Ignite Creation Date:
2024-05-06 @ 2:21 PM
Last Modification Date:
2024-10-26 @ 1:29 PM
Study NCT ID:
NCT04296942
Status:
TERMINATED
Last Update Posted:
2022-01-11
First Post:
2020-03-04
Brief Title:
BN-Brachyury Entinostat Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer BrEAsT
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
A Phase 1b Trial of Sequential Combinations of BN-Brachyury Entinostat Ado-trastuzuamb Emtansine and M7824 in Advanced Stage Breast Cancer BrEAsT
Status:
TERMINATED
Status Verified Date:
2021-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
One participant was accrued and the study was stopped due to new safety data from the company for M7824 and slow accrual
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Breast cancer is the second most common cause of United States US cancer deaths in women Immunotherapy drugs use a persons 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 HER2BC
Design
Participants will be screened with
medical history
physical exam
disease confirmation or tumor biopsy
tumor scans computed tomography magnetic resonance imaging andor 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
Breast cancer is the second most common cause of United States US cancer deaths in women Immunotherapy drugs use a persons 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 HER2BC
Design
Participants will be screened with
medical history
physical exam
disease confirmation or tumor biopsy
tumor scans computed tomography magnetic resonance imaging andor 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-BetaRII241-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 HER2BC 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 PRcomplete 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 CDK46 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 11
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-1PD-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 20 x 108 infectious units InfU
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 10 x 109 InfU
adotrastuzumab emtansine T-DM1 36mgkg via intravenous IV infusion every q3 weeks on Day 1 of each cycle
M7824 2400mg 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
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-BetaRII241-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 HER2BC 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 PRcomplete 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 CDK46 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 11
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-1PD-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 20 x 108 infectious units InfU
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 10 x 109 InfU
adotrastuzumab emtansine T-DM1 36mgkg via intravenous IV infusion every q3 weeks on Day 1 of each cycle
M7824 2400mg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 20-C-0056 | None | None | None |