Open-label Treatment in Cushing's Syndrome

Study Overview
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Brief Summary
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This is a long-term, open-label extension study of levoketoconazole in subjects with endogenous Cushing's Syndrome.

Detailed Description
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This is a long-term, OLE study of levoketoconazole in subjects with endogenous CS who have completed one or both parent studies or otherwise potentially qualify for this study, as defined in the eligibility criteria.

Official Title
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An Open-label Extension Study of Levoketoconazole (2S,4R-ketoconazole) in the Treatment of Endogenous Cushing's Syndrome

Conditions
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Cushing Syndrome, Cushing Disease

Intervention / Treatment
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* Drug: Levoketoconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completed the Extended Evaluation Phase of Study COR-2012-01 (i.e. M12) Completed the Restoration Phase of Study COR-2017-01 (i.e. RES2) NOTE: Subjects meeting criteria 1 or 2 above who have had a break in therapy may be eligible only after discussion with the Medical Monitor. If eligible, such subjects may require re-establishment of the Therapeutic Dose via titration. All subjects who have had a break in therapy should be discussed with the Medical Monitor to determine the starting dose of levoketoconazole. Prior to resuming treatment with levoketoconazole, other therapies for Cushing's Syndrome must undergo an appropriate washout period, with minimum durations as follows: Ketoconazole or metyrapone: 2 weeks; Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks); Octreotide acetate LAR, lanreotide Autogel, pasireotide LAR: 12 weeks; Lanreotide SR: 8 weeks; Octreotide acetate (immediate release) or short-acting pasireotide: 1 week; Mifepristone (RU 486, KORLYM): 4 weeks; Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins): 6 weeks. Currently in a named patient program or other Expanded Access Program receiving levoketoconazole Were levoketoconazole-naïve prior to entry and received early rescue therapy with open-label levoketoconazole in Study COR-2017-01. Achieved a clinically meaningful partial response (with reduction of UFC) in Study COR-2017-01 at dose level 7 or at a maximally tolerated dose of levoketoconazole but did not meet the randomization criteria for Study COR-2017-01 at the end of the Dose Titration and Maintenance Phase when randomization was open. Were levoketoconazole-naïve prior to entry and were enrolled in Study COR-2017-01 in the Dose Titration and Maintenance Phase when randomization was closed. (NOTE: Such subjects must receive at least 1 dose of levoketoconazole before transitioning to this study.) Exclusion Criteria: Discontinued levoketoconazole while participating in Study COR-2012-01 or Study COR-2017-01 or a named patient program or other Expanded Access program, due to safety or tolerability concerns or lack of efficacy. Scheduled for surgery for treatment of CS or received surgery for treatment of CS within the 6 weeks prior to Screening. Treated with mitotane within 6 months prior to enrollment. History of malignancy, including adrenal or pituitary carcinomas (other than low-risk, well-differentiated carcinomas of thyroid, breast or prostate that are very unlikely to require further treatment in the opinion of the treating physician, or squamous cell or basal cell carcinoma of the skin).

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open-Label Extension Study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levoketoconazole<br>Levoketoconazole taken twice daily up to 1200 mg daily | Drug: Levoketoconazole<br>* Levoketoconazole up to 1200 mg daily<br>* Other names: COR-003;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from Baseline in 24-h UFC | Changes or shifts from baseline in mUFC | From Baseline to final study visit or up to a maximum of 3 years, whichever comes first. | 
| Changes from Baseline in Late Night Salivary Cortisol | Changes or shifts from baseline in late night salivary cortisol levels | From Baseline to final study visit or up to a maximum of 3 years, whichever comes first. | 
| Changes from Baseline in AEs/SAEs/AESI as assessed by CTCAE V4.03 | Changes from Baseline in the incidence and severity of AEs, SAEs, AESIs | From Baseline to final study visit or up to a maximum of 3 years, whichever comes first. |