Clinical trial: Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing's Disease (NCT02484755)

Eligibility criteria:
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
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.
Subject must be at most 70 Years

Patient description (medical language): A 47-year-old man comes to the office due to weight gain and fatigue.  He is not able to lift heavy objects or climb stairs. Family history is positive for DM type 2 and HTN in his father.  Blood pressure is 165/90 mm Hg and pulse is 85/min.  On physical examination, there is symmetric proximal muscle weakness of the upper and lower extremities.  Fasting plasma glucose level is 138 mg/dL and 24-hour urinary cortisol is twice the upper normal limit.  Further evaluation reveals that high-dose, but not low-dose, dexamethasone suppresses serum cortisol levels.  Serum ACTH levels are high-normal. This patient's findings are consistent with endogenous Cushing Syndrome.

Patient description (patient's own words): I'm a 47-year-old man. I went to the clinic because I had been gaining weight and had increased fatigue over the past few weeks. I was not able to lift heavy objects or even climb the stairs. My dad was diagnosed with type 2 diabetes and high blood pressure. During the exam, they took my blood pressure, which was 165/90 mm Hg, and my pulse was 85/min. They found out that I have weaknesses in both of my arms and legs. I also did a blood test on an empty stomach, and I had a glucose level of 138 mg/dL, and twice the upper normal limit of cortisol. I had high-normal levels of ACTH. The doctor said I suffer from endogenous Cushing Syndrome.

Does the patient match the trial criteria? 0