Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)
Condition: Lung Cancer; Breast Cancer; Prostate Cancer; Tumors (Others); Ovarian Cancer
MeSH terms: Vaccinia
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - This cancer vaccine was developed to help teach the body's immune system to attack and
      destroy cancer cells. It teaches immune cells to target the 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.

      Objective:

      - To test the safety and effectiveness of giving the modified vaccinia Ankara
      (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte
      function-associated antigen 3) TRICOM vaccine to people with cancer.

      Eligibility:

      - Adults ages 18 and over whose type of cancer has not responded to standard therapies who do
      not have a history of autoimmune diseases and are capable of taking care of themselves.

      Design:

        -  Participants will be screened with a medical history and physical exam. They will have
           blood and urine tests. They may have a computed tomography (CT) scan, a positron
           emission tomography (PET) scan, and a brain magnetic resonance imaging (MRI) scan. They
           may have a bone scan. They will have an electrocardiogram (ECG) to test heart rhythm.

        -  Participants will have visits about every 4 weeks. They will have a physical exam and
           blood and urine tests. They will be injected with the vaccine under the skin into the
           upper thigh or around the armpits.

        -  CT scans or MRI scans will be done at visit 1, after 3 months on study, and again 3
           months later if still on the study. Another ECG will be done at their last vaccine
           visit.

        -  When participants stop the vaccine, they will return for visits until they recover from
           any side effects. They will have tests including physical exam, blood tests, scans, and
           x-rays.

        -  Participants will be asked to enroll in another study for long-term follow-up.
    

Detailed description: 
      Background:

        -  modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule
           1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM is a novel recombinant
           vector-based therapeutic cancer vaccine designed to induce an enhanced immune response
           against brachyury, which is overexpressed in many solid tumor types, such as lung,
           breast, ovarian, chordoma, prostate, colorectal, and pancreatic adenocarcinoma.

        -  Modified vaccinia Ankara (MVA) is a replication-deficient, attenuated derivative of
           vaccinia. It is used in the smallpox vaccination and is now being developed as a
           recombinant viral vector to produce vaccines against infectious diseases and cancer.

        -  Many MVA vector-based trials conducted in patients with cancer have demonstrated its
           safety and the immunogenicity of its transgenes.

        -  Brachyury is a member of the T-box family of transcription factors. It is overexpressed
           in cancer cells compared with normal tissue and has been linked to cancer cell
           resistance and metastatic potential.

        -  Brachyury as a vaccine target has been demonstrated to be safe in an ongoing phase I
           study of recombinant yeast-brachyury and to generate brachyury-specific T-cell
           responses.

        -  Poxviral vaccines delivering a triad of three human T-cell costimulatory molecules
           designated TRICOM (B7.1, ICAM-1 and LFA-3) have been extensively studied in both
           preclinical and clinical studies and have demonstrated their ability to induce robust
           T-cell activation and provide evidence of clinical benefit.

        -  In vitro, MVA-brachyury-TRICOM is able to effectively expand brachyury-specific cluster
           of differentiation 8 (CD8+) and cluster of differentiation 4 (CD4+) T cells from
           peripheral blood mononuclear cells.

        -  Previous work indicates that MVA-brachyury-TRICOM will induce activation a distinct
           Tcell subpopulation from that seen with yeast-brachyury vaccine already in development.

      Objectives:

      To determine the safety and tolerability of escalating doses of MVA-brachyury-TRICOM vaccine.

      Eligibility:

        -  Patients must have histologically confirmed malignancy that is metastatic or
           unresectable locally advanced malignant solid tumor. In the case of chordoma,
           unresectable, locally recurrent, or metastatic tumors are acceptable for enrollment,
           given that this represents incurable disease. As much as possible, patients enrolled
           will have tumor types with known increased expression of brachyury (such as lung,
           breast, ovarian, prostate, colorectal, pancreatic, or chordoma).

        -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry

        -  Age greater than or equal to 18 years.

        -  Prior Therapy: Completed, or disease progression on at least one prior line of disease
           appropriate therapy for metastatic disease, or not a candidate for therapy of proven
           efficacy for their disease.

      Design:

        -  This is an open-label, phase I trial with sequential cohorts of patients (3-6 patients
           per dose cohort) with dose escalation of MVA-brachyury-TRICOM vaccine.

        -  Three cohorts will receive MVA-brachyury-TRICOM vaccine administered subcutaneously as
           either 1, 2, or 4 injections of study drug (1 injection equal to 2 x 10^8 infectious
           units at monthly (28 days +/- 4 days) intervals for 3 months (treatment).

        -  Expansion cohorts of up to 10 patients may be enrolled at the two highest tolerated dose
           levels. These cohorts will allow certain standard, relatively non-toxic therapies to
           continue while patients receive vaccine.

        -  Up to 18 patients may be required to be enrolled in the 3 cohorts, plus an additional 10
           at the maximum tolerated dose (MTD) and at the dose level just below it. Thus, up to 38
           patients may be theoretically required to complete this trial. If 3 patients per month
           can be accrued, the study is expected to require 1 year to complete the necessary
           enrollment.
    

Intervention name(s): MVA-brachyury- TRICOM
Intervention type(s): Biological
Intervention description(s): It is an active cancer immunotherapy administered via subcutaneous injection.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immune Response; Maximum Tolerated Dose; Vaccine Therapy; Increased Expression of Brachyury; Immunotherapy