A Phase 1 Open Label Trial of Intravenous Administration of MVA-BN-Brachyury Vaccine in Patients With Advanced Cancer

Inclusion criteria

• Men and women > 18 years old.
• Patients must be able to understand and be willing to sign a written informed consent document.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
• Eligible patients must have one of the histologically confirmed cancers and treatment history as described:

• Chordoma

• Symptomatic, unresectable, locally recurrent, or metastatic tumors are acceptable for enrollment, given that this represents incurable disease.
• Only curative interventions are required as prior therapy (surgery or definitive radiation) as no known systemic therapies have proven benefit.
• Non-Small Cell Lung Cancer

• Metastatic or incurable locally advanced.
• Disease progression after indicated targeted therapy (EGFR-mut, ALK-fusion, BRAF-mut).
• Disease progression after one regimen of chemotherapy and anti-PD-1/L1 therapy either sequentially or concurrently.
• Small Cell Lung Cancer

• Metastatic disease.
• Disease progression after 1st line chemotherapy.
• Breast

• Metastatic disease considered to be incurable.
• Triple negative - disease progression after first line chemotherapy.
• ER+ disease - must have had disease progression through at least 2 lines of hormonal therapy and at least 1 chemotherapy regimen.
• Her2+ disease - must have had disease progression after at least 2 Her2-targeted therapy containing regimens.
• ER+ and Her2+ - must meet requirements of each tumor marker subtype (see above).
• Ovarian

• Metastatic disease.
• Disease progression after treatment with platinum-based chemotherapy.
• Prostate

• Metastatic Castration Resistant Prostate Cancer (mCRPC) AND
• Disease progression after at least one line of treatment of abiraterone or enzalutamide and docetaxel.
• Colorectal

• Metastatic disease.
• Must have received chemotherapy regimens containing 5-FU, oxaliplatin, irinotecan, and EGFR-targeted antibodies when indicated (absence of RAS mutation) with evidence of disease progression or AEs that preclude further treatment with standard therapies.
• Pancreatic

• Metastatic disease.
• Disease progression after or intolerance to standard chemotherapy regimens of known benefit (FOLFIRINOX or Gemcitabine and Abraxane).
• Hepatocellular

• Incurable disease: liver only or metastatic.
• Disease progression after at least one systemic therapy of known benefit (e.g. sorafenib).
• Bladder

• Metastatic disease.
• At least one line of chemotherapy and immune checkpoint inhibitors second line.
• Kidney

• Metastatic disease.
• After VEGF inhibitors, immune check-point inhibitors, m-TOR inhibitors.
• Patients must have measurable or evaluable disease. Measurable disease is defined by RECIST 1.1. In the case of evaluable disease, patients should have cancer-related symptoms to justify risk.

Evaluable disease is defined as any of the following:

• Elevated serum tumor marker known to be related to the patient's tumor.
• Clear radiographic or physical exam evidence of tumor which does not meet RECIST 1.1 measurement requirements.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Patients must have normal organ and bone marrow function as defined below:

Renal function:

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
• Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL]
• Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72 x serum creatinine in mg/dL]

Liver function:

• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3 x the ULN.
• Total bilirubin ≤ 1.5 x ULN (in subjects with Gilbert's syndrome a total bilirubin ≤ 3.0 x ULN), or < 5 x ULN, if liver metastases are present.

Hematological parameters (within one week of starting therapy):

• Hemoglobin > 9 g/dL.
• Platelet count ≥ 100,000/µL.
• Absolute neutrophil count (ANC) ≥ 1/ µL.
• Troponin I within normal limits.
• Electrocardiogram (ECG) without clinically significant findings.
• Any prior chemotherapy, immunotherapy and/or radiation must be completed at least 4 weeks prior to the first planned dose of MVA-BN-Brachyury vaccine, with the following exceptions, assuming any toxicity related to these therapies is well controlled or resolved and the patient has been on that therapy for at least 8 weeks at the time of enrollment:

• Prostate cancer - patients must continue to receive Gonadotropin-Releasing-Hormone (GnRH) agonist or antagonist therapy (unless orchiectomy has been done). Patients on abiraterone or enzalutamide may continue those therapies.
• Breast cancer - patients may remain on hormonal therapy if indicated (Estrogen Receptor/Progesterone Receptor positive [ER/PR+]).
• A minimum of 6 weeks from any prior antibody therapies (such as ipilimumab or anti-Programmed Death 1/Programmed Death Ligand 1[PD1/PD-L1]) is required due to prolonged half-life.
• Patients must have recovered (grade 1 or baseline) from any clinically significant toxicity associated with prior therapy.
• Women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 48 hours prior to administration of MVA-BN-Brachyury vaccine. Both men and women must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) through the trial treatment period and for at least three months after the last vaccination with MVA-BN-Brachyury vaccine.

Exclusion criteria

• Receipt of an investigational agent within 28 days of the first planned dose of MVA-BN-Brachyury vaccine.
• Concurrent chemotherapy or radiotherapy or other immunotherapy not explicitly allowed by inclusion criteria for this trial.
• Known metastatic disease to the central nervous system, unless previously treated and well controlled for at least 3 months (clinically stable, no edema, no steroid treatment required).
• History of anaphylaxis or severe allergic reaction to any vaccine, aminoglycoside antibiotics or egg products.
• Active infection within 72 hours prior to vaccination.
• Administration of antibiotics within 7 days prior to initial vaccination.
• Subjects having known evidence of being immunocompromised as listed below:

• Human immunodeficiency virus (HIV) positivity, active chronic hepatitis infection, including B and C.
• Active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, and psoriasis not requiring systemic treatment are permitted.
• Immunosuppressive therapy for post-organ transplant.
• Chronic administration (defined as > 5 consecutive days of > 15 mg of prednisone (or equivalent) per day) of systemic corticosteroids within 14 days of the first planned dose of MVA-BN-Brachyury vaccine. Use of inhaled steroids, nasal sprays, eye drops, and topical creams is allowed. Steroids premedication for CT scans is allowed.
• Vaccinations or planned vaccinations with a live vaccine within 30 days prior to the trial vaccination or with an inactivated vaccine within 14 days prior to the trial vaccination.
• Patients with history of myocardial infarction, unstable angina pectoris, history of or existing CHF (NYHA Class II -IV), other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension and hemodynamic effective pericardial effusion.
• Known history of, or any evidence of active, non-infectious pneumonitis or primary pulmonary fibrosis.
• Psychiatric illness/social situations that, in the opinion of the Investigator, would limit compliance with trial requirements.
• Pregnant or breastfeeding women.
• Any other condition, which in the opinion of the Investigator, would indicate the subject is a poor candidate for treatment with MVA-BN-Brachyury vaccine or would interfere with the evaluation of the trial endpoints.