Bifunctional fusion molecule involving PD-L1 with TGF-b sequestering agent added to a vaccine for the tumor associated antigen called brachyury.

Bifunctional fusion molecule involving PD-L1 with 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 T-DM1.

Bifunctional fusion molecule involving PD-L1 with TGF-b sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral HDAC inhibitor called entinostat. These investigational agents will be added to standard of care treatment called T-DM1.

Breast Cancer

Triple Negative Breast Cancer

HER2+ Breast Cancer

Hormone Receptor Negative Breast Cancer

Metastatic Breast Cancer

Every three 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 infection is 0.5 ml of MVA-BN-Brachyury, which consists of 2.0 x 10(8) infectious units (Inf.U).
Recombinant FPV-BN-Brachyury: 1 injection given SC inone extremity on Day 1 of Cycles 3 and beyond. Each infection is 0.5ml of FPV-BN-Brachyury, which consists of 1.0 x 10(9) Inf.U.

Brachyury-TRICOM

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

Entinostat

1800mg via IV infusion q3 weeks on Day 1 of each cycle.

M7824

3.6mg/kg via IV infusion q3 weeks on Day 1 of each cycle.

Ado-trastuzumab emtansine

National Institutes of Health Clinical Center

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

A Phase 1b Trial of Sequential Combinations of BN-Brachyury, Entinostat, Ado-trastuzuamb Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)

To determine if the addition BN-Brachyury and M7824 improves overall response rates (ORR) in triple negative breast cancer (TNBC).

To determine if the addition BN-Brachyury, M7824, and/or Entinostat to T-DM1 improves ORR in HER2+BC over T-DM1 alone.

To determine the clinical safety of BN-Brachyury, M7824, Entinostat and T-DM1 in breast cancer.

To determine if adding BN-Brachyury to M7824 improves PFS in TNBC.

To determine if adding BN-Brachyury, M7824, and/or entinostat to T-DM1 increases the PFS in patients with metastatic HER2+ metastatic breast cancer who progressed on initial treatment with THP (or intolerant to THP).

To determine if adding BN-Brachyury, M7824, and/or entinostat to T-DM1 increases stromal TILs (as measured by the Salgado method) in metastatic deposits in patients with metastatic HER2+ metastatic breast cancer.

National Cancer Institute (NCI)

Induction phase: All patients receive 3 doses of High-Dose Methotrexate (HD-MTX) every 2 weeks given intravenously and 3 doses of Intrathecal (IT) Liposomal Cytarabine (Depocyt) every 2 weeks over 6 weeks.
Consolidation phase:
2 additional doses of HD-MTX every 2 weeks and IT-Depocyt every 2 weeks for 4 more weeks.
Maintenance phase:
Monthly doses of HD-MTX (up to 6 doses) and IT-Depocyt (up to 5 doses)
Patients must stop participation anytime MRI shows progressive disease or positive CSF cytology.

Treatment (Liposomal Cytarabine, High-dose Methotrexate)

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Region of Enrollment

Neurological progression defined by either clinical impression (measured by Karnofsky Performance Status), radiographical response (using Macdonald criteria), or cytologic response (measured by CSF cytology).

Survival Free of Neurological Progression, Measured in Weeks

Overall Survival

Overall Study

Maciej M. Mrugala, MD, PhD, MPH

Central Nervous System Metastases

Leptomeningeal Metastases

Recurrent Breast Cancer

Stage IV Breast Cancer

Tumors Metastatic to Brain

methotrexate

liposomal cytarabine

quality-of-life assessment

laboratory biomarker analysis

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Liposomal Cytarabine and High-Dose Methotrexate in Treating Patients With Central Nervous System Metastases From Breast Cancer

Phase II Study of the Combination of High-Dose Methotrexate and Intrathecal Liposomal Cytarabine in Patients With Leptomeningeal Metastases With or Without Parenchymal Brain Involvement

meningeal carcinomatosis/progesterone

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

Liposomal Cytarabine and High-Dose Methotrexate in Treating Patients With Central Nervous System Metastases From Breast Cancer

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