Breast Neoplasm, Breast Neoplasm, Male, Triple Negative Breast Cancer
Conditions
Keywords
Breast Cancer, Early Stage Breast Cancer, Male breast cancer, IRX-2, Immunotherapy, Triple Negative Breast Cancer
Brief summary
The goal of this study is assess the safety and tolerability of the IRX-2 regimen in patients with early stage breast cancer (ESBC) and to estimate the pathologic complete response rate to neoadjuvant anthracycline-based and non-platinum containing chemotherapy in patients with triple-negative breast cancer who have received the IRX-2 Regimen before chemotherapy.
Detailed description
This will be a Phase Ib study conducted to determine the safety and tolerability of an IRX-2 regimen in ESBC, to be administered pre-operatively before standard-of-care surgical resection and following standard-of-care diagnostic biopsy. This study will also include triple-negative breast cancer patients who will receive the IRX-2 regimen prior to chemotherapy. Eligible subjects will have early stage breast cancer of any receptor sub-type, for which standard-of-care surgical resection is planned. To be eligible, a minimum of 1 core of tumor-bearing biopsy material must be available for research analysis. Cohort B will enroll subjects triple negative breast cancer (defined by ER\<10%, PR\<10%, and HER2-negative by NCCN guidelines), T1c+ tumors for which neoadjuvant anthracycline-based and non-platinum containing chemotherapy is planned. The IRX-2 regimen will be administered and completed preceding chemotherapy. Cohort B subjects must undergo post-IRX-2 Regimen biopsy (2-3 cores), followed by commencement of chemotherapy preferably within one week after biopsy. The IRX-2 regimen will be administered in all enrolled subjects. IRX 2 will be administered by subcutaneous injection into the periareolar skin of the affected breast.
Interventions
DRUGOmeprazole
One tablet of omeprazole daily for 21 days
DIETARY_SUPPLEMENTMultivitamin
Daily multivitamin containing 15-30 mg of zinc for 21 days.
DRUGCyclophosphamide
One dose of cyclophosphamide 300 mg/m2 IV infusion
DRUGIndomethacin
Indomethacin 25 mg three times a day for 21 days
Sponsors
Brooklyn ImmunoTherapeutics, LLC
Providence Health & Services
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Invasive breast cancer of any receptor subtype diagnosed by core-needle biopsy * To undergo surgical resection with curative intent by partial mastectomy (lumpectomy) or mastectomy or * Triple negative breast cancer (defined by ER\<10%, PR\<10%, and HER2-negative by NCCN guidelines), T1c+ tumors for which neoadjuvant anthracycline-based and non-platinum containing chemotherapy is planned * Tumor \>5 mm in maximum diameter by ultrasound or mammography. (Subjects with smaller tumors may be included at the discretion of the Principal Investigator.) * Willing and able to provide written informed consent, including consent for use of available tissue and required blood draws for research purposes * Availability of at least one tumor-bearing core specimen from the breast cancer diagnostic biopsy * Karnofsky Performance status (KPS) 70% or greater. * Female or male ≥18 years of age on day of signing informed consent. * Adequate organ function as defined by protocol specified lab results
Exclusion criteria
* Prior neoadjuvant systemic therapy is planned * Prior surgery, radiotherapy or chemotherapy for this cancer (other than core-needle biopsy) * Received an investigational agent within 4 weeks of the first dose of treatment. * Diagnosis of immunodeficiency or has received more than replacement doses of corticosteroids any other immunosuppressive therapy within 4 weeks of the first dose of treatment * Hypersensitivity to IRX 2, cyclophosphamide, indomethacin, aspirin or ciprofloxacin. * Chronic anticoagulation, not including aspirin, but including heparins, warfarin, oral anticoagulants or other platelet function inhibitors, that cannot, in the documented opinion of the investigator, safely be interrupted from at least 2 days prior to the initiation of the study regimen until after surgical resection of the tumor. * Another malignancy that required active treatment within 6 months of the first dose of treatment * History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, such that trial participation is not in the best interest of the subject, including but not limited to uncontrolled hypertension or clinically significant cardiovascular disease, myocardial infarction within the previous 3 months, active infection or pneumonitis or other pulmonary disease requiring systemic therapy, clinically significant gastritis or peptic ulcer disease (that would