Clinical trial NCT03874325
Conditions: Breast Cancer Hormone Receptor Positive Tumor
Keywords: HR+
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2019-04-26; Completion date: 2021-01-06
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is to find out if an investigational drug called Durvalumab (MEDI4736) given together with a standard of care aromatase inhibitor drug can help people with breast cancer.

Detailed description:

Arms: arm 1: Participants will be administered 1500 mg Durvalumab intravenously every 4 weeks for 6 cycles. Participants will also take standard of care 1 mg anastrozole daily by mouth for 6 months. Letrozole 2.5 mg or exemastane 25 mg may be substituted for anastrozole if an intolerance to anastrozole is exhibited. Six participants will be enrolled in the safety run in stage. If 1 or fewer of six participants have a DLT, expansion stage will open to enrollment. arm 2: Participants will be administered 1500 mg Durvalumab intravenously every 4 weeks for 6 cycles. Participants will also take standard of care 1 mg anastrozole daily by mouth for 6 months. Letrozole 2.5 mg or exemastane 25 mg may be substituted for anastrozole if an intolerance to anastrozole is exhibited.
Interventions: intervention 1: Durvalumab intervention 2: Anastrozole 1mg intervention 3: Letrozole 2.5mg intervention 4: Exemestane 25 MG
Intervention descriptions: intervention 1: 1500 mg Durvalumab will be administered intravenously every 4 weeks for 6 months. intervention 2: Participants will self administer 1 mg anastrozole by mouth daily for 6 months. intervention 3: Participants intolerant to anastrozole will self administer 2.5 mg letrozole by mouth daily for 6 months. Exemestane may be substituted. intervention 4: Participants intolerant to anastrozole will self administer 25 mg exemestane by mouth daily for 6 months. Letrozole may be substituted.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
A PHASE II TRIAL WITH SAFETY RUN-IN OF NEOADJUVANT THERAPY WITH AN 
AROMATASE INHIBITOR IN COMBINATION WITH DURVALUMAB (MEDI4736) IN 
POSTMENOPAUSAL PATIENTS WITH HORMONE-RECEPTOR-POSITIVE BREAST 
CANCER 
 
NCT03874325 
 
Version 5.1 
January 30, 2019 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
1 
 
 
 
 
A PHASE II TRIAL WITH SAFETY RUN-IN OF NEOADJUVANT THERAPY WITH AN 
AROMATASE INHIBITOR IN COMBINATION WITH DURVALUMAB (MEDI4736) IN 
POSTMENOPAUSAL PATIENTS WITH  HORMONE-RECEPTOR-POSITIVE BREAST 
CANCER 
SHORT TITLE: AI AND DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST 
CANCER 
 
Protocol Identifying Number: MCC 19803 
 
Principal Investigator:  
Hung T. Khong, MD  
10920 McKinley Dr  
Tampa, FL 33612 
Phone: 813-745-3828 
Fax: 813-745-7287 
Hung.khong@moffitt.org 
 
Statistician:  
 
Brooke Fridley, PhD  
13131 Magnolia Dr  
Tampa, FL 33612 
Phone: (813)-745-1461  
Fax: (813)-745-6107  
Brooke.fridley@moffitt.org 
 
Funded by: AstraZeneca 
Version Number:  v5.1 January 30, 2019 
 
 
 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................. 4 
PROTOCOL SIGNATURE ................................................................................................ 9 
STUDY SUMMARY........................................................................................................ 10 
1 
OBJECTIVES ........................................................................................................... 12 
1.1 
Primary Objectives and Endpoints ..................................................................... 12 
1.2 
Secondary Objectives and Endpoints ................................................................. 12 
1.3 
Exploratory Objective and Endpoints ................................................................ 12 
2 
BACKGROUND ...................................................................................................... 13 
2.1 
Disease Background ........................................................................................... 13 
2.2 
Immunotherapies ................................................................................................ 14 
2.3 
Research hypothesis ........................................................................................... 17 
2.4 
Rationale for conducting this study .................................................................... 17 
2.5 
Rationale for dose selection ............................................................................... 17 
3 
DRUG INFORMATION .......................................................................................... 19 
3.1 
Potential risks ..................................................................................................... 19 
4 
STUDY DESIGN...................................................................................................... 24 
4.1 
Description ......................................................................................................... 24 
4.2 
Dose Limiting Toxicity ...................................................................................... 24 
4.3 
Number of Patients ............................................................................................. 26 
4.4 
Number of Study Centers ................................................................................... 26 
4.5 
Duration .............................................................................................................. 26 
4.6 
Withdrawal of Subjects from Study Treatment and/or Study ............................ 26 
4.7 
Replacement of subjects ..................................................................................... 27 
5 
ELIGIBILITY CRITERIA ........................................................................................ 27 
5.1 
Inclusion Criteria ................................................................................................ 28 
5.2 
Exclusion Criteria ............................................................................................... 29 
6 
TREATMENT PLAN ............................................................................................... 32 
6.1 
Administration Schedule .................................................................................... 32 
6.2 
How Supplied, Stored, Packaged and Labeled .................................................. 32 
6.3 
Preparation and Administration ......................................................................... 32 
6.4 
Monitoring of dose administration ..................................................................... 33 
6.5 
Accountability and Compliance ......................................................................... 34 
6.6 
Disposition of unused investigational study drug .............................................. 34 
6.7 
Concomitant Medications and Treatments ......................................................... 35 
6.8 
Duration of Therapy ........................................................................................... 35 
7 
TOXICITIES AND DOSEAGE MODIFICATION ................................................. 35 
7.1 
Dose Modifications ............................................................................................ 36 
7.2 
Supportive Care .................................................................................................. 37 
8 
STUDY CALENDAR .............................................................................................. 37 
8.1 
Drug administration calendar ............................................................................. 37 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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8.2 
Schedule of events .............................................................................................. 37 
9 
STUDY PROCEDURES .......................................................................................... 40 
9.1 
Screening phase .................................................................................................. 40 
9.2 
Treatment Phase ................................................................................................. 40 
9.3 
End of Treatment ................................................................................................ 41 
9.4 
Description of Study Procedures ........................................................................ 42 
10 CRITERIA FOR EVALUATION AND ENDPOINT .............................................. 44 
10.1 Safety .................................................................................................................. 44 
10.2 Efficacy .............................................................................................................. 44 
10.3 Stopping Rules ................................................................................................... 44 
11 STATISTICAL CONSIDERATIONS...................................................................... 45 
11.1 Description of analysis sets ................................................................................ 45 
11.2 Methods of statistical analyses ........................................................................... 45 
11.3 Determination of sample size ............................................................................. 46 
12 REGISTRATION GUIDELINES ............................................................................. 46 
13 DATA SUBMISSION SCHEDULE ........................................................................ 47 
14 SPECIAL INSTRUCTIONS .................................................................................... 47 
14.1 Tumor tissue for PD-L1 testing .......................................................................... 47 
14.2 Tumor tissue for other testing ............................................................................ 48 
14.3 Other correlative Studies .................................................................................... 48 
15 ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 49 
15.1 Informed consent ................................................................................................ 49 
15.2 Institutional Review ........................................................................................... 49 
15.3 Protocol Monitoring Committee ........................................................................ 59 
15.4 Adverse Events ................................................................................................... 49 
15.5 SAE Reporting Requirements ............................................................................ 56 
15.6 Other events requiring reporting ........................................................................ 57 
15.7 Protocol Amendments ........................................................................................ 58 
15.8 Protocol Deviations ............................................................................................ 58 
15.9 FDA Annual Reporting ...................................................................................... 58 
15.10 Clinical Trials Data Bank ................................................................................... 58 
16 BIBLIOGRAPHY ..................................................................................................... 61 
17 APPENDIX ............................................................................................................... 65 
 
 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
Definition/Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AI 
Aromatase inhibitor 
ALK 
Anaplastic lymphoma kinase 
Alkphos 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APF12 
Proportion of patients alive and progression free at 12 months from randomization 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma drug concentration-time curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BICR 
Blinded Independent Central Review 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BoR 
Best objective response 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C 
Cycle 
C1D1 
Cycle 1 Day 1 
Ca++ 
Calcium 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum plasma concentration 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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Abbreviation or 
Definition/Explanation 
Cmax,ss 
Maximum plasma concentration at steady state 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss  
Trough concentration at steady state 
CV 
Coefficient of variation 
CXCL 
Chemokine (C-X-C motif) ligand 
CYP 
Cytochrome P450 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of response 
D/C 
Discontinue 
EC 
Ethics Committee, synonymous to Institutional Review Board and Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
e.g. 
Exempli gratia (for example) 
EGFR 
Epidermal growth factor receptor 
ER 
Estrogen receptor 
FACS 
Fluorescence Activated Cell Sorting  
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma Glutamyl Transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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Abbreviation or 
Definition/Explanation 
HCO3
- 
Bicarbonate 
HCV 
Hepatitis C virus 
HER-2 
Human epidermal receptor-2 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IFNγ 
Interferon-gamma 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
INR 
International normalized ratio 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
mAb 
Monoclonal antibody 
mPEPI 
Modified preoperative endocrine prognostic index 
M 
Metastasis (in pathologic tumor-node-metastasis system) 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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Abbreviation or 
Definition/Explanation 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
N 
Node (in pathologic tumor-node-metastasis system) 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamics 
PEPI 
Preoperative endocrine prognostic index 
PFS 
Progression Free Survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response; Progesterone receptor 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q2W 
Every 2 weeks 
QnW 
Every n weeks where n represents a number 
QC 
Quality control 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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Abbreviation or 
Definition/Explanation 
SAS 
Safety analysis set 
SD 
Standard deviation or stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T 
Tumor (in pathologic tumor-node-metastasis system) 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of non-childbearing potential 
 
All of these abbreviations may or may not be used in protocol.  
 
