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
Intervention: MVA-brachyury- TRICOM
Intervention description: It is an active cancer immunotherapy administered via subcutaneous injection.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Immune Response; Maximum Tolerated Dose; Vaccine Therapy; Increased Expression of Brachyury; Immunotherapy

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        (All Subjects)

          1. Patients must have a metastatic or unresectable locally advanced malignant solid
             tumor, histologically confirmed by the Laboratory of Pathology, National Cancer
             Institute (NCI). In the case of chordoma, unresectable, locally recurrent, or
             metastatic tumors are acceptable for enrollment, given that this represents incurable
             disease. 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; other tumors may be included as data on
             the level of brachyury in those tumors becomes available).

          2. Patients may have measurable or nonmeasurable but evaluable disease. Patients with
             surgically resected metastatic disease at high risk of relapse are also eligible.

          3. Prior therapy: Patients must have completed or had disease progression on at least one
             prior line of disease-appropriate therapy for metastatic disease, or not be candidates
             for therapy of proven efficacy for their disease.

          4. There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or
             radiation, with the exception of hormonal therapy for prostate and breast cancers,
             human epidermal growth factor receptor 2 (HER2)-directed therapy for HER2+ breast
             cancer (3+ immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH+),
             and erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancer in the
             expansion cohort as detailed in section. There should be a minimum of 6 weeks from any
             prior antibody therapies, (such as ipilimumab or anti-Programmed cell death protein 1
             (PD1)/Programmed death-ligand 1 (PDL1) due to prolonged half-life.

          5. Patients must have recovered (grade 1 or baseline) from any clinically significant
             toxicity associated with prior therapy. Typically, this is 3-4 weeks for patients who
             most recently received cytotoxic therapy, except for the nitrosoureas and mitomycin C,
             for which 6 weeks is needed for recovery.

          6. Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of modified vaccinia Ankara (MVA)-brachyury-B7-1,
             ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated
             antigen 3) TRICOM vaccine in patients < 18 years of age, children are excluded from
             this study but will be eligible for future pediatric trials.

          7. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
             (Karnofsky greater than or equal to 70%).

          8. Patients must have normal organ and marrow function as defined below:

               -  Serum creatinine less than or equal to 1.5 x upper limit of normal OR creatinine
                  clearance on a 24-h urine collection of greater than or equal to 50 mL/min.

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or
                  equal to 3 x the upper limits of normal.

               -  Total bilirubin less than or equal to 1.5 x upper limit of normal OR in patients
                  with Gilbert's syndrome, a total bilirubin less than or equal to 3.0.

               -  Hematological eligibility parameters (within 16 days of starting therapy):

                    -  Granulocyte count greater than or equal to 1,500/mm^3

                    -  Platelet count greater than or equal to 100,000/mm^3

          9. Patients must have baseline pulse oximetry > 90% on room air.

         10. The effects of MVA-brachyury-TRICOM on the developing human fetus are unknown. For
             this reason, women of child-bearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation and for a period of 4 months after
             the last vaccination therapy. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

         11. Patients with prostate cancer must continue to receive gonadotropin releasing hormone
             (GnRH) agonist therapy (unless orchiectomy has been done). If a patient has refused
             GnRH therapy, they may be enrolled on a dose level for which the safety has already
             been determined.

        Patients must be able to understand and be willing to sign a written informed consent
        document.

        INCLUSION CRITERIA:

        (Expansion Phase Only)

        The following inclusion criteria apply specifically to patients being considered for the
        expansion phase of the protocol.

          1. Subjects with epidermal growth factor receptor (EGFR)-mutated lung cancer may continue
             erlotinib if they have been on the drug for greater than or equal to 3 months with
             stable disease or a response. Erlotinib may also be continued in the case of a
             progressing tumor after prior response (or > 6 months stable disease).

          2. Patients with Estrogen receptor positive (ER+) breast cancer being treated with
             hormonal therapy (selective estrogen receptor modulator or aromatase inhibitor) who
             have rising tumor markers as evidence of disease progression or metastatic disease on
             scans may continue on hormonal therapy while being treated with vaccine.

          3. Patients with Her2+ breast cancer receiving Her2-directed therapy (e.g. trastuzumab)
             may continue on that therapy when enrolling into a dose level for which safety has
             been established.

          4. Subjects with metastatic colorectal cancer may continue "maintenance" therapy with
             capecitabine and/or bevacizumab.

        EXCLUSION CRITERIA:

          1. Concurrent treatment for cancer, with specific exceptions noted in inclusion criteria.

          2. Chronic hepatitis B or C infection, because potential immune impairment caused by
             these disorders may diminish the effectiveness of this immunologic therapy.

          3. Any significant disease that, in the opinion of the investigator, may impair the
             patient's tolerance of study treatment.

          4. Significant dementia, altered mental status, or any psychiatric condition that would
             prohibit the understanding or rendering of informed consent.

          5. Active autoimmune diseases requiring treatment or a history of autoimmune disease that
             might be stimulated by vaccine treatment. This requirement is due to the potential
             risks of exacerbating autoimmunity. However, patients with vitiligo or clinically
             stable autoimmune endocrine disease who are on appropriate replacement therapy (if
             such therapy is indicated) are eligible.

          6. Concurrent use of systemic steroids, except for physiologic doses of systemic steroid
             replacement or local (topical, nasal, or inhaled) steroid use. Limited pharmacologic
             doses of systemic steroids (e.g., in patients with exacerbations of reactive airway
             disease or to prevent intravenous (I.V.) contrast allergic reaction or anaphylaxis in
             patients who have known contrast allergies) are allowed.

          7. Patients who are receiving any other investigational agents within 28 days before
             start of study treatment.

          8. Patients with untreated central nervous system metastases or local treatment of brain
             metastases within the last 6 months. Patients with stable brain metastasis for 6
             months post-intervention are eligible. Subjects with chordoma will be eligible
             regardless of site of disease if other eligibility criteria are met.

          9. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MVA-brachyury-TRICOM or other agents used in study.

         10. Serious or uncontrolled intercurrent illness including, but not limited to, ongoing or
             active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of
             the investigator, would limit compliance with study requirements.

         11. Pregnant women are excluded from this study due to the unknown effects of the
             MVAbrachyury-TRICOM vaccine on the fetus or infant. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with MVA-brachyury-TRICOM, breastfeeding should be discontinued if the mother
             is treated with MVA-brachyury-TRICOM. These potential risks may also apply to other
             agents used in this study.

         12. Human immunodeficiency viruses (HIV)-positive patients are ineligible because of the
             potential for decreased immune response to the vaccine.