Cancer Vaccine Targeting Brachyury Protein in Tumors

NCT01519817 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 12005612-C-0056
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief 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. 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....

Conditions

Neoplasms; Malignant Solid Tumors; Colon Neoplasms; Adenocarcinoma

Keywords

Vaccine Therapy; Dose-Limiting Toxicity; Maximum Tolerated Dose; Clinical Response; Immune Response; Cancer; Solid Tumor

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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)

  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

Study Arms (1)

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.

Biological: GI-6301 (Yeast Brachyury Vaccine)

Interventions

GI-6301 (Yeast Brachyury Vaccine) BIOLOGICAL

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.

Also known as: Yeast-Brachyury vaccine

Yeast-Brachyury vaccine

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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.

  PMID: 11707285 BACKGROUND

• Krukovskaja 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.

  PMID: 15741768 BACKGROUND

• Palena 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.

  PMID: 17438107 BACKGROUND

• Heery 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.

  PMID: 26130065 RESULT

• Fenerty 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.

  PMID: 26596767 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Colonic Neoplasms; Adenocarcinoma

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Results Point of Contact

• Title: Dr. James Gulley
• Organization: National Cancer Institute

gulleyj@mail.nih.gov

301-480-8870

Study Officials

• James L Gulley, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Investigator

Study Record Dates

• First Submitted: January 12, 2012
• First Posted: January 27, 2012
• Study Start: January 5, 2012
• Primary Completion: March 3, 2016
• Study Completion: September 1, 2016
• Last Updated: January 29, 2018
• Results First Posted: July 31, 2017

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)