 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
9 
 
PROTOCOL SIGNATURE 
 
I confirm that I have read this protocol, I understand it, and I will work, according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable laws and regulations of the federal 
government. I will promptly submit the protocol to the applicable IRB for review and approval. 
Once the protocol has been approved by the IRB, I understand that any modifications made during 
the course of the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject.  
 
Instructions to the Principal Investigator: SIGN and DATE this signature page and PRINT your name. 
Return the original, completed and signed, to the HCI Research Compliance Office. Retain a copy in the 
regulatory binder.  
 
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator 
 
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
 
____________________________________ 
Name of Institution 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
10 
 
STUDY SUMMARY 
 
Title 
A phase II trial with safety run-in of neoadjuvant therapy with an 
aromatase inhibitor in combination with durvalumab (MEDI4736) 
in postmenopausal patients with hormone-receptor-positive breast 
cancer. 
Short Title 
Neoadjuvant study in breast cancer with durvalumab and aromatase 
inhibitor 
Protocol Number MCC 19803 
IND 
Exempt 
Clinical Phase 
Phase II 
Design 
This is a multi-center, open label, phase II study which will assess 
the efficacy and safety of an aromatase inhibitor (anastrozole) in 
combination with durvalumab in patients with hormone-receptor-
positive breast cancer.  
Study Duration 
Enrollment period: 28 months  
Follow up: Up to 5 years. 
Study Center(s) 
1. Moffitt Cancer Center; 2. TBD 
Objectives 
Primary: 
To determine the efficacy of an aromatase inhibitor with 
durvalumab in achieving the modified Preoperative Endocrine 
Prognostic Index (mPEPI) Score of 0. 
Secondary: 
1. Safety and tolerability 
2. Objective clinical response rate (cRR: clinical CR and PR) at up 
to 24 weeks.  
3. Pathologic complete response rate (pCR) at up to 24 weeks 
(defined as complete absence of invasive cancer in breast and 
axillary lymph nodes). 
4. To determine recurrence free survival. 
Exploratory: 
1. To assess immune cell changes (phenotype and functionality) in 
tumor before, during, and after treatment.  
2. To assess cytokine patterns before, during, and after treatment. 
3. To assess biomarkers that may correlate with clinical outcome. 
Number of 
Subjects 
Up to 46 expected to enroll. Up to 46 expected to be treated. 42 
expected to complete treatment (including 6 from safety run-in 
phase). 
Main Eligibility 
Inclusion Criteria: 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
11 
 
Criteria 
 Female 18 years of age or older. 
 ECOG performance status 0 or 1. 
 Postmenopausal. 
 Invasive breast cancer; clinical T2-T4c, any N, M0, with goal of 
definitive surgery after completion of neoadjuvant therapy.  
 Palpable tumor which size can be measured bidimensionally by 
tape, ruler or caliper technique, with a largest diameter > 2.0 cm.  
 Invasive breast cancer is estrogen receptor positive at > 66% or 
with an Allred score of 6, 7 or 8.  
 Invasive breast cancer is Human Epidermal Growth Factor 
Receptor 2 (HER2) negative.  
 Patients must agree to provide tissue at baseline and at definitive 
surgery (from the procedure) and undergo a biopsy at baseline 
and after one cycle of treatment.  
 Adequate laboratory parameters. 
Exclusion Criteria: 
 Inflammatory breast cancer. 
 Excisional biopsy of breast cancer. 
 Hormone replacement therapy of any type within one week prior 
to registration. 
 Surgical axillary staging procedure prior to study entry. 
 Any treatment for this cancer prior to study entry 
 History of ipsilateral invasive breast cancer regardless of 
treatment or ipsilateral ductal carcinoma in situ treated with 
radiotherapy or endocrine therapy or contralateral invasive breast 
cancer at any time. 
 History of another primary malignancy except for malignancy 
treated with curative intent and with no known active disease ≥ 5 
years or adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease or adequately treated 
carcinoma in situ without evidence of disease e.g., cervical 
cancer in situ. 
 Prior use of PD-1, PD-L1 or CTLA-4 inhibitors 
 Active or prior documented autoimmune or inflammatory 
disorders within the past 5 years. 
 Current or prior use of immunosuppressive medication within 14 
days before the first dose of study drug. 
 Clinically significant cardiovascular disease. 
 Currently active systemic infection. 
 History of HIV infection or chronic hepatitis B or C. 
 History of previous clinical diagnosis of tuberculosis, 
uncontrolled seizures, organ transplant, primary 
immunodeficiency, interstitial lung disease (ILD)/pneumonitis. 
 Receipt of live attenuated vaccination within 30 days of first 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
12 
 
dose of study drug. 
 Weighing 30 kg or less. 
Study Product, 
Dose, Route, 
Regimen 
Durvalumab, 1500 mg (equivalent to 20 mg/kg) IV Q4W, on Day 1 
of each 28-day cycle x 6 cycles (6 months)  
Anastrozole 1 mg PO QD [in the post DLT period, as per standard 
of care, it is OK to switch to another AI (letrozole 2.5 mg or 
exemestane 25 mg PO daily) for intolerance such as hot flash or 
joint ache that is attributed to AI] . 
Duration of 
administration 
Six months prior to definitive surgery 
Statistical 
Methodology 
Safety Analysis: will include all subjects who received at least 1 
dose of AI or durvalumab.  
Efficacy Analysis: will include all subjects who received at least 
one dose of AI and one dose of durvalumab. 
1 
STUDY OBJECTIVES AND ENDPOINTS 
1.1 
Study Objectives 
1.1.1 Primary Objective 
 To evaluate the efficacy of an aromatase inhibitor with durvalumab 
1.1.2 Secondary Objectives 
 To evaluate safety and tolerability of the combination of an aromatase inhibitor and 
durvalumab 
 To evaluate objective clinical response rate 
 To evaluate pathologic complete response rate (pCR)  
 To evaluate recurrence free survival. 
1.1.3 Exploratory Objective and Endpoints 
 To assess immune cell changes (phenotype and/or functionality) in tumor before, 
during and after treatment. 
 To assess cytokine patterns before, during and after treatment. 
 To evaluate biomarkers that may correlate with clinical outcome. 
 
1.2 
Study Endpoints 
1.2.1 Primary Endpoints 
 Rate of modified Preoperative Endocrine Prognostic Index (mPEPI) Score of 0. 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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1.2.2 Secondary Endpoints 
 Type, incidence, severity, attribution and timing of adverse events. 
 Objective clinical response rate (cRR = clinical CR + PR) at up to 24 weeks. 
 Pathologic complete response rate (pCR) at time of definitive surgery (defined as 
complete absence of invasive cancer in breast and axillary lymph nodes). 
 Recurrence free survival defined as the time between first treatment and disease 
recurrence. 
 
1.2.3 Exploratory Objective and Endpoints 
 Change in immune cells’ phenotype and/or functionality before, during and after 
treatment. 
 Cytokine patterns before, during and after treatment. 
 Biomarkers that may correlate with clinical outcome. 
 
2 
BACKGROUND 
2.1 
Disease Background 
2.1.1 Hormone-Receptor-Positive Breast Cancer 
In the U.S., 255,180 new cases of invasive breast cancer and 41,070 deaths due to breast cancer were 
expected in 2017 (1).  70% - 80% of breast cancer are hormone-receptor (ER) positive disease (2).  
Even though ER-positive breast cancer is considered to have a better prognosis than triple-negative 
or human epidermal growth factor receptor 2-(HER2) positive disease, late cancer recurrence is a 
major concern. 
Data from the International Breast Cancer Study Groups I-V involving 4,105 patients treated from 
1978 to 1985 showed that the recurrence rate was higher for ER-negative breast cancer during the 
first five years, but higher in ER-positive breast cancer from year 5 to 25. The cumulative incidence 
of recurrence for all sites (local, contralateral, regional, and distant) at year 5, 10, 15, 20, and 25 was 
39.4%, 53.2%, 59%, 63.4%, and 64.9%, respectively for ER-positive breast cancer versus 44.3%, 
52.5%, 55.3%, 57.7%, and 59.9%, respectively for ER-negative breast cancer.  
Similarly, the cumulative distant recurrence rate was higher for ER-negative breast cancer compared 
with ER-positive breast (27.1% versus 23.4%) for the first five year. However, ER-positive breast 
cancer had a higher cumulative distant recurrence beyond year 5, 31.9% versus 31.8% at year 10, 
35% versus 33.4% at year 15, 37.4% versus 34.1% at year 20, and 38.3% versus 35.3% (3). 
A recent meta-analysis looked at 62,923 patients with ER-positive breast cancer enrolled in 88 
clinical trials who had no recurrence after 5 years of adjuvant endocrine therapy. Even in this group 
of patients who were supposed to have a good prognosis having survived the first 5 years cancer 
free, breast cancer recurrences were found to occur throughout the follow up period over the next 15 
years. Even for small tumor (T1, < 2 cm), the risk of distant recurrence was substantial, 13%, 20%, 
and 34% for node negative (N0), 1 to 3 nodes positive (N1), and 4 to 9 nodes positive (N2), 
respectively. For medium size tumor (T2, >2 cm to < 5 cm), the risk for distant recurrence was 19%, 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
14 
 
