Rosiglitazone in Treating Patients With Newly Diagnosed ACTH-Secreting Pituitary Tumor (Cushing Disease)

Study Overview
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Brief Summary
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RATIONALE: Rosiglitazone may help pituitary tumor cells become more like normal cells, and to grow and spread more slowly. PURPOSE: This phase II trial is studying how well rosiglitazone works in treating patients with newly diagnosed ACTH-secreting pituitary tumor (Cushing disease).

Detailed Description
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OBJECTIVES: Primary To assess the effect of rosiglitazone on biochemical control in patients with newly diagnosed ACTH-secreting pituitary tumor (Cushing disease). Secondary To assess the effect of this drug on corticotrophin (CRH)-stimulated pituitary tumor ACTH secretion. To assess the overall safety and tolerability of this drug in these patients. To assess the overall quality of life of patients treated with this drug. Percentage of Reduction in 24-hour Urinary-free Cortisol Levels OUTLINE: This is a multicenter study. Patients receive oral rosiglitazone once daily for 7 weeks in the absence of disease progression or unacceptable toxicity. Blood, urine, and saliva samples are collected periodically for laboratory studies. Inflammatory markers (C-reactive protein, interleukin-6 [IL-6], serum sialic acid, soluble intracellular and vascular adhesion molecules [sICAM-1, and sVCAM-1], and amyloid A) are measured at baseline and at the completion of study treatment; salivary cortisol and 24-hour urinary-free cortisol levels are measured at baseline and weekly during study treatment; dexamethasone suppression tests with serum cortisol and corticotrophin (CRH) stimulation test are performed at baseline and at the completion of study treatment; prolactin, insulin-like growth factor-1 (IGF1), thyroid function, and sex steroid hormones are measured at baseline and at the completion of study treatment; and dynamic pituitary function testing (arginine/growth hormone-releasing hormone [GHRH] testing to measure growth hormone secretion) is performed at baseline.

Official Title
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An Open Label, Multicenter Study Evaluating the Safety and Efficacy of Short Term (6 Weeks) Rosiglitazone Treatment in Patient's With Cushing's Disease

Conditions
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Cushing's Disease

Intervention / Treatment
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* Drug: rosiglitazone maleate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Clinically demonstrable ACTH-secreting pituitary tumor Pituitary tumor demonstrated on MRI with and without contrast AND/OR evidence of a central ACTH source following inferior petrosal sinus sampling Newly diagnosed disease Biochemically active disease that is not adequately controlled, as demonstrated by the following standard criteria: Elevated 24-hour urinary-free cortisol levels on at least 2 separate 24-hour urine collections 1 week apart Lack of suppression of serum cortisol to < 1.8 μg/dL (at 8 am) following administration of 1 mg of dexamethasone at 11 pm the night before Measurable plasma ACTH levels Patient is hypercortisolemic and does not wish to receive alternate steroid-lowering therapy, such as ketoconazole and/or metyrapone Patients with evidence of optic nerve or chiasm compression on post-operative MRI must have a normal visual field evaluation by Goldman perimetry No visual field abnormalities Hypopituitarism* allowed, as evidenced by any or all of the following: Subnormal growth hormone (GH) response to arginine/growth hormone-releasing hormone (GHRH) testing (normal response is an increase of > 4 ng/mL) Low age-and sex-matched insulin-like growth factor-1 (IGF-1) levels Low thyroid-stimulating hormone (TSH) levels Low free triiodothyronine (T3) and free thyroxine (T4) levels Low estradiol levels Low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in postmenopausal female patients Low testosterone, LH, and FSH levels in male patients NOTE: *Patients who are diagnosed with hypopituitarism will initiate thyroid hormone replacement therapy prior to pituitary surgery as part of routine care. Other hormone replacement, such as sex steroids or growth hormone, will not be initiated during the study. PATIENT CHARACTERISTICS: Not pregnant or nursing Fertile patients must use effective contraception (if oral contraception is used, it must be used for ≥ 2 months prior to, during, and for 1 month after completion of study therapy) No clinically significant renal, hematologic, or hepatic abnormalities No prior or concurrent medical condition that may interfere with the conduct of the study or the evaluation of its results, in the opinion of the investigator or the DSMB compliance officer No history of immunocompromise, including HIV positivity by ELISA and western blot No alcohol or drug abuse within the past 6 months No blood donation (≥ 400 mL) within the past 2 months No other active malignant disease within the past 5 years except for basal cell carcinoma or carcinoma in situ of the cervix No active or suspected acute or chronic uncontrolled infection No severe osteoporosis, defined as bone mineral density T scores < 2.5 standard deviations below age-matched controls No history of noncompliance to medical regimens Considered reliable Able to complete the entire study PRIOR CONCURRENT THERAPY: More than 3 months since prior rosiglitazone or other thiazolidinedione No prior or concurrent radiotherapy for pituitary tumor More than 1 month since prior participation in any clinical investigation involving an investigational drug More than 30 days since prior unlicensed drugs No concurrent pituitary surgery

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rosiglitazone<br> | Drug: rosiglitazone maleate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Responders | Definition of Treatment Response The primary outcome in Cushing's disease will the % responders, a responder is defined as a patient with 2 consecutive 24h urinary free cortisols within the normal reference range in association with no clinical signs of disease progression. Secondary outcomes will include the % reduction in 24h UFC (derived by comparison of the mean of 2 baseline 24h UFC values with mean of the two lowest consecutive 24h UFC values while on study treatment in association with no clinical signs of disease progression). | 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACTH-producing pituitary tumor