17AAG to Treat Kidney Tumors in Von Hippel-Lindau Disease

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Brief Title

17AAG to Treat Kidney Tumors in Von Hippel-Lindau Disease

Official Title

A Phase II Study of 17-Allylamino-17-Demethoxygeldanamycin in Patients With Von Hippel Lindau Disease and Renal Tumors

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With a Renal Tumor Response

Secondary Outcome

 Number of Participants With a Non-renal Tumor Response

Condition

Hippel-Lindau Disease

Intervention

17 allylamino-17-demethoxygeldanamycin

Study Arms / Comparison Groups

 Von Hippel-Lindau (VHL) associated renal tumors
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

9

Start Date

July 2004

Completion Date

January 2009

Primary Completion Date

January 2009

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

William M Linehan, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00088374

Organization ID

040238

Secondary IDs

04-C-0238


Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

William M Linehan, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

July 2012