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

NCT04296942 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20005620-C-0056
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Cancer; Triple Negative Breast Cancer; HER2+ Breast Cancer; Hormone Receptor Negative Breast Cancer; Metastatic Breast Cancer

Keywords

Immuno-oncology; Immunotherapy; Vaccine; Invasive Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Overall Response (Partial Response + Complete Response) for Participants With Triple Negative Breast Cancer (TNBC)

  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.

  From start of treatment until disease progression/recurrence, approximately 5 months and 17 days.

• Overall Response (Partial Response + Complete Response) for Participants With Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer (BC)

  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.

  From start of treatment until disease progression/recurrence, approximately 5 months and 17 days.

• Number of Participants Experiencing at Least One Grade 3 to 5 Adverse Events for Each of the Three Combinations of Agents

  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.

  Date treatment consent signed to date off study, approximately 5 months and 17 days.

Secondary Outcomes (4)

• 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 (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 (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.

• 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

Other Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 5 months and 17 days.

Study Arms (3)

1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury

EXPERIMENTAL

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.

Biological: Brachyury-TRICOM; Biological: M7824

2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)

EXPERIMENTAL

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).

Biological: Brachyury-TRICOM; Biological: M7824; Biological: Ado-trastuzumab emtansine

3/M7824 + BN-Brachyury + T-DM1 + Entinostat

EXPERIMENTAL

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).

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

Interventions

Brachyury-TRICOM BIOLOGICAL

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.

1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury; 2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1); 3/M7824 + BN-Brachyury + T-DM1 + Entinostat

Entinostat DRUG

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

Also known as: SNDX-275

3/M7824 + BN-Brachyury + T-DM1 + Entinostat

M7824 BIOLOGICAL

1800mg via intravenous (IV) infusion every (q)3 weeks on Day 1 of each cycle.

Also known as: Bintrafusp alfa

1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury; 2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1); 3/M7824 + BN-Brachyury + T-DM1 + Entinostat

Ado-trastuzumab emtansine BIOLOGICAL

3.6mg/kg via intravenous (IV) infusion every (q)3 weeks on Day 1 of each cycle.

Also known as: T-DM1

2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1); 3/M7824 + BN-Brachyury + T-DM1 + Entinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

entinostat; bintrafusp alfa protein, human; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Fatima H. Karzai
• Organization: National Cancer Institute

fatima.karzai@nih.gov

301-480-7174

Study Officials

• Fatima H Karzai, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 4, 2020
• First Posted: March 5, 2020
• Study Start: May 4, 2021
• Primary Completion: October 22, 2021
• Study Completion: October 22, 2021
• Last Updated: January 11, 2022
• Results First Posted: January 11, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)