26%, and 41% for node negative (N0), 1 to 3 nodes positive (N1), and 4 to 9 nodes positive (N2), 
respectively (4). 
The meta-analysis only studied T1 and T2 disease. Given the risk of recurrence being strongly 
correlated with the original TN stages (4), this means that T3 or T4 disease with or without positive 
nodes (part of the patient population in our proposed study) will have even a much higher rate of 
distant recurrence. 
2.1.2 Neoadjuvant Endocrine Therapy Breast Cancer 
Endocrine therapy has been used extensively for the treatment of breast cancer in the adjuvant and 
metastatic setting. It has also shown similar benefit to chemotherapy in the neoadjuvant setting but 
with significantly lower toxicity, and endocrine therapy with an aromatase inhibitor (AI) is now 
considered a standard of care for the neoadjuvant treatment of postmenopausal women with ER+ 
breast cancer. In the ACOSOG Z1031 trial, the clinical response rate for anastrozole, letrozole, and 
exemestane was 69.1%, 74.8%, and 62.9%, respectively. Severe toxicity was observed in less than 
5% of patients. The most common grade 2 toxicity was hot flashes (5). 
The Preoperative Endocrine Prognostic Index (PEPI) score was developed using results of the P024 
trial to assess the risk of relapse based on pathologic tumor size, lymph node status, Ki67 level, and 
ER status of surgery specimen post neoadjuvant endocrine therapy (6). With a median follow up of 
61.2 months, patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were down-
staged to stage 1 or 0 at surgery had 100% recurrence free survival (RFS) compared with higher 
stages (P < 0.001). Multivariable testing of post-treatment tumor characteristics revealed that 
pathological tumor size, node status, Ki67 level, and ER status were independently associated with 
both RFS and breast cancer specific survival (BCSS). The PEPI model based on these factors 
predicted RFS in the IMPACT trial (P = 0.002).  
In the ALTERNATE study using fulvestrant and/or anastrozole in treating postmenopausal patients 
with stage II-III breast cancer undergoing definitive surgery (NCT01953588, sponsored by the 
Alliance for Clinical Trials in Oncology and the NCI, 2820 patients), one of the primary objectives is 
to evaluate whether patients who achieve a modified PEPI (mPEPI) score of 0, defined by pathologic 
tumor size < 5 cm, pathologic N0, Ki67 < 2.7%, at surgery post 6 months of neoadjuvant endocrine 
therapy will have  excellent long term outcome, for whom chemotherapy is unnecessary (7).  
In the combined analysis of the P024 and POL trials, no relapses were observed during a median 
follow up of 5 years in patients with PEPI 0 after neoadjuvant endocrine treatment (7).  
2.2 
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 (8).  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells (9). It has 
2 known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (10). The PD-1 and 
PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors, 
which can halt or limit the development of T cell response.  When PD-L1 binds to PD-1, an 
inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses 
T-cell proliferation.  Tumor cells exploit this immune checkpoint pathway as a mechanism to evade 
detection and inhibit immune response. 


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PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (11). Importantly, 
PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in the tumor 
microenvironment (12). PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated 
T-cells leading to the inhibition of cytotoxic T cells.  These deactivated T cells remain inhibited in 
the tumor microenvironment.  The PD-1/PD-L1 pathway represents an adaptive immune resistance 
mechanism that is exerted by tumor cells in response to endogenous anti-tumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti–PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on immune 
cells. This activity overcomes PD-L1–mediated inhibition of antitumor immunity. While functional 
blockade of PD-L1 results in T-cell reactivation, this mechanism of action is different from direct 
agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti–PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-
L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti–PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (13-18) with responses that tend to be more 
pronounced in patients with tumors that express PD-L1 (19-21). In addition, high mutational burden 
(e.g., in bladder carcinoma (22) may contribute to the responses seen with immune therapy). 
Pre-clinical data have now been added to with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as programmed death ligand 1 (PD-L1) has promising 
clinical activity. Nivolumab and pembrolizumab, two anti–PD-1 agents, and atezolizumab, avelumab 
and durvalumab, three anti–PD-L1 agents have been granted approvals by the US FDA for the 
treatment of a number of malignancies including metastatic melanoma, squamous and non-squamous 
cell non-small-cell lung cancer and urothelial carcinoma. In addition, there are data from agents in 
the anti–PD-1/PD-L1class showing clinical activity in a wide range of tumor types. 
2.2.1 Checkpoint inhibitors in breast cancer  
Checkpoint inhibitors have not been approved in the treatment of breast cancer. However, there are 
several clinical trials that are either completed or on going that looked at checkpoint inhibitors either 
as a single agent or in combination with other drugs such as chemotherapy or endocrine therapy.  
In KeyNote-012 phase Ib study, 65 patients with refractory metastatic triple negative breast cancer 
whose tumor expressed at least 1% PD-L1 were treated with single agent anti-PD1 monoclonal 
antibody (mAb) pembrolizumab. The overall response rate (ORR) was 18.5%. The median overall 
survival was 11.3 months which surpassed expectation of what would have been achieved with 
chemotherapy (23).  
In the Enhance-1 phase I study (KeyNote-150), pembrolizumab in combination with eribulin 
mesylate in triple negative patients showed an ORR for first line therapy of 41%, and 27.3% for 
second or third line therapy. Responses were seen regardless of PD-L1 status (24) 
In a phase Ib study combining the anti-PD-L1 mAb atezolimumab with nab-paclitaxel chemotherapy 
in patients with metastatic triple negative breast cancer, there was no dose limiting toxicity (DLT) or 
treatment-related death. The confirmed ORR for all patients was 42%, with an ORR for first line 


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treatment of 67%. Responses occurred in both PD-L1 positive and PD-L1 negative patients (25). In a 
follow up phase III Impassion130 study enrolling 902 patients with triple negative breast cancer 
regardless of PD-L1 expression, Roche announced in July 2018 that atezolimumab plus nab-
paclitaxel had met its co-primary endpoint of significant improvement in progression free survival 
over that of nab-paclitaxel alone with no new safety issues (26). This data will be presented at San 
Antonio Breast cancer Conference in December 2018. 
KeyNote-028 phase I study enrolled 25 patients with refractory ER-positive, HER2-negative breast 
cancer, with a median prior number of therapies of 9 (range 3 to 15). The ORR was 12%. The 
clinical benefit rate was 20%. Median duration of response was 12 months. Treatment was well 
tolerated with toxicities primarily grade 1 and 2 (27). 
Currently there are multiple ongoing clinical trials combining a checkpoint inhibitor with 
chemotherapy or endocrine therapy to treat breast cancer, including ER-positive, HER-2 negative 
breast cancer. In the neoadjuvant ISPY2 trial which Moffitt is a study site, pembrolizumab plus 
paclitaxel or the anti-PD-L1 mAb durvalumab plus olaparib and paclitaxel are two of the 
neoadjuvant treatment arms for ER-negative or ER-positive, HER2-negative breast cancer 
(NCT01042379). In a current phase II study sponsored by City of Hope Medical Center in 
collaboration with the National Cancer Institute, pembrolizumab is given together with an aromatase 
inhibitor for the treatment of metastatic ER-positive HER2-negative breast cancer (NCT02648477). 
2.2.2 Durvalumab 
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure.  
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).  The 
proposed mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 
with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the 
inhibition of immune responses, including those that may result in tumor elimination.  In vitro 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human 
T cells resulting in the restored proliferation of IFN-γ (28). In vivo studies have shown that 
durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism (28). 
Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune response 
by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been 
engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent 
cytotoxicity.  
To date durvalumab has been given to more than 6000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents.  Details on the safety profile of 
durvalumab monotherapy are summarized in Section 1.5.2.1 and Section 6.5  Refer to the current 
durvalumab Investigator’s Brochure for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics.  


