Safety and Tolerability of a Modified Vaccinia Ankara (MVA)-Based Vaccine Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-Brachyury-TRICOM)

NCT02179515 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 14014214-C-0142
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Lung Cancer; Breast Cancer; Prostate Cancer; Tumors (Others); Ovarian Cancer

Keywords

Immune Response; Maximum Tolerated Dose; Vaccine Therapy; Increased Expression of Brachyury; Immunotherapy

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  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.

  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 Dose-Limiting Toxicities (DLT)

  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.

  28 days following the first injection of vaccine.

• Maximum Tolerated Dose (MTD)

  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.

  First 28 days of treatment.

• Number of Participants With Grade 3 or Greater Adverse Events Possibly Related to Vaccine

  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.

  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.

Secondary Outcomes (7)

• 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)

• 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)

• 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)

• 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)

Other Outcomes (1)

• Correlation of Brachyury Expression in Tissue Samples With Clinical Outcomes.

  2 -3 years

Study Arms (1)

modified vaccinia Ankara (MVA)-brachyury-TRICOM vaccine

EXPERIMENTAL

Three cohorts will receive modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine administered subcutaneously as either 1, 2, or 4 injections of study drug at monthly (28 days +/4 days) intervals for 3 months. Patients with stable disease may continue to receive vaccine for up to 6 monthly doses.

Biological: MVA-brachyury- TRICOM

Interventions

MVA-brachyury- TRICOM BIOLOGICAL

It is an active cancer immunotherapy administered via subcutaneous injection.

modified vaccinia Ankara (MVA)-brachyury-TRICOM 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:

• (All Subjects)
• Patients must have a metastatic or unresectable locally advanced malignant solid tumor, histologically confirmed by the Laboratory of Pathology, National Cancer Institute (NCI). 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; other tumors may be included as data on the level of brachyury in those tumors becomes available).
• Patients may have measurable or nonmeasurable but evaluable disease. Patients with surgically resected metastatic disease at high risk of relapse are also eligible.
• Prior therapy: Patients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be candidates for therapy of proven efficacy for their disease.
• There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or radiation, with the exception of hormonal therapy for prostate and breast cancers, human epidermal growth factor receptor 2 (HER2)-directed therapy for HER2+ breast cancer (3+ immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH+), and erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancer in the expansion cohort as detailed in section. There should be a minimum of 6 weeks from any prior antibody therapies, (such as ipilimumab or anti-Programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) due to prolonged half-life.
• Patients must have recovered (grade 1 or baseline) from any clinically significant toxicity associated with prior 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.
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of modified vaccinia Ankara (MVA)-brachyury-B7-1, ICAM-1 (Intercellular Adhesion Molecule 1), and LFA-3 (lymphocyte function-associated antigen 3) TRICOM vaccine in patients \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%).
• Patients must have normal organ and marrow function as defined below:
• Serum creatinine less than or equal to 1.5 x upper limit of normal OR creatinine clearance on a 24-h urine collection of greater than or equal to 50 mL/min.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x the upper limits of normal.
• Total bilirubin less than or equal to 1.5 x upper limit of normal OR in patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0.
• Hematological eligibility parameters (within 16 days of starting therapy):
• Granulocyte count greater than or equal to 1,500/mm\^3
• Platelet count greater than or equal to 100,000/mm\^3

You may not qualify if:

• Chronic hepatitis B or C infection, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy.
• 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.
• 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 or clinically stable autoimmune endocrine disease who are on appropriate replacement therapy (if such therapy is indicated) are eligible.
• Concurrent use of systemic steroids, except for physiologic doses of systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited pharmacologic doses of systemic steroids (e.g., in patients with exacerbations of reactive airway disease or to prevent intravenous (I.V.) contrast allergic reaction or anaphylaxis in patients who have known contrast allergies) are allowed.
• Patients who are receiving any other investigational agents within 28 days before start of study treatment.
• Patients with untreated central nervous system metastases or local treatment of brain metastases within the last 6 months. Patients with stable brain metastasis for 6 months post-intervention are eligible. Subjects with chordoma will be eligible regardless of site of disease if other eligibility criteria are met.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MVA-brachyury-TRICOM or other agents used in study.
• Serious or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• Pregnant women are excluded from this study due to the unknown effects of the MVAbrachyury-TRICOM vaccine on the fetus or infant. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MVA-brachyury-TRICOM, breastfeeding should be discontinued if the mother is treated with MVA-brachyury-TRICOM. These potential risks may also apply to other agents used in this study.
• Human immunodeficiency viruses (HIV)-positive patients are ineligible because of the potential for decreased immune response to the vaccine.

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 (4)

• Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 1999 Nov 15;59(22):5800-7.

  PMID: 10582702 BACKGROUND

• Fernando RI, Litzinger M, Trono P, Hamilton DH, Schlom J, Palena C. The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells. J Clin Invest. 2010 Feb;120(2):533-44. doi: 10.1172/JCI38379. Epub 2010 Jan 11.

  PMID: 20071775 BACKGROUND

• Heery CR, Palena C, McMahon S, Donahue RN, Lepone LM, Grenga I, Dirmeier U, Cordes L, Marte J, Dahut W, Singh H, Madan RA, Fernando RI, Hamilton DH, Schlom J, Gulley JL. Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Clin Cancer Res. 2017 Nov 15;23(22):6833-6845. doi: 10.1158/1078-0432.CCR-17-1087. Epub 2017 Aug 30.

  PMID: 28855356 BACKGROUND

• 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

MeSH Terms

Conditions

Lung Neoplasms; Breast Neoplasms; Prostatic Neoplasms; Neoplasms; Ovarian Neoplasms

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders

Results Point of Contact

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

James_Gulley@nih.gov

301-480-8870

Study Officials

• James L Gulley, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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: Principal Investigator

Study Record Dates

• First Submitted: June 28, 2014
• First Posted: July 2, 2014
• Study Start: June 28, 2014
• Primary Completion: April 6, 2017
• Study Completion: February 28, 2018
• Last Updated: January 26, 2021
• Results First Posted: January 26, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)