PRIMARY OBJECTIVES:
I. To evaluate the feasibility of enrolling patients with hormone receptor positive
(HR+)/human epidermal growth factor receptor negative (HER2-) breast cancer onto a trial
evaluating investigational agents prior to initiating standard neoadjuvant chemotherapy.
II. To evaluate the safety and tolerability of tremelimumab plus durvalumab in patients with
HR+/HER2- breast cancer.
SECONDARY OBJECTIVES:
I. To assess immunologic/molecular responses to tremelimumab and durvalumab in patients with
HR+/HER2- breast cancer who receive the combination therapy.
EXPLORATORY OBJECTIVES:
I. To evaluate the pathologic response in patients with HR+/HER2- breast cancer receiving
tremelimumab plus durvalumab prior to initiating standard neoadjuvant chemotherapy.
OUTLINE:
Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on
day 1. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease
progression or unacceptable toxicity. Patients then undergo a biopsy and receive standard of
care neoadjuvant chemotherapy before undergoing surgery.
After completion of study treatment, patients are followed up until the time of surgery.
Inclusion Criteria:
- Written informed consent and any locally-required authorization (e.g., Health
Insurance Portability and Accountability Act [HIPAA]) obtained from the subject prior
to performing any protocol-related procedures, including screening evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- 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 American Society of Clinical Oncology-College of American Pathologists
(ASCO-CAP) criteria which are as follows: HER2 testing by immunohistochemistry (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
- Chemotherapy is planned for the patient in the neoadjuvant setting
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >=1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- 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
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x ULN
- Creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and
Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
- 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 study
entry
- 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
up
Exclusion Criteria:
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Participation in another clinical study with an investigational product during the
last 1 month prior to initiation of therapy
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA4, including tremelimumab
- History of another primary malignancy except for:
- 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
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease e.g., cervical
cancer in situ
- Has received therapy for this current diagnosis of breast cancer including endocrine
therapy or chemotherapy
- A single QT interval corrected for heart rate (QTc) >= 470 ms. If an electrocardiogram
(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 Fridericia's correction
- 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
- Active or prior documented autoimmune disease within the past 2 years
- NOTE: Subjects with vitiligo, Graves disease, or psoriasis not requiring systemic
treatment (within the past 2 years) are not excluded
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab or tremelimumab or any excipient
- History of hypersensitivity to the combination or comparator agent (if applicable)
- 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
- Known history of previous clinical diagnosis of tuberculosis
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab
- 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
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Subjects with uncontrolled seizures