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2.3 
Research hypothesis 
Endocrine therapy has been used extensively in the treatment of ER+ breast cancer. There are 
differences in immune modulation among different classes of endocrine agents. Tamoxifen has been 
shown to shift immune response from a Th1 to a Th2 pathway (29), which is undesirable in 
immunotherapy against cancer.  
Anastrozole has been shown to shift immunity in the other direction, i.e., from a Th2 to a Th1 
pathway, by increasing IFNγ and IL-12 and by decreasing IL-4 and IL-10. In addition, anastrozole 
has also been shown to decrease regulatory T cell numbers and function (30). Increased gene 
expression relating to inflammatory changes has been reported with anastrozole (31).  
Letrozole has been shown to enhance immune response to a MUC-1 cancer vaccine in animal model 
(32) and to decrease regulatory T cells in tumors of patients with breast cancer (33). Mean serum 
levels of IFNγ were reduced with thymosin-α treatment in patients on aromatase inhibitor who 
experienced arthralgia (34), indicating immunomodulation by aromatase inhibitors. 
IFNγ is a potent inducer of PD-L1 expression in tumor cells (35, 36). Therefore, it is possible that 
aromatase inhibitors upregulate PD-L1 expression in tumor cells through induction of expression of 
inflammatory cytokines such as IFNγ. PD-L1 expression in breast cancer has been shown to be 
associated with high Ki67 expression (37). 
Therefore, we hypothesize that combining an aromatase inhibitor with the anti-PD-L1 durvalumab 
may lead to improved clinical outcome, particularly the mPEPI score, compared to outcomes with 
each drug given as a single agent.  
2.4 
Rationale for conducting this study 
As stated in section 2.1.2, AI treatment is associated with high clinical response rate in the 
neoadjuvant treatment of breast cancer; in addition, AI treatment has also been shown to have 
immunomodulatory activity. However, breast cancer routinely develops resistance to endocrine 
therapy, leading to recurrence and progression of disease. Therefore, a combination of an AI and 
immunotherapies such as checkpoint inhibitors may yield good responses that are durable.  
As an antibody that blocks the interaction between PD-L1 and its receptors, durvalumab may relieve 
PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic activity of anti-
tumor T-cells. This hypothesis is supported by emerging clinical data from other mAbs targeting the 
PD-L1/PD-1 pathway, which provide early evidence of clinical activity and a manageable safety 
profile. Responses have been observed in patients with PD-L1-positive tumors and patients with PD-
L1-negative tumors. In addition, durvalumab monotherapy has shown durable responses in NSCLC 
in Study 1108 (see section 2.2.1). 
2.5 
Rationale for dose selection 
2.5.1 Aromatase inhibitor  
The standard dose for anastrozole is 1 mg orally (PO) daily. 
After the dose-limiting toxicity (DLT) period in the safety run-in stage, as per standard of care, 
switching AI is allowed for intolerance that is attributed to the AI. The ACOSOG Z1031 study 
demonstrated no significant difference among these AIs in terms of efficacy and side effect profiles 
(5). Additionally, the Rheumatologic Evaluation of Adjuvant Letrozole in Postmenopausal Women 


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with Breast Cancer (REAL) study showed that women who experienced ≥ grade 2 
arthralgias/myalgias while receiving anastrozole who switched to letrozole developed significantly 
less arthralgias/myalgias and had improved quality of life compared with baseline (38). 
Our institutional standard of care (SOC) guidelines allow switching from one AI to another and we 
have observed patients who experienced side effects with anastrozole but tolerated letrozole with 
minimal or no issues, and vice versa (people who had side effects with letrozole but did well on 
anastrozole).  
The standard doses for letrozole and exemestane are 2.5 mg and 25 mg PO daily, respectively. 
2.5.1.1 
Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 
(D4190C00002). 
PK/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 
0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK 
consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, 
suggesting near complete target saturation (membrane-bound and sPD-L1), and further shows that 
the durvalumab dosing frequency can be adapted to a particular regimen given the linearity seen at 
doses higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 21 
days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose range studied, 
consistent with engagement of durvalumab with PD-L1. A low level of immunogenicity has been 
observed. No patients have experienced immune-complex disease following exposure to durvalumab 
(For further information on immunogenicity, please see the current IB).  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W (39). Multiple simulations indicate that a similar overall exposure is 
expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by AUCss 
(4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median 
Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity with the 
20 mg/kg Q4W dosing regimen is anticipated to be consistent with 10 mg/kg Q2W with the 
proposed similar dose of 20 mg/kg Q4W expected to (a) achieve complete target saturation in 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and clinical 
activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; 
and (d) achieve PK exposure that yielded maximal antitumor activity in animal models. 
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg Q4W 
and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, supporting 
further development with a dose of 20 mg/kg Q4W.  
Fixed dosing for durvalumab   
A population PK model was developed for durvalumab 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). 


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Population PK analysis indicated only minor impact of body weight on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body weight-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab 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 weight of ~75 kg). A total of 1000 patients were 
simulated using body weight distribution of 40–120 kg. Simulation results demonstrate that body 
weight-based and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-subject variability with fixed dosing regimen.  
Similar findings have been reported by others (40-43). Wang and colleagues investigated 12 mAbs 
and found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies. 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.  
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 weight of 75 kg, a fixed dose 
of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study.  
Fixed dosing of durvalumab is recommended only for subjects with > 30kg body weight due to 
endotoxin exposure. Patients with a body weight less than or equal to 30 kg will not receive any 
further durvalumab.  
3 
DRUG INFORMATION 
3.1 
Potential risks 
3.1.1 Commercial drugs 
The aromatase inhibitors anastrozole, letrozole or exemestane are standard of care drugs and must be 
obtained from commercial sources. Common side effects of each drug are described in Tables 1 
through 3 below. 
Table 1. Anastrozole - adverse reactions occurring with an incidence of at least 5% in either 
treatment group during treatment, or within 14 days of the end of treatment in the Arimidex, 
Tamoxifen, Alone or in Combination (ATAC) trial (this table is from anastrozole package insert). 
Body system and adverse reactions  
Anastrozole 1 mg 
(n = 3092) 
Tamoxifen 20 mg 
(n = 3094) 
Body as a whole 
 Asthenia 
575 (19) 
544 (18) 
 Pain 
533(17) 
485 (16) 
 Back pain 
321 (10) 
309 (10) 
 Headache 
314 (10) 
249 (8) 
 Abdominal pain 
271 (9) 
276 (9) 
 Infection 
285 (9) 
276 (9) 
 Accidental injury 
311 (10) 
303 (10) 


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 Flu syndrome 
175 (6) 
195 (6) 
 Chest pain 
200 (7) 
150 (5) 
 Neoplasm 
162 (5) 
144 (5) 
 Cyst 
138 (5) 
162 (5) 
Cardiovascular 
 Vasodilatation 
1104 (36) 
1264 (41) 
 Hypertension 
402 (13) 
349 (11) 
Digestive 
 Nausea 
343 (11) 
335 (11) 
 Constipation 
249 (8) 
252 (8) 
 Diarrhea 
265 (9) 
216 (7) 
 Dyspepsia 
206 (7) 
169 (6) 
 Gastrointestinal disorder 
210 (7) 
158 (5) 
Hemic and lymphatic 
 Lymphedema 
304 (10) 
341 (11) 
 Anemia 
113 (4) 
159 (5) 
Metabolic and nutritional 
 Peripheral edema 
311 (10) 
343 (11) 
 Weight gain 
285 (9) 
274 (9) 
 Hypercholesterolemia 
278 (9) 
108 (3.5) 
Musculoskeletal 
 Arthritis 
512 (17) 
445 (14) 
 Arthralgia 
467 (15) 
344 (11) 
 Osteoporosis 
325 (11) 
226 (7) 
 Fracture 
315(10) 
209 (7) 
 Bone pain 
201 (7) 
185 (6) 
 Arthrosis 
207 (7) 
156 (5) 
 Joint Disorder 
184 (6) 
160 (5) 
 Myalgia 
179 (6) 
160 (5) 
Nervous system 
 Depression 
413 (13) 
382 (12) 
 Insomnia 
309 (10) 
281 (9) 
 Dizziness 
236 (8) 
234 (8) 
 Anxiety 
195 (6) 
180 (6) 
 Paresthesia 
215 (7) 
145 (5) 
Respiratory 
 Pharyngitis 
443 (14) 
422 (14) 
 Cough increased 
261 (8) 
287 (9) 
 Dyspnea 
234 (8) 
237 (8) 
 Sinusitis 
184 (6) 
159 (5) 
 Bronchitis 
167 (5) 
153 (5) 
Skin and appendages 
 Rash 
333 (11) 
387 (13) 


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 Sweating 
145 (5) 
177 (6) 
Special Senses 
 Cataract Specified 
182 (6) 
213 (7) 
Urogenital 
 Leukorrhea 
86 (3) 
286 (9) 
 Urinary tract infection 
244 (8) 
313(10) 
 Breast pain 
251 (8) 
169 (6) 
 Breast Neoplasm 
164 (5) 
139 (5) 
 Vulvovaginitis 
194 (6) 
150 (5) 
 Vaginal Hemorrhage 1 
122 (4) 
180 (6) 
 Vaginitis 
125 (4) 
158 (5) 
1 Vaginal Hemorrhage without further diagnosis. 
Note: The combination arm was discontinued due to lack of efficacy benefit at 33 
months of follow-up.  
Table 2. Letrozole - patients with adverse reactions (CTC Grades 1-4, irrespective of relationship to 
study drug) in the adjuvant study - monotherapy arms analysis (median follow-up 73 months; 
median treatment 60 months). This table is from letrozole package insert. 
Adverse reaction 
Grades 1-4 
Grades 3-4 
 
