Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, Recurrent Breast Carcinoma, Stage IV Breast Cancer
Conditions
Brief summary
The main purpose of this study is to determine the anti-tumor activity of MEDI4736 in combination with tremelimumab in patients with metastatic HER2-negative breast cancer. Both MEDI4736 and tremelimumab are antibodies (proteins used by the immune system to fight infections and cancers). MEDI4736 attaches to a protein in tumors called PD-L1. It may prevent cancer growth by helping certain blood cells of the immune system get rid of the tumor. Tremelimumab stimulates (wakes up) the immune system to attack the tumor by inhibiting a protein molecule called CTLA-4 on immune cells. Combining the actions of these drugs may result in better treatment options for patients with breast cancer.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate clinical benefit rate in patients with metastatic HER2 negative breast cancer treated with MEDI4736 in combination with tremelimumab. SECONDARY OBJECTIVES: I. To evaluate progression free survival (PFS) and overall survival (OS) in patients with metastatic HER2 negative breast cancer treated with MEDI4736 in combination with tremelimumab. II. To evaluate safety and tolerability. TERTIARY OBJECTIVES: I. To evaluate if tissue-based immunohistochemical expression of programmed death-ligand (PD-L)1; tumor infiltrating lymphocytes (TILs); peripheral T cell subpopulations; changes in tissue and peripheral T cell receptor genotype; human leukocyte antigen (HLA) genotype; and immune-related candidate gene signatures predict response to MEDI4736 in combination with tremelimumab. II. To demonstrate the pharmacodynamic effects of MEDI4736 and tremelimumab on tissue and serum based biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor genotype. OUTLINE: Patients receive MEDI4736 intravenously (IV) over 1 hour and tremelimumab IV over 1 hour on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Four weeks after the last combination dose, patients continue to receive MEDI4736 every 2 weeks for up to 18 additional doses in the absence of disease progression or unacceptable toxicity. Patients who achieve clinical benefit (complete response \[CR\], partial response \[PR\], or stable disease \[SD\]) until the end of the 52 week period will then enter follow-up. During follow-up patients who develop PD may be re-treated with MEDI4736 at the dose previously administered IV for an additional 52 weeks using the same guidelines as with the initial 52 week period if they meet treatment in the setting of PD criteria. Only one 52 week retreatment period will be allowed. After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, and then every 6 months for 3 years.
Interventions
BIOLOGICALAnti-B7H1 Monoclonal Antibody MEDI4736
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
BIOLOGICALTremelimumab
Given IV
Sponsors
MedImmune LLC
Avon Breast Cancer Foundation
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a histologically documented (either primary or metastatic site) diagnosis of breast cancer that is HER2 non-overexpressing by immunohistochemistry, namely 0 or 1; if they have an equivocal immunohistochemistry, 2, the tumor must be non-gene amplified by fluorescence in situ hybridization (FISH) performed upon the primary tumor or metastatic lesion (ratio \< 2 and HER2 copy number \< 4); estrogen receptor (ER) positivity is defined as 1% or greater * Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * Patients who are ER negative must have progressed through at least one prior chemotherapy regimen in the metastatic setting or within 12 months of their last adjuvant systemic treatment; patients who are ER positive must have progressed through standard hormone therapy options and have received at least one line of chemotherapy in the metastatic setting * Completion of prior chemotherapy systemic anticancer therapy at least 2 weeks prior to study entry * Radiation therapy must be completed at least 2 weeks prior to study entry; radiated lesions may not serve as measurable disease unless they have been radiated over 12 months prior to enrollment * Patients may have parenchymal brain metastases if stable (no evidence of progression) for at least 1 month after local therapy (radiation or surgery); leptomeningeal disease is excluded; must have completed any prescribed steroid taper * Patients may have had a prior diagnosis of cancer if it has been \> 5 years since their last treatment * Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 * Absolute neutrophil count \>= 1,000/mcL * Platelets \>= 50,000/mcl * Total bilirubin =\< 1.5 times the institutional upper limit of normal (ULN) (or =\< 3 times ULN in case of liver metastasis) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SPGT\]) =\< 2.5 X institutional ULN (or =\< 5 times ULN in case of liver metastasis) * Creatinine =\< 2 ng/ml * Females of child-bearing potential (FOCBP) and males must agree to use 2 methods of adequate contraception prior to study entry, for the duration of study participation, and for number (#) days following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * FOCBP must have a negative pregnancy test within 7 days prior to registration on study * Willingness to provide a fresh biopsy prior to study enrollment and after 2 cycles of treatment * Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier are not eligible. * Current or prior use of immunosuppressive therapy within 2 weeks of starting investigational therapy * Patients who are taking any herbal (alternative) medicines are NOT eligible for participation; patients must be off any such medications by the time of registration for at least 2 weeks; NOTE: Vitamin supplements are acceptable * Patients may not have received any other investigational agents within 4 weeks prior