BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)
Condition: Breast Cancer; Triple Negative Breast Cancer; HER2+ Breast Cancer; Hormone Receptor Negative Breast Cancer; Metastatic Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Brachyury-TRICOM; Entinostat; M7824; Ado-trastuzumab emtansine
Intervention description: Every three weeks, until cycle 9, then every 12 weeks: *Recombinant MVA-Bavarian Nordic (BN)-Brachyury recommended phase 2 dose (R2PD): 4 injections of vaccines with 1 given subcutaneous (SC) in each extremity on Day 1 of Cycles 1 and 2. Each injection of MVA-BN-Brachyury consists of 2.0 x 10^8 infectious units (Inf.U). *Recombinant fowlpox virus (FPV)-BN-Brachyury: 1 injection given SC in one extremity on Day 1 of Cycles 3 and beyond. Each injection of FPV-BN-Brachyury consists of 1.0 x 10^9 Inf.U.; 5mg by mouth weekly (RP2D) administered by patient on Days 1, 8 and 15 of each cycle.; 1800mg via intravenous (IV) infusion every (q)3 weeks on Day 1 of each cycle.; 3.6mg/kg via intravenous (IV) infusion every (q)3 weeks on Day 1 of each cycle.
Intervention MeSH terms: Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine; Entinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Immuno-oncology; Immunotherapy; Vaccine; Invasive Breast Cancer

Summary:

      Background:

      Breast cancer is the second most common cause of United States (U.S.) cancer deaths in women.
      Immunotherapy drugs use a person's immune system to fight cancer. Researchers want to see if
      a new combination of immunotherapy drugs can help treat breast cancer that has gone to places
      in the body outside of the breast (metastasized).

      Objective:

      To learn if a new combination of immunotherapy drugs can shrink tumors in people with
      metastatic breast cancer.

      Eligibility:

      Adults 18 and older who have been diagnosed with metastatic breast cancer, such as Triple
      Negative Breast Cancer (TNBC) or estrogen receptors (ER)-/progesterone receptors (PR)-/human
      epidermal growth factor receptor 2 (HER2)+ Breast Cancer (HER2+BC)

      Design:

      Participants will be screened with:

      medical history

      physical exam

      disease confirmation (or tumor biopsy)

      tumor scans (computed tomography, magnetic resonance imaging, and/or bone scan)

      blood and urine tests

      electrocardiogram (measures the hearts electrical activity)

      echocardiogram (creates images of the heart).

      Participants will be assigned to 1 of 3 groups. The drugs they get will be based on the group
      they are in. Drugs are given in cycles. Each cycle = 3 weeks. Participants will be seen in
      clinic every 3 weeks, prior to the start of a new cycle. At each visit, participants will
      have an clinical exam, have blood drawn and will be asked about any side effects. They will
      repeat the screening tests during the study. New scans, like a computed tomography (CT) scan,
      will be done every 6 weeks to see if the treatment is working.

      All participants will get Bavarian Nordic (BN)-Brachyury. It is 2 different vaccines - a
      prime and a boost. First the priming vaccines, called MVA-BN-Brachyury help to jump start the
      immune system. Next the boosting vaccines, called fowlpox virus (FPV)-Brachyury help to keep
      the immune system going. They are injected under the skin during different cycles.

      All participants will get M7824 (also known as Bintrafusp alfa), which is an immunotherapy
      drug. Some participants will get a commonly used drug is HER2+ breast cancer called
      adotrastuzumab emtansine (also known as T-DM1DM1 or kadcyla). For both, a needle is inserted
      into a vein to give the drugs slowly.

      Some participants will take Entinostat weekly by mouth. It is in tablet form. Participants
      will keep a pill diary.

