Official Title: “Rosiglitazone (Peroxisome Proliferating Activating Receptor-Gamma {PPAR-y} Ligand) Treatment of Pituitary Tumors”

RATIONALE: Rosiglitazone may help pituitary adenoma cells become more like normal cells, and grow and spread more slowly.

PURPOSE: This phase II trial is studying how well rosiglitazone works in treating patients with newly diagnosed or residual or recurrent pituitary adenoma.

Study Type: Interventional

Study Design: Treatment

Study Primary Completion Date: December 2009

OBJECTIVES: - To assess the effect of rosiglitazone maleate on the core biochemical parameter, 24-hour urinary free cortisol levels, in patients with recurrent or uncured pituitary-dependent Cushing disease. (Group 1) - To assess the effect of this drug on corticotropin-releasing hormone-stimulated pituitary tumor ACTH secretion in patients with recurrent or uncured pituitary-dependent Cushing disease. (Group 1) - To assess the effect of this drug on tumor growth in patients with non-secreting pituitary macroadenoma (> 10 mm) using RECIST criteria. (Group 2) - To assess the effect of this drug on pituitary tumor gonadotropin (i.e., follicle-stimulating hormone, leuteinizing hormone, and alpha-subunit) secretion in patients with non-secreting macroadenoma. (Group 2) - To assess the overall safety and tolerability of this drug in both cohorts of patients. - To assess the overall quality of life, in terms of performance status during treatment, of both cohorts of patients using the Karnofsky performance index.

OUTLINE: Patients are grouped according to adrenocorticotropic hormone (ACTH)-secreting status (yes [Group 1] vs no [Group 2]). - Group 1 (ACTH-secreting adenomas): Patients receive 4 mg oral rosiglitazone maleate once daily in week 1 and then 8 mg once daily beginning in week 2 and continuing for up to 6 months in the absence of disease progression or unacceptable toxicity. - Group 2 (non-secreting macroadenomas): Patients receive 4 mg oral rosiglitazone maleate once daily in week 1 and then 8 mg once daily beginning in week 2 and continuing for up to 12 months in the absence of disease progression or unacceptable toxicity.

Patients undergo collection of blood and urine samples at baseline and after completion of study therapy to assess pituitary function, thyroid function, and 24-hour urinary free cortisol levels. Additional assessments include corticotrophin-stimulation testing, dynamic pituitary function testing (i.e., arginine/growth-hormone releasing-hormone testing) to measure growth hormone secretion, and overnight 1 mg dexamethasone suppression testing to measure 8

a.m. serum cortisol levels. Patients also undergo MRI at baseline and after completion of study therapy to examine the effects of rosiglitazone maleate treatment on pituitary tumor size.

Patients complete a questionnaire at baseline and monthly during study for evaluation of headaches.

PROJECTED ACCRUAL: A total of 15 patients with ACTH-secreting pituitary tumor and 15 patients with non-secreting pituitary macroadenomas will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: rosiglitazone maleate
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Group 1 (ACTH-secreting adenomas)
  • Patients receive 4 mg oral rosiglitazone maleate once daily in week 1 and then 8 mg once daily beginning in week 2 and continuing for up to 6 months in the absence of disease progression or unacceptable toxicity.
• Experimental: Group 2 (non-secreting macroadenomas)
  • Patients receive 4 mg oral rosiglitazone maleate once daily in week 1 and then 8 mg once daily beginning in week 2 and continuing for up to 12 months in the absence of disease progression or unacceptable toxicity.

Primary Measures

• Efficacy of rosiglitazone maleate on Cushing disease
  • Safety Issue?: No
• Complete response in patients with non-secreting pituitary tumor
  • Safety Issue?: No
• Partial response in patients with non-secreting pituitary tumor
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Clinically demonstrable pituitary tumor, including either of the following subtypes:
• ACTH-secreting adenoma
• Residual or recurrent disease ≥ 1 month after prior pituitary surgery
• Clinically demonstrable tumor, as evidenced by both of the following:
• Elevated 24-hour urinary free cortisol (UFC) level
• Lack of suppression of 8 a.m. serum cortisol to < 1.8 µg/dL after administration of dexamethasone 1 mg at 11 p.m. the previous night
• Tumor demonstrated by MRI performed with and without contrast and/or by inferior petrosal sinus sampling with evidence of a central ACTH source
• Non-secreting pituitary adenoma
• Newly diagnosed disease or residual tumor after prior surgical debulking
• Patients underwent prior surgical debulking must be ≥ 3 months post-surgery
• More than 10 mm in widest diameter (i.e., macroadenoma), as demonstrated by pituitary MRI performed with and without gadolinium
• No biochemical evidence of any of the following:
• Acromegaly as demonstrated by normal serum insulin-like growth factor-1 (IGF-1) level
• Cushing disease as demonstrated by normal 24-hour UFC cortisol level
• Prolactinoma as demonstrated by normal to moderately elevated prolactin levels (moderate elevations in serum prolactin [< 200 ng/mL] can occur in non-secreting tumors due to pituitary stalk displacement)
• Normal visual field evaluation by Goldman perimetry
• Hypopituitarism allowed as evidenced by any or all of the following:
• Subnormal growth hormone (GH) response to arginine/GH-releasing hormone testing (normal response is an increase of 2-6 ng/me)
• Low age and sex-matched IGF-1 levels
• Low thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels
• Low estradiol levels
• Low leuteinizing hormone (LH) and low follicle-stimulating hormone (FSH) levels in post-menopausal female patients OR low testosterone, LH, and FSH levels in male patients
• Patients with Cushing disease (i.e., harboring ACTH-secreting pituitary adenomas) must meet the following criteria:
• Hypercortisolemic (i.e., uncured) despite ≥ 1 pituitary surgery
• Refuse to undergo pituitary irradiation and/or bilateral adrenalectomy
• Refuse alternate steroid-lowering therapy such as ketoconazole and/or metyrapone

PATIENT CHARACTERISTICS:

• Must be able to undergo pituitary MRI (group 2)
• No clinically significant renal, hematologic, cardiac, or hepatic abnormalities within the past month
• No other active malignancy within the past five years except basal cell carcinoma or carcinoma in situ of the cervix
• No evidence of drug or alcohol abuse
• No prior or current medical condition that may interfere with the conduct of the study or evaluation of its results, in the opinion of the Investigator or the Data Safety
• Monitoring Board compliance officer
• No postmenopausal female receiving HRT
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for at least 2 months prior to, during, and for 1 month after completion of study therapy
• No history of immunocompromise, including known HIV positivity as measured by enzyme-linked immunosorbent assay and western blot
• More than 2 months since prior blood donation > 400 mL
• No active or suspected acute or chronic uncontrolled infection
• No history of noncompliance to medical regimens, potentially unreliability, or inability to complete the study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior or concurrent radiotherapy for pituitary tumor
• More than 1 month since prior unlicensed drugs or participation in a clinical trial using an investigational drug
• More than 3 months since prior rosiglitazone maleate or other thiazolidinedione
• Patients diagnosed with hypopituitarism (except post-menopausal females) are required to initiate hormone-replacement therapy (HRT) for the 6-month duration of the study and to discontinue HRT at the end of 6 months to re-evaluate hypopituitarism
• No concurrent pituitary surgery

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Jonsson Comprehensive Cancer Center

Overall Clinical Trial Officials and Contacts

Anthony Heaney, MD Principal Investigator Jonsson Comprehensive Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00616642

Study ID Number: CDR0000586480

ClinicalTrials.gov Identifier: NCT00616642

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database