TAEK-VAC-HerBy Vaccine for Brachyury and HER2 Expressing Cancer

Inclusion Criteria:

General inclusion criteria, apply to all cohorts:

Men and women >18 years old.
Patients must have a metastatic or recurrent locally advanced malignant tumor.
ECOG performance status 0 or 1

Patients must have normal organ and bone marrow function as defined below:

Serum creatinine ≤1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) ≥40 mL/min.
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).
Hemoglobin >9 g/dL.
Platelet count ≥100,000/µL.
Absolute neutrophil count (ANC) ≥1000/µL.
Normal left ventricular ejection fraction (LVEF) ≥50%.
Troponin I within normal limits.
A maximum cumulative dose of prior doxorubicin ≤360 mg/m2 or epirubicin ≤720 mg/m2
Any prior chemotherapy, targeted therapy, immunotherapy and/or radiation must be completed at least 4 weeks prior to the first planned dose of TVH vaccine
Patients must have recovered (Grade 1 or baseline) from any clinically significant toxicity associated with prior therapy.

Additional inclusion criteria for Stage 1

Patient population:

Patients with metastatic cancer with a high probability of brachyury expression (such as chordoma, breast, ovarian, prostate, colorectal, pancreatic, hepatocellular, Merkel cell, small cell lung cancer etc) and have progressed on at least two lines of systemic therapy.
Patients with unresectable locally advanced and metastatic breast and gastric/gastroesophageal junction cancer expressing HER2 at levels lower than the threshold required for definition of HER-2 positivity by ASCO/CAP (breast, gastric/GEJ, ovarian, bladder, salivary gland, endometrial, pancreatic and non-small-cell lung cancer, etc). Patients must have progressed on at least two lines of systemic therapy.
Patients with breast and gastric HER2- positive tumors as per ASCO/CAP must have progressed after receipt of:
Breast: at least 3 lines of HER2-targeting therapy

Gastric and gastroesophageal junction cancer: at the time of progression after 2 lines of HER2-targeting therapy.

Patients must have measurable or evaluable disease. Measurable disease is defined by RECIST 1.1.

Additional inclusion criteria for Stage 2

Patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1.

Patient population:

Cohort 2: chordoma patients with extracranial lesions not amenable for surgical resection with curative intent, nor for radical radiation therapy. At least one target lesion not previously irradiated must be present, either metastatic or locoregional recurrence located outside of previously irradiated field.
Cohorts 3, 4, and 5: patients with HER2-positive tumors (breast, gastric/GEJ).
Cohort 4 will include patients on treatment with trastuzumab plus pertuzumab with less than CR (non-improving PR or SD) or as a window of opportunity at the first evidence of progression and before initiating the next line of standard treatment.
HER2 status must be determined as defined by the most recent ASCO/CAP guidelines for breast and gastric/gastroesophageal cancer.
For Cohorts 3, 4 and 5, patients must be on a stable dose of HER2 antibody(ies). Patient is defined to be on a stable dose of HER2 antibody(ies) if they have completed the chemotherapy component of regimens consisting on the combination of chemotherapy with HER2-targeting antibodies and have continued with the antibody for a minimum of 2 months.

Exclusion Criteria:

Known metastatic disease to the central nervous system, unless previously treated and responded with a minimum stable disease over 2 CT scans separated at least 4 weeks from each other, and more than 6 weeks since the last dose of dexamethasone.
History of allergy or untoward reaction to prior vaccination with vaccinia virus, aminoglycoside antibiotics, ciprofloxacin, or egg products.

Subjects should have no known evidence of being immunocompromised as listed below:

Human immunodeficiency virus (HIV) positivity, 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, 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 TAEK-VAC-HerBy vaccine. Use of inhaled steroids, nasal sprays, eye drops, and topical creams is allowed. Steroids premedication for CT scans is allowed.
Clinically significant cardiomyopathy, coronary disease, congestive heart failure (NYHA class III or IV) or reduced as per institutional standards LVEF, poorly controlled hypertension (systolic >180 mm Hg or diastolic >100 mm Hg) or cerebrovascular accident within 1 year.
Known history of, or any evidence of active, non-infectious pneumonitis or primary pulmonary fibrosis