to registration * Prior treatment with immune therapy (including but not limited to cluster of differentiation \[CD\]137, OX40, programmed death \[PD\]-1, PD-L1 or cytotoxic T-lymphocyte antigen 4 \[CTLA4\] inhibitors) * Prior severe infusion reaction to a monoclonal antibody * Patients with a history of or active autoimmune disease within the past 3 years with the following exceptions: * Vitiligo or alopecia * Hypothyroidism on stable doses of thyroid replacement therapy * Psoriasis not requiring systemic therapy within the past 3 years * History of primary immunodeficiency disease or tuberculosis * Major medical conditions that might affect study participation (uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection) are not eligible; other significant comorbid condition which the investigator feels might compromise effective and safe participation in the study * Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Uncontrolled pulmonary, renal, or hepatic dysfunction * Ongoing or active infection requiring systemic treatment * Known active or chronic viral hepatitis or human immunodeficiency virus (HIV) * Psychiatric illness/social situations that would limit compliance with study requirements * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints * Female patients who are pregnant or nursing are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles | Overall response rate is defined as the number of patients with partial response (PR), plus those with complete response (CR) using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Overall Response Rate (ORR) in Patients With Triple Negative Breast Cancer (TNBC) Treated With Durvalumab in Combination With Tremelimumab | Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and then 1 cycle = 2 weeks for up to 45 cycles | Overall response rate is defined as the number of patients with partial response (PR), plus those with complete response (CR) using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. TNBC = patients whose status for ER, PR and HER2 is negative |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles | Toxicity will be evaluated by the number, frequency, and severity of adverse events as defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE version 4.03 Events that were considered to at least be possibly related to either study drugs are reported here and in general grading is as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities Moderate (grade 2): the event causes discomfort that affects normal daily activities Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status Life-threatening (grade 4): the patient was at risk of death at the time of the event Fatal (grade 5): the event caused death |
| Overall Survival (OS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Time from treatment initiation until 3 years post treatment continuation where patients were treated up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles | OS is defined as the time from treatment initiation until death due to any cause |
| Progression Free Survival (PFS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Time from treatment initiation until 3 years post treatment continuation where patients were treated up to a maximum of 49 cycles where 1 cycle = 4 weeks,for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles | PFS is defined as the time from treatment initiation to documented disease progression. Progressive Disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) |
| Clinical Benefit Rate (CBR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles | CBR is defined as the number of patients with complete response (CR) plus those with partial response (PR) plus those with stable disease (SD) for ≥ 12 weeks using Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tumor Infiltrating Lymphocytes (TILs) Expression | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of TILs predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment |
| Programmed Death-ligand 1 (PD-L1) Expression | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of PD-L1 predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment |
| Change in T Cell Receptor Genotype | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of T cell receptor genotype predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment |
| Changes in Peripheral T Cell Subpopulations | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of peripheral T cell subpopulations predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment |
| Human Leukocyte Antigen (HLA) | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of HLA predicts response to MEDI4736 in combination with tremelimumab |
| Immune-related Candidate Gene Signatures | Baseline and at 2 months of treatment | To evaluate if tissue-based immunohistochemical expression of Immune-related candidate gene signatures predicts response to MEDI4736 in combination with tremelimumab |
Countries
United States
Participant flow
Recruitment details
The study was opened to accrual on December 18 2015, with the first patient starting treatment on January 14, 2016 and a total accrual goal of 50 patients. The study closed to further accrual July 20, 2020 with 30 patients treated on study.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (MEDI4736, Tremelimumab) Patients receive anti-B7H1 monoclonal antibody MEDI4736 IV over 1 hour and tremelimumab IV over 1 hour on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Four weeks after the last combination dose, patients continue to receive anti-B7H1 monoclonal antibody MEDI4736 every 2 weeks for up to 18 additional doses in the absence of disease progression or unacceptable toxicity. Patients achieving PD or clinical benefit (CR, PR, or SD) may be retreated with anti-B7H1 monoclonal antibody MEDI4736 for an additional 52 weeks.
