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

This study is currently recruiting patients.

Sponsored by: National Cancer Institute (NCI)
Information provided by: Warren G Magnuson Clinical Center (CC)

Purpose

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 a 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 the 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.

- Positron emission tomography (PET): Two types of PET scans may be done. One determines tumor activity by measuring the amount of sugar (glucose) the tumor absorbs, and the other measures tumor blood flow. For both studies, catheters are placed in a vein in each arm, one for giving a radioactive substance (a radiation-labeled sugar molecule for the tumor activity test and radiation-labeled water for the blood flow test), and the other for taking blood samples. The patient lies in the doughnut shaped scanner while images are obtained of various parts of the body where tumors are located.

- 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 and PET scans to measure changes in tumor activity, blood flow, and number of blood vessels in the tumor since the pre-treatment scans. They may have additional tests, including a CT scan, eye exam, and other tests to evaluate the effect of 17AAG on the tumors.

- Research blood draws: Blood samples are collected four times during the first week of treatment and then before each dose of 17AAG to determine the effects of the drug on blood counts, liver function, and other body functions, and to monitor safety.

Patients whose tumors shrink with 17AAG treatment may continue to receive the drug for another 12 weeks, followed by repeat MRI and PET scans. Those whose tumors do not shrunk or grow after 12 weeks on the study are asked to undergo surgery to remove the kidney tumors to reduce the chance of tumor spread.

Condition Treatment or Intervention Phase
Hippel-Lindau Disease
Kidney Cancer
 Drug: 17 allylamino-17-demethoxygeldanamycin
 Drug: 18 FDG
 Drug: [15-O] H2O
 Drug: EPL diluent
Phase II

MedlinePlus related topics:  Cancer;   Circulatory Disorders;   Kidney Cancer;   Neurologic Diseases

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: A Phase 2 Study of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Von Hippel Lindau Disease and Renal Tumors

Further Study Details: 

Expected Total Enrollment:  25

Study start: July 12, 2004

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 kidneys, brain, spine, adrenal glands, eyes and pancreas. The molecular hallmark of VHL disease is inactivation of the VHL gene, which leads to accumulation of a group of transcriptionally active proteins called the hypoxia inducible factors (HIF). Accumulation of HIFs results in overexpression of several genes including VEGF, GLUT-1, TGF-alpha PDGF and erythropoietin, which may play an important role in tumorigenesis, tumor growth and metastasis.

17-allylamino-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin derivative with potential antitumor activity. 17 AAG 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 the hypoxia inducible factor HIF1 is an Hsp90 client protein and is susceptible to VHL-independent, 17 AAG-induced degradation.

This open label phase II study is designed to evaluate the efficacy of 17 AAG administered as a single agent in von Hippel Lindau patients with renal tumors. The study will accrue patients with a clinical diagnosis of VHL disease having at least one localized renal tumor for which surgical resection would be the recommended approach. Patients will receive 17 AAG as an intravenous infusion at a dose of 300mg/m2 on days 1, 8, and 15 of 28 day cycles. The primary endpoint of the trial is response of renal tumors following 3 cycles of therapy. Patients who do not demonstrate a partial or complete response of their renal tumors following 3 cycles of therapy, or continue to have at least one tumor greater than or equal to 3cm despite a partial response, will be taken off study and can undergo standard resection of their renal tumor(s) to minimize their risk of metastasis. Those patients with a complete response or a partial response and no renal tumor greater than or equal to 3cm will continue therapy for a further 3 cycles. Secondary objectives of this trial include assessment of hsp 90 inhibition in resected tumor tissue and peripheral blood lymphocytes using a variety of surrogate markers such as expression of Hsp90, Hsp70, HIF and HIF-regulated genes, evaluation of tumor blood flow, vascular density and vascular permeability following treatment with 17 AAG by MRI and PET scanning, assessment of tumor uptake of fluorodeoxyglucose by PET, evaluation of response in non-renal VHL-associated tumors (pancreatic tumors, CNS hemangioblastomas, pheochromocytomas) with 17 AAG and assessment of toxicity of 17 AAG in this group of patients. The study will follow a two-stage MiniMax phase II design and will accrue a maximum of 26 patients.

Eligibility

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Patients must satisfy all 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.
Life expectancy greater than 3 months.
Performance status ECOG 0-2.
Patients must have normal organ and marrow function as defined below:
WBC count greater than or equal to 3,000/uL,
absolute neutrophil count greater than or equal to 1,500/micro L,
platelet count greater than or equal to 100,000/mirco L,
Hgb greater than10Gm/dl,
serum creatinine less than or equal to 1.0 ULN or measured 24 hr. creatinine clearance greater than 60 ml/min,
AST and ALT less than 1.0 x ULN,
total bilirubin less than or equal to ULN (less than 3 x NL in patients with Gilbert's disease).
Negative HbsAg, HIV-1 and nonreactive HCV.
No history of serious intercurrent medical illness.
At least four weeks from completion of any other 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 or 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 CTCAE 3.0) due to agents administered more than 4 weeks earlier.
Patients may not be receiving any other investigational agents (with the exception of 18-FDG and 15-H2O for PET imaging).
Patients with known metastatic renal cell cancer.
Patients with a history of serious allergy to eggs.
Concomitant therapy with CYP3A4 potent inhibitors. Patients who are on CYP3A4 substrates and inducers qualify for enrollment for this study.
Pregnant women are excluded from this study.
Breastfeeding should be discontinued if the mother is treated with 17 AAG.
HIV-positive patients are excluded from the study because of unknown but potential pharmacokinetic interactions of anti-retroviral drugs with 17 AAG.

Location and Contact Information


Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov 
TTY  1-866-411-1010 

More Information

Detailed Web Page

Publications

Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA. 1995 Feb 15;273(7):564-70. Review. No abstract available.

Clifford SC, Maher ER. Von Hippel-Lindau disease: clinical and molecular perspectives. Adv Cancer Res. 2001;82:85-105. Review.

Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore). 1997 Nov;76(6):381-91. Review.

Study ID Numbers:  040238; 04-C-0238
Record last reviewed:  July 6, 2004
Last Updated:  July 6, 2004
Record first received:  July 23, 2004
ClinicalTrials.gov Identifier:  NCT00088374
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-22
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