      Participants will continue on their assigned treatment until their cancer grows, they develop
      side effects or want to stop treatment. About 28 days after treatment ends, participants will
      have a follow-up visit or a telephone call. Then they will be contacted every 3 months for 1
      year, then every 6 months for 1 year. They may have more tumor scans or continue treatment.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed metastatic human
             epidermal growth factor receptor 2 (HER2+) breast cancer. HER2 positive or amplified
             breast cancer is defined as Immunohistochemistry (IHC) 3+ or fluorescence in situ
             hybridization (FISH) average HER2 copy number greater than or equal to 6 signals per
             cell or HER2/chromosome enumeration probe 17 (CEP17) greater than or equal to 2.0.
             HER2 testing must have been performed in a laboratory accredited by the College of
             American Pathology (CAP) or another accrediting entity.

          -  Patients must have hormone receptor negative, HER2+ breast cancer. Hormone receptor
             negative is defined as estrogen receptor < 10% by immunohistochemistry (IHC) and
             progesterone receptor < 10% by IHC.

          -  Patients must have measurable disease, per Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1.

          -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
             up to three biopsies while on trial.

          -  Patients must have received front-line treatment for metastatic disease with a taxane,
             trastuzumab and pertuzumab (THP; docetaxel or paclitaxel allowed) and progressed on
             treatment or were intolerant to treatment. Patients must have received at least one
             prior therapy in the metastatic setting. Prior ado-trastuzumab (T-DM1) therapy is
             allowed.

          -  Female or male greater than or equal to 18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

          -  Patients must have adequate bone marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL (> 1.5X 10(6)/L)

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin
                  greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed)

          -  Patients must have adequate renal function, defined as:

               -  serum creatinine less than or equal to 1.5 X upper limit of normal (ULN) OR

               -  measured or calculated creatinine clearance greater than or equal to 60 mL/min
                  for participant with creatinine levels > 1.5 X institutional ULN (Glomerular
                  filtration rate (GFR) can also be used in place of creatinine or creatinine
                  clearance (CrCl).

          -  Patients must have adequate hepatic function, defined as aspartate aminotransferase
             (AST) and alanine aminotransferase (ALT) levels less than or equal to 3 X ULN and
             total bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where
             bilirubin less than or equal to 5 mg/dL will be permitted. Gilbert's syndrome will be
             defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within
             the normal range and less than 20% of the total. Total bilirubin will be permitted up
             to 5 mg/dL, if patients have historical readings consistent with the definition of
             Gilbert's syndrome prior to entering study. Adequate hepatic function for patients
             with known liver metastases is defined as AST and ALT levels less than or equal to 5 X
             ULN.

          -  Patients must have adequate cardiac function as defined by an ejection fraction
             greater than or equal to 50%.

          -  The effects of BN-Brachyury, entinostat, M7824 and T-DM1 on the developing human fetus
             are unknown. However, the two components of T-DM1 are known to have negative fetal
             effects including oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia,
             skeletal malformations and neonatal death). For this reason:

               -  Women of child-bearing potential must agree to use adequate contraception study
                  entry, for the duration of study participation and for 7 months after the last
                  dose of study medication. Should a woman become pregnant or suspect she is
                  pregnant while she or her partner is participating in this study, she should
                  inform her treating physician immediately.

               -  Men should refrain from fathering a child or donating sperm during the study and
                  for 4 months after the last dose of study medications.

          -  Patients with well-controlled human immunodeficiency virus (HIV) infection are
             eligible for trial as long as:

               -  On an effective anti-retroviral therapy (ART) 4 weeks and with evidence of viral
                  suppression as defined as HIV viral load 400 copies/mL within the last 3 months;

               -  Cluster of differentiation 4 (CD4) greater than or equal to 200 cells/microL
                  within the last 3 months; and

               -  No reported opportunistic infections within 6 months prior to enrollment, except
                  for the following which will be allowed:

                  i. Esophageal candidiasis treated within last 6 months or currently improving
                  with antifungal treatment.

        ii. Oral and/or genital herpes simplex virus (HSV) treated within last 6 months or
        currently improving with antiviral treatment.

        iii. Mycobacterium avium infection in last 6 months or that has been treated for at least 1
        month.

          -  Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible for
             trial as long as the HBV viral load is undetectable on suppressive therapy, if
             indicated.

          -  Patients with history of hepatitis C virus (HCV) infection must have been treated and
             cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable or unquantifiable HCV ribonucleic acid (RNA) 12
             weeks or longer after definitive treatment completion.

