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Three cohorts will receive modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) 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.

It is an active cancer immunotherapy administered via subcutaneous injection.

MVA-brachyury- TRICOM

James L Gulley, M.D.

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.

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.

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

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)

Correlation of brachyury expression in tissue samples with clinical outcomes.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Dose-limiting toxicity (DLT) will be defined as any one of the following: Any grade ≥ 3 hematologic toxicity or grade ≥ 3 non-hematologic toxicity that is possibly, probably, or definitely related to study drug, except transient (≤ 48 hour) grade 3 fatigue, local reactions, flu-like symptoms, fever, headache, and laboratory abnormalities that are not associated with organ pathology. Also any ≥ grade 2 allergic and ≥ grade 2 autoimmune reaction(s) (except endocrine-related immune toxicity) will be defined as a DLT. Any grade 3 autoimmune endocrine-related toxicity that has not resolved clinically within 7 days of initiating therapy will also be defined as a DLT. Generalized erythroderma or macular or papular rash lasting less than 7 days and not associated with desquamation will not be DLTs.

The MTD will be the dose level at which no greater than 1/6 patients have a dose-limiting toxicity (DLT), and the next higher dose level has at least 2 patients with a DLT.

Number of participants with Grade 3 or greater adverse events possibly related to vaccine assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life threatening consequences, and Grade 5 is death related to adverse event.

A fluorescence activated cell sorting (FACS)-based assay for cluster of differentiation 4 (CD4) or cluster of differentiation 8 (CD8) T-cells expressing the cytokines interferon (IFN) gamma, interleukin 2 (IL2), and tumor necrosis factor (TNF) alpha, and/or cluster of differentiation 107a (CD107a) (a marker for lytic potential) was used to determine the numbers of participants showing development or enhancement of the level of brachyury-specific T-cells after vaccination.

Blood samples collected were analyzed by multicolor flow cytometry in PBMCs for cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), Natural Killer (NK), Natural Killer T (NKT), conventional dendritic cell (cDC), plasmacytoid dendritic cell (pDC), myeloid-derived suppressor cell (MDSC) and Tregs. Changes in levels PBMC subsets was a descriptive result with median and interquartile range reported. No formal statistical analysis by dose level was performed given the small sample size.

A positive brachyury antibody titer consisted of an absorbance to brachyury protein that was twice that obtained with the negative control protein Bovine serum albumin (BSA). A positive titer after vaccination may be indicative of an immune response to the vaccine.

Serum levels of Soluble CD27 (sCD27) were determined by enzyme-linked immunosorbent assay (ELISA) pre and post vaccination. Changes in levels of serum cytokines and soluble factors was a descriptive result with median and interquartile range reported. No formal statistical analysis by dose level was performed given the small sample size.

Serum levels of sCD40L, were determined by enzyme-linked immunosorbent assay (ELISA) pre and post vaccination. Changes in levels of serum cytokines and soluble factors was a descriptive result with median and interquartile range reported. No formal statistical analysis by dose level was performed given the small sample size.

Serum levels of sCD27, sCD40L, and the ratio of sCD27:sCD40L were determined by enzyme-linked immunosorbent assay (ELISA) pre and post vaccination. Changes in levels of serum cytokines and soluble factors was a descriptive result with median and interquartile range reported. No formal statistical analysis by dose level was performed given the small sample size.

Serum levels of IL-2, IL-4, IL-10, and IFNg were determined by enzyme-linked immunosorbent assay (ELISA) pre and post vaccination. Changes in levels of serum cytokines and soluble factors was a descriptive result with median and interquartile range reported. No formal statistical analysis by dose level was performed given the small sample size.

National Cancer Institute (NCI)

Principal Investigator

Participants received Modified Vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 1 injection (I injection = 2 x 10\^8 IU) 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.

Dose Level 1 - 1 Injection - Total Dose 2 x 10^8 IU

Participants received Modified Vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 2 injections (I injection = 2 x 10\^8 IU) 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.

Dose Level 2 - 2 Injections - Total Dose 4 x 10^8 IU

Participants received Modified Vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 4 injections (I injection = 2 x 10\^8 IU) 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.

Dose Level 3 - 4 Injections - Total Dose 8 x 10^8 IU

Participants received Modified Vaccinia Ankara (MVA)-brachyury-modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 1 injection (I injection = 2 x 10\^8 IU) 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.

Participants received Modified Vaccinia Ankara (MVA)-brachyury-modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 2 injections (I injection = 2 x 10\^8 IU) 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.

Participants received Modified Vaccinia Ankara (MVA)-brachyury-modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as 4 injections (I injection = 2 x 10\^8 IU) 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.

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Chordoma

Ovarian Ca

Pancreatic Ca

Colon Ca

Lung Ca

Breast Ca

Prostate Ca

Cholangiocarcinoma

Cancer Diagnosis

1 Prior Treatment

2 Prior Treatments

3 Prior Treatments

4 Prior Treatments

5 Prior Treatments

No prior systemic therapy

Prior Treatments

Dr. James Gulley

Participants received Modified Vaccinia Ankara (MVA)-brachyury-TRICOM vaccine administered subcutaneously as 1 injection (I injection = 2 x 10\^8 IU) 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.

Participants received Modified Vaccinia Ankara (MVA)-brachyury-TRICOM vaccine administered subcutaneously as 2 injections (I injection = 2 x 10\^8 IU) 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.

Participants received Modified Vaccinia Ankara (MVA)-brachyury-TRICOM vaccine administered subcutaneously as 4 injections (I injection = 2 x 10\^8 IU) 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.

