A Pilot Study of EZN-2968, an Antisense Oligonucleotide Inhibitor of HIF-1alpha, in Adults With Advanced Solid Tumors With Liver Metastases
Condition: Neoplasms; Liver Metastases
MeSH terms: Neoplasm Metastasis; Liver Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - A protein called HIF is believed to be involved both in forming cancers and helping them to
      grow after they are formed. EZN-2968 is a new type of cancer drug that goes into the cancer
      cell and switches off the production of the HIF protein. Researchers are interested in
      testing EZN-2968 in people who have liver cancer because studies have shown that this drug
      travels to the liver and stays there when the drug is given through a vein.

      Objectives:

      - To determine the safety and effectiveness of EZN-2968 on liver cancer.

      Eligibility:

      - Individuals 18 years of age and older who have been diagnosed with liver cancer that has
      not responded to standard treatments.

      Design:

        -  Participants will have an initial screening visit with a physical examination, blood and
           urine tests, and imaging studies to assess tumor size. Tumor biopsies may also be taken
           for research purposes.

        -  Participants will have an undefined number of 6-week treatment cycles of EZN-2968, given
           once a week for 3 weeks followed by 3 weeks without the drug.

        -  During each cycle, participants will have additional blood tests and imaging scans to
           assess tumor response to treatment.

        -  Cycles of treatment with EZN-2968 may continue until the treatment is not effective,
           illness requires participants to stop taking the study drug, or the participant chooses
           to withdraw from the study.
    

Detailed description: 
      Background:

        -  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.

      Primary Objective:

      - Determine the modulation of HIF-1alpha mRNA in tumor biopsies pre- and post-administration
      of EZN-2968.

      Secondary Objectives:

        -  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.

      Eligibility:

        -  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.

      Design:

        -  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
           2 cycles.
    

Intervention name(s): EZN-2968
Intervention type(s): Drug
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anti-Angiogenesis; Targeted Therapy; HIF; Antisense; VEGF; Cancer; Solid Tumor; Liver Metastasis