Safety and Tolerability of a Modified Vaccinia Ankara (MVA) Priming Followed by Fowlpox Booster Vaccines Modified to Express Brachyury and T-Cell Costimulatory Molecules (MVA-BN-Brachyury/FPV-Brachyury)

Breast Cancer Clinical Trial

Official title:

Safety and Tolerability of a Modified Vaccinia Ankara (MVA) Priming Followed by Fowlpox Booster Vaccines Modified to Express Brachyury and T-Cell Costimulatory Molecules (MVA-BN-Brachyury/FPV-Brachyury)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03411486
• Other study ID #: 180048
• Secondary ID: 18-C-0048
• Status: Not yet recruiting
• Phase: Phase 1
• First received: January 25, 2018
• Last updated: January 31, 2018
• Start date: February 6, 2018
• Est. completion date: December 31, 2019

Study information

• Verified date: January 19, 2018
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Diana Martin, R.N.
• Phone: (240) 760-7969
• Email: diana.martin[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Brachyury controls the expression of other genes in our cells. How this happens is not fully understood. Research shows that in some cancers, brachyury is over-expressed. This may play a role in cancer growth and metastasis. Researchers want to test a vaccine that turns the immune system against brachyury. The vaccine is made up of 2 viruses: Modified Vaccinia Ankara (MVA) and Fowlpox virus (FPV). The goal is to teach the immune system to kill the tumor cells that express the Brachyury protein.

Objectives:

To test if the booster doses of FPV-Brachyury Fowlpox are safe and can improve the immune response and make it last longer in people with advanced cancer.

Eligibility:

Adults 18 85 years old with cancer that has not responded to standard therapies.

Design:

Participants will be screened with medical history, review of their tumor sample, and physical exam. They will have blood and urine tests. They will have scans and X-rays to assess their cancer. They will have a heart test.

Participants will get the vaccine in shots under the skin, close to lymph nodes. Shots will be given every 4 12 weeks for 2 years as long as participants can and are willing to continue to participate. At these visits, they will repeat some or all the screening tests, except the tumor sample review.

After 2 years, participants will get phone calls every 3 months for 5 years. They will talk about any symptoms they have had.

Description:

Background:

• MVA/FPV-Brachyury-TRICOM is a novel recombinant vector-based therapeutic cancer vaccine comprising a priming vector, Modified Vaccinia Ankara (MVA-brachyury-TRICOM), and a boost vector, fowlpox (FPV-brachyury-TRICOM), designed to induce an enhanced immune response against brachyury, which is overexpressed in many solid tumor types, such as lung, breast, ovarian, chordoma, prostate, colorectal, and pancreatic adenocarcinoma.

• Modified Vaccinia Ankara (MVA) is a replication-deficient, attenuated derivative of vaccinia. It is used in the smallpox vaccination and is now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. Fowlpox is also replication incompetent in human cells and can be used for multiple booster vaccinations due to weak host-neutralizing antibody responses against the vector.

• Poxviral vaccines delivering a triad of three human T-cell costimulatory molecules designated TRICOM (B7.1, ICAM-1 and LFA-3) have been extensively studied in both preclinical and clinical studies and have demonstrated their ability to induce robust Tcell activation and provide evidence of clinical benefit.

• Brachyury is a member of the T-box family of transcription factors. It is overexpressed in cancer cells compared with normal tissue and has been linked to cancer cell resistance and metastatic potential.

• A previous phase I trial of MVA-brachyury-TRICOM demonstrated immunogenicity and safety of the priming dose and established a recommended phase 2 dose. Evaluation was limited due to the lack of long-term booster dosing.

• This study will evaluate safety and tolerability of MVA-brachyury-TRICOM priming dose followed by FPV-brachyury-TRICOM booster dose (prime-boost strategy)

Objective:

• To determine the safety and tolerability of MVA-brachyury-TRICOM followed by FPVbrachyury-TRICOM vaccine.

Eligibility:

• Histologically confirmed malignancy

• 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. As much as possible, patients enrolled will have tumor types with known increased expression of brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic, hepatocellular, Merkel cell, small cell lung cancer or chordoma).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at study entry

• Age greater than or equal to 18 years.

• Prior Therapy: Completed, or disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not a candidate for therapy of proven efficacy for their disease.

Design:

• This is an open-label, phase I trial. One dose level will be evaluated of MVA-brachyury-TRICOM priming vaccine followed by fowlpox-brachyury-TRICOM booster vaccine.

