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

Kidney Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00088374
• Other study ID #: 040238
• Secondary ID: 04-C-0238040238
• Status: Completed
• Phase: Phase 2
• First received: July 23, 2004
• Last updated: July 23, 2012
• Start date: July 2004
• Est. completion date: January 2009

Study information

• Verified date: July 2012
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00089375

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: January 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Hippel-Lindau Disease
• Kidney Cancer
• Kidney Neoplasms
• Von Hippel-Lindau Disease

Intervention

Drug:
• 17 allylamino-17-demethoxygeldanamycin
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.
• 18 FDG (Fludeoxyglucose 18F)
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.
• [15-O] H2O
[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.
• EPL diluent
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.

Locations

Country	Name	City	State
United States	National Cancer Institute, National Institutes of Health	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With a Renal Tumor Response	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.	12 weeks	No
Secondary	Number of Participants With a Non-renal Tumor Response	Number of patients who have a PR or CR of non-renal lesions (pancreatic tumors, pheochromocytomas, and hemangioblastomas). The effect of treatment on the lesions will be evaluated at baseline and at the time of restaging (12 weeks) per RECIST criteria. RECIST is defined as changes in only the largest diameter (unidimensional measurement) of the tumor lesions. Lesions are either measurable or non-measurable using the criteria. See the protocol Link module for the full criteria if desired.	Baseline and 12 weeks	No
Secondary	The Number of Participants With Adverse Events	Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.; The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for adverse event reporting. For a detailed description see the link in the Protocol Link module.	1 yr, 364 days	Yes
Secondary	The Number of Participants With HIF, HSP90, and HSP70 Modulation in Resected Tumor Tissue and/or Peripheral Blood Lymphocytes	Measurement of HIF, HSP90 and HSP70 levels by Western Blot in tumor tissue and/or lymphocytes to assess modulation of these biomarkers in response to 17 AAG treatment. Pretreatment tumor samples (when available) and resected tumors (in those patients who did not have a response and underwent surgical resection of their tumor) were to be used for this analysis. Levels of Hsp90, Hsp70, HIF and HIF transcriptional targets in resected tumor will be compared to respective levels in tumors previously resected from other VHL patients (not treated with 17AAG).	Baseline and 12 weeks	No
Secondary	Number of Patients in Whom Renal Tumors Could be Identified by Positron Emission Tomography (PET)Based on Fludeoxyglucose 18F (18FDG) Uptake	Images were acquired after the intravenous administration of 18FDG and H2015 and used to analyze glucose uptake and estimate blood flow. The parameter to be measured is SUV (standard uptake value(s)) and/or mL/min/gm.	Baseline and at 12 weeks	No
Secondary	Number of Participants With Flow Dynamics Measured by DCE MRI Within the Renal and Non-renal Tumor	Dynamic images will be acquired before and after the intravenous administration of 0.1 mmol/kg of Gadolinium Diethylene triamine pentaacetic acid (DTPA). Time activity curves will be generated over a period of ten minutes. The parameter to be measured is the forward contrast transfer rate (Ktrans), the reverse contrast transfer rate (Kep), and/or the extravascular extracellular space volume fraction (Ve). Flow dynamics are a measure of blood flow changes in the tumor and are determined using the parameters we had previously defined (Ktrans, Kep, etc.).	Baseline and during therapy (12 weeks)	No

External Links

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