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Number of Participants With Dose-Limiting Toxicities (DLT)

All participants in Dose Level 1 - 1 injection - Total Dose 2 x 10\^8 IU, Dose Level 2 - 2 injections - Total Dose 4 x 10\^8 IU, and Dose Level 3 - 4 injections - Total Dose 8 x 10\^8 IU.

All Participants

Maximum Tolerated Dose (MTD)

Only one Grade 3 adverse event (diarrhea) possibly related to vaccine occurred on this trial; and no Grade 4 and 5 adverse events possibly related to vaccine.

Number of Participants With Grade 3 or Greater Adverse Events Possibly Related to Vaccine

CD107a + CD4 T-cell response (d29 vs pre)

IFN gamma + CD4 T-cell response (d29 vs pre)

IL2 + CD4 T-cell response (d29 vs pre)

TNF alpha + CD4 T-cell response (d29 vs pre)

CD107a + CD8 T-cell response (d29 vs pre)

IFN gamma + CD8 T-cell response (d29 vs pre)

IL2 + CD8 T-cell response (d29 vs pre)

TNF alpha + CD8 T-cell response (d29 vs pre)

Any T-cell response (d29 vs pre)

CD107a + CD4 T-cell response (d57 vs pre)

IFN gamma + CD4 T-cell response (d57 vs pre)

IL2 + CD4 T-cell response (d57 vs pre)

TNF alpha + CD4 T-cell response (d57 vs pre)

CD107a + CD8 T-cell response (d57 vs pre)

IFN gamma + CD8 T-cell response (d57 vs pre)

IL2 + CD8 T-cell response (d57 vs pre)

TNF alpha + CD8 T-cell response (d57 vs pre)

Any T-cell response (d57 vs pre)

CD107a + CD4 T-cell response (d85 vs pre)

IFN gamma + CD4 T-cell response (d85 vs pre)

IL2 + CD4 T-cell response (d85 vs pre)

TNF alpha + CD4 T-cell response (d85 vs pre)

CD107a + CD8 T-cell response (d85 vs pre)

IFN gamma + CD8 T-cell response (d85 vs pre)

IL2 + CD8 T-cell response (d85 vs pre)

TNF alpha + CD8 T-cell response (d85 vs pre)

Any T-cell response (d85 vs pre)

Sufficient peripheral blood mononuclear cells (PBMCs) were available before and after vaccination from 34 of 38 patients to analyze brachyury-specific CD4 and CD8 T-cell responses.

Number of Participants With Brachyury-Specific T-cell Responses Developed After 1, 2, and 3 Vaccinations

CD4 Pre

CD4 D29

CD4 D85

CD8 Pre

CD8 D29

CD8 D85

Treg Pre

Treg D29

Treg D85

B cells Pre

B cells D29

B cells D85

NK cells Pre

NK cells D29

NK cells D85

NK-T cells Pre

NK-T cells D29

NK-T cells D85

cDC Pre

cDC D29

cDC D85

pDC Pre

pDC D29

pDC D85

MDSC Pre

MDSC D29

MDSC D85

Sufficient peripheral blood mononuclear cells (PBMCs) were available before and after vaccination from 36 of 38 patients to analyze peripheral immune cell subsets.

Percentage of Total Peripheral Blood Mononuclear Cells (PBMCs) in Peripheral Blood Before Vaccination, and After 1 and 3 Vaccinations

Anti-Brachyury Antibodies Pre

Anti-Brachyury Antibodies D29

Anti-Brachyury Antibodies D57

Anti-Brachyury Antibodies D85

Sufficient serum was available before and after vaccination from 34 of 38 patients to analyze anti-brachyury antibodies.

Number of Participants With Positive Anti-Brachyury Antibodies

sCD27 Pre

sCD27 D29

sCD27 D85

Sufficient serum was available before and after vaccination from 36 of 38 patients to analyze serum cytokines and soluble factors.

Changes in Serum Cytokines Soluble CD27 (sCD27) and Soluble Factors

sCD40L Pre

sCD40L D29

sCD40L D85

Changes in Serum Cytokines Soluble CD40 Ligand (sCD40L) and Soluble Factors

sCD27:sCD40L Pre

sCD27:sCD40L D29

sCD27:sCD40L D85

Changes in the Ratio of Serums Soluble CD27 (sCD27):Soluble CD40 Ligand (sCD40L)

IL-2 Pre

IL-2 D29

IL-2 D85

IL-10 Pre

IL-10 D29

IL-10 D85

IL-4 Pre

IL-4 D29

IL-4 D85

IFNg Pre

IFNg D29

IFNg D85

Changes in Serum Cytokines Interleukin 2 (IL2), Interleukin 4 (IL4), Interleukin 10 (IL10), and Interferon Gamma (IFNg)

Tissue collection was optional and insufficient tissue was obtained to perform this analysis.

Correlation of Brachyury Expression in Tissue Samples With Clinical Outcomes.

Participants received Modified Vaccinia Ankara (MVA)-brachyury-modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOMvaccine administered subcutaneously as 2 injections (I injection = 2 x 10\^8 IU) 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.

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)	NCT02179515	Lung Cancer Breast Cancer Prostate Cancer Tumors (Others) Ovarian Cancer	MVA-brachyury- ...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)	NCT02179515	Lung Cancer Breast Cancer Prostate Cancer Tumors (Others) Ovarian Cancer	MVA-brachyury- ...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for tumors (others)