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

Phase 1

Terminated

Conditions: Breast Cancer
Triple Negative Breast Cancer
HER2+ Breast Cancer
Hormone Receptor Negative Breast Cancer
Metastatic Breast Cancer

Interventions: Biological: Brachyury-TRICOM
Biological: M7824
Drug: Entinostat
Biological: Ado-trastuzumab emtansine

Registration Number: NCT04296942

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed Description: 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 (Bintrafusp alfa) is a novel bifunctional fusion protein composed of a monoclonal antibody against human programmed death-ligand 1 (PD-L1) fused to the soluble extracellular domain of human transforming growth factor (TGF)-Beta receptor II (TGF-BetaRII(241-R2), 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 human epidermal growth factor receptor 2 (HER2+) breast cancer (HER2+BC). T-DM1 activates antibody-dependent cellular cytotoxicity (ADCC), dendritic cell maturation, increases tumor infiltrating lymphocytes (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 - estrogen receptors (ER)-/progesterone receptors (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 (overall response rate (ORR); partial response (PR)+complete response (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 immunohistochemistry (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 fluorescence in situ hybridization (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 (selective estrogen receptor modulators (SERM), AI, fulvestrant) with one prior treatment including a cyclin-dependent kinase 4 (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

* Eastern Cooperative Oncology Group (ECOG) 0 or 1

* Measurable metastatic disease per Response Evaluation Criteria in Solid Tumors (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 (ejection fraction (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 programmed cell death protein 1 (PD-1)/PD-L1 antibody within 4 weeks prior to study enrollment; radiotherapy less than or equal to 4 weeks of study entry.

* Symptomatic central nervous system (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 New York Heart Association (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 triple-negative breast cancer (TNBC).

* If this doublet is determined to have acceptable toxicity (0-1 dose limiting toxicities (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 docetaxel (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 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)-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.

* adotrastuzumab emtansine (T-DM1) 3.6mg/kg via intravenous (IV) infusion every (q)3 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 recommended phase 2 dose (RP2D) administered by patient on Days 1, 8 and 15 of each cycle.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury	Brachyury-TRICOM	Arm 1 - Triple Negative Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury.
1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury	M7824	Arm 1 - Triple Negative Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury.
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)	Ado-trastuzumab emtansine	Arm 2 - Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1).
3/M7824 + BN-Brachyury + T-DM1 + Entinostat	Brachyury-TRICOM	Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2)+ Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral histone deacetylase (HDAC) inhibitor called entinostat. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1). (T-DM1).
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)	Brachyury-TRICOM	Arm 2 - Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1).
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)	M7824	Arm 2 - Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1).
3/M7824 + BN-Brachyury + T-DM1 + Entinostat	M7824	Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2)+ Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral histone deacetylase (HDAC) inhibitor called entinostat. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1). (T-DM1).
3/M7824 + BN-Brachyury + T-DM1 + Entinostat	Ado-trastuzumab emtansine	Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2)+ Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral histone deacetylase (HDAC) inhibitor called entinostat. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1). (T-DM1).
3/M7824 + BN-Brachyury + T-DM1 + Entinostat	Entinostat	Estrogen receptor (ER)-/progesterone receptor (PR)-/Human Epidermal Growth Factor Receptor 2 (HER2)+ Breast Cancer. Bifunctional fusion molecule involving programmed death-ligand 1 (PD-L1) with transforming growth factor beta (TGF-b) sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral histone deacetylase (HDAC) inhibitor called entinostat. These investigational agents will be added to standard of care treatment called Ado-trastuzumab emtansine (T-DM1). (T-DM1).

Primary Outcome Measures

Name	Time	Method
Overall Response (Partial Response + Complete Response) for Participants With Triple Negative Breast Cancer (TNBC)	From start of treatment until disease progression/recurrence, approximately 5 months and 17 days.	Overall response is defined as the best response (Partial Response + Complete Response) recorded from the start of treatment until disease progression/recurrence assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progression is at least a 20% increase in the sum of diameters of target lesions. appearance of new lesions. Appearance of one or more new lesions.
Overall Response (Partial Response + Complete Response) for Participants With Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer (BC)	From start of treatment until disease progression/recurrence, approximately 5 months and 17 days.	Overall response is defined as the best response (Partial Response + Complete Response) recorded from the start of treatment until disease progression/recurrence. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progression is at least a 20% increase in the sum of diameters of target lesions. appearance of new lesions. Appearance of one or more new lesions.
Number of Participants Experiencing at Least One Grade 3 to 5 Adverse Events for Each of the Three Combinations of Agents	Date treatment consent signed to date off study, approximately 5 months and 17 days.	Adverse events were recorded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) in Triple Negative Breast Cancer (TNBC)	From start of treatment to time of progression or death, whichever occurs first, approximately 5 months and 17 days.	Progression free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. In the absence of progression or death, PFS is censored at the date of last disease evaluation. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions. appearance of new lesions. Appearance of one or more new lesions.
Progression Free Survival (PFS) in Participants With Metastatic Hormone Receptor (HR)-/Human Epidermal Growth Factor Receptor 2 (HER2) + Metastatic Breast Cancer Who Progressed on Initial Treatment With THP	From start of treatment to time of progression or death, whichever occurs first, approximately 5 months and 17 days.	Progression free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. In the absence of progression or death, PFS is censored at the date of last disease evaluation. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions. appearance of new lesions. Appearance of one or more new lesions.
Progression Free Survival (PFS) in Participants With Metastatic Human Epidermal Growth Factor Receptor 2 (HER2+) Metastatic Breast Cancer Who Progressed on Initial Treatment With Docetaxel (THP)	From start of treatment to time of progression or death, whichever occurs first, approximately 5 months and 17 days.	Progression free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. In the absence of progression or death, PFS is censored at the date of last disease evaluation. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions. appearance of new lesions. Appearance of one or more new lesions.
Absolute Percentage of Stromal Tumor Infiltrating Lymphocytes (TILs) in Metastatic Deposits in Participants With Metastatic Human Epidermal Growth Factor Receptor 2 (HER2+) Metastatic Breast Cancer	Baseline and on Cycle 3 Day 1	The absolute percentage of stromal TILs was measured by the Salgado method in metastatic deposits in participants with metastatic HER2+ metastatic breast cancer. The Salgado method is a standardized approach for measuring the percentage of stromal TILs in primary breast tumor specimens before therapy, using visual assessment of standard hematoxylin and eosin (H\&E)-stained sections.