Letrozole 
n = 2448 
n (%) 
Tamoxifen 
n = 2447 
n (%) 
Letrozole 
n = 2448 
n (%) 
Tamoxifen 
n = 2447 
n (%) 
Pts with any adverse event 
2310 (94.4) 
2214 (90.5) 
635 (25.9) 
604 (24.7) 
Hypercholesterolemia 
1280 (52.3) 
700 (28.6) 
11 ( 0.4) 
6 ( 0.2) 
Hot Flashes/Flushes 
821 (33.5) 
929 (38.0) 
0 - 
0 - 
Arthralgia/Arthritis 
618 (25.2) 
501 (20.4) 
85 ( 3.5) 
50 ( 2.0) 
Night Sweats 
357 (14.6) 
426 (17.4) 
0 - 
0 - 
Bone Fractures2 
338 (13.8) 
257 (10.5) 
- - 
- - 
Weight Increase 
317 (12.9) 
378 (15.4) 
27 ( 1.1) 
39 ( 1.6) 
Nausea 
283 (11.6) 
277 (11.3) 
6 ( 0.2) 
9 ( 0.4) 
Bone Fractures1 
247 (10.1) 
174 ( 7.1) 
- - 
- - 
Fatigue (Lethargy, Malaise, 
Asthenia) 
235 ( 9.6) 
250 (10.2) 
6 ( 0.2) 
7 ( 0.3) 
Myalgia 
217 ( 8.9) 
212 ( 8.7) 
18 ( 0.7) 
14 ( 0.6) 
Edema 
164 ( 6.7) 
160 ( 6.5) 
3 ( 0.1) 
1 ( < 0.1) 
Weight Decrease 
140 ( 5.7) 
129 ( 5.3) 
8 ( 0.3) 
5 ( 0.2) 
Vaginal Bleeding 
128 ( 5.2) 
320 (13.1) 
1 ( < 0.1) 
8 ( 0.3) 
Back Pain 
125 ( 5.1) 
136 ( 5.6) 
7 ( 0.3) 
11 ( 0.4) 
Osteoporosis NOS 
124 ( 5.1) 
66 ( 2.7) 
10 ( 0.4) 
5 ( 0.2) 
Bone pain 
123 ( 5.0) 
109 ( 4.5) 
6 ( 0.2) 
4 ( 0.2) 
Depression 
119 ( 4.9) 
114 ( 4.7) 
16 ( 0.7) 
14 ( 0.6) 
Vaginal Irritation 
111 ( 4.5) 
77 ( 3.1) 
2 ( < 0.1) 
2 ( < 0.1) 


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Headache 
105 ( 4.3) 
94 ( 3.8) 
9 ( 0.4) 
5 ( 0.2) 
Pain in extremity 
103 ( 4.2) 
79 ( 3.2) 
6 ( 0.2) 
4 ( 0.2) 
Osteopenia 
87 ( 3.6) 
74 ( 3.0) 
0 - 
2 ( < 0.1) 
Dizziness/Light-Headedness 
84 ( 3.4) 
84 ( 3.4) 
1 ( < 0.1) 
6 (0.2) 
Alopecia 
83 ( 3.4) 
84 ( 3.4) 
0 - 
0 - 
Vomiting 
80 ( 3.3) 
80 ( 3.3) 
3 ( 0.1) 
5 (0.2) 
Cataract 
49 ( 2.0) 
54 ( 2.2) 
16 ( 0.7) 
17 ( 0.7) 
Constipation 
49 ( 2.0) 
71 ( 2.9) 
3 ( 0.1) 
1 ( < 0.1) 
Breast pain 
37 ( 1.5) 
43 ( 1.8) 
1 ( < 0.1) 
0 - 
Anorexia 
20 ( 0.8) 
20 ( 0.8) 
1 ( < 0.1) 
1 ( < 0.1) 
Endometrial Hyperplasia/ 
Cancer2, 3 
11/1909 ( 0.6) 
70/1943 ( 3.6) 
- 
- 
Endometrial Proliferation 
Disorders 
10 (0.3) 
71 (1.8) 
0 - 
14 (0.6) 
Endometrial Hyperplasia/ 
Cancer1, 3 
6/1909 ( 0.3) 
57/1943 (2.9) 
- 
- 
Other Endometrial Disorders 
2 ( < 0.1) 
3 ( 0.1) 
0 
0 
Myocardial Infarction1 
24 ( 1.0) 
12 ( 0.5) 
- 
- 
Myocardial Infarction2 
37 ( 1.5) 
25 (1.0) 
- 
- 
Myocardial Ischemia 
6 ( 0.2) 
9 ( 0.4) 
- 
- 
Cerebrovascular Accident1 
52 ( 2.1) 
46 ( 1.9) 
- 
- 
Cerebrovascular Accident2 
70 ( 2.9) 
63 ( 2.6) 
- 
- 
Angina1 
26 ( 1.1) 
24 ( 1.0) 
- 
- 
Angina2 
32 ( 1.3) 
31 ( 1.3) 
- 
- 
Thromboembolic Event1 
51 ( 2.1) 
89 ( 3.6) 
- 
- 
Thromboembolic Event2 
71 ( 2.9) 
111 ( 4.5) 
- 
- 
Other Cardiovascular1 
260 (10.6) 
256 (10.5) 
- 
- 
Other Cardiovascular2 
312 (12.7) 
337 (13.8) 
- 
- 
Second Malignancies1 
53 ( 2.2) 
78 ( 3.2) 
- 
- 
Second Malignancies2 
102 ( 4.2) 
119 ( 4.9) 
- 
- 
1 During study treatment, based on Safety Monotherapy population.  
2 Any time after randomization, including post treatment follow-up.  
3 Excluding women who had undergone hysterectomy before study entry.  
Note: Cardiovascular (including cerebrovascular and thromboembolic), skeletal and 
urogenital/endometrial events and second malignancies were collected life-long. All of these events 
were assumed to be of CTC Grade 3 to 5 and were not individually graded. 
Table 3. Exemestane - incidence (%) of adverse events of all grades and illnesses occurring in (≥ 
5%) of patients in any treatment group in the Intergoup Exemestane Study (IES) in postmenopausal 
women with early breast cancer. This table is from exemestane package insert. 
Body system and adverse event1 
% of patients 
Exemestane 25 mg daily  
(n = 2252) 
Tamoxifen 20 mg daily2  
(n = 2280) 
Eye 


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 Visual disturbances3 
5 
3.8 
Gastrointestinal 
 Nausea3 
8.5 
8.7 
General Disorders 
 Fatigue3 
16.1 
14.7 
Musculoskeletal 
 Arthralgia 
14.6 
8.6 
 Pain in limb 
9.0 
6.4 
 Back pain  
8.6 
7.2 
 Osteoarthritis 
5.9 
4.5 
Nervous System 
 Headache3  
13.1 
10.8 
 Dizziness3 
9.7 
8.4 
Psychiatric 
 Insomnia3  
12.4 
8.9 
 Depression 
6.2 
5.6 
Skin & Subcutaneous Tissue 
 Increased sweating3  
11.8 
10.4 
 Vascular 
 Hot flushes3  
21.2 
19.9 
 Hypertension 
9.8 
8.4 
1 Graded according to Common Toxicity Criteria;  
2 75 patients received tamoxifen 30 mg daily;  
3 Event actively sought. 
Please refer to the current Food and Drug Administration (FDA)-approved package inserts provided 
with the medications or the Physicians’ Desk Reference for additional information about possible 
side effects and instructions for preparation, handling, and storage of the drugs. 
3.1.2 Durvalumab monotherapy 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, 
hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in 
creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, 
myositis/polymyositis, other rare or less frequent inflammatory events including neurotoxicities, 
infusion-related reactions, hypersensitivity reactions and infections/serious infections.  
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. 
Further information on these risks can be found in the current version of the durvalumab IB. 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. Approximately 
9% of patients experienced an AE that resulted in permanent discontinuation of durvalumab and 


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approximately 6% of patients experienced an SAE that was considered to be related to durvalumab 
by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, 
and in the case of events suspected to have an immune basis, the use of established treatment 
guidelines for immune-mediated (Appendix 1). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of the 
durvalumab IB. 
4 
STUDY DESIGN 
4.1 
Description 
This is a multi-center, open label phase II with safety run-in study. This study will assess the 
efficacy and safety of an aromatase inhibitor (anastrozole) in combination with durvalumab in 
patients with hormone-receptor-positive breast cancer. The objectives are to obtain data on the 
clinical efficacy and to assess the safety of the drug combination. 
The study will test a fixed dose of durvalumab in combination with an AI. Initially, six patients will 
be enrolled in the safety run-in stage.  If <1/6 patients have a DLT, then the expansion stage will be 
open for enrollment. If >2/6 patients have a DLT, we will amend the protocol.  
Anastrozole 1 mg daily will be taken orally (PO) starting on Day 1 of each cycle for 6 months prior 
to definitive surgery. After the first 6 months, the patients will continue taking the AI at the 
discretion of the treating physician as per standard of care. 
It is acceptable to switch to another AI (letrozole 2.5 mg or exemestane 25 PO mg daily) for 
intolerance such as hot flash or joint ache attributable to the AI). In the safety run-in phase, 
switching to another AI is allowed only after the post DLT period.  
Table 4. Dosage for durvalumab and AI combination. 
Durvalumab (IV) 
AI (PO) 
1500 mg Q4W on Day 1 of each 
28-day cycles for 6 cycles 
Anastrozole 1 mg (or letrozole 
2.5 mg or exemestane 25 mg, if 
intolerance of anastrozole) for 6 
months 
4.1.1 Dose expansion phase 
All patients will also receive a daily dose of the aromatase inhibitor anastrozole (1 mg PO). Patients 
will be allowed to switch to another AI for toxicity reasons as described in section 2.5.1 at any time 
their treating physicians deems it necessary. 
4.2 
Dose Limiting Toxicity  
Dose-limiting toxicities (DLTs) will be evaluated during the safety run-in phase of the trial. The 
period for evaluating DLTs will be the first cycle of treatment (from the time of first administration 
of durvalumab until the clinic evaluation prior to C2D1 dosing). Subjects who do not remain on the 
study up to this time for reasons other than DLT will be replaced with another subject. Grading of 


