Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing's Disease

NCT02484755 | Unknown Phase 2 DMC

• 1 other identifier: KY2015-167
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cushing's Disease; Corticotrophin Adenoma

Outcome Measures

Primary Outcomes (1)

• Change in levels of 24 hour urinary free cortisol after 4 weeks

  Full response is defined as the reduction of 24 hour urinary free cortisol more than 50% or normalized. Partial response is defined as the reduction of 24 hour urinary free cortisol between 25%\~ 50%. Poor response or resistance is defined as the reduction of 24 hour urinary free cortisol less than 25%.

  Baseline, Week 4

Secondary Outcomes (6)

• Number of participants with a normalized 24 hour urinary free cortisol after 4 weeks

  4 weeks

• Change in levels of Late-Night Salivary Cortisol after 4 weeks

  Baseline, Week 4

• Change in levels of pituitary hormones （a composite of pituitary panel)

  Baseline, Week 4

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  4 weeks

• Changes in tumor size

  Baseline, Week 4

Study Arms (1)

gefitinib

EXPERIMENTAL

gifitinib 250 mg oral administration once daily for a total of 4 weeks.

Drug: Gefitinib

Interventions

Gefitinib DRUG

See Arm Description

gefitinib

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (1)

Huashan Hospital

Shanghai, Shanghai Municipality, 200040, China

RECRUITING

MeSH Terms

Conditions

Pituitary ACTH Hypersecretion

Interventions

Gefitinib

Condition Hierarchy (Ancestors)

Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Yao Zhao, MD

  Department of Neurosurgery, Huashan Hospital, Fudan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ming Shen, MD

CONTACT

+86 13818795785; samshenming@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: associate professor

Study Record Dates

• First Submitted: June 21, 2015
• First Posted: June 30, 2015
• Study Start: June 1, 2015
• Primary Completion: September 1, 2015
• Last Updated: June 30, 2015

Record last verified: 2015-06

Locations

CN (1)