A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab [MEDI4736]) Plus Anti-CTLA-4 Antibody (Tremelimumab) in Patients With Hormone Receptor Positive, HER2 Negative Breast Cancer
Phase: EARLY_PHASE1
Conditions: Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Estrogen Receptor Positive, HER2/Neu Negative, Progesterone Receptor Positive, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

2016-0902 
 5 October, 2018 
1 
 
1 
 
Investigational Drug  Durvalumab (MEDI4736) and 
tremelimumab 
Study Number 
ESR-16-12034 
Version Number 
11 
Date 
5 October 2018 
A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab
[MEDI4736]) Plus Anti-CTLA-4 Antibody (Tremelimumab) in Patients with 
Hormone Receptor Positive, HER2 Negative Breast Cancer 
Sponsor:  The University of Texas MD Anderson Cancer Center 
 
 
 

2016-0902 
 5 October, 2018 
2 
 
2 
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol 2016-0902 IND 134400 
Study Title:  A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-
CTLA-4 Antibody (Tremelimumab) in Patients with Hormone Receptor Positive, HER2 Negative 
Breast Cancer  
Clinical Phase:  Pilot 
Study Duration:  24 months 
Investigational Product(s) and Reference Therapy: 
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 
50 mg/mL for intravenous (IV) administration. 
 
Tremelimumab is supplied as a sterile solution for IV infusion, filled in 20 mL clear glass vials with 
a rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL, 
accounting to 400 mg/vial) of tremelimumab, in an isotonic solution at pH 5.5. 
Research Hypothesis 
Our hypotheses are: 1) that it will be feasible to enroll patients with hormone receptor (HR)-positive, 
HER2-negative breast cancer onto a trial evaluating anti-CTLA-4 (cytotoxic T-lymphocyte-
associated antigen-4) therapy (tremelimumab)  plus anti-PD-L1 (programmed cell death ligand 1) 
therapy (durvalumab) prior to initiating standard neoadjuvant chemotherapy, 2) that the combination 
of tremelimumab plus durvalumab therapy will have an acceptable safety profile in HR+/HER2- 
breast cancer patients; and 3) that tremelimumab plus durvalumab therapy will lead to measurable 
immunologic changes, with identification of novel biomarkers that can be used for immune 
monitoring and clinical correlation in the setting of HR+/HER2- breast cancer. 
Objectives: 
Primary Objectives: 
• 
To evaluate the feasibility of enrolling patients with HR+/HER2- breast cancer onto a trial 
evaluating investigational agents prior to initiating standard neoadjuvant chemotherapy. 
• 
To evaluate the safety and tolerability of tremelimumab plus durvalumab in patients with 
HR+/HER2- breast cancer. 

2016-0902 
 5 October, 2018 
3 
 
3 
 
Secondary Objective(s): 
To assess immunologic/molecular responses to tremelimumab and durvalumab in patients with 
HR+/HER2- breast cancer who receive the combination therapy. 
Exploratory Objective(s): 
To evaluate the pathologic response in patients with HR+/HER2- breast cancer receiving 
tremelimumab plus durvalumab prior to initiating standard neoadjuvant chemotherapy. 
Study Design: 
Open-label, single-arm, presurgical pilot study in patients with HR+/HER2- breast cancer 
Number of Centers: 1 
Number of Subjects: 15 
Study Population: 
Breast cancer patients with HR+/HER2- disease planned to receive neoadjuvant chemotherapy 
 

2016-0902 
 5 October, 2018 
4 
 
4 
 
Inclusion Criteria: 
For inclusion in the study, patients should fulfill the following criteria: 
 
• 
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 
 
• 
Age > 18 years at time of study entry  
• 
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 
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: 
• 
Single-probe average HER2 copy number ≥6.0 signals/cell. 
• 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 copy 
number ≥4.0 signals/cell 
• 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 
• 
copy number <4.0 signals/cell 
• 
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  
• 
Adequate normal organ and marrow function as defined below:   
- Hemoglobin ≥ 9.0 g/dL 
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
- Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
- 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 

2016-0902 
 5 October, 2018 
5 
 
5 
 
be allowed only in consultation with their physician, Principal Investigators (PI) or co-PIs 
approval 
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
- 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: 
Males: 
 
Creatinine 
CL 
(mL/min) 
Weight 
(kg) 
x 
(140 
– 
Age)  
72 x serum creatinine (mg/dL) 
 
 
Females: 
 
Creatinine 
CL 
(mL/min) 
Weight 
(kg) 
x 
(140 
– 
Age) 
 
x0.85 
72 x serum creatinine (mg/dL) 
 
• 
Female subjects must either be of non-reproductive potential (ie, 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. 
 

2016-0902 
 5 October, 2018 
6 
 
6 
 
Exclusion Criteria: 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
 
• 
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 eg, 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 ECG is interpreted to 
be a prolonged QT interval, 2 additional ECGs will be obtained. 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 
• 
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, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 
years) are not excluded. 

2016-0902 
 5 October, 2018 
7 
 
7 
 
• 
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. 
 

2016-0902 
 5 October, 2018 
8 
 
8 
 
Investigational Product(s), Dose, and Mode of Administration: 
Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 2 doses/cycles in patients ≥ 30 kg 
Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for 2 doses/cycles in patients ≥30 kg 
Weight-based dosing should be utilized for patients <30 kg durvalumab 20 mg/kg Q4 and 
tremelimumab 1 mg/kg Q4  
Study Assessments and Criteria for Evaluation: 
The study’s primary endpoints are to evaluate the feasibility of enrolling patients with HR+/HER2- 
breast cancer onto a trial evaluating investigational agents prior to initiating standard neoadjuvant 
chemotherapy and to evaluate the safety and tolerability of tremelimumab plus durvalumab in patients 
with HR+/HER2- breast cancer. 
Feasibility Assessments: 
Feasibility will be measured by 2 achievements.  If both are met, then upfront treatment with 
tremelimumab plus durvalumab will be feasible for future trials in HR+/HER2- breast cancer patients.  
The 2 measures are: 
• 
Patients are willing to enroll.  This will be established if we can enroll all 15 patients within 
12 months of starting the study.  
• 
Patients can complete the protocol.  If at least 10 patients complete the study and have 
available immune data, the trial meets this feasibility criterion. 
Safety Assessments: 
All patients who receive at least one dose of study drug will be included in the safety monitoring and 
safety analysis.  For trial monitoring and decisions about future trials, a patient will be determined to 
have an extreme toxicity (ETOX) if either condition is met: 
 
• 
The patient experiences any grade 3 or higher adverse event (AE) that is possibly, probably, 
or definitely related to therapy received on this protocol and occurs up to 90 days after the 
last dose of therapy (durvalumab + tremelimumab).  As an exception, any such AE that is 
potentially treatable with steroids will only count as an ETOX if it does not improve to grade 
1 or better within 2 weeks. 
 
• 
The patient has a delay in surgery of 6 weeks or more due to AE, even if that AE does not 
meet the definition of ETOX 
 

2016-0902 
 5 October, 2018 
9 
 
9 
 
Statistical Methods and Data Analysis: 
Feasibility will be assessed according to the endpoint definition provided above.  Since it is not known 
whether durvalumab plus tremelimumab can be safely used in the presurgical setting in patients with 
HR+, HER2- breast cancer, our other primary endpoint is safety.  Adverse events will be tabulated by 
CTCAE grade and ETOX status.  Surgery delay will be reported with the numbers of patients with 
any delay, as well as the median, IQR, min and max for delay times.  If 6 or more patients experience 
ETOX, then this combination will be determined to be too toxic for these patients. 
 
For blood and tumor measures, descriptive statistics including plots, tabulations, mean, median and 
standard deviations will be used to summarize data.  Differences and/or percent changes will be 
calculated between pre- and post-therapy samples from each patient and described as continuous 
measures. 
Sample Size Determination: 
The selection of 15 patients for this pilot trial is to provide preliminary information for feasibility and 
safety, as well as to have at least 10 patients with full immune measures pre and post treatment for 
hypothesis generation and testing in the next trial.  An accrual rate of 2 patients per month is 
anticipated.  A maximum sample size of 15 patients will be enrolled.  No hypotheses will be formally 
tested, but with 15 patients we can determine whether an unreasonable proportion of patients have 
high grade toxicities and gather estimates of immune and molecular changes in tumor and peripheral 
blood.  These measures will be used to design a larger, hypothesis-driven trial. 
 
 
 
 
 
 
 
 
 
 
 
 

2016-0902 
 5 October, 2018 
10 
 
10 
 
SCHEDULE OF STUDY ASSESSMENTS 
 
 
Study Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
Prior 
to 
Neoadjuvant 
Therapy 
Surgery 
Study Cycle 
 
1 
2 
 
 
Cycle Day 
-28 
to 0 
1 
8 
15 28 1 
8 
15 28 
Within 
28 
days 
Within 56 days of 
completing 
neoadjuvant 
therapy 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
General Physical1 
X 
X2  
 
  
X 
 
 
 
X 
 
Height, Weight3 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X4  
 
 
X4 
 
 
 
X 
 
Performance Status 
(ECOG) 
X 
X2  
 
 
X 
 
 
 
X 
 
Baseline 
Symptoms/Toxicity 
review 
 
X 
 
X2 
 
 
 
X 
 
 
 
X 
 
Review 
of 
concomitant 
medications 
X 
X2  
 
 
X 
 
 
 
 
 
CBC 
X 
X7     
 
 
X 
 
 
 
 
 
aPTT and INR5 
X 
 
 
 
 
 
 
 
 
 
 
Chemistries6 
X 
X7  
 
 
X 
 
 
 
X 
 
TSH, free T4, free 
T38 
X 
X7  
 
 
X 
 
 
 
X 
 
HBsAg, Anti HCV, 
HIV 
antibody, 
Hepatitis 
A 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance X 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Test 
(urine)9 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis10 
X 
X 
 
 
 
X 
 
 
 
 
 
Mammogram 
X 
 
 
 
 
 
 
 
 
 
 
Breast Ultrasound11 
X 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG12 
X 
X 
 
 
 
 
 
 
 
 
 
Core Biopsy  
X13 
 
 
 
 
 
 
 
 
X 
 
Surgical Specimen 
 
 
 
 
 
 
 
 
 
 
X 

2016-0902 
 5 October, 2018 
11 
 
11 
 
Blood for PBMCs      X 
 
 
 
 
 
 
 
 
X 
X 
Serum 
X 
 
 
 
 
 
 
 
 
X 
X 
Durvalumab 
 
X 
  
 
 
X 
 
 
 
 
 
Tremelimumab 
 
X 
 
 
 
X 
 
 
 
 
 
Gamma 
glutamyltransferase 
X 
X7  
 
 
 
 
 
 
 
 
 
 
1. Full physical examination at baseline; targeted physical examination at other time points 
2. If completed within 7 days of the date of treatment initiation, these do not need to be repeated. 
3. Height only needs to be measured and recorded at the baseline assessment. 
4. Subjects will have their blood pressure and pulse measured before, during, and after the infusion 
at the following times (based on a 60-minute infusion):   
a. At the beginning of the infusion (at 0 minutes) 
b. At 30 minutes during the infusion (±10 minutes) 
c. At the end of the infusion (60 minutes ±10 minutes) 
d. In the 1 hour observation period post-infusion:  30 and 60 minutes after the infusion (i.e. 
90 and 120 minutes from the start of the infusion) (±10 minutes) – for the first infusion 
only and then for subsequent infusions as clinically indicated 
e. If the infusion lasts longer than 60 minutes, then blood pressure and pulse measurements 
should follow the principles as described above or more frequently if clinically 
indicated. 
5. Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as 
clinically indicated. 
6. Chemistries include: albumin, alkaline phosphatase, ALT, AST, amylase, lipase, calcium, 
bicarbonate, chloride, creatinine, glucose, LDH, magnesium, potassium, sodium, total bilirubin, 
total protein, BUN, uric acid. If total bilirubin is ≥ 2x ULN (and no evidence of Gilbert’s 
syndrome), then bilirubin should be fractionated into direct and indirect bilirubin. 
7. If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need 
to be repeated at Day 1. Results for safety bloods must be available and reviewed before 
commencing an infusion. Gamma glutamyltransferase tested at Screening, Day 1 and as 
clinically indicated.  
8. Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured 
if there is clinical suspicion of an adverse event related to the endocrine system. 
9. Pre-menopausal female subjects of childbearing potential only 
10. Urinalysis performed at Screening, Day 1, then at Cycle 1, Day 1 and Cycle 2 Day 1, and as 
clinically indicated. Microscopy should be used as appropriate to investigate white blood cells 
and use the high power field for red blood cells. 
11. Ultrasound evaluation of the breast tumor and nodal basins will use tumor volume to estimate 
changes in the tumor in the breast from baseline until after investigational therapy.  Tumor 
volume = (length x width x height x π)/6 
12. ECG during screening and on cycle 1 Day 1 within 1 hour prior to start of the first study 
treatment. Subsequent ECGs as clinically indicated.  If an ECG is interpreted to be a prolonged 
QT interval, 2 additional ECGs will be obtained and the PI will then evaluate all 3 ECGs to 
determine whether the patient should be excluded. 