Anti-B7H1 Monoclonal Antibody MEDI4736: Given IV
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Tremelimumab: Given IV | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Continued Treatment After 1st Response | Adverse Event | 1 |
| Continued Treatment After 1st Response | Progressive disease | 7 |
| Reached 1st Response Assessment | Adverse Event | 2 |
| Reached 1st Response Assessment | Progressive Disease | 2 |
| Reached 1st Response Assessment | Protocol Violation | 1 |
| Reached 1st Response Assessment | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (MEDI4736, Tremelimumab) |
|---|---|
| Age, Continuous | 53.0 years |
| ER Status Negative | 15 Participants |
| ER Status Positive | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| HER 2 Status Negative | 30 Participants |
| HER 2 Status Positive | 0 Participants |
| PR Status Negative | 22 Participants |
| PR Status Positive | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Received prior chemotherapy No | 1 Participants |
| Received prior chemotherapy yes | 29 Participants |
| Received prior systemic therapies for breast cancer | 30 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 0 Participants |
| Triple Negative Breast Cancer (TNBC) No | 15 Participants |
| Triple Negative Breast Cancer (TNBC) Yes | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 22 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 18 / 30 |
Outcome results
Primary
Overall Response Rate (ORR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
Overall response rate is defined as the number of patients with partial response (PR), plus those with complete response (CR) using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
Population: number of HER2 negative breast cancer patients that met criteria to be evaluable for this endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Overall Response Rate (ORR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | 4 participants |
Primary
Overall Response Rate (ORR) in Patients With Triple Negative Breast Cancer (TNBC) Treated With Durvalumab in Combination With Tremelimumab
Overall response rate is defined as the number of patients with partial response (PR), plus those with complete response (CR) using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. TNBC = patients whose status for ER, PR and HER2 is negative
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and then 1 cycle = 2 weeks for up to 45 cycles
Population: number of triple negative breast cancer patients that met criteria to be evaluable for this endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Overall Response Rate (ORR) in Patients With Triple Negative Breast Cancer (TNBC) Treated With Durvalumab in Combination With Tremelimumab | 4 participants |
Secondary
Clinical Benefit Rate (CBR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
CBR is defined as the number of patients with complete response (CR) plus those with partial response (PR) plus those with stable disease (SD) for ≥ 12 weeks using Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
Population: Per protocol patients were required to complete 2 months of study treatment to be evaluable for this endpoint, however all patients who had a response are reported here as the study did not meet its total sample size. number of patients HER2 negative breast cancer patients that met criteria to be evaluable for this endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Clinical Benefit Rate (CBR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | 5 participants |
Secondary
Overall Survival (OS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
OS is defined as the time from treatment initiation until death due to any cause
Time frame: Time from treatment initiation until 3 years post treatment continuation where patients were treated up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
Population: number of HER2 negative breast cancer patients that met criteria to be evaluable for this endpoint
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Overall Survival (OS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | 11.3 months |
Secondary
Progression Free Survival (PFS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
PFS is defined as the time from treatment initiation to documented disease progression. Progressive Disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.)
