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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 2
- 主要终点
- Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
时间窗: 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)
时间窗: 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
时间窗: 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)
时间窗: 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.
次要结局
- 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))
- 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))
- 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))
- 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))
- Changes in Serum Cytokines Soluble CD27 (sCD27) and Soluble Factors(Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations))
- Changes in Serum Cytokines Soluble CD40 Ligand (sCD40L) and Soluble Factors(Pre (Baseline), and approximately D29 (Post 1 vaccination), and D85 (post 3 vaccinations))
- 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))
研究者
James Gulley, M.D.
Principal Investigator
National Cancer Institute (NCI)