BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)
BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)
Background:

 Breast cancer is the second most common cause of 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 ER-/PR-/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 heart s 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 CT scan, will be done every 6
 weeks to see if the treatment is working.

 All participants will get 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 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.
Background:

 -  Current greater than or equal to 2nd line treatments for metastatic breast cancer
 provide modest response rates, and modest improvement in progression-free survival but
 no treatments are curative.

 -  Bavarian-Nordic (BN)-Brachyury vaccine is a recombinant poxvirus vaccine against the
 transcription factor brachyury, which plays an important role in the
 epithelial-to-mesenchymal transition in breast cancer. A recently completed phase 1
 study of BN-Brachyury vaccine showed the vaccine was well tolerated and generated an
 immune response.

 -  M7824 is a novel bifunctional fusion protein composed of a monoclonal antibody against
 human PD-L1 fused to the soluble extracellular domain of human TGF-Beta receptor II
 (TGF-BetaRII), which functions as a TGF-Beta trap.

 -  Ado-trastuzumab emtansine (T-DM1 or Kadcyla) is an antibody drug conjugate used in
 second- and third- line treatment of metastatic HER2+ breast cancer (HER2+BC). T-DM1
 activates ADCC, dendritic cell maturation, increases TILs, increased PD-L1 expression,
 and increased immunomodulatory cytokines.

 -  Entinostat is a class 1 histone deacetylase inhibitor (HDACi) which suppresses tumor
 initiating cells, regulatory T-cells and myeloid-derived suppressor cells (MDSCs), as
 well as enhances cytotoxic T-cell mediated lysis, direct natural killer (NK) lysis, NK
 cell activation, increases PD-L1 expression and antibody-dependent cellular cytotoxicity
 (ADCC). In addition, entinostat may also be able to overcome HER2 resistance.

 -  We propose a Phase 1b trial to evaluate the safety and efficacy of the stepwise
 combination of the BN-Brachyury vaccine, M7824, T-DM1 and entinostat in metastatic
 breast cancer.

 -  Arm 1 - Triple Negative Breast Cancer (TNBC); M7824 + BN-Brachyury

 -  Arm 2 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1

 -  Arm 3 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1+ Entinostat

 Objectives:

 Primary Objectives:

 -  Arms 1-3: Overall response rate (ORR; PR+CR)

 -  Arms 1-3: Safety for each of the three combinations of agents explored in the arms

 Eligibility:

 Selected Inclusion Criteria

 -  Histologically confirmed metastatic breast cancer with appropriate IHC testing by a
 certified lab:

 -  For Arm 1: Triple negative breast cancer. Hormone receptor negative is defined by
 estrogen receptor < 10% and progesterone receptor < 10%. HER2 negative breast
 cancer is defined as HER2 per IHC 0 or 1+ or 2+ with negative FISH.

 -  For Arms 2 and 3: Hormone receptor negative, HER2+ breast cancer as defined by
 estrogen receptor < 10% and progesterone receptor < 10%. HER2 positive as per IHC
 3+ or 2+ with positive FISH.

 -  Prior treatment:

 -  For Arm 1: greater than or equal to 1 prior therapy in the metastatic setting.
 Patients with known PD-L1 positive tumors must have received prior treatment with
 atezolizumab + nab-paclitaxel. Patients with ER 1-9% must have received treatment
 with at least two lines of endocrine treatment (SERM, AI, fulvestrant) with one
 prior treatment including a CDK4/6 inhibitor + endocrine therapy for their
 metastatic cancer and should be considered endocrine therapy resistant.

 -  For Arms 2 and 3: greater than or equal to 1 prior treatment in the metastatic
 setting with a taxane (docetaxel or paclitaxel), herceptin and pertuzumab.

 -  Females or males greater than or equal to 18 years old

 -  ECOG 0 or 1

 -  Measurable metastatic disease per RECIST 1.1.

 -  For Cohort 3, Arms 2 and 3: At least one biopsiable lesion and willingness to undergo up
 to three research biopsies.

 -  Adequate hematopoietic, hepatic, renal and cardiac (EF greater than or equal to 50%)
 function.

 Selected Exclusion Criteria

 -  Patients who have received chemotherapy, including trastuzumab and pertuzumab in the
 previous 3 weeks; other investigational agents within 4 weeks or a PD-1/PD-L1 antibody
 within 4 weeks prior to study enrollment; radiotherapy less than or equal to 4 weeks of
 study entry.

 -  Symptomatic CNS metastases and leptomeningeal disease are excluded but treated brain
 metastases (no radiotherapy within 6 weeks) or asymptomatic brain metastasis are
 allowed.

 -  History of invasive malignancy less than or equal to 3 years prior to enrollment.

 -  History of congestive heart failure (CHF) as defined as NYHA class 3 or 4 or
 hospitalization for CHF (any NYHA class) within 6 months of trial start.

 -  Concurrent use of chronic systemic steroids except for physiologic systemic steroids for
 replacement defined as 10mg of prednisone or an equivalent dose.

 Design:

 This study contains three separate, single arm phase 1b trials.

 -  Arm 1 will evaluate M7824 and BN-Brachyury in patients with TNBC.

 -  If this doublet is determined to have acceptable toxicity (0-1 DLTs of the first 6
 patients), up to 19 patients will be enrolled on Arm 2 in which BN-Brachyury, M7824 and
 T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease progression
 after treatment with THP or intolerance to THP.

 -  If this triplet is determined to have acceptable toxicity (0-1 DLTs of the first 6
 patients), 19 patients will be enrolled on Arm 3 in which BN-Brachyury, entinostat,
 M7824 and T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease
 progression after treatment with THP or intolerance to THP.

 -  Up to 51 evaluable patients will be recruited for this study, with an accrual ceiling
 set at 65 patients.

 Trial Drugs

 -  BN-Brachyury vaccine every 3 weeks until cycle 9, then every 12 weeks:

 -  Recombinant MVA-BN-Brachyury (R2PD): 4 injections of vaccines with 1 given 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 FPV-Brachyury: 1 injection given SC in one extremity on Day 1 of Cycles
 3 and beyond. Each infection of FPV-Brachyury consists of 1.0 x 10(9) Inf.U.

 -  T-DM1 3.6mg/kg via IV infusion q3 weeks on Day 1 of each cycle.

 -  M7824 2,400mg via IV infusion q3 weeks on Day 1 of each cycle.

 -  Entinostat 5mg by mouth weekly (RP2D) administered by patient on Days 1, 8 and 15 of
 each cycle.
-  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. 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 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 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 (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, 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 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;

 -  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 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 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 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 NCI-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
 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 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 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 stud...