2016-0902 
 5 October, 2018 
12 
 
12 
 
13. Initial core biopsy will be completed after the patient is determined to be eligible for the study, 
prior to beginning therapy. 

2016-0902 
 5 October, 2018 
13 
 
13 
 
TABLE OF CONTENTS 
PAGE 
PROTOCOL SYNOPSIS .................................................................................................... 2 
SCHEDULE OF STUDY ASSESSMENTS…………………………………………..…10 
TABLE OF CONTENTS .................................................................................................. 13 
ABBREVIATIONS AND DEFINITION OF TERMS ..................................................... 16 
1. 
INTRODUCTION ............................................................................................................. 20 
1.1 
Immunotherapy and Breast Cancer ................................................................................... 20 
1.1.1 
Immunotherapies ............................................................................................................... 21 
1.1.2 
Durvalumab ....................................................................................................................... 21 
1.1.3 
Tremelimumab .................................................................................................................. 22 
1.1.4 
Durvalumab in combination with tremelimumab ............................................................. 23 
1.2 
Research hypotheses ......................................................................................................... 24 
1.3 
Rationale for conducting this study ................................................................................... 25 
2. 
STUDY OBJECTIVE ....................................................................................................... 26 
2.1.1 
Primary objective(s) .......................................................................................................... 26 
2.1.2 
Secondary objective .......................................................................................................... 26 
2.1.3 
Exploratory objective ........................................................................................................ 25 
3. 
STUDY DESIGN .............................................................................................................. 25 
3.1 
Overview of study design .................................................................................................. 25 
3.2 
Study schema .................................................................................................................... 26 
3.3 
Study Oversight for Safety Evaluation .............................................................................. 26 
4. 
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................................. 28 
4.1 
Inclusion criteria ................................................................................................................ 28 
4.2 
Exclusion criteria .............................................................................................................. 29 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study .......................................... .31 
4.4 
Replacement of subjects .................................................................................................... 32 
5. 
INVESTIGATIONAL PRODUCT(S) .............................................................................. 32 
5.1 
Durvalumab and tremelimumab ........................................................................................ 32 
5.1.1 
Formulation/packaging/storage ......................................................................................... 32 
5.2 
Dose and treatment regimens ............................................................................................ 32 
5.2.1 
Treatment regimens ........................................................................................................... 32 

2016-0902 
 5 October, 2018 
14 
 
14 
 
5.2.2 
Duration of treatment ........................................................................................................ 33 
5.2.3 
Study drug preparation of durvalumab and tremelimumab ............................................... 33 
5.2.4 
Monitoring of dose administration .................................................................................... 36 
5.2.5 
Accountability and dispensation ....................................................................................... 36 
5.2.6 
Disposition of unused investigational study drug ............................................................. 36 
6. 
TREATMENT PLAN ....................................................................................................... 36 
6.1 
Subject enrollment ............................................................................................................ 36 
6.1.1 
Procedures for handling subjects incorrectly enrolled ...................................................... 37 
6.2 
Dosage and Administration ............................................................................................... 37 
6.3 
Dose Modification and Toxicity Management .................................................................. 37 
6.3.1 
Durvalumab and tremelimumab ........................................................................................ 37 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .............................................................................................................. 38 
7.1 
Restrictions during the study ............................................................................................. 38 
7.2 
Concomitant treatment(s) .................................................................................................. 39 
7.2.1 
Permitted concomitant medications .................................................................................. 39 
7.2.2 
Excluded Concomitant Medications ................................................................................. 40 
8. 
STUDY PROCEDURES .................................................................................................. 41 
8.1 
Schedule of study procedures ............................................................................................ 41 
8.1.1 
Screening Phase ................................................................................................................ 41 
8.1.2 
Treatment Phase ................................................................................................................ 42 
8.1.3 
End of Treatment ............................................................................................................... 42 
8.2 
Description of study procedures ........................................................................................ 42 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital 
signs................................................................................................................................... 42 
8.2.2 
Physical examination ........................................................................................................ 42 
8.2.3 
Electrocardiograms ........................................................................................................... 42 
8.2.4 
Vital signs.......................................................................................................................... 43 
8.2.5 
Clinical laboratory tests ..................................................................................................... 44 
8.3 
Biospecimen collections .................................................................................................... 45 
8.3.1 
Tumor biopsies and surgical specimen ............................................................................. 46 
8.3.2 
Peripheral blood and serum samples ................................................................................. 46 
9. 
DISEASE EVALUATION AND METHODS.................................................................. 46 
10. 
ASSESSMENT OF SAFETY ........................................................................................... 48 
10.1 
Safety Parameters .............................................................................................................. 48 
10.1.1 
Definition of adverse events .............................................................................................. 48 
10.1.2 
Definition of serious adverse events ................................................................................. 48 
10.1.3 
Durvalumab + tremelimumab adverse events of special interest ...................................... 50 

2016-0902 
 5 October, 2018 
15 
 
15 
 
10.1.4 
Immune-related adverse events ......................................................................................... 52 
10.2 
Assessment of safety parameters ....................................................................................... 53 
10.2.1 
Assessment of severity ...................................................................................................... 53 
10.3 
Recording of adverse events and serious adverse events .................................................. 54 
10.3.1 
Study recording period and follow-up for adverse events and serious adverse 
events................................................................................................................................. 55 
10.3.2 
Investigator Communications with AstraZeneca .............................................................. 56 
10.3.2.1 
Reporting of deaths ........................................................................................................... 56 
10.3.3 
Other events requiring reporting ....................................................................................... 57 
10.3.3.1 
Overdose ........................................................................................................................... 57 
10.3.3.2 
Hepatic function abnormality ............................................................................................ 57 
10.3.3.3 
Pregnancy .......................................................................................................................... 58 
10.3.3.4 
Maternal exposure ............................................................................................................. 58 
10.3.4 
Paternal exposure .............................................................................................................. 58 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ....................... 59 
11.1 
Description of analysis sets ............................................................................................... 59 
11.1.1 
Safety analysis set ............................................................................................................. 59 
11.1.2 
Efficacy analysis set .......................................................................................................... 59 
11.2 
Goals……………………………………………………………………………………...59 
11.3 
Endpoints........................................................................................................................... 59 
11.3.1 
Primary Endpoints ............................................................................................................. 59 
11.3.2 
Secondary Endpoint .......................................................................................................... 60 
11.3.3 
Exploratory Endpoint ........................................................................................................ 60 
11.4 
Sample Size Considerations .............................................................................................. 60 
11.5 
Interim Analysis: Safety Monitoring ................................................................................. 60 
11.6 
Analysis Plan. .................................................................................................................... 61 
12. 
LIST OF REFERENCES .................................................................................................. 62 
 
LIST OF TABLES 
Table 1. Stopping criteria for excessive toxicities based on ETOX  ................................................... 27 
Table 2. Operating characteristics of toxicity monitoring  .................................................................. 27 
Table 3. Effective methods of contraception (2 methods must be used)  ............................................ 39 
Table 4. Prohibited and Rescue Medications  ..................................................................................... 40 
Table 5. Hematology Laboratory Tests  .............................................................................................. 44 
Table 6. Clinical chemistry (Serum or Plasma) Laboratory Tests  ..................................................... 45 
Table 7. Urinalysis Tests ..................................................................................................................... 45 

2016-0902 
 5 October, 2018 
16 
 
16 
 
 
LIST OF FIGURES 
Figure 1. Study Schema  ..................................................................................................................... 26 
 
LIST OF APPENDICES 
Appendix 1. Dose modification and toxicity management guidelines for immune-mediated, 
infusion-related, and non immuned-mediated reactions for the 
combination of durvalumab and tremelimumab ................................................. 66 
Appendix 2. Durvalumab DOSE CALCULATIONS ......................................................................... 87 
Appendix 3. Durvalumab DOSE VOLUME CALCULATIONS  ...................................................... 88 
Appendix 4. Tremelimumab DOSE CALCULATIONS  ................................................................... 89 
Appendix 5. Tremelimumab DOSE VOLUME CALCULATIONS .................................................  90 
 

2016-0902 
 5 October, 2018 
17 
 
17 
 
ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation 
or 
special term 
Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 

2016-0902 
 5 October, 2018 
18 
 
18 
 
Abbreviation 
or 
special term 
Explanation 
HR 
 
Hormone receptor 
 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 

2016-0902 
 5 October, 2018 
19 
 
19 
 
Abbreviation 
or 
special term 
Explanation 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SoC 
Standard of Care 
T3 
Triiodothyronine 
T4 
Thyroxine 
TIL 
Tumor infiltrating lymphocytes 
TNBC 
Triple negative breast cancer 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
 

2016-0902 
 5 October, 2018 
20 
 
20 
 
1. 
INTRODUCTION 
1.1 
Immunotherapy and Breast Cancer 
Historically breast cancer has been considered a nonimmunogenic tumor.  More recent data demonstrates 
that there are tumor infiltrating lymphocytes (TIL) in breast tumors and that the extent of infiltrate varies 
with breast cancer subtype.  In a study from Loi et al. across subtypes, the median percentage of 
infiltration of stromal lymphocytes was 10%; interquartile range 7.5% to 20% (Loi et al 2013).  The 
percentage was  lowest in HR+/HER2- tumors and highest in triple negative (TNBC).  Based in part on 
this observation, the majority of studies conducted to date evaluating immunotherapy, specifically drugs 
targeting the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, 
have focused on TNBC.   
In the KEYNOTE-012 trial, a multicenter, nonrandomized phase Ib trial of single-agent pembrolizumab 
(anti-PD-1), investigators reported that in 32 metastatic TNBC patients whose tumors expressed PD-L1, 
the drug was well tolerated with the majority of patients experiencing low grade toxicities to include 
arthralgia, fatigue, myalgia and nausea.  Among the 27 patients evaluable for antitumor activity, the 
overall response rate (defined as the percentage of patients with a best overall response of complete 
response [CR] or partial response [PR]) was 18.5% with the median duration of response not reached; 
and with 3 responders remaining on study and receiving treatment for > 1 year (Nanda et al 2016).  At 
the 2016 ASCO meeting, investigators reported on a phase Ib study evaluating the anti-PD-L1 antibody 
atezolizumab in combination with nab-paclitaxel in patients with metastatic TNBC.  The combination 
was well tolerated and in 24 patients evaluable for efficacy, the overall response rate (defined as CR, PR 
or stable disease [SD]) was 42% (Adams et al 2016).  
Other studies have evaluated single agent therapy targeting PD-1/PD-L1 in HR+/HER2- disease.  At the 
2015 San Antonio Breast Cancer Symposium, data from the Javelin trial, a phase IB study of avelumab 
(anti-PD-L1) was presented.  The trial enrolled patients with locally advanced or metastatic breast cancer 
unselected for ER/PR and HER2.  Among the 72 patients with HR+/HER2- disease, the response rate 
was only 2.8% (Dirix et al 2015).  At that same meeting, results of the KEYNOTE-028 study evaluating 
pembrolizumab in patients with HR+ tumors was presented.  In that study, there were 25 patients with 
HR+ MBC with an overall response rate of 12% (Rugo et al 2015).   
It is possible that the low response rate to anti-PD-1 or anti-PD-L1 in HR+/HER2- breast cancer is due 
to the low rate of TIL in these tumors which could be described as nonimmunogenic (“cold”).  In order 
to enhance response to anti-PD-1/anti-PD-L1 therapy, it is likely that an immune response will need to 
be stimulated thereby converting these “cold” tumors to immunogenic, “hot” lesions (Sharma and 
Allison 2015).  One strategy to enhance the immune infiltrate is to treat with the anti-CTLA-4 antibody 
tremelimumab.  Unpublished data from our collaborator, Dr. James Allison has shown that, in prostate 
cancer, also an immunologically “cold” tumor, tremelimumab induces an intratumoral T cell  infiltrate.  
That T cell infiltrate is notable for increased PD-1 expression thereby justifying the combination with 
the anti-PD-L1 antibody durvalumab.   

2016-0902 
 5 October, 2018 
21 
 
21 
 
1.1.1 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004).  Studies in 
mouse models of transplantable tumors have demonstrated that manipulation of co-stimulatory or co-
inhibitory signals can amplify T-cell responses against tumors (Peggs et al 2009).  This amplification 
may be accomplished by blocking co-inhibitory molecules, such as cytotoxic T-lymphocyte-associated 
antigen 4 (CTLA-4) or programmed cell death 1 (PD-1), from binding with their ligands, B7 or B7-H1 
(programmed cell death ligand 1 [PD-L1]).   
1.1.2 
Durvalumab  
The non-clinical and clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure (IB Version 9.0).   
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass 
that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the 
treatment of 
cancer.  
(MedImmune 
is a wholly 
owned 
subsidiary 
of 
AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.)  As durvalumab 
is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity or complement-
dependent cytotoxicity.  The proposed mechanism of action for durvalumab is interference of the 
interaction of PD-L1. 
Durvalumab has been given to humans as part of ongoing studies as a single drug or in combination with 
other drugs As of the DCO dates (15Apr2015 to 18Sep2015), a total of 1,910 subjects have been 
enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored and 
10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 
received durvalumab in combination with tremelimumab or other anticancer agents, 14 received 
other agents (1 gefitinib, 13 MEDI6383), and 163 have been treated with blinded investigational 
product. No studies have been completed or terminated prematurely due to toxicity.  
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose-expansion 
phases of Study CD-ON-durvalumab-1108 following treatment with durvalumab 0.1 to 10 mg/kg every 
2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum observed concentration (Cmax) 
increased in an approximately dose-proportional manner over the dose range of 0.1 to 15 mg/kg. The 
area under the concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than 
dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 
3 mg/kg. These results suggest durvalumab exhibits nonlinear PK likely due to saturable target-mediated 
CL at doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete target saturation 
(soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) is expected with durvalumab 
≥ 3 mg/kg Q2W. Exposures after multiple doses showed accumulation consistent with PK parameters 
estimated from the first dose. In addition, PK simulations indicate that following durvalumab 10 mg/kg 
Q2W dosing, > 90% of subjects are expected to maintain PK exposure ≥ 40 µg/mL throughout the 
dosing interval. 

2016-0902 
 5 October, 2018 
22 
 
22 
 
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 subjects (1 
subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) were ADA positive 
with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg cohort. 
Durvalumab is currently being evaluated in a number of breast cancer specific studies including: 1) an 
open label single arm trial evaluating durvalumab in combination with paclitaxel (NCT02628132), 2) an 
open label pilot study evaluating the safety, tolerability and efficacy of the combination of durvalumab 
with Vigil™ autologous tumor cell immunotherapy (NCT02725489), 3) a phase Ib pharmacodynamics 
study in patients with HER2+ metastatic breast cancer receiving trastuzumab (NCT02649686), 4) a 
single arm neoadjuvant phase I/II study of durvalumab in combination with weekly Nab-paclitaxel and 
dose-dense doxorubicin/cyclophosphamide for clinical stage I-III TNBC (NCT02489448), and 5) a 
randomized phase II study investigating the addition of durvalumab to a taxane-anthracycline containing 
chemotherapy regimen in TNBC (NCT02685059).   
1.1.3 
Tremelimumab 
The non-clinical and clinical experience is fully described in the current version of the tremelimumab 
Investigator’s Brochure (IB Version 7.0).   
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152)  This is an immunomodulatory 
therapy (IMT) that is being developed by AstraZeneca for use in the treatment of cancer.   
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, which 
limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to B7 ligands and 
enhance human T-cell activation as demonstrated by increased cytokine (interleukin [IL]-2 and 
interferon [IFN] gamma) production in vitro in whole blood or peripheral blood mononuclear cell 
(PBMC) cultures (Tarhini and Kirkwood 2008).  In addition, blockade of CTLA-4 binding to B7 by anti-
CTLA-4 antibodies results in markedly enhanced T-cell activation and anti-tumor activity in animal 
models, including killing of established murine solid tumors and induction of protective anti-tumor 
immunity.  (Refer to the tremelimumab IB, Edition 5.0, for more information.)  Therefore, it is expected 
that treatment with an anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation 
of the human immune system, increasing anti-tumor activity in patients with solid tumors.   
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab both as 
monotherapy and combination therapy with conventional anticancer agents to support various cancer 
indications using different dose schedules.  As of the data cut-off date of 12 November 2014 (for all 
studies except D4190C00006, which has a cut-off date of 4 December 2014), 973 patients have received 
tremelimumab monotherapy (not including 497 patients who have been treated in the blinded Phase 2b 
study, D4880C00003) and 208 patients have received tremelimumab in combination with other agents.  
Refer to the current tremelimumab IB for a complete summary of non-clinical and clinical information; 
see Section 6.6 for guidance on management of tremelimumab-related toxicities.   

2016-0902 
 5 October, 2018 
23 
 
23 
 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days.  Overall, 
a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.   
1.1.4 
Durvalumab in combination with tremelimumab 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012) 
because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, AstraZeneca is 
also investigating the use of durvalumab + tremelimumab combination therapy for the treatment of 
cancer. 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and preliminary 
anti-tumor activity of durvalumab + tremelimumab combination therapy in patients with advanced 
NSCLC.  The dosing schedule utilized is durvalumab every 2 weeks (q2w) or every 4 weeks (q4w) up 
to Week 50 and 48 (12 months), combined with tremelimumab q4w up to Week 24 for 7 doses then 
every 12 weeks for 2 additional doses for up to 12 months.  The study is ongoing and continues to accrue.   
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK (n = 26) data 
were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following durvalumab every 4 
weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W regimens. An approximately 
dose-proportional increase in PK exposure (Cmax and area under the concentration-time curve from 0 to 
28 days [AUC0-28]) of both durvalumab and tremelimumab was observed over the dose range of 3 to 15 
mg/kg durvalumab Q4W and 1 to 10 mg/kg tremelimumab Q4W. Exposures following multiple doses 
demonstrated accumulation consistent with PK parameters estimated from the first dose. It is to be noted 
that steady state PK parameters are based on limited numbers of subjects. The observed PK exposures 
of durvalumab and tremelimumab following combination were consistent with respective monotherapy 
data, indicating no PK interaction between these 2 agents. 
As of 20Feb2015, ADA data were available from 60 subjects for durvalumab and 53 subjects for 
tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for anti-durvalumab 
antibodies post treatment. One of 53 subjects was ADA positive for anti-tremelimumab antibodies post 
treatment. There was no clear relationship between ADA and the dose of either durvalumab or 
tremelimumab, and no obvious association between ADA and safety or efficacy. 
The combination of tremelimumab and durvalumab is currently being investigated in several trials 
enrolling patients with metastatic breast cancer including:  1) a phase I study evaluating the safety and 
tolerability of the combination in patients with advanced ovarian cancer, colorectal cancer, non-triple 
negative breast cancer, renal cell carcinoma or cervical cancer (NCT01975831), 2) a phase I trial of 
hypofractionated radiotherapy in combination with tremelimumab and durvalumab for patients with 
metastatic melanoma, non-small cell lung cancer, breast cancer or pancreatic adenocarcinoma 
(NCT02639026), and 3) a single arm phase II study evaluating the efficacy and safety of the combination 
in patients with metastatic HER2- breast cancer (NCT02536794). 
Durvalumab has also been combined with other anticancer agents, including gefitinib, dabrafenib, and 
trametinib. To date, no PK interaction has been observed between durvalumab and these agents.  

2016-0902 
 5 October, 2018 
24 
 
24 
 
A population PK model was developed for MEDI4736 using monotherapy data from a Phase 1 study 
(study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK 
analysis indicated only minor impact of body weight (WT) on PK of MEDI4736 (coefficient of ≤ 0.5). 
The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of MEDI4736 was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 95th percentiles) using 
the population PK model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on 
median body WT of ~75 kg). A total of 1000 patients were simulated using body WT distribution of 40–
120 kg. Simulation results demonstrate that body WT-based and fixed dosing regimens yield similar 
median steady state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen.   
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 through 
Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) (Wang et al 2009). 
Population PK model indicated minor impact of body WT on PK of tremelimumab (coefficient of ≤ 0.5). 
The WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on median body WT of ~75 
kg) regimens were compared using predicted PK concentrations (5th, median and 95th percentiles) using 
population PK model in a simulated population of 1000 patients with body weight distribution of 40 to 
120 kg. Similar to MEDI4736, simulations indicated that both body WT-based and fixed dosing 
regimens of tremelimumab yield similar median steady state PK concentrations with slightly less 
between-subject variability with fixed dosing regimen.  
 
Similar findings have been reported by others (Ng et al 2006; Wang et al 2009; Zhang S et al 2012; 
Narwal R et al 2013). Wang and colleagues investigated 12 monoclonal antibodies and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang et al 2009). In addition, they investigated 18 therapeutic proteins and peptides and showed that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-subject variability in 
pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012).  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible 
to switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W 
MEDI4736 (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) 
is included in the current study. Fixed dosing of durvalumab and tremelimumab is recommend only for 
subjects with > 30kg body weight due to endotoxin exposure.  Patients with a body weight less than or 
equal to 30 kg should be dosed using a weight-based dosing schedule.  
1.2 
Research hypotheses 
This study will address the following hypotheses:  
1. That it will be feasible to enroll patients with hormone receptor (HR)-positive, HER2-negative 
breast cancer onto a trial evaluating anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen-
4) therapy (tremelimumab)  plus anti-PD-L1 (programmed cell death ligand 1) therapy 
(durvalumab) prior to initiating standard neoadjuvant chemotherapy. 

2016-0902 
 5 October, 2018 
25 
 
25 
 
2. That the combination of tremelimumab plus durvalumab therapy will have an acceptable safety 
profile in HR+/HER2- breast cancer patients. 
3. That tremelimumab plus durvalumab therapy will lead to measurable immunologic changes, 
with identification of novel biomarkers that can be used for immune monitoring and clinical 
correlation in the setting of HR+/HER2- breast cancer. 
1.3 
Rationale for conducting this study 
At The University of Texas MD Anderson Cancer Center, we are initiating a trial platform to evaluate 
immunotherapeutic and targeted agents to turn nonimmunogenic (“cold”) hormone receptor positive, 
HER2 negative breast cancers into immunogenic (“hot”) lesions (Sharma and Allison 2015).  The trials 
will each enroll 15 patients with newly-diagnosed hormone receptor positive, HER2 negative breast 
cancer that are planned for neoadjuvant chemotherapy. The investigational agent or combination of 
agents will be administered prior to initiation of chemotherapy.  All patients will undergo pre- and post-
treatment biopsies which will be analyzed for immunologic responses to the investigational agents.  
These immune studies will be performed by the immunotherapy platform under the direction of Drs. Jim 
Allison and Padmanee Sharma.  The strength of this trial platform is that each study will require only 15 
patients and because of the robust immunologic analysis performed on pre- and post-treatment 
specimens, promising agents that can be moved forward into more definitive clinical trials will be 
identified quickly. 
 
This trial platform is similar to that employed by our collaborator Dr. Sharma.  A previous study 
performed at MD Anderson by Dr. Sharma evaluated the use of an anti-CTLA-4 antibody (ipilimumab) 
as pre-surgical therapy in patients with localized urothelial carcinoma of the bladder (Carthon et al 2010).  
Immunological analyses of pre- and post-treatment tumor tissues indicate that ipilimumab therapy 
resulted in significant activation of immune cells and infiltration of immune cells into tumor tissues 
(Chen et al 2009; Liakou et al 2008).  The rationale for combining durvalumab and tremelimumab is 
that the mechanisms of CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways 
may have additive or synergistic activity (Pardoll 2012).  This has been demonstrated in preclinical 
models (Curran et al 2011; Duraiswamy et al 2013) as well as in clinical trials where combining 
immunotherapy agents has been shown to result in improved response rates (RRs) relative to 
monotherapy.  For example, the concurrent administration of nivolumab and ipilimumab to patients with 
advanced melanoma induced higher objective response rates (ORRs) than those obtained with single-
agent therapy.  Importantly, responses appeared to be deep and durable (Wolchok et al 2013).  Similar 
results have been observed in an ongoing study of durvalumab + tremelimumab in NSCLC (Antonia et 
al 2014), with further updated details presented in this clinical study protocol. 
 
This study will allow us to evaluate the feasibility of enrolling patients with HR+/HER2- breast cancer 
onto a trial evaluating investigational immunotherapeutic agents prior to initiating standard neoadjuvant 
chemotherapy, and to evaluate the safety and tolerability of the combination of tremelimumab plus 
durvalumab in patients with HR+/HER2- breast cancer.  Importantly, we will also be able to assess the 
immunologic/molecular responses to the combination of tremelimumab plus durvalumab in patients with 

2016-0902 
 5 October, 2018 
26 
 
26 
 
HR+/HER2- breast cancer as well as to evaluate the pathologic response in HR+/HER2- breast cancer 
patients receiving the combination prior to initiation of standard neoadjuvant chemotherapy.  The study 
will therefore allow us to test the clinical activities of these immune checkpoint therapies against 
HR+/HER2- breast cancer as well to identify biomarkers to guide potential use of these agents in the 
setting of HR+/HER2- breast cancer.  The study will therefore inform the design of subsequent studies 
evaluating these agents in both the neoadjuvant setting for patients with disease as well as in the setting 
of metastatic HR+/HER2- breast cancer. 
2. 
STUDY OBJECTIVE 
2.1.1 
Primary objective(s) 
• 
To evaluate the feasibility of enrolling patients with HR+/HER2- breast cancer onto a trial evaluating 
investigational agents prior to initiating standard neoadjuvant chemotherapy. 
• 
To evaluate the safety and tolerability of tremelimumab plus durvalumab in patients with 
HR+/HER2- breast cancer. 
2.1.2 
Secondary objective 
To assess immunologic/molecular responses to tremelimumab and durvalumab in patients with 
HR+/HER2- breast cancer who receive the combination therapy. 
2.1.3 
Exploratory objective 
To evaluate the pathologic response in patients with HR+/HER2- breast cancer receiving tremelimumab 
plus durvalumab prior to initiating standard neoadjuvant chemotherapy. 
3. 
STUDY DESIGN 
3.1 
Overview of study design 
This is an open-label, single-arm, presurgical pilot study in patients with HR+/HER2- breast cancer. 
 
There will be 15 patients enrolled. 
 
Patients will receive durvalumab at 1500 mg plus tremelimumab at 75 mg every 4 weeks for a total of 2 
doses.  A standard regimen of neoadjuvant chemotherapy will be initiated within 4 weeks after the last 
infusion of durvalumab and tremelimumab.  A biopsy will be obtained after the last infusion of 
durvalumab and tremelimumab before neoadjuvant chemotherapy is started. 
 
Patients will undergo surgery after the completion of standard neoadjuvant chemotherapy. 
 
 

2016-0902 
 5 October, 2018 
27 
 
27 
 
3.2 
Study schema 
Figure 1.  Study Schema 
 
 
Notes: 
A.  Eligible patients include those with HR+/HER2- breast cancer, clinical stage II-III, planned for 
neoadjuvant chemotherapy. 
B. The first day of dosing is considered Day 1.  Tremelimumab will be administered first.  The 
duration of tremelimumab infusion will be 1 hour.  Durvalumab infusion will start 
approximately 1 hour after the end of the tremelimumab infusion.  The duration of durvalumab 
infusion will be 1 hour. 
C. Neoadjuvant systemic therapy will begin within 28 days of the last infusion of tremelimumab 
and durvalumab. 
D. Surgery will be performed within 8 weeks of completing neoadjuvant systemic therapy.   
3.3 
Study Oversight for Safety Evaluation 
The study would be stopped if an unacceptable number of patients experience an extreme toxicity 
(ETOX).  For trial monitoring, a patient will be determined to have an ETOX if either condition is met: 
• 
The patient experiences any grade 3 or higher adverse event (AE) that is possibly, probably, or 
definitely related to therapy (durvalumab + tremelimumab) received on this protocol and occurs 
up to 90 days after the last dose of therapy.  As an exception, any such AE that is potentially 
treatable with steroids will only count as an ETOX if it does not improve to grade 1 or better 
within 2 weeks. 
 

2016-0902 
5 October 2018 
28 
  
28 
 
• 
The patient has a delay in initiation of neoadjuvant systemic therapy of 6 weeks or more due to 
AE, even if that AE does not meet the definition of ETOX. 
Based on the method of Thall (Thall et al 1995), we will monitor ETOX continually after the 5th patient 
receives treatment.  We assume ƟT ~ beta (0.20, 0.8) for the current study, where ƟT is the probability 
of a patient experiencing an ETOX.  Our stopping rule is given by the following probability statement: 
PT(ƟT>0.20 | data) > 0.90.  That is, we will stop the trial if, at any time during the study, we determine 
that there is more than an 90% chance that the ETOX rate is more than 20%. 
The stopping boundaries for this toxicity rule are to terminate the trial if the number of patients with 
ETOX compared to the number of patients on trial exceed the limits in table 1, with operating 
characteristics for this rule in table 2.  After 5 patients, this table will be consulted prior to enrolling each 
patient.  Enrollment will not require waiting for complete information for the previous patient, unless an 
ETOX in that patient would result in hitting the stopping rule. 
 
Table 1.  Stopping Criteria for Excessive Toxicities Based on ETOX 
If there are this many patients with ETOX 
3 
4 
5 
6 or 
more 
Stop if this many patients (or fewer) have been evaluated at least once 
for toxicity 
6 
10 
13 
15* 
* The trial will stop at 15 patients, but if 6 or more patients experience ETOX, this regimen will be too 
toxic for further study in this population. 
 
Table 2.  Operating Characteristics for Toxicity Monitoring 
 
True ETOX rate 
Probability of 
Stopping Early 
 
Median 
(25th %ile, 75th %ile) 
Average 
Number 
of 
Patients 
Average 
Number 
Patients with 
ETOX 
0.05 
0.003 
15 (15, 15) 
15.0 
0.75 
0.10 
0.02 
15 (15, 15) 
14.8 
1.5 
0.20 
0.17 
15 (15, 15) 
13.7 
2.7 
0.30 
0.45 
15 (6, 15) 
11.6 
3.5 
0.40 
0.72 
8 (5, 15) 
9.3 
3.7 
 

2016-0902 
5 October 2018 
29 
  
29 
 
4. 
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion criteria 
(Section 4.2) for this study.   
4.1 
Inclusion criteria 
For inclusion in the study, patients should fulfill the following criteria: 
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: 
• 
Single-probe average HER2 copy number ≥6.0 signals/cell. 
• 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 copy 
number ≥4.0 signals/cell 
• 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 
• 
copy number <4.0 signals/cell 
• 
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: 
− 
Haemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 

2016-0902 
5 October 2018 
30 
  
30 
 
− 
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, 
Principle Principal Investigators (PI) or co-PI approval. 
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN 
− 
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: 
Males: 
 
 
Creatinine 
CL 
(mL/min) 
= 
Weight 
(kg) 
x 
(140 
– 
Age)  
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine 
CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        x 
0.85 
72 x serum creatinine (mg/dL) 
 
7. 
Female subjects must either be of non-reproductive potential (ie, 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 
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 up 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
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: 

2016-0902 
5 October 2018 
31 
  
31 
 
• 
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 eg, 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. If an ECG is interpreted to be a prolonged 
QT interval, 2 additional ECGs will be obtained and the PI will then evaluate all 3 ECGs to 
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, ulcerative colitis) 
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 

2016-0902 
5 October 2018 
32 
  
32 
 
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 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of study treatment with durvalumab and tremelimumab  
An individual subject will not receive any further investigational product if any of the following occur 
in the subject in question: 
1. 
Withdrawal of consent or lost to follow-up 
2. 
Adverse event that, in the opinion of the investigator or AstraZeneca/MedImmune, 
contraindicates further dosing 
3. 
Subject is determined to have met one or more of the exclusion criteria for study participation 
at study entry and continuing investigational therapy might constitute a safety risk 
4. 
Pregnancy or intent to become pregnant 
5. 
Any AE that meets criteria for discontinuation as defined in Section 10.3 
6. 
Grade ≥ 3 infusion reaction 
7. 
Subject noncompliance that, in the opinion of the investigator or AstraZeneca/MedImmune, 
warrants withdrawal; eg, refusal to adhere to scheduled visits 
8. 
Initiation of alternative anticancer therapy including another investigational agent 
9. 
Confirmation of PD and investigator determination that the subject is no longer benefiting 
from treatment with durvalumab + tremelimumab 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.  
 
Subjects who are permanently discontinued from receiving investigational product will be 

2016-0902 
5 October 2018 
33 
  
33 
 
followed for safety, including the collection of any protocol-specified blood specimens, unless consent 
is withdrawn or the subject is lost to follow-up or enrolled in another clinical study.   
 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or further study 
observation.  
4.4 
Replacement of subjects 
Should a patient withdraw or not be able to complete therapy with durvalumab and tremelimumab and 
study biopsy, additional subjects can be enrolled at the discretion of Dr. Litton and/or Dr. Mittendorf to 
complete the 15 patient accrual with scheduled biopsies. 
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab and tremelimumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab and 
tremelimumab to the investigator as a solution for infusion after dilution.   
5.1.1 
Formulation/packaging/storage 
Durvalumab 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after dilution. The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 
10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Durvalumab must be used within the individually assigned expiry date on the label. 
Tremelimumab 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after dilution. 
The solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine hydrochloride, 222 mM 
trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM disodium edetate dihydrate (EDTA); it 
has a pH of 5.5. The nominal fill volume is 20 mL. Investigational product vials are stored at 2°C to 8°C 
(36°F to 46°F) and must not be frozen. Tremelimumab must be used within the individually assigned 
expiry date on the label. 
5.2 
Dose and treatment regimens 
5.2.1 
Treatment regimens 
Durvalumab + tremelimumab combination therapy 

2016-0902 
5 October 2018 
34 
  
34 
 
Patients will receive 1500 mg durvalumab via IV infusion q4w ± 3 days for 2 doses/cycles and 75 mg 
tremelimumab via IV infusion q4w ± 3 days for 2 doses/cycles.  Dosing outside the window should be 
discussed with Dr. Litton and/or Dr. Mittendorf.  Tremelimumab will be administered first.  Durvalumab 
infusion will start approximately 1 hour after the end of tremelimumab infusion.  The duration will be 
approximately 1 hour for each infusion.  A 1-hour observation period is required after the first infusion 
of durvalumab and tremelimumab.  If no clinically significant infusion reactions are observed during or 
after the first cycle, subsequent infusion observation periods will be 30 minutes +/- 5 minutes unless 
otherwise specified by the investigator.   
5.2.2 
Duration of treatment  
Patients will receive 1500 mg durvalumab via IV infusion q4w +/- 3 days for 2 doses/cycles and 75 mg 
tremelimumab via IV infusion q4w +/- 3 days for up to 2 doses/cycles. A standard regimen of 
neoadjuvant chemotherapy will be initiated within 28 days after the last infusion of durvalumab and 
tremelimumab.  A biopsy will be obtained after the last infusion of durvalumab and tremelimumab 
before chemotherapy is started. 
 
5.2.3 
Study drug preparation of durvalumab and tremelimumab 
Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg 
Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study.  
 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared using aseptic technique.  Total time from 
needle puncture of the durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500mg durvalumab for patients ≥30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline, with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  Remove 30.0 mL of IV 
solution from the IV bag prior to addition of durvalumab.  Next, 30.0 mL of durvalumab (ie, 1500 mg 
of durvalumab) is added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV bag 
volumes 100 to 1000 mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the 
bag. 

2016-0902 
5 October 2018 
35 
  
35 
 
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% change in 
weight.  Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard.   
For patients <30kg, Calculate the dose volume of durvalumab and tremelimumab and number of vials 
needed for the subject to achieve the accurate dose. 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via 
an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 
minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline  equal to the priming volume 
of the infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line was not 
flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.  The table below summarizes time allowances and 
temperatures. 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in the table, a 
new dose must be prepared from new vials.  Durvalumab does not contain preservatives, and any unused 
portion must be discarded. 
Preparation of tremelimumab doses for administration with an IV bag 
The dose of tremelimumab for administration must be prepared using aseptic technique.  Total time from 
needle puncture of the tremelimumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) until 
needed. If storage time exceeds these limits, a new dose must be prepared from new vials. The 

2016-0902 
5 October 2018 
36 
  
36 
 
refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room temperature 
for about 2 hours prior to administration. Tremelimumab does not contain preservatives and any unused 
portion must be discarded. 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have been 
observed. Doses of 75 mg tremelimumab for patients ≥30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging from 0.1 mg/mL to 10 
mg/mL, and delivered through an IV administration set with a 0.2 μm or 0.22 μm in-line filter. Remove 
3.8 mL of IV solution from the IV bag prior to addition of tremelimumab.  Next, 3.8 mL of 
tremelimumab (ie, 75 mg of tremelimumab) is added to the IV bag such that final concentration is within 
0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 mL).  Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
Patient weight at baseline should be used for dosing calculations unless there is a  ≥10% change in 
weight.  Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard.   
For patients <30 kg, Calculate the dose volume for tremelimumab and number of vials needed for subject 
to achieve the accurate dose. 
Tremelimumab will be administered at room temperature (approximately 25°C ) by controlled infusion 
via an infusion pump into a peripheral or central vein. Following preparation of tremelimumab,  the 
entire contents of the IV bag should be administered as an IV infusion over approximately 60 minutes 
(±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of 0.9% (w/v) saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line was not 
flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.  The table below summarizes time allowances and 
temperatures. 
Tremelimuab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 

2016-0902 
5 October 2018 
37 
  
37 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in the table, a 
new dose must be prepared from new vials.  Tremelimumab does not contain preservatives, and any 
unused portion must be discarded. 
5.2.4 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs as per Schedule 
of Study Assessments.  
A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab.  
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased by 
50% or interrupted until resolution of the event and re-initiated at 50% of the initial rate until completion 
of the infusion.  For patients with a ≤Grade 2 infusion-related reaction, subsequent infusions may be 
administered at 50% of the initial rate.  Acetaminophen and/or an antihistamine (eg, diphenhydramine) 
or equivalent medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is ≥Grade 3 or higher in severity, study drug will be 
discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis.  The study site must have immediate access 
to emergency resuscitation teams and equipment in addition to the ability to admit patients to an intensive 
care unit if necessary. 
5.2.5 
Accountability and dispensation 
Drug accountability and dispensation will occur through the Department of Pharmacy Investigational 
Drugs and all standard operating procedures of the University of Texas MD Anderson Cancer Center. 
5.2.6 
Disposition of unused investigational study drug 
The site will account for all investigational study drug dispensed and also for appropriate destruction.  
Certificates of delivery and destruction must be maintained as part of Institutional current standard 
operating procedures. 
6. 
TREATMENT PLAN 
6.1 
Subject enrollment  
Patients who have signed informed consent and have undergone screening will be enrolled onto this 
study and can begin therapy.  There is no randomization.  This is a single arm, open-label presurgical 
pilot study prior to the initiation of standard neoadjuvant chemotherapy of the physician’s choice for 
patients with clinical stage II-III HR+/HER2- breast cancer.  Patients who are unable to complete all 

2016-0902 
5 October 2018 
38 
  
38 
 
scheduled study requirements including the pre and post treatment breast biopsies can be replaced at the 
request of Dr. Litton and/or Dr. Mittendorf and/or the study team. 
6.1.1 
Procedures for handling subjects incorrectly enrolled 
Subjects who are incorrectly enrolled, but not yet initiated on treatment will be withdrawn from the study 
and replaced. 
6.2 
Dosage and Administration 
Patients will receive 1500 mg durvalumab via IV infusion q4w +/- 3 days for 2 doses/cycles and 75 mg 
tremelimumab via IV infusion q4w +/- 3 days for 2 doses/cycles. Dosing outside the window should be 
discussed with Dr. Litton and/or Dr. Mittendorf.  Tremelimumab will be administered first.  Durvalumab 
infusion will start approximately 1 hour after the end of tremelimumab infusion.  The duration will be 
approximately 1 hour for each infusion.  A 1-hour observation period is required after the first infusion 
of durvalumab and tremelimumab.  If no clinically significant infusion reactions are observed during or 
after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion 
(suggested 30 minutes after each durvalumab and tremelimumab infusion).   
6.3 
Dose Modification and Toxicity Management 
6.3.1 
Durvalumab and tremelimumab 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab the 
following dose adjustment guidance may be applied: 
• 
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab or tremelimumab along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for durvalumab and 
tremelimumab (see Appendix 1). 
• 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of durvalumab or 
tremelimumab can be modified based on toxicities observed (see Appendix 1).   
Based on the mechanism of action of durvalumab or tremelimumab leading to T-cell activation and 
proliferation, there is the possibility of observing immune related Adverse Events (irAEs) during the 
conduct of this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the absence of an 

2016-0902 
5 October 2018 
39 
  
39 
 
alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, hepatitis, and 
endocrinopathy should be considered to be immune-related.   
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Appendix 1.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed in 
appendix 1. All toxicities will be graded according to NCI CTCAE v4.03.  
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the specific times 
before and after: 
− 
Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception (Table 3) from the time of 
screening and must agree to continue using such precautions for 180 days after the last dose of 
durvalumab + tremelimumab combination therapy. Non-sterilized male partners of a female 
patient must use male condom plus spermicide throughout this period. Cessation of birth control 
after this point should be discussed with a responsible physician.  Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control.  Female patients should also refrain from breastfeeding 
throughout this period. 
N.B Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.   
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 

2016-0902 
5 October 2018 
40 
  
40 
 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical 
sterilization 
(bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 3.  Note that 
some contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-
copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 
where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills). 
Table 3 
Highly Effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine 
system (eg, Mirena®)a 
 
• 
Etonogestrel implants: e.g. Implanon or 
Norplan 
• 
Intravaginal device: e.g. ethinylestradiol 
and etonogestrel 
• 
Medroxyprogesterone 
injection: 
e.g. 
Depo-Provera  
• 
Normal and low dose combined oral 
contraceptive pill 
• 
Norelgestromin/ethinylestradiol  
transdermal system 
• 
Cerazette (desogestrel) 
a 
This is also considered a hormonal method 
 
7.2 
Concomitant treatment(s) 
The Principal Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit).  Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the electronic 
medical record.   
Restricted, prohibited, and permitted concomitant medications are described in the following tables.   
7.2.1 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for 
those medications identified as “excluded” as listed in Section 7.2.2. 

2016-0902 
5 October 2018 
41 
  
41 
 
7.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), immunotherapy, 
biologic or hormonal therapy for cancer treatment. 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at doses 
not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α 
blockers. Use of immunosuppressive medications for the management of investigational 
product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of 
inhaled and intranasal corticosteroids is permitted. A temporary period of steroids will be 
allowed for different indications, at the discretion of the principal investigator (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, etc). 
4. Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (ie, 30 days 
prior to the first dose, during treatment with durvalumab and tremelimumab for 30 days post 
discontinuation of durvalumab and tremelimumab.  Inactivated vaccines, such as the injectable 
influenza vaccine, are permitted. 
Table 4. Prohibited and Rescue Medications 
Prohibited medication/class of drug: 
Usage: 
Additional investigational anticancer therapy 
concurrent with those under investigation in this 
study 
Should not be given whilst the patient is on IP 
treatment   
mAbs against CTLA-4, PD-1, or PD-L1 
Should not be given whilst the patient is on IP 
treatment  through 90 days after the last dose of IP. 
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, 
eg, 
radiotherapy, 
surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment 
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Concurrent use of 
hormones 
for 
non-cancer-related 
conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.) 
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or its 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers   
Should not be given whilst the patient is on IP 
treatment 
(including 
SoC). 
 
(Use 
of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 

2016-0902 
5 October 2018 
42 
  
42 
 
Prohibited medication/class of drug: 
Usage: 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP (including SoC) during the study 
 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, 
except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
8. 
STUDY PROCEDURES 
8.1 
Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed measurements 
is to ensure adequate safety and tolerability assessments.  Clinical evaluations and laboratory studies 
may be repeated more frequently if clinically indicated.   
8.1.1 
Screening Phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified.  All 
subjects must first read, understand, and sign the IRB -approved ICF before any study-specific screening 
procedures are performed.  After signing the ICF, completing all screening procedures, and being 
deemed eligible for entry, subjects will be enrolled in the study.  Procedures that are performed prior to 
the signing of the ICF and are considered standard of care may be used as screening assessments if they 
fall within the 28-day screening window. Refer to the Study Calendar for complete list of all the 
procedures that will be performed during the Screening Visit. 

2016-0902 
5 October 2018 
43 
  
43 
 
8.1.2 
Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the Schedule of 
Assessments.  Screening procedures performed within 7 days of Cycle 1 Day 1 (C1D1) do not need to 
be repeated on C1D1. 
8.1.3 
End of Treatment 
End of treatment is defined as the last planned dose of tremelimumab and durvalumab.  This will be 
followed by physician’s choice of systemic therapy, followed by standard of care surgical intervention.  
Any further adjuvant therapy is at the discretion of the treating physician.  Also, should the treating 
physician deem it is in the patient’s best interest to proceed with surgery after the completion of the 2 
doses each of tremelimumab and durvalumab, the physician may proceed with surgery with adjuvant 
therapies as per physician discretion.  
All subjects will be followed until the time of breast surgery. 
8.2 
Description of study procedures 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital signs 
Findings from medical history (obtained at screening) and physical examination shall be given a baseline 
grade according to the procedure for AEs. Increases in severity of pre-existing conditions during the 
study will be considered AEs, with resolution occurring when the grade returns to the pre-study grade 
or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
8.2.2 
Physical examination 
Physical examinations will be performed according to the assessment schedule.  Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the respiratory, 
cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, hematologic/lymphatic, 
and endocrine systems.  Height will be measured at Screening only.  Targeted physical examinations are 
to be utilized by the Investigator on the basis of clinical observations and symptomatology.  Situations 
in which physical examination results should be reported as AEs are described in Section 10.   
8.2.3 
Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study.  
ECGs should be obtained after the patient has been in a supine position for 5 minutes and recorded while 
the patient remains in that position. 
At Screening, a single ECG will be obtained on which QTcF must be <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 3 
ECGs to determine whether the patient should be excluded. 

2016-0902 
5 October 2018 
44 
  
44 
 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-
lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the finding.   
Situations in which ECG results should be reported as AEs are described in Section 10.0.   
8.2.4 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to 
the assessment schedules.   
On infusion days, patients will be monitored during and after infusion of durvalumab + tremelimumab 
as presented in the bulleted list below.   
BP will be measured using a semi-automatic BP recording device with an appropriate cuff size, after the 
patient has rested for at least 5 minutes.  BP and pulse will be collected from patients receiving 
durvalumab + tremelimumab treatment before, during, and after each infusion at the following times 
(based on a 60-minute infusion):   
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 0 
minutes [ie, the beginning of the infusion]).   
Halfway through the infusion (approximately 30 minutes ± 10 minutes).   
At the end of the infusion (approximately 60 minutes ± 10 minutes), 30 minutes, and 60 minutes after 
the infusion (i.e. 90 and 120 minutes from the start of the infusion) (±10 minutes) – for the first infusion 
only and then for subsequent infusions as clinically indicated.   
A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. If no 
clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab 
and tremelimumab infusion).   
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated.  The date and time of 
collection and measurement will be recorded on the appropriate electronic medical record.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard clinical 
practice or as clinically indicated.   
Situations in which vital signs results should be reported as AEs are described in Section 10.3.  A 
complete physical examination will be performed and will include an assessment of the following (as 
clinically indicated): general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and 
extremities), genital/rectal, and neurological systems and at screening only, height.   

2016-0902 
5 October 2018 
45 
  
45 
 
8.2.5 
Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments): 
• 
Coagulation parameters: Activated partial thromboplastin time and International normalized ratio to 
be assessed at baseline and as clinically indicated  
• 
Pregnancy test (female subjects of childbearing potential only) 
o Urine human chorionic gonadotropin 
• 
Thyroid Stimulating Hormone 
o free T3 and free T4 only if TSH is abnormal 
• 
Other laboratory tests 
o Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
o HIV antibody for patients with known history 
 
Table 5. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean 
corpuscular 
haemoglobin 
concentration 
 
 
 
 

2016-0902 
5 October 2018 
46 
  
46 
 
 
Table 6. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb 
Uric acid 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect  bilirubin 
b At Screening, Day 1, and as clinically indicated. 
 
Table 7. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field 
for red blood cells 
8.3 
Biospecimen collections 
Blood and tissue specimens will be collected as specified in the Schedule of Study Assessments.  
Specimens will be de-identified and labelled with a unique study identification number for use in 
immune monitoring assays.  Assays will be performed in research laboratories at the University of Texas 
MD Anderson Cancer Center to include the Immunotherapy Platform.  

2016-0902 
5 October 2018 
47 
  
47 
 
 
8.3.1 
Tumor biopsies and surgical specimen 
All patients will have biopsies performed before starting treatment with tremelimumab + 
durvalumab and post-treatment with tremelimumab + durvalumab (before starting neoadjuvant 
chemotherapy).  These biopsies will be obtained by core needle using a needle gauge of 14 or 
larger, with up to five cores obtained at each time point.  Surgical resection specimens will be 
obtained with the amount of tissue provided determined by the attending breast pathologist 
performing the gross sectioning at the time of surgical resection. 
All samples will be collected and analyzed as per a separate IRB-approved lab protocol (PA13-
0291). The Immunotherapy Platform will perform immune monitoring, including but not 
limited to evaluation of CD4 and CD8 T cells in available tumor samples as previously 
published (Liakou et al 2008; Carthon et al 2010; Tang et al 2013; Chen et al 2014; Eng et al 
2015; Chen et al 2016; Subudhi et al 2016; Gao et al 2016). 
8.3.2 
Peripheral blood and serum samples 
Multiple blood draws will be required for this trial (pre-treatment, post-treatment, at time of 
surgery).   All blood collections will be compliant with the institutional safety standards and 
will not exceed the maximum blood draw per venipuncture policy.  All samples will be collected 
and analyzed as per a separate IRB-approved lab protocol (PA13-0291). The Immunotherapy 
Platform will perform immune monitoring, including but not limited to evaluation of CD4 and 
CD8 T cells in available blood samples as previously published (Liakou et al 2008; Carthon et 
al 2010; Tang et al 2013; Chen et al 2014; Eng et al 2015; Chen et al 2016; Subudhi et al 2016; 
Gao et al 2016).  
9. 
DISEASE EVALUATION AND METHODS 
As this is a pre-surgical pilot study, evaluations will be done primarily by mammogram and 
breast ultrasound at baseline and then by ultrasound at the completion of the 2 cycles of 
investigational therapy. 
At the time of surgery the residual tissue will be described by Residual Cancer Burden (RCB) 
(Symmans et al 2007). The RCB is a continuous variable derived from the primary tumor 
dimensions, cellularity of the tumor bed, and axillary nodal burden. RCB can be divided into 
four classes (RCB-0 to RCB-III) and will be collected as part of the study. 
RCB-0 (pCR), Minimal RCB (RCB-I), Moderate RCB (RCB-II), and Extensive RCB (RCB-
III) 
The following parameters are required from pathologic examination in order to calculate 

2016-0902 
5 October 2018 
48 
  
48 
 
Residual Cancer Burden (RCB) after neoadjuvant treatment: 
 
1. 
The largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor 
bed if multicentric disease) 
2. 
Submission of the entire largest cross-sectional area of the residual tumor bed for 
histologic mapping, with specific identification of those slides in the pathology report 
(e.g. "the largest cross-sectional area of primary tumor bed was submitted in cassettes 
A5 - A9") 
• 
If the residual tumor is large (i.e. largest diameter > 5 cm), then at least 5 
representative cassettes from the largest cross-sectional area are sufficient, but 
should be identified in the original pathology report (e.g. "representative sections 
from the largest cross- sectional area of primary tumor bed were submitted in 
cassettes A5 - A9") 
3. 
Histologic assessment of the percentage of the tumor bed area that contains carcinoma 
(all carcinoma, i.e. invasive and in situ), select one of the following: 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 
 
• 
To assess cellularity it is helpful to scan across the sections of tumor bed and 
then estimate the average cellularity from the different microscopic fields. 
• 
When estimating percentage cancer cellularity in any microscopic field, compare 
the involved area with obvious standards, e.g. more or less than half, one quarter, 
one fifth, one tenth, one twentieth, etc. 
• 
Expect there to be variable cellularity within the cross section of any tumor bed, 
but estimate the overall cellularity from the average of the estimates in different 
microscopic fields of the tumor bed. 
• 
e.g. if cellularity in different fields of the tumor bed were estimated as 20%, 10%, 
20%, 0%, 20%, 30%, then an average estimate of overall cellularity would be 
20%. 
 
4. 
Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, 
select one of the following: 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 
5. 
The number of positive (metastatic) lymph nodes 
6. 
The largest diameter (mm) of the largest nodal metastasis 
The RCB can be accessed online: www.mdanderson.org/breastcancer_RCB.  The RCB will be 
determined using this online calculator and documented by the study staff in the patient’s 
electronic medical record as part of the off study note. 

2016-0902 
5 October 2018 
49 
  
49 
 
10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar with 
the content of this section. 
10.1 
  
Safety Parameters 
10.1.1 
Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6 
(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change beyond the 
range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or other 
untoward medical event that begins after written informed consent has been obtained but before the 
subject has received investigational product. Only AEs related to study drug (durvalumab + 
tremelimumab) will be followed.  Non-treatment-emergent AEs will not be followed.  In addition, AEs 
attributable to the preplanned neoadjuvant chemotherapy or surgery will not be collected. 
The term AE is used to include both serious and non-serious AEs. 
10.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, treatment, 
wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability or incapacity  
Is a congenital abnormality or birth defect in offspring of the subject 

2016-0902 
5 October 2018 
50 
  
50 
 
Is an important medical event that may jeopardize the patient or may require medical intervention to 
prevent one of the outcomes listed above:  
• 
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or 
drug abuse (21 CFR 312.32). 
Important medical events, as defined above, also may be considered SAEs. Any important medical event 
can and will  be reported as an SAE if deemed appropriate by the Principal Investigator or The University 
of Texas MD Anderson Cancer Center’s IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlines in the “The University 
of Texas MD Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Serious Unanticipated Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 
5 working days of knowledge or the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office. 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to 
the IND Office and The University of Texas MD Anderson Cancer Center IRB. 
SAEs will be captured from the time of the first protocol-specific intervention, until 90 days after the 
last dose of study drug (durvalumab + tremelimumab), unless the participant withdraws consent. 
SAEs must be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
Additionally, any serious adverse events that occur after the 90 day time period that are related to the 
study treatment must be reported to the IND Office. This may include development of a secondary 
malignancy. 
Reporting to FDA: 
SAEs will be forwarded to the FDA by the IND Sponsor (Safety Project Manager IND Office) according 
to 21 CFR 312.32. 
The Principal Investigator and research team will ensure SAEs are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 

2016-0902 
5 October 2018 
51 
  
51 
 
10.1.3 
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to AstraZeneca. Durvalumab + 
tremelimumab adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid communication 
by the investigator to AstraZeneca/MedImmune. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These AESIs 
are being closely monitored in clinical studies with durvalumab monotherapy and combination therapy. 
An immune-related adverse event (irAE) is defined as an adverse event that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is no clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used 
to support an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the Investigator 
should promptly contact Dr. Litton and/or Dr. Mittendorf. 
AESIs observed with durvalumab and tremelimumab include: 
• 
Colitis 
• 
Pneumonitis 
• 
ALT/AST increases / hepatitis / hepatotoxicity  
• 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• 
Dermatitis 
• 
Nephritis 
• 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase)   
• Infusion related / Hypersensitivity / Anaphylactic reactions  
• Other immune-mediated events that are rare could be reported (e.g. uveitis) 
 

2016-0902 
5 October 2018 
52 
  
52 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the 
durvalumab and tremelimumab Investigator Brochure. For durvalumab and tremelimumab, AESIs will 
comprise the following:    
Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with use of 
anti-PD-1 mAbs (but not with anti-PD-L1 mAbs).  Initial work-up should include a high-resolution CT 
scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is highly recommended. 
Guidelines for the management of patients with immune-related AEs (irAEs) including pneumonitis are 
provided in Appendix 1.   
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to AstraZeneca 
and are defined, for the purpose of this protocol, as all AEs occurring from the start of IP infusion up to 
48 hours after the infusion start time.  For all infusion reactions,  SAEs should be reported to AstraZeneca 
Patient safety as described in Section 10.3.   
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L1 and 
anti-PD-1 therapy (Brahmer et al 2012).  As with the administration of any foreign protein and/or other 
biologic agents, reactions following the infusion of mAbs can be caused by various mechanisms, 
including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAbs and serum 
sickness.  Acute allergic reactions may occur, may be severe, and may result in death.  Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting, and unresponsiveness.  Guidelines for the management of patients with 
hypersensitivity (including anaphylactic reaction) and infusion-related reactions are provided in 
Appendix 1.    
Hepatic function abnormalities (hepatotoxicity) 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in total bilirubin to be greater than 2 × ULN.  Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other.  Follow-
up investigations and inquiries will be initiated promptly by the investigational site to determine whether 
the findings are reproducible and/or whether there is objective evidence that clearly supports causation 
by a disease (eg, cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other 
than the IP.  Guidelines for management of patients with hepatic function abnormality are provided in 
Appendix 1.   
Lab abnormalities meeting the Potential Hy’s Law criteria (increase in serum ALT or AST ≥ 3 x ULN 
together with total bilirubin ≥ 2 x ULN, irrespective of serum alkaline phosphatase, at any point during 
the study following the start of the immunotherapy agent) or Hy’s Low (increase in serum ALT or AST 

2016-0902 
5 October 2018 
53 
  
53 
 
≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, where no other reason can be found to explain the 
combination of increases, for example, elevated serum alkaline phosphatase indicating cholestasis, viral 
hepatitis, or another suspect drug) will be handled as per Astra-Zeneca standard operating procedures 
(Appendix 1). 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is used 
as monotherapy.  In rare cases, colon perforation may occur that requires surgery (colectomy) or can 
lead to a fatal outcome if not properly managed.  Guidelines on management of diarrhea and colitis in 
patients receiving tremelimumab are provided in Appendix 1. 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine events 
are provided in Appendix 1. 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase elevation.  
Guidelines for the management of patients with immune-mediated pancreatic disorders are provided in 
Appendix 1. 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients with 
immune-mediated neurotoxic events are provided in Appendix 1. 
Nephritis 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. routine urinalysis,  elevated serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, proteinuria, etc.).  
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, 
infections etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low grade events 
(Grade 2), in order to prevent potential progression to higher grade event.   Guidelines for the 
management of patients with immune-mediated neurotoxic events are provided in Appendix 1. 
10.1.4 
Immune-related adverse events 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation and 
proliferation, there is a possibility of observing irAEs during the conduct of this study.  Potential irAEs 
may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-1 mAb), and BMS-
936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, dermatitis, hepatitis 

2016-0902 
5 October 2018 
54 
  
54 
 
(hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al 2010, Brahmer et al 2012, Topalian et 
al 2012).  These AEs are inflammatory in nature and can affect any organ.  With anti-PD-L1 and anti-
CTLA-4 combination therapy, the occurrence of overlapping or increasing cumulative toxicities that 
include irAEs could potentially occur at higher frequencies than with either durvalumab or 
tremelimumab monotherapy.  Patients should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (eg, infection or PD), an immune-related etiology should be considered 
for signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In 
addition to the dose modification guidelines provided in Table 1, it is recommended that irAEs are 
managed according to the general treatment guidelines outlined for ipilimumab (Weber et al 2012).  
These guidelines recommend the following: 
• 
Patients should be evaluated to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory 
nature should be considered immune related. 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
Systemic corticosteroids should be considered for a persistent low-grade 
event or for a severe event. 
• 
More potent immunosuppressives should be considered for events not 
responding to systemic steroids (eg, infliximab or mycophenolate). 
10.2 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should immediately contact Dr. Litton and/or Dr. Mittendorf.    Assessment of 
safety parameters 
10.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below. 
Grade 1 (mild)  
 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
 
Grade 2 (moderate)  
An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm 
to the subject. 

2016-0902 
5 October 2018 
55 
  
 
55 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
 
Grade 4 (life threatening)  
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of daily 
living (eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
 
Death (loss of life) as a result of an event. 
 
It is important to distinguish between serious criteria and severity of an AE. A Grade 3 AE need not 
necessarily be considered an SAE. For example, a Grade 3 headache that persists for several hours may 
not meet the regulatory definition of an SAE and would be considered a nonserious event, whereas a 
Grade 2 seizure resulting in a hospital admission would be considered an SAE. 
10.3 
Recording of adverse events and serious adverse events 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately reflects 
the event. Adverse events will be assessed by the investigator for severity, relationship to the 
investigational product, possible etiologies, and whether the event meets criteria of an SAE and therefore 
requires immediate notification to AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected and recorded in RedCap for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against durvalumab or tremelimumab (yes or no)  
• 
Action taken with regard to durvalumab + tremelimumab/comparator/combination agent 
• 
Outcome 
 
In addition, the following variables will be collected and recorded in RedCap for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to <<criteria>> 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 

2016-0902 
5 October 2018 
56 
  
 
56 
 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE during the 
study. 
10.3.1 
Study recording period and follow-up for adverse events and serious adverse events 
Adverse events and serious adverse events will be recorded from time of first protocol intervention, 
throughout the treatment period and including the follow-up period (90 +/-7 days after the last dose 
of durvalumab + tremelimumab). 
During the course of the study all AEs and SAEs should be proactively followed up for each subject. 
Every effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the patient 
is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, even 
if this extends beyond study participation. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit (90 days post End of Treatment) in the study are 
followed up by the investigator for as long as medically indicated, but without further recording.  After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be followed 
for safety. 
AstraZeneca/MedImmune and the IND Office retain the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study subjects after 
the 90-day safety follow-up period for patients treated with durvalumab + tremelimumab.  However, if 
an investigator learns of any SAEs, including death, at any time after the subject has been permanently 
withdrawn from study, and he/she considers there is a reasonable possibility that the event is related to 
study treatment, the investigator should notify the study The University of Texas MD Anderson Cancer 
Center and AstraZeneca/MedImmune Drug Safety. 

2016-0902 
5 October 2018 
57 
  
 
57 
 
10.3.2 
Investigator Communications with AstraZeneca 
All SAE reports and accompanying cover pages will be sent, by way of email, to AstraZeneca’s 
designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com. 
* A cover page should accompany the MD Anderson IRB SAE form indicating the following: 
• 
“Notification from an Investigator Initiated Study” 
• 
The MD Anderson IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-##-#####) 
* The University of Texas MD Anderson Cancer Center must also indicate, either in the SAE report or 
the cover page, the causality of events in relation to all study medications and if the SAE is related to 
disease progression, as determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca. 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly.  
10.3.2.1 
Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab + tremelimumab safety follow-up period must be reported as follows: 
• 
Death that is clearly the result of disease progression should be documented 
but should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to as a SAE within 
24 hours (see Section 10.3.2 for further details).  The report should contain 
a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   

2016-0902 
5 October 2018 
58 
  
 
58 
 
Deaths that occur following the protocol-defined 90-day post-last-dose of MEDI4736 and/or 
Tremelimumab safety follow-up period will be documented, but will not be reported as an SAE. If the 
death is possibly related to durvalumab and/or tremelimumab, it will be reported as an SAE. 
10.3.3 
Other events requiring reporting 
10.3.3.1 
Overdose 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab + tremelimumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to The University of 
Texas MD Anderson Cancer Center and AstraZeneca/MedImmune Patient Safety or designee using the 
designated Safety e-mailbox (see Section 10.3.2 for contact information). If the overdose results in an 
AE, the AE must also be recorded as an AE (see Section 10.3). Overdose does not automatically make 
an AE serious, but if the consequences of the overdose are serious, for example death or hospitalization, 
the event is serious and must be recorded and reported as an SAE (see Section 10.3 and Section 10.3.2). 
There is currently no specific treatment in the event of an overdose of durvalumab or tremelimumab.  
The investigator will use clinical judgment to treat any overdose. 
10.3.3.2 
Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.) in a study subject, with or without associated 
clinical manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to The University of Texas MD Anderson Cancer Center and 
AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox (see Section 10.3.2 for 
contact information), unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or 
bile duct obstruction) that is unrelated to investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated 
by the The University of Texas MD Anderson Cancer Center and AstraZeneca/MedImmune.  

2016-0902 
5 October 2018 
59 
  
 
59 
 
10.3.3.3 
Pregnancy 
10.3.3.4 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may have 
interfered with the effectiveness of a contraceptive medication.  Congenital abnormalities or birth defects 
and spontaneous miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up 
and documented even if the patient was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel should 
inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but no later than 24 
hours of when he or she becomes aware of it.   
The designated AstraZeneca representative will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 calendar days for 
SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   
10.3.4 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 180 days 
after the last dose of durvalumab + tremelimumab combination therapy, whichever is the longer time 
period.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose should, 
if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner.  Therefore, the local study team should 
adopt the generic ICF template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   

2016-0902 
5 October 2018 
60 
  
 
60 
 
11. 
STATISTICAL 
METHODS 
AND 
SAMPLE 
SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
11.1.1 
Safety analysis set 
All patients who receive at least one dose of study drug will be included in the safety monitoring 
and safety analysis. 
11.1.2 
 Efficacy analysis set 
All enrolled patients will be included in the primary feasibility analysis.  Only patients with 
surgical specimens and immune measures will be included in secondary and exploratory 
analyses requiring that information. 
11.2 
 Goals 
Since this combination has not been previously evaluated in the presurgical setting in hormone 
receptor positive, HER2 negative breast cancer, this trial will: 1) assess the feasibility of 
enrolling patients onto a trial evaluating investigational agents prior to initiating standard 
neoadjuvant chemotherapy, 2) determine the safety of durvalumab and tremelimumab in 
patients with hormone receptor positive, HER2 negative breast cancer, as well as 3) gather 
preliminary immunologic information for designing future trials.   
11.3 
Endpoints 
11.3.1 
Primary Endpoints 
The primary endpoints will be 
: 
1. Feasibility.  This will be measured by 2 achievements.  If both are met, then upfront 
treatment with durvalumab plus tremelimumab will be feasible for future trials in these 
breast cancer patients. Otherwise, other strategies for implementing these treatments will 
need to be designed.  The 2 measures are: 
 
a. Patients are willing to enroll: This will be established if we can enroll all 15 
patients within 12 months of starting the study.  The start date for measuring 
feasibility will be the date the first patient is screened.  
b. Patients can complete the protocol: If at least 10 patients complete the study and 
have available immune data the trial meets this feasibility criterion.  If fewer than 
8 finish then this dose/schedule is infeasible. If 8 or 9 complete the study with 
immune data then clinical judgment combining toxicity, efficacy, and physician 

2016-0902 
5 October 2018 
61 
  
 
61 
 
experience with the protocol will be used to determine whether adjustments to 
the treatment are needed before a future trial. 
 
2. Adverse events will be recorded according to CTCAE 4.03.  
 
11.3.2 
Secondary Endpoint 
Immune and molecular measures in peripheral blood and tumor tissues pre and post treatment. 
 
11.3.3 
Exploratory Endpoint 
Pathologic response at surgery will be recorded for each patient. 
11.4 
Sample Size Considerations 
The selection of 15 patients for this pilot trial is to provide preliminary information for 
feasibility and safety, as well as to have at least 10 patients with full immune measures pre and 
post treatment for hypothesis generation and testing in the next trial.  An accrual rate of 2 
patients per month is anticipated.  A maximum sample size of 15 patients will be enrolled.  No 
hypotheses will be formally tested, but with 15 patients we can determine whether an 
unreasonable proportion of patients have high grade toxicities and gather estimates of immune 
and molecular changes in tumor and peripheral blood.  These measures will be used to design a 
larger, hypothesis-driven trial. 
11.5 
Interim Analysis: Safety Monitoring 
Any patient who received the first dose of study medication will be included in the ongoing 
safety monitoring.  For trial monitoring and decisions about future trials, a patient will be 
determined to have an extreme toxicity (ETOX) if either condition is met: 
• 
The patient experiences any grade 3 or higher adverse event (AE) that is possibly, 
probably, or definitely related to therapy received on this protocol and occurs up to 
90 days after the last dose of therapy (durvalumab + tremelimumab).  As an 
exception, any such AE that is potentially treatable with steroids will only count as 
an ETOX if it does not improve to grade 1 or better within 2 weeks. 
• 
The patient has a delay in surgery of 6 weeks or more due to AE, even if that AE does 
not meet the definition of ETOX. 
 
Based on the method of Thall (1995)9, we will monitor ETOX continually after the 5th patient 
receives treatment.  Continuous monitoring will occur monthly. We assume ƟT ~ beta (0.20, 
0.8) for the current study, where ƟT is the probability of a patient experiencing an ETOX.  Our 
stopping rule is given by the following probability statement: PT(ƟT>0.20 | data) > 0.90.  That 
is, we will stop the trial if, at any time during the study, we determine that there is more than an 
90% chance that the ETOX rate is more than 20%. 
 
The stopping boundaries for this toxicity rule are to terminate the trial if the number of patients 
with ETOX compared to the number of patients on trial exceed the limits in table 1, with 

2016-0902 
5 October 2018 
62 
  
 
62 
 
operating characteristics for this rule in table 2.  After 5 patients, this table will be consulted 
prior to enrolling each patient.  Enrollment will not require waiting for complete information 
for the previous patient, unless an ETOX in that patient would result in hitting the stopping rule. 
Boundaries and operating characteristics were calculated in Multc Lean v2.1. 
 
Table 1.  Stopping Criteria for Excessive Toxicities Based on ETOX 
If there are this many patients with ETOX 
3 
4 
5 
6 or 
more 
Stop if this many patients (or fewer) have been evaluated at 
least once for toxicity 
6 
10 
13 
15* 
* The trial will stop at 15 patients, but if 6 or more patients experience ETOX, this regimen will 
be too toxic for further study in this population. 
 
Table 2.  Operating Characteristics for Toxicity Monitoring 
 
True 
ETOX 
rate 
Probability of 
Stopping Early 
 
Median 
(25th %ile, 75th %ile) 
Average 
Number 
of 
Patients 
Average 
Number 
Patients with 
ETOX 
0.05 
0.003 
15 (15, 15) 
15.0 
0.75 
0.10 
0.02 
15 (15, 15) 
14.8 
1.5 
0.20 
0.17 
15 (15, 15) 
13.7 
2.7 
0.30 
0.45 
15 (6, 15) 
11.6 
3.5 
0.40 
0.72 
8 (5, 15) 
9.3 
3.7 
 
The Investigator is responsible for completing the summary report and submitting it to the IND 
Office Medical Monitor for review and approval. A Feasibility/Safety summary will be 
submitted after the first 5 evaluable patients complete study treatment, and monthly thereafter. 
11.6 
Analysis Plan 
Feasibility will be assessed according to the endpoint definition provided above.  Additionally, 
the total number of patients screened to achieve 15 enrolled patients will be reported.  Since it 
is not known whether durvalumab plus tremelimumab can be safely used in the presurgical 
setting in patients with HR+, HER2- breast cancer, our other primary endpoint is safety.  
Adverse events will be tabulated by CTCAE grade and ETOX status.  A 95% credible interval 
will be presented for the ETOX rate among patients in the safety analysis set.  Surgery delay 
will be reported with the numbers of patients with any delay, as well as the median, IQR, min 

2016-0902 
5 October 2018 
63 
  
 
63 
 
and max for delay times.  If 6 or more patients experience ETOX, then this combination will be 
determined to be too toxic for these patients. 
 
For blood and tumor measures, descriptive statistics including plots, tabulations, mean, median 
and standard deviations will be used to summarize data.  Differences and/or percent changes 
will be calculated between pre- and post-therapy samples from each patient and described as 
continuous measures. 
12. 
LIST OF REFERENCES 
Adams et al 2016 
Adams S, Diamond JR, Hamilton EP, Pohlmann PR, Tolaney SM, Molinero L, et al.  Phase Ib trial of 
atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast 
cancer.  J Clin Oncol 2016;34 (suppl; abstr 1009) 
Antonia et al 2014 
Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1 open-
label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell death-ligand 1 
(PD-L1) antibody, in combination with tremelimumab in patients with advanced non-small cell lung 
cancer (NSCLC). Poster presented at European Society of Medical Oncology (ESMO) Meeting; 2014 
Sep 26-30; Madrid, Spain. 
Brahmer et al 2012 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-
PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65. 
Carthon et al 2010 
Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al.  Preoperative CTLA-4 blockade:  
tolerability and immune monitoring in the setting of a presurgical clinical trial.  Clin Cancer Res 
2010;16(10):2861-71. 
 
Chen et al 2009 
Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, et al. Anti-CTLA-4 therapy results in 
higher CD4+ICOSHi T cell frequency and IFN-gamma levels in both nonmalignant and malignant 
prostate tissues.  Proc Natl Acad Sci USA 2009;106(8):2729-4. 
 
Curran et al 2011 
Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP.  Combination CTLA-4 blockade and 
4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine 
production.  PLoS One 2011;6(4):e19499. 
 

2016-0902 
5 October 2018 
64 
  
 
64 
 
Chen et al 2014 
Chen H, Fu T, Suh WK, Tsavachidou D, Wen S, Gao J, et al.  CD4 T Cells Require ICOS-Mediated 
PI3K Signaling to Increase T-Bet Expression in the Setting of Anti-CTLA-4 Therapy. Cancer Immunol 
Res 2014;2(2):167-76.   
 
Chen et al 2016 
Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures 
in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance 
to immune checkpoint blockade.  Cancer Discov 2016:6(8):827-837. 
 
Dirix et al 2015 
Dirix LY, Takacs I, Nikolinakos P, et al.  Avelumab (MSB0010718C), an anti-PD-L1 antibody, in 
patients with locally advanced or metastatic breast cancer:  A phase Ib JAVELIN solid tumor trial.  San 
Antonio Breast Cancer Symposium 2015; abstract S1-04. 
 
Dunn et al 2004 
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60. 
Duraiswamy J et al 2013 
Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G.  Dual blockade of PD-1 and CTLA-4 combined 
with tumor vaccine effectively restores T-cell rejection function in tumors.  Cancer Res 
2013;73(12):3591-603. 
 
Eng C 2015 
Eng C. Circulating DNA biomarkers: a primer for metastatic colorectal cancer. Lancet Oncol 
2015;16(8):878-9.  
 
Gao J et al 2016 
Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, et al. Loss of IFN-γ Pathway Genes in Tumor Cells as 
a Mechanism of Resistance to Anti-CTLA-4 Therapy. Cell 2016;167(2):397-404. 
 
Hodi et al 2010 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, et al. Improved survival with 
ipilimumab in patients with metastatic melanoma [published erratum appears in N Engl J Med 
2010;363(13):1290]. N Engl J Med 2010;363(8):711-23. 
 
Liakou et al 2008 
Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al.  CTLA-4 blockade increases IFN-
gamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.  
Proc Natl Acad Sci USA 2008;105(39):87-92. 
 

2016-0902 
5 October 2018 
65 
  
 
65 
 
Loi et al 2013 
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al.  Prognostic and predictive value of 
tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive 
breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy:  
BIG 02-98. J Clin Oncol 2013;31(7):860-7.  
Narwal 2013 
Narwal R, Roskos LK, Robbie GJ.Population Pharmacokinetics of Sifalimumab, an Investigational 
Anti-Interferonalpha Monoclonal Antibody, in Systemic Lupus Erythematosus. Clin Pharmacokinet 
2013;52(11):1017-27. 
 
Ng 2006 
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D.  Rationale for fixed dosing of pertuzumab in cancer 
patients based on population pharmacokinetic analysis.  Pharm Res 2006;23(6):1275-1284. 
Pardoll 2012 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12(4):252-64. 
Peggs et al 2009 
Peggs KS, Quezada SA, Allison JP. Cancer immunotherapy: co-stimulatory agonists and coinhibitory 
antagonists. Clin Exp Immunol 2009;157:9-19. 
Rugo et al 2015 
Rugo HS, Delord JP, Im SA, et al.  Preliminary efficacy and safety of pembrolizumab (MK-3475) in 
patients with PD-L1 positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer 
enrolled in Keynote-028.  San Antonio Breast Cancer Symposium 2015; abstract S5-07. 
 
Sharma and Allison 2015 
Sharma P, Allison JP.  The future of immune checkpoint therapy.  Science 2015;348(6230):56-61. 
 
Subudhi et al 2016 
Subudhi SK, Aparicio A, Gao J, Zurita AJ, Araujo JC, Logothetis CJ, et al. Clonal expansion of CD8 T 
cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad 
Sci USA 2016;113(42):11919-1192 
 
Symmans et al 2007 
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual 
breast cancer burden to predict survival after neoadjuvant chemotherapy.  J Clin Oncol 
2007;25(28):4414-22. 
 
Tang et al 2013 

2016-0902 
5 October 2018 
66 
  
 
66 
 
Tang DN, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, et al. Increased Frequency of ICOS+ CD4 T 
Cells as a Pharmacodynamic Biomarker for Anti-CTLA-4 Therapy. Cancer Immunol Res 
2013;1(4):229-234.  
 
Thall et al 1995 
Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for single-arm clinical trials 
with multiple outcomes.  Stat Med 1995;14(4):357-379. 
 
Topalian et al 2012 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and 
immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443-54. 
Wang  et al 2014 
Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K.  Population pharmacokinetic and 
pharmacodynamics analysis of tremelimumab in patients with metastatic melanoma.  J Clin Pharmacol 
2014;54(10):1108-16. 
 
Wang et al 2012 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials.  J Clin Pharmacol 2009;49(9):1012-1024.Wolchok 
et al 2013 
 
Wolchok et al 2013 
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus 
ipilimumab in advanced melanoma. N Engl J Med 2013;369(2):122-33. 
Zhang et al 2012 
Zhang S, Shi R, Li C, Parivar K, Wang DD.  Fixed dosing versus body size-based dosing of therapeutic 
peptides and proteins in adults.  J Clin Pharmacol 2012;52(1):18-28. 
 
 
 
 
 
 

2016-0902 
5 October 2018 
67 
  
 
67 
 
 
 
Appendix 1.  Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and 
Non Immune-mediated Reactions (MEDI4736 Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab Monotherapy) 19 August 2016 Version 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
It is recommended that management of irAEs follows the guidelines presented in this 
table: 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression, concomitant medications, and infections). 
− 
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [eg, up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (eg, infliximab) 
(also refer to the individual sections of the irAE for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit/risk analysis for that patient. 

2016-0902 
5 October 2018 
68 
  
 
68 
 
Appendix 1.  Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and 
Non Immune-mediated Reactions (MEDI4736 Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab Monotherapy) 19 August 2016 Version 
Dose Modifications 
Toxicity Management 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: For Grade 3 and above asymptomatic amylase or lipase levels hold study 
drug/regimen and if complete work up shows no evidence of pancreatitis, may 
continue or resume study drug/regimen 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; irAE  Immune-related adverse event; IV  intravenous; 
NCI  National Cancer Institute; PO  By mouth. 

2016-0902 
5 October 2018 
69 
  
 
69 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ILD 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic work-
up for other etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider pulmonary and infectious disease consult. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 

2016-0902 
5 October 2018 
70 
  
 
70 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
or anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections (Category 2B 
recommendation)a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with Dr. Litton and/or Dr. 
Mittendorf. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[eg, tracheostomy or 
intubation]) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain pulmonary and infectious disease consult. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patients is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Enterocolitis 
Any Grade 
General Guidance 
For Any Grade: 

2016-0902 
5 October 2018 
71 
  
 
71 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(stool frequency of 
<4 over baseline per 
day) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(stool frequency of 4 to 
6 over baseline per 
day) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can 
be resumed after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 

2016-0902 
5 October 2018 
72 
  
 
72 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
workup, such as imaging and/or colonoscopy, to confirm 
colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab. 
− 
Consult Dr. Litton and/or Dr. Mittendorf if no resolution to 
Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 

2016-0902 
5 October 2018 
73 
  
 
73 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Hepatitis (elevated 
LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
AST or ALT > to 3 × 
ULN and/or TB > to 
1.5 × ULN) 
No dose modifications. 
• 
If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or ALT > 3 to 
5 × ULN and/or TB 
>1.5 to 3.0 × ULN) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (eg, every 1 to 2 
days) until elevations of these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, discuss with Dr. 
Litton and/or Dr. Mittendorf. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil)a Discuss with 
Dr. Litton and/or Dr. Mittendorf if mycophenolate mofetil is 
not available. Infliximab should NOT be used. 

2016-0902 
5 October 2018 
74 
  
 
74 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST or ALT 
>5 to 20 × ULN and/or 
TB >3.0 to 10 × ULN) 
 
(Grade 4: AST or ALT 
>20 × ULN and/or TB 
>10 × ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For elevations in transaminases 
>8 × ULN or elevations in bilirubin >5 × 
ULN, discontinue study drug/study 
regimen. 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with Dr. Litton and/or Dr. 
Mittendorf if mycophenolate is not available. Infliximab 
should NOT be used. 
− 
Perform hepatology consult, abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 

2016-0902 
5 October 2018 
75 
  
 
75 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
initial findings of cholestasis (ie, elevated 
alkaline P04) and in the absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or 
proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
Grade 1 
(Serum creatinine > 1 
to 1.5 × baseline; > 
ULN to 1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4. 

2016-0902 
5 October 2018 
76 
  
 
76 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 
to 6.0 × ULN; 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 

2016-0902 
5 October 2018 
77 
  
 
77 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 4: serum 
creatinine >6.0 × ULN) 
− 
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, DR. 
LITTON AND/OR DR. MITTENDORF SHOULD BE 
CONTACTED AND STUDY DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, discuss with Dr. 

2016-0902 
5 October 2018 
78 
  
 
78 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
regimen after completion of steroid 
taper. 
Litton and/or Dr. Mittendorf and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
General Guidance 
For Any Grade: 
− 
Consult endocrinologist. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension, and weakness. 

2016-0902 
5 October 2018 
79 
  
 
79 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
hypopituitarism, and 
adrenal insufficiency) 
v4.03 for defining the 
CTC grade/severity) 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, or infections). 
− 
Monitor and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy. 
− 
If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (eg, thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing. 
 
Grade  1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism, hold study drug/study 
regimen dose until patient is clinically 
stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Initiate hormone replacement as needed for management. 
− 
Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan. 
− 
For patients with abnormal endocrine work up, except for 
those with isolated hypothyroidism, consider short-term 
corticosteroids (eg, 1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 

2016-0902 
5 October 2018 
80 
  
 
80 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as 
per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
relevant hormone replacement (eg, levothyroxine, 
hydrocortisone, or sex hormones). - 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
For Grade 3 or 4: 
− 
Consult endocrinologist. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent 
− 
Administer hormone replacement therapy as necessary. 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Once the patient is improving, gradually taper 
immunosuppressive steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 

2016-0902 
5 October 2018 
81 
  
 
81 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes, or medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade 
≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade 
≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid taper. 
For Grade 2: 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (eg, IV IG). 

2016-0902 
5 October 2018 
82 
  
 
82 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (eg, IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations that 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
that may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability. 
− 
Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 

2016-0902 
5 October 2018 
83 
  
 
83 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
essential to have a low threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” 
if myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated by 
means of a neurology consultation. 
− 
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult unless the symptoms are very 
minor and stable. 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if it does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
For Grade 2: 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider that 
steroid therapy (especially with high doses) may 

2016-0902 
5 October 2018 
84 
  
 
84 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
result in transient worsening of myasthenia and 
should typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 irAE does 
not resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Discuss with Dr. Litton and/or Dr. Mittendorf. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 

2016-0902 
5 October 2018 
85 
  
 
85 
 
Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or IV 
IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-Barre 
is not typically considered effective. 
o 
Patients requiring treatment should be started with 
IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
a 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE  Acetylcholine esterase; ADL  Activities of daily living; AE  Adverse event; ALP  Alkaline phosphatase test; ALT  Alanine aminotransferase; AST  Aspartate 
aminotransferase; BUN  Blood urea nitrogen; CT  Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; 
irAE  Immune-related adverse event; IG  Immunoglobulin; IV  Intravenous; GI  Gastrointestinal; LFT  Liver function tests; LLN  Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; 
TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-stimulating hormone; ULN  Upper limit of normal. 

2016-0902 
5 October 2018 
86 
  
 
86 
 
Infusion-related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (eg, fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (eg, generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer Institute. 

2016-0902 
5 October 2018 
87 
  
 
87 
 
Non-immune-mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (ie, events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration.  Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the AstraZeneca/MedImmune.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Dr. Litton and/or Dr. 
Mittendorf.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 
 
 
 
 
 

2016-0902 
5 October 2018 
88 
  
 
88 
 
Appendix 2. Durvalumab DOSE CALCULATIONS  
For durvalumab dosing done depending on subject weight: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle are only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of 
vials from the following formula: 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials 
 

2016-0902 
5 October 2018 
89 
  
 
89 
 
Appendix 3. Durvalumab DOSE VOLUME CALCULATIONS 
For durvalumab flat dosing: 
1. Cohort dose: X g 
2. Dose to be added into infusion bag:  
Dose (mL) = X g × 1000 / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL).  
3. The theoretical number of vials required for dose preparation is the next greatest whole number of 
vials from the following formula: 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
Example:  
1. Cohort dose: 1.5 g 
2. Dose to be added into infusion bag:  
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30.0 mL 
3. The theoretical number of vials required for dose preparation:  
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials 
 
 
 
 
 
 

2016-0902 
5 October 2018 
90 
  
 
90 
 
Appendix 4. Tremelimumab DOSE CALCULATIONS  
For tremelimumab dosing done depending on subject weight: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 20 (mg/mL)  
where 20 mg/mL is tremelimumab nominal concentration. 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle are only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of 
vials from the following formula: 
Number of vials = Dose (mL) / 20.0 (mL/vial) 
Example:  
1. Cohort dose: 1 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 1.5 (mL) / 20.0 (mL/vial) = 1 vials 
 

2016-0902 
5 October 2018 
91 
  
 
91 
 
Appendix 5. Tremelimumab DOSE VOLUME CALCULATIONS  
For tremelimumab flat dosing: 
1. Cohort dose: X mg 
2. Dose to be added into infusion bag:  
Dose (mL) = X mg / 20 (mg/mL)  
where 20 mg/mL is tremelimumab nominal concentration  
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL).  
3. The theoretical number of vials required for dose preparation is the next greatest whole number of 
vials from the following formula: 
Number of vials = Dose (mL) / 20 (mL/vial) 
Example:  
1. Cohort dose: 75 mg 
2. Dose to be added into infusion bag:  
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL 
3. The theoretical number of vials required for dose preparation:  
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial