17AAG to Treat Kidney Tumors in Von Hippel-Lindau Disease
17AAG to Treat Kidney Tumors in Von Hippel-Lindau Disease
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.
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.
Inclusion Criteria:

 -  Patients must satisfy all of the following inclusion criteria to be eligible for study
 enrollment.

 -  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.

 -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
 currently available on the use of 17 AAG in patients less than 18 years of age,
 children are excluded from this study.

 -  Life expectancy less than 3 months.

 -  Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.

 -  Patients must have normal organ and marrow function as defined below: white blood
 cells (WBC)count greater than or equal to 3,000/microliter, absolute neutrophil count
 greater than or equal to 1,500/microliter, platelet count greater than or equal to
 100,000/microliter, Hgb greater than 10Gm/dl, serum creatinine less than or equal to
 1.0 upper limit of normal (ULN) or measured 24 hour creatinine clearance greater than
 60 ml/min,aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less
 than 1.0 times the ULN, total bilirubin less than or equal to ULN(less than 3 times
 the normal limit (NL) in patients with Gilbert's disease).

 -  Negative hepatitis B surface antigen (HbsAg), human immunodeficiency virus type 1
 (HIV-1) and nonreactive hepatitis C virus (HCV).

 -  No history of serious intercurrent illness.

 -  At least four weeks from completion of any surgical or investigational therapy for von
 Hippel Lindau disease.

 -  Willingness to undergo resection of renal tumor at the time point defined in the
 protocol.

 -  All men and women of childbearing potential must use effective contraception as
 determined by the principal investigator or protocol chair.

 -  Ability to understand and the willingness to sign a written informed consent document.

 Exclusion Criteria:

 -  Prior or concomitant non-von Hippel Lindau associated malignancy with the exception of
 adequately treated basal or squamous cell carcinoma of the skin or any other
 malignancy from which the patient has remained disease free for more than five years.

 -  Any renal tumor greater than 4cm in size.

 -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
 nitrosoureas or mitomycin C) prior to entering the study or those who have not
 recovered from adverse events (to grade 1 or less toxicity according to Common
 Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) due to agents
 administered more than 4 weeks earlier.

 -  Patients may not be receiving any other investigational agents.

 -  Patients with known metastatic renal cell cancer.

 -  Patients with a history of serious allergy to eggs.

 -  Concomitant therapy with cytochrome P450 3A4 (CYP3A4) potent inhibitors.

 -  Patients who are on CYP3A4 substrates and inducers qualify for enrollment for this
 study.

 -  Pregnant women are excluded from this study because 17 AAG has the potential for
 teratogenic or abortifacient effects, and no data regarding its safety in pregnant
 women is available. Because there is an unknown but potential risk for adverse events
 in nursing infants secondary to treatment of the mother with 17 AAG, breastfeeding
 should be discontinued if the mother is treated with 17 AAG.

 -  Human immunodeficiency virus (HIV)-positive patients are excluded from the study
 because of unknown but potential pharmacokinetic interactions of anti-retroviral drugs
 with 17 AAG.

 -  Use of any medications that prolong or may prolong corrected QT interval (QTc).

 -  Patients who have significant cardiac disease including heart failure that meets New
 York Heart Association (NYHA)class III and IV definitions, uncontrolled dysrhythmias
 requiring anti-arhythmic drugs, or patients with active ischemic heart disease
 including myocardial infarction and poorly controlled angina within 12 months of study
 entry.

 -  Patients who have a history of serious ventricular arrhythmia (ventricular tachycardia
 (VT) or ventricular fibrillation (VF),greater than or equal to 3 beats in a row), QTc
 greater than or equal to 450msec for men and 470msec for women, or left ventricular
 ejection fraction (LVEF) below lower limit of normal by multi gated acquisition
 scan(MUGA).

 -  Patients with a history of prior chest radiation or radiation that potentially
 included the heart in the treatment field.

 -  Patients with congenital long Q wave, T wave (QT) syndrome.

 -  Patients with left bundle branch block.

 -  Patients with symptomatic pulmonary disease requiring medication, including the
 following:dyspnea, dyspnea on exertion, paroxysmal nocturnal dyspnea, oxygen
 requirement and significant pulmonary disease, including chronic obstructive pulmonary
 disease, patients meeting Medicare criteria for home oxygen.

 -  Carbon monoxide diffusing capacity (DLCO) less than or equal to 80%.

 -  Patients with a prior history of cardiac or pulmonary toxicity after receiving
 anthracyclines, such as doxorubicin, daunorubicin, mitoxantrone, bleomycin, or
 carmustine (BCNU).

 -  Patients with greater than or equal to grade 2 baseline pulmonary or cardiac symptoms.