An Open Label Phase I Study to Evaluate the Safety and Tolerability of GI-6301 Vaccine Consisting of Whole, Heat-Killed Recombinant Saccharomyces Cerevisiae (Yeast) Genetically Modified to Express Brachyury Protein in Adults With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 2
- 主要终点
- Number of Participants With Brachyury-Specific T-cell Responses
研究概览
简要总结
Background:
- Cancer vaccines are being developed to help teach the body's immune system to attack and destroy cancer cells. A new vaccine being tested targets 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.
Objectives:
- To test the safety and effectiveness of a cancer vaccine that targets Brachyury protein in tumor cells.
Eligibility:
- Individuals at least 18 years of age who have advanced cancers that have not responded or are no longer responding to standard treatments.
- Because the vaccine is made with yeast, people with yeast allergies will not be eligible.
Design:
- Participants will be screened with a medical history and physical exam. Imaging studies will be used to examine the cancer. Heart and thyroid function tests will be conducted. Blood and urine samples will also be collected.
- Participants will receive vaccine injections every 2 weeks, for a total of seven visits. After seven visits, if the cancer has shrunk or stopped growing, participants will continue to have the vaccine about once a month.
- Treatment will be monitored with frequent blood tests and imaging studies. Other tests will be given as directed by the study doctors. Some participants will have apheresis to collect additional blood cells for study.
- Participants will continue to receive the vaccine as long the tumor does not start growing again and there are no serious side effects....
详细描述
Background:
- Vaccines based on recombinant heat inactivated yeast have been shown to be immunogenic and well tolerated in animals and humans.
- Using a computer-based differential display analysis tool to conduct global comparison of expressed sequence tag (EST) clusters in the Unigene database, the gene encoding for the transcription factor Brachyury was identified as highly represented in tumor-derived libraries and rarely observed in normal tissue-derived libraries. By using reverse-transcription followed by polymerase chain reaction (RT-PCR), investigators in the LTIB have identified the overexpression of Brachyury in gastrointestinal, bladder, kidney, ovary, uterus, and testicular carcinomas. Similar studies also found over-expression of Brachyury mRNA in cell lines of lung, colon and prostate cancers, but not in the majority of normal tissues tested, with the exception of expression in the testis, thyroid and low levels of expression in B cells pooled from multiple normal donors.
- Brachyury is a member of the T-box family of transcription factors, characterized by a highly conserved DNA-binding domain designated as T-domain. Data indicates that the transcription factor Brachyury confers on the tumor cells a mesenchymal phenotype, as well as migratory and invasive abilities and enhances tumor cell progression.
- A murine model of MC38 cells engineered to over express human Brachyury gene has demonstrated increased metastatic potential of Brachyury over-expressing MC38 cells.
- Brachyury specific T cells can lyse human cancer cells expressing Brachyury in an MHC restricted manner.
- GI-6301 (Yeast-Brachyury vaccine) has been tested in vitro and in the mouse model. These studies showed Brachyury-specific T cell responses and decreased metastasis in mice treated with vaccine.
- An ongoing study of a Hepatitis B vaccine (GS-4774) using the yeast platform (heat killed Saccharomyces cerevisiae) indicated safety of 80 YU dose (4 injection sites at 20 YU injections per site).
Objectives:
-The primary objectives are to:
- Determine the safety and tolerability of escalating doses of GI-6301 (Yeast-Brachyury vaccine) a heat-killed yeast-based vaccine
- Determine in an expanded cohort if a significant change in Brachyury specific T cells will be detectable post vaccine.
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
研究组 & 干预措施
Yeast-Brachyury vaccine
Yeast-Brachyury vaccine will be administered subcutaneously at 4 sites on 7 visits, then monthly until patients meet off-treatment criteria.
干预措施: GI-6301 (Yeast Brachyury Vaccine) (Biological)
结局指标
主要结局
Number of Participants With Brachyury-Specific T-cell Responses
时间窗: Baseline (pre-vaccination) and approximately day 84 (after 6 vaccinations)
A fluorescense 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.
Count of Participants With Adverse Events of Escalating Doses of Yeast Brachyury ( GI- 6301) Vaccine
时间窗: 4 years and 25 days
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in 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. A non-serious adverse event is any untoward medical occurrence.
次要结局
- Number of Participants With a Clinical Benefit Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)(3 and 5 months restaging)
- Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)(Pre (Baseline) and Day 85 after 6 vaccinations)
- Changes in Serum Levels of Cytokines(Pre (Baseline) and Day 85 after 6 vaccinations)
- Changes in Soluble Cluster of Differentiation 27 (sCD27)(Pre (Baseline) and Day 85 after 6 vaccinations)
- Median Ratio of Soluble Cluster of Differentiation 27:40L (sCD27:sCD40L)(Pre (Baseline) and Day 85 after 6 vaccinations)
- Changes in Soluble Cluster of Differentiation 40L (sCD40L)(Pre (Baseline) and Day 85 after 6 vaccinations)
研究者
James Gulley, M.D.
Senior Investigator
National Cancer Institute (NCI)