NeoplasmsPhase 1NCT01519817
Cancer Vaccine Targeting Brachyury Protein in Tumors
A Phase 1 study testing GI-6301 (Yeast Brachyury Vaccine) in people with Neoplasms and Malignant Solid Tumors, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Neoplasms, Malignant Solid Tumors, Colon Neoplasms
- What is being tested?
- GI-6301 (Yeast Brachyury Vaccine)
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Jan 2012to 1 Sep 2016
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participants must meet the following criteria for participation:
- Diagnosis: Patients must have histologically confirmed malignancy by the Laboratory of Pathology, National Cancer Institute (NCI), 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. Efforts will be made, as much as possible, to enroll patients with tumor types with known increased expression of Brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic, or chordoma).
- Patients may have disease that is measurable or non-measurable but evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry (Karnofsky greater than or equal to 70)
- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Yeast Brachyury vaccine in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
- Prior Therapy: Completed or had disease progression on at least one prior line of diseaseappropriate therapy for metastatic disease, or not be a candidate for therapy of proven efficacy for their disease.
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- Patients must have normal organ and marrow function as defined below:
- Serum creatinine 1.5 times upper limit of normal OR creatinine clearance on a 24-h urine collection of 60 mL/min.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 times the upper limits of normal.
- Total bilirubin less than or equal to 1.5 times upper limit of normal OR in patients with Gilbert's syndrome, a total bilirubin 3.0.
- Hematological eligibility parameters (within16 days of starting therapy):
- Granulocyte count 1,500/mm(3)
- Platelet count 100,000/m(3)
- Patients must have baseline pulse oximetry > 90% on room air.
- Recovered completely (Grade 1 or baseline) from any reversible toxicity associated with recent therapy. Typically this is 3 4 weeks for patients who most recently received cytotoxic therapy, except for the nitrosoureas and mitomycin C for which 6 weeks is needed for recovery.
- There should be a minimum of 2 weeks from any prior chemotherapy, immunotherapy and/or radiation.
- Prior immune therapy is allowed.
- Men and women of child-bearing potential must agree to use effective birth control or abstinence during and for a period of 4 months after the last vaccination therapy.
- Patients with prostate cancer must continue to receive gonadotropin-releasing hormone (GnRH) agonist therapy (unless orchiectomy has been done). If a patient has refused GnRH therapy, they may be enrolled on a dose level for which the safety has already been determined.
- Patients with estrogen-receptor positive (ER+) breast cancer being treated with adjuvant hormonal therapy (selective estrogen receptor modulator or aromatase inhibitor) who have rising tumor markers as evidence of disease progression or metastatic disease on scans may continue on hormonal therapy while being treated with vaccine.
- Patients must be negative for yeast allergy skin test
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Patients with any of the following will not be eligible for participation in this study:
- Patients should have no evidence of immune dysfunction as listed below.
- Human immunodeficiency virus (HIV) positivity due to the potential for decreased immune response to the vaccine.
- Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment. This requirement is due to the potential risks of exacerbating autoimmunity. However, patients with vitiligo, diabetes mellitus, and hashimoto s thyroiditis on appropriate replacement therapy may be
- enrolled.
- --Concurrent use of systemic steroids, except for physiologic doses of systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited doses of systemic steroids (e.g., in patients with exacerbations of reactive airway disease or to prevent intravenous (IV) contrast allergic reaction or anaphylaxis in patients who have known contrast allergies) are allowed.
Show all 17Show fewer
- History of allergy or untoward reaction to yeast-based products (any hypersensitivity to yeast-based products will be excluded).
- Pregnant or breast-feeding women, due to the unknown effects of the Yeast Brachyury vaccine on the fetus or infant.
- Serious intercurrent medical illness which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis.
- Untreated brain metastases (or local treatment of brain metastases within the last 6 months) and or spinal cord metastasis.
- Patients with pericardial masses >1 cm will be excluded.
- Concurrent chemotherapy. (However, the following anti-tumor therapies will be allowed: Trastuzumab for human epidermal growth factor receptor 2 (HER2+) breast cancer and hormonal therapy for breast (e.g., selective estrogen receptor modulators, aromatase inhibitors) and prostate cancer (e.g., GnRH antagonists/agonists or antagonists and androgen receptor antagonists).
- Chronic hepatitis infection, including B and C, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy.
- Patients requiring continuous tricyclic antidepressant therapy should be excluded due to the interference with the yeast skin test in creating false negative test results.
- Participation in another interventional clinical trial within 28 days before start of study treatment.
- Any significant disease that, in the opinion of the investigator, may impair the patient s tolerance of study treatment.
- Significant dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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
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.
Read more
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....
Read the detailed description
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.
