Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Adult patients (18 years and older)

• Confirmed biochemical diagnosis of Cushing s disease (primary or recurrent) asevidenced by increased 24-hour urine free cortisol (UFC), normal or increasedmorning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excessACTH.

• Surgical candidate for resection of ACTH producing pituitary adenoma

• Enrolled in 03-N-0164, Evaluation of Neurosurgical Disorders.

• Able to provide written informed consent at the time of study enrollment.

• Participants who are physically able to become pregnant must use an effective formof birth control from 14 days prior to enrollment through 6 months following thelast dose of vorinostat. Participants who are able to father a child must use aneffective form of birth control from Day 0 through 3 months following the last doseof vorinostat.

EXCLUSION CRITERIA:

• Patients who have been previously treated with vorinostat.

• Patients who have received sellar radiation.

• Significant medical illnesses that in the investigator s opinion cannot beadequately controlled or would compromise the patient s ability to tolerate thisvorinostat.

• Any history of cancer, unless in complete remission and off of all therapy for thatdisease for a minimum of 3 years.

• History of thromboembolic disorder or deep vein thrombosis

• Presence of abnormal hematological and biochemical parameters, (such as anemia orthrombocytopenia) as defined as:

• Neutrophil count < 1.5 K//micro L

• Hemoglobin < 8.0 g/dL.

• Hematocrit < 0.75x LLN (lower limit of normal)

• RBC count < 0.75x LLN

• Platelet count < 100 x 10^3 cells/micro L.

• Prothrombin time-international normalized ratio (PT-INR) > 1.5x ULN orActivated partial thromboplastin time (aPTT) > 1.5x ULN, with the exception ofpatients on prophylactic anticoagulation therapy

• Serum bilirubin level > 1.5x ULN.

• Active infection being currently treated with systemic antibiotics.

• Serious concurrent medical illness including renal failure (creatinine >3.0x - 6.0xULN) liver failure (ALT/AST >5.0x - 20.0x ULN) or severe cardio-respiratory disease.

• Pregnancy or lactation.

• Presence of any disease that will obscure toxicity or dangerously alter drugmetabolism (such as uncontrolled diabetes or bleeding disorders)

• Currently receiving other investigational agents.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to vorinostat, such as valproate.

• Currently taking another HDACi, such as valproate.

• Currently taking coumadin or its derivative anticoagulants.

• Currently taking any other medication to reduce cortisol or ACTH levels