Treatment for Endogenous Cushing's Syndrome

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the clinical responder rate, defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.

Detailed Description
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This is an open label, single arm study with a Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation Phase designed to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with endogenous CS. Following an initial screening and washout period, as applicable, this study will be conducted in three treatment phases as follows: Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Dose titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Maintenance Phase: 6 months of treatment at the Therapeutic Dose following the Dose Titration Phase. Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four adequately collected 24 hour urine collections for UFC measurements, subjects will enter into the Maintenance Phase of the study and will be asked to return to the clinic monthly for 6 months for assessment of efficacy and safety. During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary at the discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of Maintenance Phase Visit, four complete 24 hour urine collections will be obtained and subjects may enter the Extended Evaluation Phase. Extended Evaluation Phase: 6 months of continued treatment after the Maintenance Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 90 days (±14 days) for safety and efficacy evaluations. Efficacy will be assessed primarily by measuring mean UFC concentrations at specified times as described in the clinical protocol. Safety will be assessed primarily by physical examinations with vital sign measurements, adverse events, clinical laboratory measures, electrocardiography, and pituitary MRI. An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. Membership of the DSMB is described in a Charter.

Official Title
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An Open Label Study to Assess the Safety and Efficacy of COR-003 (Levoketoconazole) in the Treatment of Endogenous Cushing's Syndrome

Conditions
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Endogenous Cushing's Syndrome

Intervention / Treatment
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* Drug: Levoketoconazole


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female ≥18 years of age Able to provide written informed consent prior to any study procedures being performed; eligible subjects must be able to understand the informed consent form prior to inclusion into the study. Confirmed diagnosis of newly diagnosed, persistent or recurrent Cushing's disease (CD) or endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy within the 18 months after enrollment. Previous medical records will be collected and used to support the diagnosis of CD or endogenous CS of other etiology, including the following etiologies: Ectopic adrenocorticotropic hormone (ACTH) secretion, i.e. ACTH not of pituitary origin Ectopic corticotropin-releasing hormone (CRH) secretion Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia, etc.) Etiology unknown. Must have elevated mean 24 hour UFC levels ≥1.5X ULN based on the normative range of the central lab assay and on a minimum of four measurements from adequately collected urine. In addition to elevated mean UFC, presence of abnormal values from one of the following tests: Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 micrograms/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 before start of Screening Phase; in that case previous test results and details of conduct will need to be available by the Baseline Visit) Elevated late night salivary cortisol concentrations (at least two measurements) >ULN Previously irradiated subjects with CD or endogenous CS of other etiology will be allowed as long as the radiation treatment occurred > 4 years ago and subjects have not exhibited evidence for improvement in their underlying CD for 6 months prior to the Screening visit. The total number of previously irradiated subjects enrolled in this study will not exceed 10. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse surgery, or in whom surgery will be delayed for at least 18 months following enrollment. Subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has been inadequate or not well tolerated must agree to minimum washout periods prior to the Baseline Visit as specified. Key Exclusion Criteria Subjects with Pseudo-Cushing's syndrome based on assessment of the Investigator. Subjects with cyclic CS based on assessment of the Investigator Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH. Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex Subjects with adrenal carcinoma History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with QTc interval of >470 msec during the Screening Phase. Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed). History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals. Subjects who receive any prohibited concomitant medication and cannot discontinue it safely prior to the Baseline Visit.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose titration
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levoketoconazole DL0<br>Levoketoconazole Tablets Dose Level 0 Once Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL1<br>Levoketoconazole Tablets Dose Level 1 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL2<br>Levoketoconazole Tablets Dose Level 1 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL3<br>Levoketoconazole Tablets Dose Level 3 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL4<br>Levoketoconazole Tablets Dose Level 4 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL5<br>Levoketoconazole Tablets Dose Level 5 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL6<br>Levoketoconazole Tablets Dose Level 6 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|
| Experimental: Levoketoconazole DL7<br>Levoketoconazole Tablets Dose Level 7 Twice Daily | Drug: Levoketoconazole<br>* Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole<br>* Other names: COR-003;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization in Urinary Free Cortisol in Patients With Endogenous Cushing's Syndrome. | The response to COR-003 is defined as mean UFC concentration ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase. The proportion of responders at the End of Maintenance Phase visit, following 6 months of treatment in the Maintenance Phase, for all dose groups combined was estimated using a generalized linear model with repeated measurements based on a binomial distribution with a logit link function and with region (US vs. non-US), concurrent CS medical conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded median split based on the ITT population), sex, disease duration (years), prior CS medication (Yes/No), prior radiation therapy (Yes/No) as Baseline covariates and visit as an independent factor. The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in the Maintenance Phase alongside its 95% Wald CI is presented. | 6 months of maintenance phase therapy without a prior dose increase during that phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cushing's disease, ectopic ACTH, adrenal Cushing's