The goal of this clinical research study is to find the highest dose combination of
tremelimumab and durvalumab [also called MEDI4736]) that can be given before standard of
care pre-surgery chemotherapy to patients with HR+, HER2- breast cancer. Researchers also
want to learn more about how certain immune cells may change in the body when they are given
the drug combination. Researchers also want to find out how patients with HR+, HER2- breast
cancer respond to the study drugs before they receive standard chemotherapy treatment.
Study Drug Administration:
If you are found to be eligible to take part in this study, you will receive both study
drugs in 2 study cycles that are each 4 weeks long. On Day 1 of each cycle, you will first
receive tremelimumab by vein over about 1 hour. You will then be monitored for side effects
for about 1 hour. You will then receive durvalumab by vein over about 1 hour, followed by
another hour of monitoring for side effects.
Length of Study:
You will receive up to 2 cycles of the study drugs. You will no longer be able to take the
study drug if the disease gets worse, if intolerable side effects occur, or if you are
unable to follow study directions.
Your participation on the study will be over after the follow-up visits.
Before you receive the study drugs for the first time:
- You will have a core breast tumor biopsy before you begin treatment to collect tissue
to test for immune cells and other biomarkers. Biomarkers are found in the blood/tissue
and may be related to your reaction to the study drug. To perform a core biopsy, the
area is numbed and a sample of tissue is removed using a hollow core needle that has a
- If your screening blood test was performed more than 3 days before you begin receiving
the study drugs, blood (about 14 teaspoons) will be drawn for the same testing
performed during the screening.
On Day 1 of Cycles 1 and 2:
- You will have a physical exam.
- Blood (about 5 tablespoons) and urine will be collected for routine tests.
- You will have an EKG to check your heart function (Cycle 1 only).
At the end of Cycle 2:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine tests and to check for immune
cells and other biomarkers.
- You will have a second ultrasound of your breast.
- You will have a second core breast tumor biopsy to compare to the tissue taken before
you started treatment.
After this visit, you will then begin receiving the standard of care treatment for the
disease (pre-surgery chemotherapy followed by surgery). During your surgery, blood and tumor
samples will be collected to compare to the samples taken during the study. However, no
additional tissue or blood will be collected beyond what is already collected for the
standard purposes of the surgery.
This is an investigational study. Tremelimumab is FDA approved to treat mesothelioma.
Durvalumab is FDA approved to treat a certain type of bladder cancer. It is investigational
to give these 2 drugs in combination to patients with HR+, HER2- breast cancer. The study
doctor can describe how the study drugs are designed to work.
Up to 15 participants will be enrolled in this study. All will take part at MD Anderson.
1. Written informed consent and any locally-required authorization (e.g., HIPAA)
obtained from the subject prior to performing any protocol-related procedures,
including screening evaluations
2. Age >/= 18 years at time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Hormone receptor positive (defined as estrogen receptor [ER] and/or progesterone
receptor [PR] positive), HER2 negative breast cancer that is clinically staged II-III
with no known metastatic disease. ER and/or PR defined as positive if expression >10%
by immunohistochemistry (IHC). HER2 negative or non-amplified as determined by the
current ASCO-CAP criteria which are as follows: HER2 testing by IHC as 0 or 1+. If
HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if: IHC
3+ based on circumferential membrane staining that is complete, intense ISH positive
based on: 1)Single-probe average HER2 copy number >/= 6.0 signals/cell, 2) Dual-probe
HER2/CEP17 ratio >/= 2.0;c,e with an average HER2 copy number >/= 4.0 signals/cell,
3) Dual-probe HER2/CEP17 ratio >/= 2.0;c,e with an average HER2 copy number <4.0
signals/cell, 4) Dual-probe HER2/CEP17 ratio < 2.0;c,e with an average HER2 copy
number >/= 6.0 signals/cell
5. Chemotherapy is planned for the patient in the neoadjuvant setting
6. Adequate normal organ and marrow function as defined below: 1) Hemoglobin >/=9.0
g/dL, 2) Absolute neutrophil count (ANC) >/=1.5 x 109/L (>/=1500 per mm3), 3)
Platelet count >/=100 x 109/L (>/=100,000 per mm3), 4) Serum bilirubin </=1.5 x
institutional upper limit of normal (ULN). This will not apply to subjects with
confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
predominantly unconjugated in the absence of hemolysis or hepatic pathology), who
will be allowed only upon treating physician, Principal Investigators (PI) or co-PIs
approval. 5) AST (SGOT)/ALT (SGPT) </=2.5 x institutional upper limit of normal
unless liver metastases are present, in which case it must be </=5 x ULN, 6) Serum
creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or
by 24-hour urine collection for determination of creatinine clearance.
7. Female subjects must either be of non-reproductive potential (i.e., post-menopausal
by history: >/= 60 years old and no menses for >/= 1 year without an alternative
medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR
history of bilateral oophorectomy) or must have a negative urine pregnancy test upon
8. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
2. Participation in another clinical study with an investigational product during the
last 1 month prior to initiation of therapy
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA4, including tremelimumab
4. History of another primary malignancy except for: 1) Malignancy treated with curative
intent and with no known active disease >/= 5 years before the first dose of study
drug and of low potential risk for recurrence, 2) Adequately treated non-melanoma
skin cancer or lentigo maligna without evidence of disease, 3) Adequately treated
carcinoma in situ without evidence of disease e.g., cervical cancer in situ
5. Has received therapy for this current diagnosis of breast cancer including endocrine
therapy or chemotherapy
6. A single QT interval corrected for heart rate (QTc) >/= 470 ms. If an ECG is
interpreted to be a prolonged QT interval, 2 additional ECGs will be obtained and the
PI will then evaluate all three ECGs and determine whether the patient should be
excluded. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from
3 electrocardiograms (ECGs) using Fredericia's Correction
7. Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are not to
exceed 10 mg/day of prednisone, or an equivalent corticosteroid
8. Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.
9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
10. History of primary immunodeficiency
11. History of allogeneic organ transplant
12. History of hypersensitivity to durvalumab or tremelimumab or any excipient
13. History of hypersensitivity to the combination or comparator agent (if applicable)
14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent
15. Known history of previous clinical diagnosis of tuberculosis
16. History of leptomeningeal carcinomatosis
17. Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab
18. Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control
19. Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
20. Subjects with uncontrolled seizures