          -  Patients must be able to understand and willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          -  Patients who have received chemotherapy, including herceptin and/or pertuzumab in the
             prior 3 weeks (6 weeks for nitrosoureas or mitomycin); other investigational agents or
             a programmed cell death protein 1/programmed death-ligand 1 (PD-1/L1) agent within 4
             weeks prior to study enrollment.

          -  Patients who have received radiotherapy within 4 weeks prior to study entry.

          -  Patients with active brain metastases or leptomeningeal metastases should be excluded
             from this clinical trial because of their poor prognosis and because they often
             develop progressive neurologic dysfunction that would confound the evaluation of
             neurologic and other adverse events. However, patients with treated brain metastases
             are eligible if there is no magnetic resonance imaging (MRI) evidence of progression
             for 6 weeks after treatment is complete (no radiotherapy within 6 weeks) and within 28
             days prior to the first dose of trial drug or asymptomatic brain metastasis. Patients
             requiring immunosuppressive doses of systemic corticosteroids (> 10mg/day prednisone
             equivalent) for palliation are excluded.

          -  Patients with a history of another invasive malignancy less than or equal to 3 years
             prior to enrollment (patients with non-melanoma skin cancers, carcinoma in situ of the
             breast or cervix are eligible).

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to agents used in study. For example, reaction to prior vaccination with
             vaccinia virus or known hypersensitivity reaction to fully humanized monoclonal
             antibodies (Grade greater than or equal to 3 National Cancer Institute (NCI)-Common
             Terminology Criteria for Adverse Events (CTCAEv5).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing active
             infection that requires systemic treatment with ongoing antibiotics (eligible if can
             stop antibiotics on day of enrollment), unstable angina pectoris, cardiac arrhythmia,
             or psychiatric illness/social situation that in the opinion of the primary
             investigator would prohibit the patient from complying with study requirements.

          -  Known history of a gastrointestinal illness that in the investigator's opinion would
             prevent the absorption of entinostat, which is an oral agent. (Arm 3 ONLY)

          -  Patients with bone metastases who have initiated denosumab or a bisphosphonate therapy
             within 28 days prior to or after Cycle 1 Day 1. Continuation of prior therapy is
             allowed.

          -  Patients with inherited bleeding disorders, a history of bleeding diathesis such as
             von Willebrand Factor (VWF) deficiency or recent (within 3 months prior to enrollment)
             clinically significant bleeding events that, in the judgment of the investigator,
             would interfere with patient's ability to carry out the treatment program.

          -  Patients should have no evidence of being immunocompromised as listed below:

               -  Active, known or suspected autoimmune disease. Patients are permitted to enroll
                  if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
                  an autoimmune condition only requiring hormone replacement, psoriasis not
                  requiring systemic treatment or conditions not expected to recur in the absence
                  of an external trigger in the opinion of the primary investigator.

               -  Altered immune function, that in the judgement of the principal investigator (PI)
                  that may affect a patient's ability to adequately engage the immune system and
                  respond to the immunotherapy agents being administered, including but not limited
                  to: inflammatory bowel disease; active infectious enteritis; eosinophilic
                  enteritis; lupus erythematous; ankylosing spondylitis; scleroderma; multiple
                  sclerosis. These criteria do not include all disease with an immune-related
                  component but are not autoimmune in nature or have a primary alteration in the
                  general immune function that may interfere with the vaccine mechanism of action,
                  for example celiac disease.

               -  Immunosuppressive therapy post-organ transplant.

          -  Concurrent use of chronic use of systemic steroids, except for physiologic doses of
             systemic steroids for replacement, defined as 10mg of prednisone per day or
             equivalent, or local (topical, nasal, ophthalmic or inhaled) steroid use or prior
             concomitant use with chemotherapy. Systemic steroids must have been discontinued >2
             weeks prior to trial start. Prior use of corticosteroids in short-term schemes
             (duration shorter than 3 days) for indications such as prophylaxis of reactions to
             intravenous contrast for imaging studies or chemotherapy-related adverse events (AEs)
             are not considered part of this exclusion. Prior use of corticosteroids for brain
             metastasis ending at least 14 days prior to enrollment is not considered part of this
             exclusion criteria.

