This study will evaluate whether the drug mifepristone can improve the symptoms of Cushing's syndrome in people with ectopic adrenal corticotrophin hormone (ACTH) secretion. Cushing's syndrome occurs when the adrenal glands produce too much cortisol, a hormone that helps to regulate the body's use of salt and food. Excessive cortisol is usually the result of too much ACTH, the hormone that causes the adrenal glands to make cortisol. The extra ACTH is made either by a tumor in the pituitary gland (called Cushing's disease) or by a tumor somewhere else (called ectopic ACTH secretion). Mifepristone blocks the action of cortisol in the body. The drug has been used safely to treat a few people with Cushing's syndrome and patients with certain kinds of cancer, gynecological diseases and psychiatric disorders.

People between 18 and 85 years of age with Cushing's syndrome caused by EXCESS ACTH secretion may be eligible for this study. Candidates are admitted to the hospital for evaluation to confirm Cushing's syndrome and to determine its cause. The evaluation includes blood and urine tests, imaging tests, dexamethasone and corticotropin-releasing hormone tests and inferior petrosal sinus sampling. Patients determined to have Cushing's syndrome due to ECTOPIC ACTH secretion undergo imaging studies (CT, MRI and a nuclear medicine scan) and begin mifepristone therapy.

Participants remain in the hospital for the following tests and procedures:

• Physical examination, electrocardiogram (EKG) and blood and urine tests
• Completion of medical questionnaires
• DEXA scan to determine bone mineral density and body composition
• Glucose tolerance test
• Urine pregnancy test and ultrasound to measure uterine lining thickness (for women)

Patients take mifepristone by mouth 3 times a day. The dose is increased every week or so until symptoms improve or the highest dosage allowed is reached. Patients may remain in the hospital for all or part of the dose-finding part of the study. During this period (usually 2 to 4 weeks), blood pressure, glucose tolerance and blood chemistries are measured and EKG and urinalysis done every 5 to 14 days. When the mifepristone dose is stable patients remain on that dose for at least 2 weeks and are then re-evaluated. Patients then return to the hospital for evaluations every 3 months. Those who do well on the drug may continue to take it for up to 12 months.

Between 10% and 20% of patients with hypercortisolism (Cushing's Syndrome) have tumoral ectopic production of adrenocorticotropin hormone (ACTH) that causes cortisol excess. If an ectopic tumor cannot be found or if surgery cannot be done, the treatment options include medicines that reduce cortisol production and bilateral adrenalectomy. The available medications that reduce cortisol production have important adverse effects and are not effective in some patients and adrenalectomy leads to lifelong requirements for medical hormone replacement. Thus, additional treatment options would be welcome. This study evaluates a potential new medication for the treatment of these patients; mifepristone blocks the effects of cortisol rather than decreasing its production. The purpose of this study is to see whether this agent can improve diabetes or other symptoms of Cushing's syndrome in subjects with ectopic ACTH secretion. Another purpose is to evaluate adverse effects with this drug. Patients with presumed ectopic ACTH secretion and diabetes will take mifepristone 600 mg daily by mouth, and the effect on diabetes and other symptoms of Cushing's syndrome will be measured. Subjects will return to the hospital at 2, 3, 6, 9, and 12 months after starting mifepristione for evaluation of diabetes and other symptoms. The agent will be available for up to 12 months for patients in whom it is effective.

Patients take mifepristone by mouth 3 times a day. Each dose will contain 200 mg. Patients may remain in the hospital for all or part of the initial safety studies, every two weeks for eight weeks. During this period blood pressure, glucose tolerance and blood chemistries are measured and EKG and urinalysis done every two weeks. The mifepristone dose can be decreased or stopped if there are adverse effects. When the mifepristone dose is stable for eight weeks, patients will be re-evaluated. Patients then return to the hospital for evaluations one month later and then every 3 months. Those who do well on the drug may continue to take it for up to 12 months.

• INCLUSION CRITERIA:

Subjects will be included if they have ALL of the three following criteria:

1. Hypercortisolism from Cushing's syndrome caused by ACTH ectopic secretion

   AND

2. Glycemic disorder that is considered to be caused or worsened by the hypercortisolism

   AND

3. At least one symptom attributable to the Cushing's syndrome.

   EXCLUSION CRITERIA:

   • Evidence for Cushing's disease as judged by positive inferior petrosal sinus sampling or a lesion on pituitary MRI with positive CRH test
   • Suspected or known adrenocortical cancer or adenomas, as judged by ACTH values less than 10 pg/ml and adrenal mass
   • Subjects with cyclic Cushing's syndrome defined by any measurement of Urinary Free Cortisol over the previous 2 months less than 2 N
   • Children (age less than 18) and patients over 85 years
   • Pregnant or lactating women. A urinary pregnancy test will be performed in women of childbearing potential unless they have a history of menopause prior to Cushing's syndrome or hysterectomy
   • Life expectancy less than two months
   • Surgery planned within 8 weeks after inclusion, especially bilateral adrenalectomy
   • Uncontrolled diabetes (plasma glucose greater than 15.0 mmol/L (270 mg/L) and/or HbA1c greater than 10%)
   • Uncontrolled hypertension (blood pressure greater than 180/110 mmHg)
   • Recent (less than two weeks prior to inclusion) initiation of corrective treatments for depression
   • Clinically significantly impaired cardiovascular function (e.g. stage IV cardiac failure)
   • Severe liver disease (liver enzymes greater than or equal to 3 x the institutional upper limit of normal range)
   • Severe renal impairment (serum creatinine greater than or equal to 2.2 mg/dl or creatinine clearance less than 30 ml/min)
   • Severe hypokalemia (plasma K below 3.0 mmol/L)
   • Uncontrolled severe active infection
   • In women, known endometrial cancer, history of endometrial hyperplasia or vaginal bleeding of unknown cause
   • Premenopausal women with hemorrhagic disorders or on anticoagulants
   • Recent (less than two weeks prior to inclusion) initiation of or significant change in dose of anti-tumor therapy
   • Previous treatment with approved or experimental steroidogenesis inhibitors, somatostatin analogues within one week of admission (eight weeks for patients on octreotide LAR or on lanreotide autogel)
   • Plasma mitotane concentration greater than 5 microgram/ml
   • Impaired mental capacity or markedly abnormal psychiatric evaluation that precludes informed consent
   • Body weight over 136 kg, which is the limit for the tables used in the scanning areas
   • Inherited porphyria
   • Positive pregnancy test at inclusion
   • Use of antiretroviral agents, midazolam, cabergoline, erythromycin, or grapefruit juice within two weeks of the study