Clinical trial NCT01519817: Cancer Vaccine Targeting Brachyury Protein in Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Malignant Solid Tumors
Colon Neoplasms
Adenocarcinoma
Keywords: Vaccine Therapy
Dose-Limiting Toxicity
Maximum Tolerated Dose
Clinical Response
Immune Response
Cancer
Solid Tumor
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-01-27
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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....

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.

Eligibility criteria: * INCLUSION CRITERIA:

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.
* 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.

EXCLUSION CRITERIA:

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.
* 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.

Primary outcomes:
measure: Number of Participants With Brachyury-Specific T-cell Responses
timeFrame: Baseline (pre-vaccination) and approximately day 84 (after 6 vaccinations)
measure: Count of Participants With Adverse Events of Escalating Doses of Yeast Brachyury ( GI- 6301) Vaccine
timeFrame: 4 years and 25 days
Secondary outcomes:
measure: Number of Participants With a Clinical Benefit Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: 3 and 5 months restaging
measure: Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)
timeFrame: Pre (Baseline) and Day 85 after 6 vaccinations
measure: Changes in Serum Levels of Cytokines
timeFrame: Pre (Baseline) and Day 85 after 6 vaccinations
measure: Changes in Soluble Cluster of Differentiation 27 (sCD27)
timeFrame: Pre (Baseline) and Day 85 after 6 vaccinations
measure: Median Ratio of Soluble Cluster of Differentiation 27:40L (sCD27:sCD40L)
timeFrame: Pre (Baseline) and Day 85 after 6 vaccinations
measure: Changes in Soluble Cluster of Differentiation 40L (sCD40L)
timeFrame: Pre (Baseline) and Day 85 after 6 vaccinations
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: James L Gulley, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.