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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Given IV
Correlative studies
Correlative studies
Given IV
Northwestern University
Chicago, Illinois, United States
Northwestern University- Lake Forest Hospital
Lake Forest, Illinois, United States
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
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
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
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
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
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
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