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

Phase 1

Completed

Conditions: Prostate Cancer
Tumors (Others)
Lung Cancer
Breast Cancer
Ovarian Cancer

Interventions: Biological: MVA-brachyury- TRICOM

Registration Number: NCT02179515

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
modified vaccinia Ankara (MVA)-brachyury-TRICOM vaccine	MVA-brachyury- TRICOM	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Date treatment consent signed to date off study, approximately 9 months and 6 days for DL1, 17 months and 3 days for DL2, and 23 months and 13 days for DL3.	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.
Maximum Tolerated Dose (MTD)	First 28 days of treatment.	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	Date treatment consent signed to date off study, approximately 9 months and 6 days for DL1, 17 months and 3 days for DL2, and 23 months and 13 days for DL3.	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.
Number of Participants With Dose-Limiting Toxicities (DLT)	28 days following the first injection of vaccine.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Positive Anti-Brachyury Antibodies	Pre (Baseline), and approximately D29 (Post 1 vaccination), D57 (post 2 vaccinations) and D85 (post 3 vaccinations)	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.
Percentage of Total Peripheral Blood Mononuclear Cells (PBMCs) in Peripheral Blood Before Vaccination, and After 1 and 3 Vaccinations	Pre (Baseline), and approximately D29 (Post 1 vaccination) and D85 (post 3 vaccinations)	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.
Changes in the Ratio of Serums Soluble CD27 (sCD27):Soluble CD40 Ligand (sCD40L)	Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations)	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.
Number of Participants With Brachyury-Specific T-cell Responses Developed After 1, 2, and 3 Vaccinations	Baseline (pre-vaccination), approximately day 29 (after 1 vaccination), approximately day 57 (after 2 vaccinations), and approximately day 85 (after 3 vaccinations)	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.
Changes in Serum Cytokines Soluble CD27 (sCD27) and Soluble Factors	Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations)	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.
Changes in Serum Cytokines Soluble CD40 Ligand (sCD40L) and Soluble Factors	Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations)	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.
Changes in Serum Cytokines Interleukin 2 (IL2), Interleukin 4 (IL4), Interleukin 10 (IL10), and Interferon Gamma (IFNg)	Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations)	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.