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DLTs will follow the guidelines provided in the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. 
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation 
period and meets the criteria below. Toxicity that is clearly and directly related to the primary 
disease or to another etiology is excluded from this definition. The following will be DLTs: 
 Any Grade 4 irAE (as defined in section 15.4.4 and 15.4.5). 
 Any Grade ≥ 3 colitis. 
 Any Grade ≥ 3 noninfectious pneumonitis irrespective of duration. 
 Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of 
maximal supportive care. 
 Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days of onset despite optimal medical management including systemic 
corticosteroids or does not downgrade to Grade ≤ 1 or baseline within 14 days. 
 Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN. 
 Grade 3 or 4 febrile neutropenia 
 Any treatment interruption greater than 2 weeks due to an AE. 
 Any ≥ Grade 3 non-irAE, except for the exclusions listed below. 
The definition excludes the following conditions:  
 Grade 3 fatigue lasting ≤ 7 days. 
 Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy and the 
subject is asymptomatic. 
 Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.). 
 Concurrent vitiligo or alopecia of any AE grade. 
 Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) 
that resolves within 6 hours with appropriate clinical management. 
 Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that improves 
by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be a DLT 
regardless of duration or reversibility. 
 Grade 3 or 4 lymphopenia. 
 Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days. 
 Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days. 
Immune-related AEs are defined as AEs of an immune nature (i.e., inflammatory) in the absence of a 
clear alternative etiology. In the absence of a clinically significant abnormality, repeat laboratory 
testing will be conducted to confirm significant laboratory findings prior to designation as a DLT.  


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4.3 
Number of Patients 
Safety run-in phase: 6 patients  
Expansion phase: A total of 42 evaluable patients are required, when considering a rate of non-
evaluability of 10%, a total of 46 patients are expected to enroll in the study (the 6 patients in the 
safety run-in phase are included in this total). 
4.4 
Number of Study Centers 
The study will be conducted at two centers. 
4.5 
Duration 
The total enrollment period for the study will be 28 months. Follow-up will be required for up to 5 
years. 
4.6 
Withdrawal of Subjects from Study Treatment and/or Study 
4.6.1 Permanent discontinuation of investigational product 
An individual patient will not receive any further investigational product if any of the following 
occur in the patient in question: 
1.     
An individual patient will not receive any further durvalumab if their weight falls to 30kg or 
less 
2.     
Withdrawal of consent or lost to follow-up 
3.     
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing 
4.     
Patient 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 
5.     
Any AE that meets criteria for discontinuation as defined in Section 10.3 and Appendix 1. 
6.     
Dose-limiting toxicity (as defined in section 4.2) 
7.     
Grade ≥3 infusion reaction 
8.     
Patient noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
9.     
Initiation of alternative anticancer therapy including another investigational agent 
10.     Confirmation of PD and investigator determination that the patient is no longer benefiting 
from treatment with durvalumab  
11.     Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 15.4 and Appendix 1, including the collection of any protocol-


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specified blood specimens, unless consent is withdrawn or the subject is lost to follow-up or 
enrolled in another clinical study. All subjects will be followed for recurrence free survival. 
Subjects who decline to return to the site for evaluations will be offered follow-up by phone 
every 3 months as an alternative. 
4.6.2 
Withdrawal of consent 
Patients are free to withdraw from the study at any time (from investigational product and 
assessments) without prejudice to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further 
investigational product or further study observation, with the exception of follow-up for survival, 
which will continue until the end of the study unless the patient has expressly withdrawn their 
consent to survival follow-up. Note that the patient may be offered additional tests or tapering of 
treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
 all further participation in the study including any further follow up (e.g., survival contact 
telephone calls) 
 withdrawal of consent to the use of their study generated data 
 withdrawal to the use of any samples  
4.6.3 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the Principal Investigator will ensure 
that any stored samples are disposed of or destroyed, the action is documented, and the subject is 
notified of the samples’ disposal. As collection of the biological samples is an integral part of the 
study, the subject will also be withdrawn from further study participation. 
4.7 
Replacement of subjects 
Patients enrolled in the safety run-in phase of the study may be replaced if they are not evaluable for 
DLT (i.e., patients did not receive study treatment or withdrawn from the study for reasons other 
than drug-related toxicity) will need to be replaced to provide adequate evaluation of safety at the 
tested dose level. 
Patients enrolled in the safety run-in phase who withdraw from the study after completing the first 
treatment cycle (DLT period) will not need to be replaced on the study. 
Patients enrolled in the expansion phase of the study will not be replaced. 
5 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with signature in the patient 
research chart.  


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Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this study. 
Under no circumstances will there be exceptions to this rule.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
_____ 5.1.1 
Able to provide a written informed consent and any locally-required 
authorization (e.g., HIPAA in the USA) prior to performing any protocol-
related procedures, including screening evaluations. 
_____ 5.1.2 
Female age ≥ 18 years at time of study. 
_____ 5.1.3 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
_____ 5.1.4  Postmenopausal, defined as meeting at least 1 of the following criteria: 
 Age > 60 
 Prior bilateral oophorectomy 
 Age < 60 with a uterus AND amenorrhea for at least the past 12 months 
(in the absence of chemotherapy, tamoxifen, toremifene, or ovarian 
suppression) 
 Age < 60 without a uterus AND follicular stimulating hormone (FSH) 
and estradiol in the postmenopausal range per local normal range 
_____ 5.1.5  Clinical T2-T4c, any N, M0 by AJCC 8th edition, with the goal being 
definitive surgery after completion of neoadjuvant therapy.  
 The tumor is palpable and its size can be measured bidimensionally by 
tape, ruler or caliper technique 
 The largest tumor diameter is > 2.0 cm 
_____ 5.1.6  Pathologic confirmation of invasive breast cancer that is estrogen receptor 
(ER) positive with an Allred score of 6, 7 or 8. If an Allred Score is not 
reported on the diagnostic pathology report, ER positivity in > 66% cells is 
eligible. If ER positivity is < 66%, the staining intensity (weak, intermediate, 
strong) is needed to calculate the Allred Score to determine eligibility. 
_____ 5.1.7  Invasive breast cancer is Human Epidermal Growth Factor Receptor 2 
(HER2) negative defined as 0 or 1+ by immunohistochemistry (IHC) or with 
an in situ hybridization (ISH) ratio (HER2 gene copy/chromosome 17) < 2. 
_____ 5.1.8  Documentation of mammogram and ultrasound [including ductal carcinoma in 
situ (DCIS) and invasive cancer] of the diseased breast performed within 60 
days prior to enrollment. Mammogram for the unaffected contralateral breast 
is required within 12 months prior to enrollment. 


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_____ 5.1.9  Adequate organ and marrow function as defined below, laboratory values 
obtained ≤ 14 days prior to enrollment: 
 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 be allowed 
only in consultation with their physician 
 AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal. 
 Serum creatinine clearance > 40 mL/min by the Cockcroft-Gault 
formula (1976) or by 24-hour urine collection for determination of 
creatinine clearance 
_____ 5.1.10  Subjects must be willing to undergo a research biopsy at baseline and after 
one cycle of treatment and to provide tissue obtained at surgery for biomarker 
and correlative studies.  
_____ 5.1.11  Subjects must be 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.  
_____ 5.1.12  If taking herbal or natural remedies that may have immune modulatory 
effects, subjects must be willing to discontinue it prior to first dose of 
durvalumab.  
_____ 5.1.13  Body weight > 30 kg. 
 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
 
_____ 5.2.1  Participation in another clinical study with an investigational product during 
the last 4 weeks. 
_____ 5.2.2  Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an 
interventional study 
_____ 5.2.3  Inflammatory breast cancer defined as clinically significant erythema of the 
breast and/or documented dermal lymphatic invasion (not direct skin invasion 
by tumor or peau d'orange without erythema). 
_____ 5.2.4  An excisional biopsy of this breast cancer. 


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_____ 5.2.5  Hormone replacement therapy of any type, megestrol acetate, or raloxifene 
within one week prior to registration. 
_____ 5.2.6  Surgical axillary staging procedure prior to study entry. Note: Fine needle 
aspiration (FNA) or core needle biopsy of axillary node is permitted. 
_____ 5.2.7  Treatment for this cancer including surgery, radiation therapy, chemotherapy, 
biotherapy, hormonal therapy or investigational agent prior to study entry. 
_____ 5.2.8  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab 
_____ 5.2.9  History of another primary malignancy except for malignancy treated with 
curative intent and with no known active disease ≥ 5 years or adequately 
treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease or adequately treated carcinoma in situ without evidence of disease 
e.g., cervical cancer in situ. 
_____ 5.2.10 History of ipsilateral invasive breast cancer regardless of treatment or 
ipsilateral ductal carcinoma in situ (DCIS) treated with radiotherapy or 
endocrine therapy or contralateral invasive breast cancer at any time. 
_____ 5.2.11 Current or prior use of immunosuppressive medication within 14 days before 
the first dose of durvalumab, with the exceptions of intranasal, inhaled, topical 
steroids, or local steroid injections (e.g., intra-articular injection); systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid; or steroids as premedication for 
hypersensitivity reactions (e.g., CT scan premedication). 
_____ 5.2.12  Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis 
[with the exception of diverticulosis], systemic lupus erythematosus, 
Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with 
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). 
The following are exceptions to this criterion: 
 
Patients with vitiligo or alopecia 
 
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
 
Any chronic skin condition that does not require systemic therapy 
 
Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
 
Patients with celiac disease controlled by diet alone 
_____ 5.2.13  History of primary immunodeficiency. 


