Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing's Disease
Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing's Disease
The USP8 gene and its downstream target, epidermal growth factor receptor (EGFR), is a
 potential therapeutic target of Cushing disease. The EGFR inhibitor, Gefitinib, has been
 shown to reduce the production of ACTH both in vitro and in vivo, especially in USP8-mutated
 corticotrophin adenomas. The investigators hypothesize that Gefitinib will suppress pituitary
 corticotroph tumor ACTH production and normalize urinary free cortisol levels in patients
 with USP8-mutated Cushing's disease. Gefitinib is an FDA approved drug used to treat
 non-small cell lung cancer. However, in this study, the drug will be used to treat
 corticotrophin adenoma.
Inclusion Criteria:

 -  Male or female patients aged 18 years or greater

 -  Patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by

 -  Mean urinary free cortisol of four 24-hour urine samples collected within 2
 weeks, at least 1.5 times the upper limit of the laboratory normal range

 -  Morning plasma ACTH within the normal or above normal range

 -  Either MRI confirmation of pituitary macroadenoma (greater than or equal to 1
 cm), or inferior petrosal sinus gradient >3 after CRH stimulation for those
 patients with a microadenoma (tumor less than 1 cm)*, or for patients who have
 had prior pituitary surgery, histopathology confirming an ACTH staining adenoma.

 -  if IPSS had previously been performed without CRH (e.g.with DDAVP), then a
 central to peripheral pre-stimulation gradient > 2 is required. If IPSS had
 not previously been performed, IPSS with CRH stimulation is required.

 -  Patients with de novo Cushing's disease can be included only if they are not
 considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically
 unapproachable tumors, patients who refuse to have surgical treatment)

 -  Confirmatory testing prior to IPSS (low-dose dexamethasone suppression testing or
 dexamethasone-CRH testing) has to be performed for patients with UFC ≤ 3.0 X ULN and a
 pituitary microadenoma in order to exclude possible pseudo-Cushing's syndrome.

 -  Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to
 care for most of this personal needs)

 -  For patients on medical treatment for Cushing's disease the following washout periods
 must be completed before baseline efficacy assessments are performed

 -  Inhibitors of steroidogenesis (ketoconazole, metyrapone, rosiglitazone): 1 week

 -  Dopamine agonists (bromocriptine, cabergoline): 4 weeks

 -  Octreotide LAR and Lanreotide autogel: 8 weeks

 -  Lanreotide SR: 4 weeks

 -  Octreotide (immediate release formulation): 1 week

 -  Patients with a known history of impaired fasting glucose or DM may be included,
 however blood glucose and antidiabetic treatment must be monitored closely throughout
 the trial and adjusted as necessary

 Exclusion Criteria:

 -  Patients who have received pituitary irradiation within the last ten years prior to
 visit 1, as the onset time of the radiation effects cannot be determined

 -  Patients who have treated with mitotane during the last 6 months prior to Visit 1

 -  Patients with compression of the optic chiasm causing any visual field defect, in
 order to exclude patients with a tumor causing chiasma compression requiring surgery

 -  Patients with Cushing's syndrome due to ectopic ACTH secretion

 -  Patients with hypercortisolism secondary to adrenal tumors or nodular (primary)
 bilateral adrenal hyperplasia

 -  Patients who have a known inherited syndrome as the cause for hormone over secretion
 (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)

 -  Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)

 -  Patients who are hypothyroid and not on adequate replacement therapy

 -  Patients who have undergone major surgery within 1 month prior to starting the study

 -  Patients with symptomatic cholelithiasis

 -  Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly
 controlled as evidenced by HbA1C >8%

 -  Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)

 -  Patients receiving anticoagulants that affect PT or PTT

 -  Patients who have congestive heart failure (NYHA Class III or IV), unstable angina,
 sustained ventricular tachycardia, clinically significant bradycardia, advanced heart
 block, history of acute MI less than one year prior to study entry or clinically
 significant impairment in cardiovascular function

 -  Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTc
 >480 ms, hypokalemia, family history of long QT syndrome, and concomitant medications
 known to prolong QT interval

 -  Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic
 persistent hepatitis, or patients with ALT/AST more than 2 X ULN, serum creatinine
 >2.0 X ULN, serum bilirubin >2.0 X ULN, serum albumin < 0.67 X LLN

 -  Patients with WBC <3 X 109/L; Hgb < LLN; PLT <100 X 109/L

 -  Patients who have any current or prior medical condition that can interfere with the
 conduct of the study or the evaluation of its results in the opinion of the
 investigator or the sponsor's medical monitor

 -  Female patients who are pregnant or lactating, or are of childbearing potential and
 not practicing a medically acceptable method for birth control. Female patients must
 use barrier contraception with condoms. If oral contraception is used, the patient
 must have been practicing this method for at least two months prior to enrollment and
 must agree to continue the oral contraceptive throughout the course of the study and
 for one month after the last dose of study drug. Male patients who are sexually active
 are required to use condoms during the study and for 1 month afterwards

 -  History of immunocompromise, including a positive HIV test result (Elisa and Western
 blot). An HIV test will not be required, however, previous medical history will be
 reviewed

 -  Patients who have a history of alcohol or drug abuse in the 6 month period prior to
 receiving pasireotide

 -  Patients who have given a blood donation (of 400 ml or more) within 2 months before
 receiving gefitinib

 -  Patients who have participated in any clinical investigation with an investigational
 drug within 1 month prior to dosing and patients who have previously been treated with
 gefitinib

 -  Known hypersensitivity to gefitinib

 -  Patients with active malignant disease within the last five years (with the exception
 of basal cell carcinoma or carcinoma in situ of the cervix)

 -  Patients with the presence of active or suspected acute or chronic uncontrolled
 infection

 -  Patients with a history of non-compliance to medical regimens or who are considered
 potentially unreliable or will be unable to complete the entire study