preclude the use of indomethacin), stroke of other symptoms of cerebral vascular insufficient within the last 3 months, autoimmune disease that has required systemic treatment within the past 2 years (other than hormone replacement doses), or uncontrolled psychiatric or substance abuse disorders. * Pregnancy or lactation. * Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Establish the Safety of the IRX-2 Regimen When Administered Pre-operatively in Early Stage Breast Cancer (ESBC) Patients | Day 1 to Day 26 | The safety of IRX-2 will be determined by any surgical delays associated with administration of the study regimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Infiltrating Lymphocytes | At time of pre-surgical biopsy and time of tumor specimen resection at day 26 | Change in tumor infiltrating lymphocyte (TIL) score as measured by hematoxylin and eosin tumor infiltrating lymphocytes (H&E TIL) count according to Salgado criteria from pre-surgical biopsy to resected tumor specimen |
Other
| Measure | Time frame | Description |
|---|---|---|
| Characterization of Peripheral Lymphocytes | Day 1 to Day 26 | Fold change of peripheral lymphocytes including activated T-cells, T-regulatory cells, natural killer (NK) cells, and myeloid cells |
| TIL Phenotype | Day 1 to 26 | Post-IRX mean density of T-regulatory cells, activated T-cells, myeloid lineages and dendritic cells post-IRX within stromal tissue compartments. |
| Intratumoral T-cell Clonality Response | Day 1-26 | Change in T-cell clonal responses by T-cell receptor DNA deep sequencing |
| Intratumoral Immune Response | Day 1-26 | The Nanostring PanCancer Immune panel was used to estimate increase in PD-L1 mRNA expression among tumor-bearing FFPE specimens. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer Enrolled subjects with early stage breast cancer will receive a single dose of cyclophosphamide (300 mg/m2) by IV infusion on Day 1. Also starting on Day 1 and continuing until Day 21, subjects will take daily oral indomethacin (25 mg three times each day), daily oral omeprazole (one tablet) and daily oral multivitamin containing 15-30 mg of zinc. On any 10 consecutive day period between Days 4-17, patients will receive two 1 mL subcutaneous periareolar injections of IRX-2.
Cyclophosphamide: One dose of cyclophosphamide 300 mg/m2 IV infusion
Indomethacin: Indomethacin 25 mg three times a day for 21 days
Omeprazole: One tablet of omeprazole daily for 21 days
Multivitamin: Daily multivitamin containing 15-30 mg of zinc for 21 days. | 16 |
| IRX-2 Regimen -Triple Negative Breast Cancer Enrolled subjects with triple negative breast cancer will receive a single dose of cyclophosphamide (300 mg/m2) by IV infusion on Day 1. Also starting on Day 1 and continuing until Day 21, subjects will take daily oral indomethacin (25 mg three times each day), daily oral omeprazole (one tablet) and daily oral multivitamin containing 15-30 mg of zinc. On any 10 consecutive day period between Days 4-17, patients will receive two 1 mL subcutaneous periareolar injections of IRX-2.
Cyclophosphamide: One dose of cyclophosphamide 300 mg/m2 IV infusion
Indomethacin: Indomethacin 25 mg three times a day for 21 days
Omeprazole: One tablet of omeprazole daily for 21 days
Multivitamin: Daily multivitamin containing 15-30 mg of zinc for 21 days. | 0 |
| Total | 16 |
Baseline characteristics
| Characteristic | IRX-2 Regimen -Early Stage Breast Cancer | Total |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants |
| Family History of Breast/Ovarian Cancer No | 10 Participants | 10 Participants |
| Family History of Breast/Ovarian Cancer Unknown/Not Reported | 1 Participants | 1 Participants |
| Family History of Breast/Ovarian Cancer Yes | 5 Participants | 5 Participants |
| Known BRCA 1/2 Mutation No | 1 Participants | 1 Participants |
| Known BRCA 1/2 Mutation Unknown | 12 Participants | 12 Participants |
| Known BRCA 1/2 Mutation Yes | 3 Participants | 3 Participants |
| Menstrual Status Post-menopausal | 10 Participants | 10 Participants |
| Menstrual Status Premenopausal | 6 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 15 Participants |
| Region of Enrollment United States | 16 Participants | 16 Participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 0 |
| other Total, other adverse events | 16 / 16 | 0 / 0 |
| serious Total, serious adverse events | 0 / 16 | 0 / 0 |
Outcome results
Primary
Establish the Safety of the IRX-2 Regimen When Administered Pre-operatively in Early Stage Breast Cancer (ESBC) Patients
The safety of IRX-2 will be determined by any surgical delays associated with administration of the study regimen.
