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

Phase 2
18 Years
Not Enrolling
Hippel-Lindau Disease, Kidney Cancer

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Trial Information

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


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.


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


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


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

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

- 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

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With a Renal Tumor Response

Outcome Description:

Response is defined as the number of patients who experience a disease response (complete response (CR) or partial response (PR) of renal tumors)per RECIST criteria. CR is the disappearance of all target lesions. PR is at least a 20% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. See the protocol Link module for the full criteria if desired.

Outcome Time Frame:

12 weeks

Safety Issue:


Principal Investigator

William M Linehan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

July 2004

Completion Date:

January 2009

Related Keywords:

  • Hippel-Lindau Disease
  • Kidney Cancer
  • Kidney Cancer
  • VHL
  • 17 AAG
  • Chemotherapy
  • Von Hippel Lindau Disease
  • Renal Tumor
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Von Hippel-Lindau Disease



National Cancer Institute, National Institutes of Health Bethesda, Maryland  20892