• Up to 10 patients, assuming no more than 1/6 patients experience a dose limiting toxicity, will be treated with 2 doses of MVA-brachyury-TRICOM priming vaccine administered subcutaneously with 4 injections of study drug (1 injection = 2 x 10(8) infectious units (IU) at monthly (28 days +/ 4 days) intervals for 2 months followed by monthly doses of fowlpox-brachyury-TRICOM at 1 x 109 Infectious units (Inf.U) given as a single subcutaneous injection monthly (28 days +/- 4 days).

• If 3 patients per month can be accrued, the study is expected to require 3-4 months to complete the necessary enrollment.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: December 31, 2019
• Est. primary completion date: December 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

-INCLUSION CRITERIA:

1. Patients must have a histologically confirmed 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, hepatocellular, Merkel cell, small cell lung cancer or chordoma; other tumors may be included as data on the level of brachyury in those tumors becomes available). Every attempt will be made to collect archival tissue, preferably metastatic disease.

2. Patients may have measurable or nonmeasurable but evaluable disease. Patients with surgically resected metastatic disease at high risk of relapse or patients with metastatic disease with a complete response after palliative chemotherapy with at high risk of relapse (such as small cell lung cancer, etc) are also eligible.

3. 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.

4. There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or radiation, with the following exceptions:

1. Prostate cancer - patients must continue to receive GnRH agonist therapy (unless orchiectomy has been done). Patients on combined androgen blockade therapy may continue those therapies as well (bicalutamide, nilutamide, flutamide, enzalutamide and abiraterone).

2. Breast cancer patients may remain on hormonal therapy if indicated (ER/PR+), HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+).

3. Epidermal Growth Factor Receptor-mutated lung cancer patient may remain on first line Epidermal Growth Factor Receptor inhibiting therapy (tyrosine kinase inhibitors) if they have had stable disease or ongoing response to therapy. Patients with T790M mutations may continue receiving osimertinib while receiving vaccine.

4. Mestastatic colorectal cancer may continue maintenance therapy with capecitabine and/or bevacizumab.

5. There should be a minimum of 6 weeks from any prior antibody therapies, (such as ipilimumab or anti-Programmed Death 1/Programmed Death Ligand 1) due to prolonged half-life.

6. 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.

7. Age 18 to 85 years. Because no dosing or adverse event data are currently available on the use of BN-Brachyury vaccine in patients < 18 years of age, children are excluded from this trial but will be eligible for future pediatric trials.

8. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%)

9. 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 3x 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 1,000/mm(3)

• Platelet count greater than or equal to 100,000/mm(3)

10. The effects of BN-Brachyury (MVA-BN-Brachyury & FPVBrachyury) on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to trial entry and for the duration of trial participation and for a period of 4 months after the last vaccination therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, she should inform her treating physician immediately.

11. Patients must be able to understand and be willing to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Concurrent treatment for cancer, with specific exceptions noted in inclusion criteria.

2. Chronic hepatitis B or C infection, because potential immune impairment caused by these disorders may diminish the effectiveness of this immunologic therapy.

3. Any significant disease that, in the opinion of the investigator, may impair the patient s tolerance of trial treatment.

4. Significant dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.

5. 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.

6. 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 (IV) contrast allergic reaction or anaphylaxis in patients who have known contrast allergies) are allowed.

7. Patients who are receiving any other investigational agents within 28 days before start of trial treatment.

8. 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 postintervention are eligible. Subjects with chordoma will be eligible regardless of site of disease if other eligibility criteria are met.

9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to BN-Brachyury or other agents used in trial. History of allergic reaction to aminoglycoside antibiotics or egg products.

10. 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 trial requirements.

11. Pregnant women are excluded from this trial due to the unknown effects of the BN-Brachyury 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 BN-Brachyury, breastfeeding should be discontinued if the mother is treated with BN-Brachyury. These potential risks may also apply to other agents used in this trial.

12. Human Immunodeficiency Virus (HIV)-positive patients are ineligible because of the potential for decreased immune response to the vaccine.

13. Patients with a cardiac event within 6 months of the screening visit.

Related Conditions & MeSH terms

• Breast Cancer
• Lung Cancer
• Ovarian Cancer
• Prostate Cancer
• Tumors (Others)
• Vaccinia

Intervention

Biological:
• MVA-BN-Brachyury vaccine (prime) followed by FPV-Brachyury (boost)
Each dose of MVA-BNbrachyury priming vaccine will be administered subcutaneously as 4 separate injections at monthly intervals for 2 doses. Subsequently, patients will receive 1 booster dose of FPVBrachyury adminstered as one injection at monthly intervals for 6 doses, then at 12 week intervals thereafter.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patients with Dose Limiting Toxicity	Fraction of patients who experience a (Dose Limiting Toxicity) DLT	up to 8 weeks

External Links

•   NIH Clinical Center Detailed Web Page