A Pilot Study of EZN-2968, an Antisense Oligonucleotide Inhibitor of HIF-1alpha, in Adults With Advance Solid Tumors
- Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor
tissue to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where
it is involved in the upregulation of many gene products essential for invasion,
migration, angiogenesis, and survival, including vascular endothelial growth factor
(VEGF). Blocking HIF-1 activity inhibits the expression of VEGF, resulting in the
inhibition of tumor growth in vitro and in vivo.
- EZN-2968 is an antisense oligonucleotide that specifically targets HIF-1 alpha, one of
the subunits of HIF-1. Safety and preliminary suggestion of activity have been
demonstrated in two Phase I trials; one patient with hepatocellular carcinoma, one with
renal cell cancer, and one with angiosarcoma of the face treated with EZN-2968 had
objective evidence of shrinkage of large masses. In vivo data show evidence of
intracellular uptake of EZN-2968 into tumor cells, and in the Phase I trial,
preliminary data show that eleven patients had prolonged stable disease (> 90 days
duration on study), three of which had objective evidence of tumor shrinkage, thus
demonstrating proof of principle for this approach.
- Determine the modulation of HIF-1alpha mRNA in tumor biopsies pre- and post-administration
- Assess the safety of EZN-2968 in patients with advanced solid tumors.
- Determine the modulation of HIF-1 alpha protein levels in tumor biopsies pre- and
post-administration of EZN-2968.
- Evaluate anti-tumor response as determined by RECIST.
- Evaluate the expression of HIF-1 alpha target genes by real-time PCR in tumor biopsies.
- Assess tumor angiogenesis using DCE-MRI.
- Adult patients with histologically or cytologically confirmed solid malignancies will
be included in the study.
- Patients must have disease that is not amenable to potentially curative resection.
- Patients must have failed at least one line of prior therapy for metastatic disease or
have a disease for which no standard curative therapy exists.
- Lesion must be amenable to biopsy.
- EZN-2968 will be administered as a 2-hour IV infusion at a dose of 18 mg/kg once a week
for 3 consecutive weeks followed by a 3-week period without drug. Each cycle will be 6
weeks, i.e., 3 weeks of therapy followed by 3 weeks without drug.
- Tumor biopsies and other correlative imaging and pharmacodynamic studies will be
performed at baseline and after the third dose. Tumor restaging will be performed every
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the modulation of HIF-1 alpha mRNA in tumor biopsies pre- and post- administration of EZN-2968.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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