A Phase 1b Trial of Sequential Combinations of BN-Brachyury, Entinostat, Ado-trastuzuamb Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Overall Response (Partial Response + Complete Response) for Participants With Triple Negative Breast Cancer (TNBC)
研究概览
简要总结
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.
详细描述
Background:
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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.
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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.
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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.
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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.
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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.
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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.
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Arm 1 - Triple Negative Breast Cancer (TNBC); M7824 + BN-Brachyury
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Arm 2 - estrogen receptors (ER)-/progesterone receptors (PR-)/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1
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Arm 3 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1+ Entinostat
Objectives:
Primary Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury
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.
干预措施: Brachyury-TRICOM (Biological)
1/M7824 (Bintrafusp alfa) + Bavarian Nordic (BN)-Brachyury
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.
干预措施: M7824 (Biological)
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)
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).
干预措施: Brachyury-TRICOM (Biological)
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)
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).
干预措施: M7824 (Biological)
2/M7824 + BN-Brachyury + Ado-trastuzumab emtansine (T-DM1)
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).
干预措施: Ado-trastuzumab emtansine (Biological)
3/M7824 + BN-Brachyury + T-DM1 + 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).
干预措施: Brachyury-TRICOM (Biological)
3/M7824 + BN-Brachyury + T-DM1 + 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).
干预措施: Entinostat (Drug)
3/M7824 + BN-Brachyury + T-DM1 + 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).
干预措施: M7824 (Biological)
3/M7824 + BN-Brachyury + T-DM1 + 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).
干预措施: Ado-trastuzumab emtansine (Biological)
结局指标
主要结局
Overall Response (Partial Response + Complete Response) for Participants With Triple Negative Breast Cancer (TNBC)
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- 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)
研究者
Fatima Karzai, M.D.
Principal Investigator
National Cancer Institute (NCI)