Clinical trial: Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease (NCT03774446)

Eligibility criteria:
Inclusion criteria:

          -  Male and female patients at least 18 years old

          -  Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH)
             production:

               -  Persistent hypercortisolemia established by two consecutive 24 h UFC levels at
                  least 1.5x the upper limit of normal

               -  Normal or elevated ACTH levels

               -  Pituitary macroadenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS)
                  central to peripheral ACTH gradient >2 at baseline and >3 after
                  corticotropin-releasing hormone (CRH) stimulation

               -  Recurrent or persistent Cushing disease defined as pathologically confirmed
                  resected pituitary ACTH-secreting tumor or IPSS central to peripheral ACTH
                  gradient >2 at baseline and >3 after CRH stimulation, and 24 hour UFC above the
                  upper limit of normal reference range beyond post-surgical week 6

               -  Patients on medical treatment for Cushing disease. The following washout periods
                  must be completed before screening assessments are performed:

                    -  Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks

                    -  Somatostatin receptor ligand pasireotide: short-acting, 2 weeks;
                       long-acting, 4 weeks

                    -  Progesterone receptor antagonist (mifepristone): 2 weeks

                    -  Dopamine agonists (cabergoline): 4 weeks

                    -  CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6
                       times the half-life of drug

        Exclusion criteria:

          -  Patients with compromised visual fields, and not stable for at least 6 months

          -  Patients with abutment or compression of the optic chiasm on MRI and normal visual
             fields

          -  Patients with Cushing's syndrome due to non-pituitary 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, Multiple endocrine neoplasia (MEN) 1

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

          -  Patients with cyclic Cushing's syndrome defined by any measurement of UFC over the
             previous 1 months within normal range

          -  Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism due to
             overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled
             depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and
             uncontrolled diabetes mellitus

          -  Patients who have undergone major surgery within 1 month prior to screening

          -  Patients with serum K+< 3.5 while on replacement treatment

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

          -  Patients who have clinically significant impairment in cardiovascular function or are
             at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV),
             unstable angina, sustained ventricular tachycardia, clinically significant
             bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one
             year prior to study entry

          -  Patients with liver disease or history of liver disease such as cirrhosis, chronic
             active hepatitis B and C, or chronic persistent hepatitis, or patients with alanine
             aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum
             total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal
             (LLN) at screening

          -  Serum creatinine > 2 x ULN

          -  Patients not biochemically euthyroid

          -  Patients who have any current or prior medical condition that can interfere with the
             conduct of the study or the evaluation of its results, such as

               -  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

               -  Presence of active or suspected acute or chronic uncontrolled infection

               -  History of, or current alcohol misuse/abuse in the 12 month period prior to
                  screening

          -  Female patients who are pregnant or lactating, or are of childbearing potential and
             not practicing a medically acceptable method of birth control. If a woman is
             participating in the trial then one form of contraception is sufficient (pill or
             diaphragm) and the partner should use a condom. If oral contraception is used in
             addition to condoms, the patient must have been practicing this method for at least
             two months prior to screening and must agree to continue the oral contraceptive
             throughout the course of the study and for 3 months after the study has ended. Male
             patients who are sexually active are required to use condoms during the study and for
             three month afterwards as a precautionary measure (available data do not suggest any
             increased reproductive risk with the study drugs)

          -  Patients who have participated in any clinical investigation with an investigational
             drug within 1 month prior to screening or patients who have previously been treated
             with seliciclib

          -  Patients with any ongoing or likely to require additional concomitant medical
             treatment to seliciclib for the tumor

          -  Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors.

          -  Patients who were receiving mitotane and/or long-acting somatostatin receptor ligands
             octreotide long-acting release (LAR) or lanreotide

          -  Patients who have received pituitary irradiation within the last 5 years prior to the
             baseline visit

          -  Patients who have been treated with radionuclide at any time prior to study entry

          -  Patients with known hypersensitivity to seliciclib

          -  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

          -  Patients with presence of Hepatitis B surface antigen (HbsAg)

          -  Patients with presence of Hepatitis C antibody test (anti-HCV)
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.


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? Contradiction