects treated with radiation, efficacy is observed in <4 years.
4. Subjects who refuse surgery or in whom surgery will be delayed beyond the projected duration of this study will be permitted to participate.
5. Confirmed diagnosis of persistent or recurrent endogenous hypercortisolemia as defined by elevated 24-hour UFC levels on repeated determinations (described in Inclusion #2) caused by either ACTH-dependent or ACTH-independent etiologies.
• Cushing’s Disease (CD) which is specifically defined as mean 24-hour UFC level of ≥1.5X ULN on repeated determination, morning plasma corticotropin (ACTH) level of 5 ng/L (1.1 nmol /L) or more, a confirmed pituitary source of CD (documentation of ACTH immunoreactivity on pathological evaluation), and as determined by medical records (including surgical reports and pituitary imaging scans), or bilateral inferior petrosal sinus sampling (BIPSS) with a central to peripheral ratio of >2 before or >3 after corticotropin-releasing hormone (CRH) administration)
• Ectopic ACTH secretion, not of pituitary origin Ectopic CRH secretion
• Adrenal-dependent CS (adrenal adenoma, adrenal autonomy)
• Etiology unknown
6. Subjects whose CS is due to Cushing’s disease with or without radiographically visible adenomas may be enrolled based on a pituitary magnetic resonance imaging (MRI) scan may be enrolled as long as biochemical criteria in Inclusion Criteria #5 are met.
7. Subjects on treatment for CS for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods as determined by the nature of their treatment before baseline assessments are performed for participation in this study:
• Inhibitors of steroidogenesis (including ketoconazole): 2 weeks
• Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks)
• Octreotide acetate LAR and lanreotide Autogel®: 12 weeks
• Lanreotide SR/long-acting pasireotide: 8 weeks
• Octreotide acetate (immediate release formulation) or short-acting pasireotide: 1 week
• Mifepristone (RU 486): 4 weeks
8. Subjects on megesterol acetate (medroxyprogesterone acetate) must agree to a wash out of ≥6 weeks prior to receiving the first dose of the study medication
9. Subjects with impaired fasting glucose, diabetes and/or hypertension may be enrolled
10. A female is eligible to enter and participate in the study if she is of:

Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy. However in questionable cases, a blood sample with FSH > 40MIU/ml and estradiol < 40pg/ml (<140 pmol/L) is confirmatory.

OR

Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study – screening to follow-up contact):

• Complete abstinence from intercourse; or
• Male partner is sterile prior to female subject entry into the study, and this male partner is the sole partner for that subject; or
• Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or
• Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or
• Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository); or
• An intrauterine device (IUD); or
• Estrogenic vaginal ring; or
• Percutaneous contraceptive patches
11. 12-lead ECGs show no acute ischemia or clinically significant abnormality needing medical intervention.
12. Ability to comprehend and comply with procedures.
13. Agree to commit to participate in the current protocol.
14. Subjects provide written informed consent prior to any study procedures being performed (all subjects should be able to understand the informed consent form and any other documents that subjects are required to read).

1. De novo Cushing´s disease AND a candidate for pituitary surgery
• If surgery is to be delayed for >6 months, subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery.
2. Subjects treated with radiation within the previous 4 years or >4 years and with evidence of improvement in their disease within 6 months prior to Screening.
• In the majority of subjects treated with radiation, efficacy is observed in <4 years.
3. Subjects who have been treated with mitotane within 6 months of screening or have levels exceeding 5 μg/mL.
4. Pseudo-Cushing’s syndrome based on clinical assessment of the investigator. Appendix H describes a number of conditions in which elevated cortisol levels may be observed in the absence of Cushing’s syndrome, sometimes referred to as Pseudo-Cushing’s syndrome
5. Subjects with adrenal carcinoma.
6. Body habitus preventing repeated venipuncture as required by protocol.
7. Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or 5 half-lives of screening, whichever is longer.
8. Male and female subjects with QTc interval of >470 msec.
9. History of Torsades des Pointes or ventricular tachycardia or ventricular fibrillation or history of prolonged QT syndrome (including family history) or use of medications resulting in QT/QTc prolongation or hypokalemia <3.0 meq/L.
10. Subjects with a non-endogenous source of hypercortisolemia such as exogenous source of glucocorticoids or therapeutic use of ACTH.
11. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to Screening. Subjects with history of carcinoma must have a life expectancy of >1 year and must be on stable doses of their specific therapies. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled.
12. Diagnosis of HIV.
13. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical intervention.
14. Subjects with hypercholesterolemia who are on current atorvastatin or simvistatin and not willing or unable to change to alternative therapies as noted (pravastatin, fluvastatin, and rosuvastatin) within 2 weeks of study screening. Subjects may sign informed consent and then immediately begin screening assessments once they have discontinued the prohibited statin.
15. Subjects requiring repeated frequent hospitalizations for management of hyperglycemic episodes.
16. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using MDRD equation for estimating renal function (eGFR).
17. Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion (for example, New York Heart Association (NYHA) class III or IV congestive heart failure).
18. Known hepatic disease, other than mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic steatohepatitis [NASH]).
19. History of recurrent gall stone attacks or pancreatitis.
20. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test.
21. Liver function tests (LFT) must not be above the following cut-offs at screening: ALT and/or AST >3.0X ULN, GGT >2X ULN, and total bilirubin >2X ULN. If all LFTs are within normal limits (WNL) and total bilirubin is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with indirect total bilirubin up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other LFTs are WNL.
22. History of documented clinically significant liver function abnormalities requiring drug discontinuation on ketoconazole or closely related chemical analogues (for example, itraconazole).
23. Presence of any other clinically significant medical condition, as determined by the Investigator that would preclude the subject from being able to follow instructions or to perform the necessary procedures (for example, psychiatric instability or severe disability).
24. Compression of the optic chiasm.
25. Abnormal free T4. Subjects with TSH
26. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.
27. The subject is currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (which inhibit absorption of COR-003). A list of orally acceptable antacids (for example, Mylanta and Maalox) will be provided, and can only be taken a minimum of 2 hours after dosing of COR-003.
28. The subject is receiving the following concomitant therapies:
• Weight loss medications (prescription or over the counter)
• Acetaminophen >3 g total daily dose (due to increased hepatotoxicity)
• Co-administration of strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with COR-003 and cannot be discontinued prior to dosing (see Section 10.2 and Appendix K for further details)
• Statins other than pravastatin, fluvastatin and rosuvastatin
• The following herbal medicines are prohibited: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and Salboku-to).
• Topical or inhaled steroids.
• Carbamazipine, fenofibrate, carbenoxolone.
• Excessive ingestion of genuine licorice.
29. Pregnant women or lactating women, or women of child bearing potential not practicing a medically acceptable method for birth control or sexually active men not using contraception. Women must agree to continue to use an acceptable method of contraception and men must use condoms, if sexually active. All forms of contraception, used by male and female subjects, must be used during the course of the study and for 2 weeks after the study is completed.
30. Any other condition which would jeopardize the risk of subject participation in the trial in the opinion of the Investigator