Eligibility:
- Adults with histologically proven metastatic or locally advanced solid tumors for which standard curative or palliative measures are no longer effective. Efforts will be made, as much as possible, to enroll patients with tumor types with known increased expression of Brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic or chordoma).
- Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
- Patients with acquired immune defects, systemic autoimmune disease, concurrent use of steroids, pericardial mass > 1 cm, chronic infections, concurrent tricyclic antidepressant therapy, or allergy to yeast or yeast-based products will be excluded.
Design:
- This is an open label, phase I trial with sequential dose escalation cohorts of patients (3-6 patients per dose cohort) for 3 doses of GI-6301 (Yeast-Brachyury vaccine).
- GI-6301 (Yeast-Brachyury vaccine) will be administered subcutaneously at 4 sites biweekly for 7 visits (day 1, 15, 29, 43, 57, 71, 85), then monthly until patients meet off-study criteria (patients who have been on study for one year or more and have had stable disease or better (PR, CR) have the option to receive vaccine once every 3 months instead of monthly).
- All patients on a given dose level will have completed 28 days on-study without DLT before enrollment can begin on the next dose level or on the expansion phase (see statistical analysis section).
- Expansion Phase: 10 additional patients will be enrolled on the MTD dose level (or the highest dose level explored in the event that a true MTD is not reached), receiving the same treatment regimen, to assess for immunologic responses and clinical responses.
- Amended dose escalation: 10 patients will be enrolled at an additional dose level (80 YU per dose, 4 injection sites at 20 YU per site) to determine the safety of this dose level.
- Up to 33 total patients may be required to complete enrollment of this study.
- Conditions
- Neoplasms, Malignant Solid Tumors, Colon Neoplasms, Adenocarcinoma
- Being tested
- GI-6301 (Yeast Brachyury Vaccine)
- Keywords
- Vaccine Therapy, Dose-Limiting Toxicity, Maximum Tolerated Dose, Clinical Response, Immune Response, Cancer, Solid Tumor
- Medical subject headings
- Neoplasms, Colonic Neoplasms, Adenocarcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GI-6301 (Yeast Brachyury Vaccine)Biological
Also called Yeast-Brachyury vaccine
GI-6301 is a heat-killed, recombinant yeast-based vaccine engineered to express the transcription factor, Brachyury. The Brachyury gene is used to transfect the parental yeast strain (S. cerevisiae W303 - a haploid strain with known mutations from wildtype yeast) to produce the final recombinant vaccine product.
| Study group | Role | What they receive |
|---|---|---|
| Yeast-Brachyury vaccine | Experimental | Yeast-Brachyury vaccine will be administered subcutaneously at 4 sites on 7 visits, then monthly until patients meet off-treatment criteria. Receives: Biological: GI-6301 (Yeast Brachyury Vaccine) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Brachyury-Specific T-cell Responses
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.
Measured: Baseline (pre-vaccination) and approximately day 84 (after 6 vaccinations)
Count of Participants With Adverse Events of Escalating Doses of Yeast Brachyury ( GI- 6301) Vaccine
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.
Measured: 4 years and 25 days
Secondary outcomes (6)
Number of Participants With a Clinical Benefit Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)
Clinical benefit is defined as partial response (PR) or stable disease (SD) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Partial response is ≥30% decrease in the sum of greatest diameters/no new lesions. Progressive disease is ≥20% increase in the sum of greatest diameters/new lesions. Stable disease does not meet criteria for complete response (disappearance of all lesions; no new lesions), partial response, or progressive disease.
Measured: 3 and 5 months restaging
Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)
Blood samples will be collected via apheresis and 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), Tregs, CD4 central memory (CD4 CM), CD4 effector memory (CD4 EM), CD4 terminal effector memory (CD4 EMRA), CD4 naïve, CD8 CM, CD8 EM, CD8 EMRA, and CD8 naïve cells. Significance of changes in immune cells was determined by p value (Wilcoxon test) and the median and interquartile range of data.
Measured: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Serum Levels of Cytokines
Blood samples were collected and changes in serum levels of cytokines interferon gamma (IFNg), Interleukin 10 (IL-10), Interleukin 12 (IL-12)p70, Interleukin 1b (IL-1b), Interleukin 2 (IL-2), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and tumor necrosis factor (TNF) were assessed by the multiplexed mesoscale assay. Significance of changes in serum levels of cytokines was determined by p value (Wilcoxon test) and the median and interquartile range of data.
Measured: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Soluble Cluster of Differentiation 27 (sCD27)
Blood samples were collected and changes in serum levels of soluble sCD27 were assessed by enzyme-linked immunosorbent assay (ELISA). Significance of changes in soluble sCD27 was determined by p value (Wilcoxon test) and the median and interquartile range of data.
