Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)
- 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.
- To test the safety and effectiveness of giving the MVA-brachyury-TRICOM vaccine to people with cancer.
- 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.
- 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.
Biological: MVA-brachyury- TRICOM
|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)|
- Safety and tolerability of escalating doses of MVA-brachyury-TRICOM vaccine. [ Time Frame: 2 -3 years ] [ Designated as safety issue: Yes ]
- 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 ]
|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)|
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.
- 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.
To determine the safety and tolerability of escalating doses of MVA-brachyury-TRICOM vaccine.
- 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.
- 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).
- 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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02179515
|Contact: Isreal O Oyelakin, R.N.||(301) email@example.com|
|Contact: Christopher R Heery, M.D.||(301) firstname.lastname@example.org|
|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|
|Principal Investigator:||Christopher R Heery, M.D.||National Cancer Institute (NCI)|