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_____ 5.2.14  History of allogeneic organ transplant. 
_____ 5.2.15  Known allergy or history of hypersensitivity to durvalumab, or any excipient. 
_____ 5.2.16  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, , or psychiatric illness/social 
situations that would limit compliance with study requirements or 
compromise the ability of the subject to give written informed consent. 
_____ 5.2.17  Known active infection including tuberculosis (clinical evaluation that 
includes clinical history, physical examination and radiographic findings, and 
TB testing in line with local practice), hepatitis B (known positive HBV 
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency 
virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and 
absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) 
antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA. Note: This is applied only to patients with known infection. Screening 
tests for TB, hepatitis B and C, or HIV are not required. 
_____ 5.2.18  Receipt of live attenuated vaccination within 30 days prior to receiving 
durvalumab. Note: Patients, if enrolled, should not receive live vaccine while 
receiving durvalumab and up to 30 days after the last dose of durvalumab. 
_____ 5.2.19  Any condition that, in the opinion of the investigator, would interfere with 
evaluation of study treatment or interpretation of patient safety or study 
results. 
_____ 5.2.20  Subjects with uncontrolled seizures. 
_____ 5.2.21  Patients with multi-centric breast cancer (defined as more than one lesion is 
invasive breast cancer in the same breast separated by ≥ 2 cm of normal breast 
tissue 
 
_____ 5.2.22  Major surgical procedure (as defined by the Investigator) within 28 days prior 
to the first dose of investigational product. 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
 
______________________________ 
 
_______________ 
       _______________ 
Investigator Signature  
 
 
 
Date 
 
                    Time 


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6 
TREATMENT PLAN 
6.1 
Administration Schedule 
6.1.1 Aromatase inhibitors 
Anastrozole will be administered at a fixed dose of 1 mg PO once daily (QD) regardless of the 
subject’s weight.  
On cycle 1 day 1 (C1D1), patients are to take anastrozole prior to the infusion of durvalumab. 
Patients will then be encouraged to take their daily dose of anastrozole at approximately the same 
time each day at their convenience. Doses must be taken at least 18 hours apart.  
If patients need to switch to another AI for intolerance reasons (such as hot flash or joint ache) in the 
post DLT period, they will be given letrozole (2.5 mg PO QD) or exemestane (25 mg PO QD).  
6.1.2 Durvalumab 
Durvalumab will be administered as follows:  
  
Durvalumab, 1500 mg via IV infusion Q4W (equivalent to 20 mg/kg Q4W) on Day1 
of each 28-day cycle for 6 cycles (6 doses – 6 months).  
6.2 
How Supplied, Stored, Packaged and Labeled  
6.2.1 Commercial products 
The aromatase inhibitors anastrozole, letrozole or exemestane are standard of care drugs and must be 
obtained from commercial sources. Please refer to the current FDA-approved package inserts 
provided with the medications or the Physicians’ Desk Reference for instructions for preparation, 
handling, and storage. 
6.2.2 Investigational drugs 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab 
(MEDI4736) to the investigator as a 500-mg vial solution for infusion after dilution. Durvalumab 
will be supplied to the study as a commercial product. 
6.2.2.1 Formulation/packaging/storage 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution.  The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10.0 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
secondary packaging until use to prevent excessive light exposure.  
6.3 
Preparation and Administration 
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator or site 
designated investigational product (IP) manager using aseptic technique.  
Fixed doses will be used based on an average body weight of 75 kg:  


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 Durvalumab: 1500 mg Q4W (equivalent to 20 mg/kg Q4W). 
 
Total time from needle puncture of the vials to start of administration should not exceed 24 hours at 
2 °C - 8 °C (36°F to 46°F) or 4 hours at room temperature. 
Infusion solutions must be allowed to equilibrate to room temperature prior to beginning 
administration.  
A dose of 1500mg (for patients >30kg in weight) will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging 
from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500mg of durvalumab [MEDI4736]) to the IV 
bag. The IV bag size should be selected such that the final concentration is within 1 to 15 mg/mL. 
Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
Standard infusion time is 1 hour.  In the event that there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent 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. 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from 
new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any unused portion must 
be discarded.  
6.4 
Monitoring of dose administration 
Patients will be monitored before, during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood pressure) 
every 30 minutes during the infusion period (including times where infusion rate is slowed or 
temporarily stopped). 
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 (up to 4 hours) 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 (e.g., 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. The standard infusion time is one hour, however if there 
are interruptions during infusion, the total allowed time from infusion start to completion of infusion 
should not exceed 4 hours at room temperature, with maximum total time at room temperature not 
exceeding 4 hours (otherwise requires new infusion preparation). For management of patients who 
experience an infusion reaction, please refer to the toxicity and management guidelines in Error! 
Reference source not found.appendix 1. 


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A 1 hour observation period is required after the first infusion of durvalumab. If no clinically 
significant infusion reactions are observed during or after the first two cycles, subsequent infusion 
observation periods can be at the Investigator’s discretion (suggested 30 minutes after each 
durvalumab infusion).  
Instructions for the management of infusion-related reactions or allergic reactions can be found in 
section 15.4.4 and Appendix 1.  
6.5 
Accountability and Compliance 
The investigator will not supply investigational drug to any patient not enrolled in the study, or to 
any physicians or scientists except those designated as sub-investigators. 
The investigator must ensure that patients receive study drug only from personnel who fully 
understand the procedures for dosing and administering the drug. 
Each shipment of study drug for a study will contain an Investigational Drug Shipping Request 
(IDSR) form to assist the investigator in maintaining current and accurate inventory records. 
The IDSR form will identify for each shipment the subject identification code (if applicable), the lot 
number, and the quantity of vials contained in the shipment. Upon receipt of the investigational drug, 
the designated recipient will visually inspect the shipment and verify the number and condition of 
vials received. The designated recipient will complete the lower portion of the IDSR form. A copy of 
the signed form is to be filed with the inventory/drug accountability records. The original completed 
form will be mailed back to Astra Zeneca in the envelope provided with the drug shipment. 
Only authorized personnel should have access to the drug. For accurate accountability, the following 
information must be noted when drug supplies are used during the study: the patient identification, 
the lot number of the drug dispensed for that patient, and the date and quantity of drug dispensed. 
Study drug accountability records should also document receipt and return or destruction of study 
drug supplies. 
Drug accountability records must be readily available for inspection by representatives of Astra 
Zeneca and are open to inspection by regulatory authorities at any time. 
Compliance of the oral AI will be assessed and recorded by the investigator and/or study personnel 
at each patient visit. A dosing log will be used. 
6.6 
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 signed. 
Return of all drug supplies must be coordinated with Astra Zeneca prior to shipment. When unused 
drug supplies are returned, the number of vials being returned and the lot numbers should be noted in 
the site inventory log and the Investigational Drug Return Form provided by Astra Zeneca should be 
completed. 
Upon completion of this study, appropriate site personnel should verify that all unused drug supplies 
have either been returned or destroyed and that no investigational drug remains in the investigator's 
possession. For all drug supplies that are not returned, officially signed and dated written 
documentation of proper disposal or destruction of the drug in accordance with the appropriate 


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35 
 
institutional guidelines must be maintained in the drug accountability records. A copy of the drug 
accountability records must be returned to Astra Zeneca at the end of the study. 
6.7 
Concomitant Medications and Treatments 
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).  
The following medications are considered exclusionary:  
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, other than any stated 
comparator or combination regimens. Concurrent use of hormones for non-cancer-related 
conditions (e.g., insulin for diabetes) is acceptable. Estrogen-containing hormone 
replacement therapy is not acceptable.  
3. Herbal and natural remedies which may have immune-modulating effects. 
4. 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).  
5. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days prior to the first 
dose, during treatment with durvalumab for 30 days post discontinuation of durvalumab. 
Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
In addition, subjects should not donate blood while participating in this study or for at least 90 days 
following the last infusion of durvalumab. 
6.8 
Duration of Therapy 
Individual study patients may remain on treatment with an AI in combination with durvalumab until 
they experience intolerable toxicity, confirmed disease progression, or the investigator determines 
that the subject is no longer benefiting from treatment (more details are provided in section 4.6.1).  
Patients will receive a maximum treatment with 6 cycles of durvalumab. 
After the first 6 months, patients will continue receiving the AI at the discretion of the treating 
physician as per standard of care. 
Patients who discontinue active treatment will be followed for recurrence free survival for up to 5 
years or until the sponsor ends the study. 
7 
TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for adverse event and serious adverse event reporting. A copy of the CTCAE Version 
5.0 can be downloaded: (http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx). 