Measured: Pre (Baseline) and Day 85 after 6 vaccinations
Median Ratio of Soluble Cluster of Differentiation 27:40L (sCD27:sCD40L)
Blood samples were collected and changes in serum levels of the ratio of soluble sCD27:sCD40L was assessed by enzyme-linked immunosorbent assay (ELISA). Significance of changes in soluble sCD27:sCD40L was determined by p value (Wilcoxon test) and the median and interquartile range of data.
Measured: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Soluble Cluster of Differentiation 40L (sCD40L)
Blood samples were collected and changes in serum levels of soluble sCD27 were assessed by enzyme-linked immunosorbent assay (ELISA). Significance of changes in soluble sCD40L was determined by p value (Wilcoxon test) and the median and interquartile range of data.
Measured: Pre (Baseline) and Day 85 after 6 vaccinations
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2012 (estimated)
- Study start5 Jan 2012
- Primary completion3 Mar 2016
- Study completion1 Sep 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, James Gulley, M.D., National Cancer Institute (NCI)
- Investigators
- James L Gulley, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01519817
- Sponsor's protocol ID
- 120056
- Other IDs
- 12-C-0056
- Status last verified
- Jan 2018
- First submitted
- 12 Jan 2012
- Last updated
- 29 Jan 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Baranova AV, Lobashev AV, Ivanov DV, Krukovskaya LL, Yankovsky NK, Kozlov AP. In silico screening for tumour-specific expressed sequences in human genome. FEBS Lett. 2001 Nov 9;508(1):143-8. doi: 10.1016/s0014-5793(01)03028-9.
PubMed 11707285Krukovskaja LL, Baranova A, Tyezelova T, Polev D, Kozlov AP. Experimental study of human expressed sequences newly identified in silico as tumor specific. Tumour Biol. 2005 Jan-Feb;26(1):17-24. doi: 10.1159/000084182. Epub 2005 Feb 28.
PubMed 15741768Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, Baranova AV, Kozlov AP, Schlom J. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy. Clin Cancer Res. 2007 Apr 15;13(8):2471-8. doi: 10.1158/1078-0432.CCR-06-2353.
PubMed 17438107Heery CR, Singh BH, Rauckhorst M, Marte JL, Donahue RN, Grenga I, Rodell TC, Dahut W, Arlen PM, Madan RA, Schlom J, Gulley JL. Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Cancer Immunol Res. 2015 Nov;3(11):1248-56. doi: 10.1158/2326-6066.CIR-15-0119. Epub 2015 Jun 30.
PubMed 26130065Fenerty KE, Patronas NJ, Heery CR, Gulley JL, Folio LR. Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden? J Digit Imaging. 2016 Jun;29(3):357-64. doi: 10.1007/s10278-015-9846-9.
PubMed 26596767
Study at a glance
From the registry record, last updated by the sponsor on 29 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01519817
- Acronym / sponsor ID
- 120056
- Conditions
- Neoplasms, Malignant Solid Tumors, Colon Neoplasms, Adenocarcinoma
- Keywords
- Vaccine Therapy, Dose-Limiting Toxicity, Maximum Tolerated Dose, Clinical Response, Immune Response, Cancer, Solid Tumor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 5 Jan 2012 (actual)
- Primary completion
- 3 Mar 2016 (actual)
- Study completion
- 1 Sep 2016 (actual)
- First posted
- 27 Jan 2012 (estimated)
- Results
- Posted 31 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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....
Detailed description
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.
Eligibility:
- Adults with histologically proven metastatic or locally advanced solid tumors for which standard curative or palliative measures are no longer effective. Efforts will be made, as much as possible, to enroll patients with tumor types with known increased expression of Brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic or chordoma).
- Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
- Patients with acquired immune defects, systemic autoimmune disease, concurrent use of steroids, pericardial mass > 1 cm, chronic infections, concurrent tricyclic antidepressant therapy, or allergy to yeast or yeast-based products will be excluded.
Design:
- This is an open label, phase I trial with sequential dose escalation cohorts of patients (3-6 patients per dose cohort) for 3 doses of GI-6301 (Yeast-Brachyury vaccine).
- GI-6301 (Yeast-Brachyury vaccine) will be administered subcutaneously at 4 sites biweekly for 7 visits (day 1, 15, 29, 43, 57, 71, 85), then monthly until patients meet off-study criteria (patients who have been on study for one year or more and have had stable disease or better (PR, CR) have the option to receive vaccine once every 3 months instead of monthly).
- All patients on a given dose level will have completed 28 days on-study without DLT before enrollment can begin on the next dose level or on the expansion phase (see statistical analysis section).
- Expansion Phase: 10 additional patients will be enrolled on the MTD dose level (or the highest dose level explored in the event that a true MTD is not reached), receiving the same treatment regimen, to assess for immunologic responses and clinical responses.