Time frame: Day 1 to Day 26
Population: No patients were enrolled into Arm B due to poor accrual and opted against Arm B in favor of the NeoIRX trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | Establish the Safety of the IRX-2 Regimen When Administered Pre-operatively in Early Stage Breast Cancer (ESBC) Patients | 0 Participants |
| IRX-2 Regimen -Triple Negative Breast Cancer | Establish the Safety of the IRX-2 Regimen When Administered Pre-operatively in Early Stage Breast Cancer (ESBC) Patients | 0 Participants |
Secondary
Tumor Infiltrating Lymphocytes
Change in tumor infiltrating lymphocyte (TIL) score as measured by hematoxylin and eosin tumor infiltrating lymphocytes (H&E TIL) count according to Salgado criteria from pre-surgical biopsy to resected tumor specimen
Time frame: At time of pre-surgical biopsy and time of tumor specimen resection at day 26
Population: Due to poor patient accrual we opted against enrolling into Cohort B in favor of the neoIRX trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | Tumor Infiltrating Lymphocytes | 0.4 percentage of stromal area |
Other Pre-specified
Characterization of Peripheral Lymphocytes
Fold change of peripheral lymphocytes including activated T-cells, T-regulatory cells, natural killer (NK) cells, and myeloid cells
Time frame: Day 1 to Day 26
Population: Due to poor accrual we opted against enrolling in Cohort B in favor of the neoIRX trial.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, Any PD-L1: T-Cell (any type) | 2.01 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, Any PD-L1: Helper T-Cell | 2.05 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, Any PD-L1: Cytotoxic T-Cell | 2.55 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, Any PD-L1: Regulatory T-Cell | 0.91 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, Any PD-L1: Macrophage | 0.86 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, PD-L1-positive: T-Cell (any type) | 3.54 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, PD-L1-positive: Helper T-Cell | 3.58 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, PD-L1-positive: Cytotoxic T-Cell | 2.98 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, PD-L1-positive: Regulatory T-cell | 1.38 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stroma, PD-L1-positive: Macrophage | 1.63 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, Any PD-L1: T-Cell (any type) | 1.07 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, Any PD-L1: Helper T-Cell | 0.77 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, Any PD-L1: Cytotoxic T-Cell | 1.36 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, Any PD-L1: Regulatory T-Cell | 0.79 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, Any PD-L1: Macrophage | 0.65 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, PD-L1-positive: T-Cell (any type) | 1.50 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, PD-L1-positive: Helper T-cell | 1.07 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, PD-L1-positive: Cytotoxic T-Cell | 1.68 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, PD-L1-positive: Regulatory T-Cell | 0.64 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Tumor, PD-L1-positive: Macrophage | 0.87 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Characterization of Peripheral Lymphocytes | Stoma and tumor, PD-L1-positive: PD-L1+ IC^3 | 3.14 fold change |
Other Pre-specified
Intratumoral Immune Response
The Nanostring PanCancer Immune panel was used to estimate increase in PD-L1 mRNA expression among tumor-bearing FFPE specimens.
Time frame: Day 1-26
Population: Due to poor patient accrual we opted against enrolling into Cohort B in favor of the neoIRX trial.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 1 | .9 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 2 | .6 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 3 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 4 | .7 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 5 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 6 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 7 | .5 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 8 | -.5 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 9 | .5 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 10 | 1.5 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 11 | 1.8 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 12 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 13 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 14 | 0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 15 | 1.6 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral Immune Response | Patient 16 | .7 fold change |
Other Pre-specified
Intratumoral T-cell Clonality Response
Change in T-cell clonal responses by T-cell receptor DNA deep sequencing
Time frame: Day 1-26
Population: Due to poor patient accrual we opted against enrolling into Cohort B in favor of the neoIRX trial.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 1 | 0.7 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 3 | -0.3 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 4 | 0.00 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 5 | 0.2 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 6 | 0.0 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 7 | 0.1 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 8 | 0.2 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 2 | -0.2 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 9 | -0.3 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 10 | 0.2 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 11 | 0.1 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 12 | -0.1 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 13 | -0.1 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 14 | NA fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 15 | -0.2 fold change |
| IRX-2 Regimen -Early Stage Breast Cancer | Intratumoral T-cell Clonality Response | Patient 16 | 1.5 fold change |
Other Pre-specified
TIL Phenotype
Post-IRX mean density of T-regulatory cells, activated T-cells, myeloid lineages and dendritic cells post-IRX within stromal tissue compartments.
Time frame: Day 1 to 26
Population: Due to poor patient accrual we opted against enrolling into Cohort B in favor of the neoIRX trial.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | PD-L1-positive: Cytotoxic T-Cell | 0.19 count/pixel | Standard Deviation 0.21 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | PD-L1-positive: Regulatory T-Cell | 0.05 count/pixel | Standard Deviation 0.05 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | PD-L1-positive: Macrophage | 0.14 count/pixel | Standard Deviation 0.11 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | Any PD-L1: Regulatory T-cell | 0.07 count/pixel | Standard Deviation 0.06 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | Any PD-L1: Macrophage | 0.19 count/pixel | Standard Deviation 0.12 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | PD-L1-positive: T-cell (any type) | 0.7 count/pixel | Standard Deviation 0.59 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | PD-L1-positive: Helper T-Cell | 0.47 count/pixel | Standard Deviation 0.46 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | Any PD-L1: T-cell (any type) | 1.27 count/pixel | Standard Deviation 0.15 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | Any PD-L1: Helper T-cell | 0.79 count/pixel | Standard Deviation 0.59 |
| IRX-2 Regimen -Early Stage Breast Cancer | TIL Phenotype | Any PD-L1: Cytotoxic T-cell | 0.42 count/pixel | Standard Deviation 0.3 |