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.

Inclusion Criteria

• - 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

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.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
Margaret Elena Gatti-mays

• Primary ID 200056
• Secondary IDs NCI-2020-01659, 20-C-0056
• Clinicaltrials.gov ID NCT04296942