- Amended dose escalation: 10 patients will be enrolled at an additional dose level (80 YU per dose, 4 injection sites at 20 YU per site) to determine the safety of this dose level.
- Up to 33 total patients may be required to complete enrollment of this study.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Yeast-Brachyury vaccine | Experimental | Biological: GI-6301 (Yeast Brachyury Vaccine)Yeast-Brachyury vaccine will be administered subcutaneously at 4 sites on 7 visits, then monthly until patients meet off-treatment criteria. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Diagnosis: Patients must have histologically confirmed malignancy by the Laboratory of Pathology, National Cancer Institute (NCI), 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. Efforts will be made, as much as possible, to enroll patients with tumor types with known increased expression of Brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic, or chordoma).
- Patients may have disease that is measurable or non-measurable but evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry (Karnofsky greater than or equal to 70)
- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Yeast Brachyury vaccine in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
- Prior Therapy: Completed or had disease progression on at least one prior line of diseaseappropriate therapy for metastatic disease, or not be a candidate for therapy of proven efficacy for their disease.
Key exclusion criteria (17 listed)
- Patients should have no evidence of immune dysfunction as listed below.
- Human immunodeficiency virus (HIV) positivity due to the potential for decreased immune response to the vaccine.
- Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment. This requirement is due to the potential risks of exacerbating autoimmunity. However, patients with vitiligo, diabetes mellitus, and hashimoto s thyroiditis on appropriate replacement therapy may be
- enrolled.
- --Concurrent use of systemic steroids, except for physiologic doses of systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited doses of systemic steroids (e.g., in patients with exacerbations of reactive airway disease or to prevent intravenous (IV) contrast allergic reaction or anaphylaxis in patients who have known contrast allergies) are allowed.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GI-6301 (Yeast Brachyury Vaccine)Also: Yeast-Brachyury vaccineGI-6301 is a heat-killed, recombinant yeast-based vaccine engineered to express the transcription factor, Brachyury. The Brachyury gene is used to transfect the parental yeast strain (S. cerevisiae W303 - a haploid strain with known mutations from wildtype yeast) to produce the final recombinant vaccine product. | Biological | Yeast-Brachyury vaccine |
Primary outcome
Number of Participants With Brachyury-Specific T-cell Responses
Time frame: 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
Time frame: 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.
6 secondary outcomes
Number of Participants With a Clinical Benefit Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: 3 and 5 months restaging
Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)
Time frame: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Serum Levels of Cytokines
Time frame: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Soluble Cluster of Differentiation 27 (sCD27)
Time frame: Pre (Baseline) and Day 85 after 6 vaccinations
Median Ratio of Soluble Cluster of Differentiation 27:40L (sCD27:sCD40L)
Time frame: Pre (Baseline) and Day 85 after 6 vaccinations
Changes in Soluble Cluster of Differentiation 40L (sCD40L)
Time frame: Pre (Baseline) and Day 85 after 6 vaccinations
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jan 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11707285Baranova AV, Lobashev AV, Ivanov DV, Krukovskaya LL, Yankovsky NK, Kozlov AP. In silico screening for tumour-specific expressed sequences in human genome. FEBS Lett. 2001 Nov 9;508(1):143-8. doi: 10.1016/s0014-5793(01)03028-9.
- Background: PubMed 15741768Krukovskaja LL, Baranova A, Tyezelova T, Polev D, Kozlov AP. Experimental study of human expressed sequences newly identified in silico as tumor specific. Tumour Biol. 2005 Jan-Feb;26(1):17-24. doi: 10.1159/000084182. Epub 2005 Feb 28.
- Background: PubMed 17438107Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, Baranova AV, Kozlov AP, Schlom J. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy. Clin Cancer Res. 2007 Apr 15;13(8):2471-8. doi: 10.1158/1078-0432.CCR-06-2353.
- Results publication: PubMed 26130065Heery CR, Singh BH, Rauckhorst M, Marte JL, Donahue RN, Grenga I, Rodell TC, Dahut W, Arlen PM, Madan RA, Schlom J, Gulley JL. Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Cancer Immunol Res. 2015 Nov;3(11):1248-56. doi: 10.1158/2326-6066.CIR-15-0119. Epub 2015 Jun 30.
- Derived from this study: PubMed 26596767Fenerty KE, Patronas NJ, Heery CR, Gulley JL, Folio LR. Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden? J Digit Imaging. 2016 Jun;29(3):357-64. doi: 10.1007/s10278-015-9846-9.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James L Gulley, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing GI-6301 (Yeast Brachyury Vaccine) in people with Neoplasms and Malignant Solid Tumors, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Brachyury-Specific T-cell Responses (time frame: Baseline (pre-vaccination) and approximately day 84 (after 6 vaccinations)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01519817, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jan 2018.