Time frame: Time from treatment initiation until 3 years post treatment continuation where patients were treated up to a maximum of 49 cycles where 1 cycle = 4 weeks,for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
Population: number HER2 negative breast cancer patients that met criteria to be evaluable for this endpoint
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Progression Free Survival (PFS) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | 4.86 months |
Secondary
Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
Toxicity will be evaluated by the number, frequency, and severity of adverse events as defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE version 4.03 Events that were considered to at least be possibly related to either study drugs are reported here and in general grading is as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities Moderate (grade 2): the event causes discomfort that affects normal daily activities Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status Life-threatening (grade 4): the patient was at risk of death at the time of the event Fatal (grade 5): the event caused death
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Grade 1 or 2 Adverse Event | 27 participants |
| Treatment (MEDI4736, Tremelimumab) | Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Grade 3 or 4 Adverse Event | 12 participants |
| Treatment (MEDI4736, Tremelimumab) | Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Grade 1 or 2 Serious Adverse Event | 6 participants |
| Treatment (MEDI4736, Tremelimumab) | Toxicity in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Grade 3 or 4 Serious Adverse Event | 7 participants |
Other Pre-specified
Change in T Cell Receptor Genotype
To evaluate if tissue-based immunohistochemical expression of T cell receptor genotype predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment
Time frame: Baseline and at 2 months of treatment
Other Pre-specified
Changes in Peripheral T Cell Subpopulations
To evaluate if tissue-based immunohistochemical expression of peripheral T cell subpopulations predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment
Time frame: Baseline and at 2 months of treatment
Other Pre-specified
Human Leukocyte Antigen (HLA)
To evaluate if tissue-based immunohistochemical expression of HLA predicts response to MEDI4736 in combination with tremelimumab
Time frame: Baseline and at 2 months of treatment
Other Pre-specified
Immune-related Candidate Gene Signatures
To evaluate if tissue-based immunohistochemical expression of Immune-related candidate gene signatures predicts response to MEDI4736 in combination with tremelimumab
Time frame: Baseline and at 2 months of treatment
Post Hoc
Overall Response Rate (ORR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab (All Included)
Overall response rate is defined as the number of patients with partial response (PR), plus those with complete response (CR) using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
Population: This includes patients who did not complete 2 months of treatment but would otherwise be evaluable for the endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Overall Response Rate (ORR) in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab (All Included) | 4 participants |
Other Pre-specified
Programmed Death-ligand 1 (PD-L1) Expression
To evaluate if tissue-based immunohistochemical expression of PD-L1 predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment
Time frame: Baseline and at 2 months of treatment
Post Hoc
Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab
Patients response is defined as the best response to treatment whilst on study using Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 with the following definitions: Complete Response - Disappearance of all lesions Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.)
Time frame: Up to a maximum of 49 cycles where 1 cycle = 4 weeks for the first 4 cycles and than 1 cycle =2 weeks for 45 cycles
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (MEDI4736, Tremelimumab) | Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Complete Response | 1 Participants |
| Treatment (MEDI4736, Tremelimumab) | Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Partial Response | 3 Participants |
| Treatment (MEDI4736, Tremelimumab) | Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Stable Disease | 4 Participants |
| Treatment (MEDI4736, Tremelimumab) | Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Progressive Disease | 19 Participants |
| Treatment (MEDI4736, Tremelimumab) | Response in Patients With Metastatic HER2 Negative Breast Cancer Treated With Durvalumab in Combination With Tremelimumab | Not evaluable | 3 Participants |
Other Pre-specified
Tumor Infiltrating Lymphocytes (TILs) Expression
To evaluate if tissue-based immunohistochemical expression of TILs predicts response to MEDI4736 in combination with tremelimumab. Changes will also be analyzed to assess for pharmacodynamic effects of treatment
Time frame: Baseline and at 2 months of treatment