Conditions: Hippel-Lindau Disease Kidney Cancer
Keywords: Kidney Cancer VHL 17 AAG Chemotherapy Von Hippel Lindau Disease Renal Tumor
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This study will examine whether the drug 17AAG (17-allylamino 17-demethoxygeldanamycin) can shrink kidney tumors in patients with Von Hippel-Lindau disease (VHL), a rare, inherited syndrome in which patients develop tumors in certain parts of the body. 17AAG contributes to the destruction of proteins in cells that may play in role in causing cancer and spurring tumor growth. The study will also look at the effect of 17AAG on other tumors patients may have that are caused by VHL, on the amount of blood vessels in the tumors, on the biologic activity of the tumor, and on cells circulating in the bloodstream, as well as the safety of the drug and its impact on the kidney tumor in patients whose tumor(s) is removed.

Patients 18 years of age and older with von Hippel-Lindau disease who have at least one kidney tumor large enough to pose a risk of metastasis (spread of cancer to other parts of the body) may be eligible for this study. Candidates are screened with a medical history and physical examination, computed tomography (CT) scan, brain magnetic resonance imaging (MRI), see below), and blood and urine tests. Additional tests, including a 24-hour urine collection, ultrasound of the testicles in men, hearing test, eye exam, and MRI of the spine, may be done if recent test results are not available.

Participants undergo the following tests and procedures:

MRI: This test uses a strong magnetic field and radio waves to show structural and chemical changes in tissue. During the scan, the patient lies on a table in a narrow cylinder containing a magnetic field, wearing earplugs to muffle loud noises that occur with electrical switching of the magnetic fields. A catheter (plastic tube) is inserted into the patient's arm to administer a contrast dye that enhances the images.

17AAG treatment: Patients receive 17AAG infusions into a vein once a week for 3 weeks out of every 4, for 3 months. The infusions last up to 1 to 2 hours.

Repeat testing: After 3 months, patients have repeat MRI scans to measure changes in tumor activity, blood flow, and number of blood vessels in the tumor since the pretreatment scans. They may have additional tests, including a CT scan, eye exam, and other tests to evaluate the effect of 17AAG on the tumors.

Detailed description:
Background:

Von Hippel-Lindau disease is a hereditary cancer syndrome in which affected individuals are at risk for developing tumors in a number of organs, including the brain, spine, adrenal glands, eyes and pancreas.

The molecular hallmark of VHL is inactivation of the VHL gene which leads to accumulation of the hypoxia inducible factors (HIF); this, in turn results in overexpression of several genes including vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), transforming growth factor alpha (TGF-α), platelet-derived growth factor (PDGF) and erythropoietin, which play an important role in tumorigenesis, tumor growth and metastasis.

17-allylamino-17-demethoxygeldanamycin (17AAG) is an inhibitor of the cellular chaperone heat shock protein 90 (Hsp90), and its interaction with Hsp90 leads to destabilization and degradation of several proteins, that depend on Hsp90 for their stability.

The alpha subunit of HIF1 is one such Hsp90 client protein' and is susceptible to VHL independent, 17AAG-induced degradation.

Objectives:

To evaluate the efficacy of 17 AAG administered as a single agent in von Hippel Lindau patients with renal tumors. The primary endpoint of the trial is response of renal tumors following 3 cycles of therapy.

To study the safety and tolerability of 17 AAG. To evaluate PD modulation of hsp90, and to explore the utility dynamic contrast enhanced MRI in evaluation of blood flow and metabolic changes in renal tumors before and during therapy

Eligibility:

Adults with clinical diagnosis of von Hippel Lindau disease Presence of one or more localized renal tumors for which surgical resection would be considered the standard approach

Design:

Patients will receive 17 AAG as an intravenous infusion at a dose of 300mg/m(2) on days 1, 8, and 15 of 28 day cycles.

The study will follow a two-stage MinMax phase II design and will accrue a maximum of 26 patients.

Arms:
arm 1: None

Interventions: intervention 1: 17 allylamino-17-demethoxygeldanamycin intervention 2: 18 FDG (Fludeoxyglucose 18F) intervention 3: [15-O] H2O intervention 4: EPL diluent
Intervention descriptions: intervention 1: 17 allylamino-17-demethoxygeldanamycin (17 AAG) given intravenously at a dose of 300 mg/m2 on days 1,8 and 15 of 28 day cycles. intervention 2: 18FDG PET performed at baseline and 12 weeks after treatment. At each timepoint participants can receive 250mCi 0-15 water and 15 mCi F18-FDG. intervention 3: \[15-0\] H20 performed at baseline and 12 weeks after treatment. At each time point participants can receive 250mCi 0-15 water and 15 mCi F18-FDG. The water scans were done as several intravenous injections for several scans but not over a total of 250 mCi. intervention 4: 17AAG is formulated with this diluent. Supplied in a 50 mL flint vial containing 48 mL of 2% egg phospholipids, and 5% dextrose in Water for Injection, USP. Patients with a history of serious allergic reactions to eggs should not receive this agent.

Protocol document: