Cancer Vaccine Targeting Brachyury Protein in Tumors
Condition: Neoplasms; Malignant Solid Tumors; Colon Neoplasms; Adenocarcinoma
MeSH terms: Neoplasms; Colonic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Cancer vaccines are being developed to help teach the body's immune system to attack and
      destroy cancer cells. A new vaccine being tested targets Brachyury protein. This protein is
      present in some tumor cells, and it can help tumor cells spread to other parts of the body.
      Researchers want to see whether the new Brachyury protein vaccine can help treat people with
      advanced carcinomas.

      Objectives:

      - To test the safety and effectiveness of a cancer vaccine that targets Brachyury protein in
      tumor cells.

      Eligibility:

        -  Individuals at least 18 years of age who have advanced cancers that have not responded
           or are no longer responding to standard treatments.

        -  Because the vaccine is made with yeast, people with yeast allergies will not be
           eligible.

      Design:

        -  Participants will be screened with a medical history and physical exam. Imaging studies
           will be used to examine the cancer. Heart and thyroid function tests will be conducted.
           Blood and urine samples will also be collected.

        -  Participants will receive vaccine injections every 2 weeks, for a total of seven visits.
           After seven visits, if the cancer has shrunk or stopped growing, participants will
           continue to have the vaccine about once a month.

        -  Treatment will be monitored with frequent blood tests and imaging studies. Other tests
           will be given as directed by the study doctors. Some participants will have apheresis to
           collect additional blood cells for study.

        -  Participants will continue to receive the vaccine as long the tumor does not start
           growing again and there are no serious side effects....
    

Detailed description: 
      Background:

        -  Vaccines based on recombinant heat inactivated yeast have been shown to be immunogenic
           and well tolerated in animals and humans.

        -  Using a computer-based differential display analysis tool to conduct global comparison
           of expressed sequence tag (EST) clusters in the Unigene database, the gene encoding for
           the transcription factor Brachyury was identified as highly represented in tumor-derived
           libraries and rarely observed in normal tissue-derived libraries. By using
           reverse-transcription followed by polymerase chain reaction (RT-PCR), investigators in
           the LTIB have identified the overexpression of Brachyury in gastrointestinal, bladder,
           kidney, ovary, uterus, and testicular carcinomas. Similar studies also found
           over-expression of Brachyury mRNA in cell lines of lung, colon and prostate cancers, but
           not in the majority of normal tissues tested, with the exception of expression in the
           testis, thyroid and low levels of expression in B cells pooled from multiple normal
           donors.

        -  Brachyury is a member of the T-box family of transcription factors, characterized by a
           highly conserved DNA-binding domain designated as T-domain. Data indicates that the
           transcription factor Brachyury confers on the tumor cells a mesenchymal phenotype, as
           well as migratory and invasive abilities and enhances tumor cell progression.

        -  A murine model of MC38 cells engineered to over express human Brachyury gene has
           demonstrated increased metastatic potential of Brachyury over-expressing MC38 cells.

        -  Brachyury specific T cells can lyse human cancer cells expressing Brachyury in an MHC
           restricted manner.

        -  GI-6301 (Yeast-Brachyury vaccine) has been tested in vitro and in the mouse model. These
           studies showed Brachyury-specific T cell responses and decreased metastasis in mice
           treated with vaccine.

        -  An ongoing study of a Hepatitis B vaccine (GS-4774) using the yeast platform (heat
           killed Saccharomyces cerevisiae) indicated safety of 80 YU dose (4 injection sites at 20
           YU injections per site).

      Objectives:

      -The primary objectives are to:

        -  Determine the safety and tolerability of escalating doses of GI-6301 (Yeast-Brachyury
           vaccine) a heat-killed yeast-based vaccine

        -  Determine in an expanded cohort if a significant change in Brachyury specific T cells
           will be detectable post vaccine.

      Eligibility:

        -  Adults with histologically proven metastatic or locally advanced solid tumors for which
           standard curative or palliative measures are no longer effective. Efforts will be made,
           as much as possible, to enroll patients with tumor types with known increased expression
           of Brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic or
           chordoma).

        -  Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.

        -  Patients with acquired immune defects, systemic autoimmune disease, concurrent use of
           steroids, pericardial mass > 1 cm, chronic infections, concurrent tricyclic
           antidepressant therapy, or allergy to yeast or yeast-based products will be excluded.

      Design:

        -  This is an open label, phase I trial with sequential dose escalation cohorts of patients
           (3-6 patients per dose cohort) for 3 doses of GI-6301 (Yeast-Brachyury vaccine).

        -  GI-6301 (Yeast-Brachyury vaccine) will be administered subcutaneously at 4 sites
           biweekly for 7 visits (day 1, 15, 29, 43, 57, 71, 85), then monthly until patients meet
           off-study criteria

      (patients who have been on study for one year or more and have had stable disease or better
      (PR, CR) have the option to receive vaccine once every 3 months instead of monthly).

        -  All patients on a given dose level will have completed 28 days on-study without DLT
           before enrollment can begin on the next dose level or on the expansion phase (see
           statistical analysis section).

        -  Expansion Phase: 10 additional patients will be enrolled on the MTD dose level (or the
           highest dose level explored in the event that a true MTD is not reached), receiving the
           same treatment regimen, to assess for immunologic responses and clinical responses.

        -  Amended dose escalation: 10 patients will be enrolled at an additional dose level (80 YU
           per dose, 4 injection sites at 20 YU per site) to determine the safety of this dose
           level.

        -  Up to 33 total patients may be required to complete enrollment of this study.
    

Intervention name(s): GI-6301 (Yeast Brachyury Vaccine)
Intervention type(s): Biological
Intervention description(s): GI-6301 is a heat-killed, recombinant yeast-based vaccine engineered to express the transcription factor, Brachyury. The Brachyury gene is used to transfect the parental yeast strain (S. cerevisiae W303 - a haploid strain with known mutations from wildtype yeast) to produce the final recombinant vaccine product.
Other intervention name(s): Yeast-Brachyury vaccine
Intervention MeSH terms: Vaccines
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Vaccine Therapy; Dose-Limiting Toxicity; Maximum Tolerated Dose; Clinical Response; Immune Response; Cancer; Solid Tumor