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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
William M Linehan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Cancer Institute, National Institutes of Health||Bethesda, Maryland 20892|