Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02179515
First received: June 28, 2014
Last updated: July 4, 2014
Last verified: June 2014
  Purpose

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 MVA-brachyury-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.

Condition Intervention Phase
Lung Cancer
Breast Cancer
Prostate Cancer
Tumors (Others)
Biological: MVA-brachyury- TRICOM
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Phase I Study to Evaluate the Safety and Tolerability of a Modified Vaccinia Ankara (MVA) Based Vaccine Modified to Express Brachyury and T-Cell Costimulatory Molecules (MVA Brachyury-TRICOM)

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety and tolerability of escalating doses of MVA-brachyury-TRICOM vaccine. [ Time Frame: 2 -3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • CD8 and CD4 immunologic response as measured by an increase in brachyury-specific T cells. [ Time Frame: 2 -3 years ] [ Designated as safety issue: No ]
  • Evidence of clinical benefit, such as progression-free survival, RECIST criteria, reduction in serum markers, and/or reduction in circulating tumor cells. [ Time Frame: 2 -3 years ] [ Designated as safety issue: No ]
  • Frequency of immune cell subsets in peripheral blood and changes in serum levels of cytokines and antibodies to brachyury. [ Time Frame: 2 -3 years ] [ Designated as safety issue: No ]
  • Correlation of brachyury expression in tissue samples with clinical outcomes. [ Time Frame: 2 -3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 28
Study Start Date: June 2014
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Three cohorts will receive MVA-brachyury-TRICOM vaccine administered subcutaneously as either 1, 2, or 4 injections of study drug at monthly (28 days +/ 4 days) intervals for 3 months. Patients with stable disease may continue to receive vaccine for up to 6 monthly doses.
Biological: MVA-brachyury- TRICOM
It is an active cancer immunotherapy administered via subcutaneous injection.

Detailed Description:

Background:

  • MVA-brachyury-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 CD8+ and 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 up to +14 days) intervals for 3 months (treatment).
  • Patients with stable disease may continue to receive vaccine for up to 6 monthly doses.
  • Up to 18 patients may be required to be enrolled in the 3 cohorts, plus an additional 10 at the MTD. Thus, up to 28 patients may be theoretically required to complete this trial. If 2 patients per month can be accrued, the study is expected to require 1 year to complete the necessary enrollment.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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, 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.
  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, HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+), and erlotinib in 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-PD1/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 MVA-brachyury-TRICOM vaccine in patients < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
  7. 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.
    • ALT and AST less than or equal to 2.5 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 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.
  12. Women with HER2+ breast cancer who have rising tumor markers as evidence of disease progression or metastatic disease on scans may continue trastuzumab while being treated with vaccine.
  13. 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, as described in Section 8.

  1. Subjects with 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 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.

EXLCUSION 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 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. HIV-positive patients are ineligible because of the potential for decreased immune response to the vaccine.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02179515

Contacts
Contact: Isreal O Oyelakin, R.N. (301) 594-4738 israel.oyelakin@nih.gov
Contact: Christopher R Heery, M.D. (301) 443-7767 heerycr@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Christopher R Heery, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT02179515     History of Changes
Other Study ID Numbers: 140142, 14-C-0142
Study First Received: June 28, 2014
Last Updated: July 4, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immune Response
Maximum Tolerated Dose
Vaccine Therapy
Increased Expression of Brachyury
Immunotherapy

Additional relevant MeSH terms:
Breast Neoplasms
Lung Neoplasms
Prostatic Neoplasms
Vaccinia
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Prostatic Diseases
Poxviridae Infections
DNA Virus Infections
Virus Diseases
Metronidazole
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antiprotozoal Agents
Antiparasitic Agents
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on August 21, 2014