          -  Pregnant and breastfeeding women are excluded from this study because of the potential
             for teratogenic or abortifacient effects with all of the agents involved in this
             trial.

          -  Clinically significant cardiomyopathy, coronary disease, chronic heart failure (CHF;
             New York Heart Association class III or IV or hospitalization for CHF), or
             cerebrovascular accident within 6 months prior to enrollment.

          -  Patients with a history of myocarditis are excluded due to the potential of
             myocarditis with anti-PD-L1 antibodies.

          -  Patients with pulse oximetry < 92% on room air will be excluded due to the potential
             of pneumonitis with anti-PD-L1 antibodies.

          -  Any other condition, which would, in the opinion of the Principal Investigator or
             Medical Monitor, indicated the subject is a poor candidate for the clinical trial or
             would jeopardize the subject or the integrity of the data obtained.

        ELIGIBILITY CRITERIA FOR ARMS 2 AND 3: M7824, BN-BRACHYURY, T-DM1 +/- ENTINOSTAT IN HER2+BC

        INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed metastatic HER2+ breast
             cancer. HER2 positive or amplified breast cancer is defined as IHC 3+ or FISH average
             HER2 copy number greater than or equal to 6 signals per cell or HER2/CEP17 greater
             than or equal to 2.0. (117) HER2 testing must have been performed in a laboratory
             accredited by the College of American Pathology (CAP) or another accrediting entity.

          -  Patients must have hormone receptor negative, HER2+ breast cancer. Hormone receptor
             negative is defined as estrogen receptor < 10% by IHC and progesterone receptor <10%
             by IHC.

          -  Patients must have measurable disease, per RECIST 1.1.

          -  Patients in Cohort 3 must have at least one lesion deemed safe to biopsy and be
             willing to undergo up to three biopsies while on trial.

          -  Patients must have received front-line treatment for metastatic disease with a taxane,
             trastuzumab and pertuzumab (THP; docetaxel or paclitaxel allowed) and progressed on
             treatment or were intolerant to treatment. Patients must have received at least one
             prior therapy in the metastatic setting. Prior T-DM1 therapy is allowed.

          -  Female or male greater than or equal to 18 years.

          -  ECOG performance status 0 or 1

          -  Patients must have adequate bone marrow function as defined below:

               -  absolute neutrophil count greater than or equal to1,500/mcL (greater than or
                  equal to 1.5X 106/L)

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin
                  greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed)

          -  Patients must have adequate renal function, defined as:

               -  serum creatinine less than or equal to 1.5 X upper limit of normal (ULN) OR

               -  measured or calculated creatinine clearance greater than or equal to 60 mL/min
                  for participant with creatinine levels > 1.5 X institutional ULN (GFR can also be
                  used in place of creatinine or CrCl).

          -  Patients must have adequate hepatic function, defined as AST and ALT levels less than
             or equal to 3 X ULN and total bilirubin < 1.5 X ULN, unless known diagnosis of
             Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dL will be permitted.
             Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated
             (direct) bilirubin within the normal range and less than 20% of the total. Total
             bilirubin will be permitted up to 5 mg/dL, if patients have historical readings
             consistent with the definition of Gilbert's syndrome prior to entering study. Adequate
             hepatic function for patients with known liver metastases is defined as AST and ALT
             levels less than or equal to 5 X ULN.

          -  Patients must have adequate cardiac function as defined by an ejection fraction
             greater than or equal to 50%.

          -  The effects of BN-Brachyury, entinostat, M7824 and T-DM1 on the developing human fetus
             are unknown. However, the two components of T-DM1 are known to have negative fetal
             effects including oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia,
             skeletal malformations and neonatal death). For this reason,

               -  Women of child-bearing potential must agree to use adequate contraception study
                  entry, for the duration of study participation and for 7 months after the last
                  dose of study medication. Should a woman become pregnant or suspect she is
                  pregnant while she or her partner is participating in this study.