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7.1 
Dose Modifications 
7.1.1 Aromatase inhibitor 
Dose modifications are allowed in case of toxicities thought to be related to the AI. Dose 
modifications will follow standard of care guidelines and will be at the discretion of the treating 
physician and Principal Investigator. 
Switching to a different AI is permitted. In the safety run-in phase, switching is only allowed outside 
of the DLT window (details can be found in section 2.5.1).  
Dose reductions in AI are not permitted but dose interruptions for up to 14 consecutive days for 
toxicity reasons is acceptable. Patients may continue to receive durvalumab per the dosing schedule 
if the toxicity is thought to be caused by the AI. 
Patients who can’t resume AI treatment after a 14 day hold will discontinue study treatment. 
7.1.2 Durvalumab  
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. 
 Hold the agent suspected of causing the toxicity when required. 
 Dose reductions are not permitted. 
 If the symptoms promptly resolve with supportive care, consideration should be given to 
resuming or continuing the regular dosing schedule of durvalumab along with appropriate 
continuing supportive care. If medically appropriate, dose delays or interruptions are 
permitted (see Appendix 1). 
 All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
Following the first dose of durvalumab, subsequent administrations can be modified based on 
toxicities observed (see Appendix 1). In addition, there are certain circumstances in which 
durvalumab should be permanently discontinued (see Appendix 1). 
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, there 
is the possibility of observing 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 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 
Section 15.4.4. 


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7.2 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
physician including but not limited to the items outlined in the table below: 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments (e.g., 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 
8 
STUDY CALENDAR 
8.1 
A calendar cycle will last 28 days. Cycles begin the day of a durvalumab infusion. For 
all visits, there is a ± 3 day window if not explicitly specified otherwise.  
Drug administration calendar 
Drug 
Cycle 
length 
(days) 
C1 
C2 
C3 
C4 
C5 
C6 
D1 
D1 
D1 
D1 
D1 
D1 
Anastrozole 
28 
daily 
daily 
daily 
daily 
daily 
daily 
Durvalumab 
28 
X 
X 
X 
X 
X 
X 
  Patients who experienced intolerance/toxicities attributable to anastrozole will be allowed to  
  switch to a different AI. For patients in the safety run-in phase, this is allowed only after they have  
   
  completed the DLT period. 
 
8.2 
Schedule of events 
Examination 
Screening1 
C1 
C2 
C3 
C4 
C5 
C6 
EOT136 
Surgery 
Follow 
up17 
D1 
D1 
D1 
D1 
D1 
D1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility review  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Tumor tissue 
collection 
X2 
 
X 
 
 
 
 
 
X 
 
Physical 
examination with 
ECOG3 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECGs5 
X 
X 
 
 
 
 
 
 
 
 


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38 
 
 
 
 
 
 
Abbreviations: C, cycle; Conmeds, concomitant medications; D, day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group performance status; EOT, end of treatment; mPEPI, modified Prepoperative Endocrine 
Prognostic Index.  
1     Screening laboratory assessments performed within 7 days prior to C1D1 do not need to be repeated. 
2 Core biopsy will be obtained at baseline, after one cycle (1 month +/- 7 days) and at definitive surgery (mandatory). 
Baseline core biopsy may be omitted at the discretion of the PI. 
3 
Full physical examination at screening; targeted physical examination at minimum at other time points. If physical 
exam, including tumor assessment, is performed within 7 days prior to C1D1 of treatment, no need to repeat physical 
exam on C1D1. 
4 
Blood pressure (BP) and pulse will be measured before, during, and after the infusion at the following time points: 
beginning of infusion (0 min), halfway through the infusion (30 ± 5 min), end of the infusion (60 ± 5 min), 60 min of 
observation after the end of C1 infusion (120 ± 5 min). If no issue with C1, observation period can be shortened to 30 
minutes after the end of each subsequent cycle. More frequent monitoring can be done as clinically indicated. For 
infusions taking ≥ 60 min, BP and pulse should be measured following the principles described above. After the first 
infusion monitoring can be as clinically indicated. 
5   In Screening, 12-lead ECGs (in triplicate 2-5 minutes apart). On C1D1, A 12-lead ECG within 1 hour pre-infusion 
and 0-3 hours post end of infusion . Other ECGs as clinically indicated. In case of a clinically significant ECG 
abnormality, including QTcF value > 470 ms, two additional ECGs collected 2-5 minutes apart should be obtained to 
confirm the findings. In this case, the final QTcF value will be the mean QTcF value calculated from all 3 ECGs. 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Conmeds 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology56 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Chemistry67 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Endocrine 
function tests78 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation89 
X 
 
 
 
 
 
 
 
 
 
Urinalysis910 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum & plasma 
collection101 
 
X 
X 
 
X 
 
 
X 
 
 
 
Tumor 
assessment12 
X 
 
X 
 
 
 
 
X 
 
 
Assessment of 
response by 
exam13 
 
X 
X 
 
 
 
 
X 
 
 
Assessment of 
response by 
MRI14 
X 
 
X 
 
 
 
 
X 
 
 
mPEPI15 
 
 
 
 
 
 
 
 
X 
 


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6 Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (total neutrophil 
count including lymphocyte, monocyte, eosinophil and basophil counts), platelet count, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration. 
7   Clinical chemistry: sodium, potassium, chloride, carbon dioxide, alkaline phosphatase, AST, ALT, BUN, glucose, 
creatinine, calcium, total protein, albumin, total bilirubin (direct and indirect bilirubin will be measured if total 
bilirubin is ≥ 2 x ULN with no evidence of Gilbert’s syndrome), lactate dehydrogenase (LDH), magnesium, uric acid, 
amylase, lipase, GGT. Clinical chemistries due at screening, prior to each infusion, and at EOT. Results for liver panel 
(AST, ALT, alkaline phosphatase, bilirubin) must be available and reviewed before starting an infusion. Amylase and 
lipase due at screening, the start of each new cycle, and EOT. GGT due at screening, C1D1, and as clinically 
indicated. 
8  Endocrine function tests: Thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine (T4), 
cortisol, adrenocorticotropic hormone (ACTH). TSH due at screening and the start of each new cycle. Free T3 and free 
T4 due if TSH is abnormal or if there is suspicion of an endocrine-related AE. Cortisol and ACTH due as clinically 
indicated. 
9   Coagulation parameters: prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio 
(INR) 
10   Urinalysis: color and appearance, pH, specific gravity, bilirubin, blood protein, glucose, ketones. Microscopy should 
be used as appropriate to investigate white blood cells and use the high power field for red blood cells.  
11 To be collected prior to C1D1, prior to C2D1, prior to C4D1, and at end of C6. For 11, prior = either the day before or 
prior to therapy. 
12 Mammogram, ultrasound of the ipsilateral breast within 60 days of the start of treatment. MRI of ipsilateral breast at 
baseline, end of cycle 1 (+/- 7 days), and at end of treatment prior to definitive surgery. Mammogram of the 
contralateral breast within 12 months of the start of treatment. Staging scans (CT chest, abdomen +/- pelvis and bone 
scan or PET/CT) should be considered, per institutional standard practice. Otherwise, staging scans should be 
obtained if clinically indicated. 
13 If tumor assessment by exam is performed at screening within 7 days prior to C1D1 of treatment, no need to repeat 
tumor assessment by exam on C1D1. 
14 MRI of ipsilateral breast at end of cycle 1 may be omitted at the discretion of the PI. 
15 mPEPI score will include tumor size and nodal status based on final pathology report for the definitive surgery as 
well as Ki67 value of the tumor from the definitive surgery. 
16 EOT is defined as the end of cycle 6 (28 +/- 7 days from C6D1) . For subjects who discontinue treatment early, EOT 
is considered as visit where the decision is made to discontinue treatment. All required procedures may be completed 
within ± 7 days of the EOT visit.  Repeat imaging disease assessment is not required if performed within 28 days 
prior to the end of treatment visit. 
17  First follow up visit will occur 90 to 97 days from last study treatment (durvalumab). The time to first follow up visit 
may be longer than 97 days, but in no case should it be <90 days. If first study visit is competed before 90 days after 
last durvalumab, the patient will be contacted 90 to 97 days following the last treatment to assess for adverse events. 
After all study therapy has been completed, patients will be followed for recurrence and survival for up to 5 years after 
registration (every 6 months +/- 1 month per either medical records or phone calls). 
 


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Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
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40 
 
9 
STUDY PROCEDURES 
9.1 
Screening phase 
The following screening procedures will be performed up to 28 days before Day 1, unless 
otherwise specified. Procedures that are performed prior to the signing of the informed 
consent form (ICF) and are considered standard of care may be used as screening 
assessments if they fall within the 28-day screening window. There is no time limitation 
on the standard of care biopsy to establish the diagnosis and to determine the receptor 
status.  
 Informed consent. 
 Review of eligibility criteria. 
 Medical history and demographics. 
 Review of prior/concomitant medications. 
 Complete physical exam including assessment of palpable tumor and ECOG 
Performance Status. 
 Vital signs, weight and height 12-lead ECGs (in triplicate 2-5 minutes apart). 
 Staging scans (CT chest, abdomen +/- pelvis or PET/CT) are not mandatory but 
should be considered as per institutional standard of practice. Otherwise, staging 
scans should be obtained if clinically indicated. 
 Archival tumor tissue (detailed requirements in section 9.4.6) and fresh tumor 
biopsy. Fresh tumor biopsy at baseline may be omitted at the discretion of the PI. 
 Clinical laboratory tests (see section 9.4.5 for details): 
o Hematology  
o Clinical chemistry  
o Thyroid function tests (TSH, free T3, free T4) 
o Coagulation  
o Creatinine Clearance 
o Urinalysis  
9.2 
Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Events (sections 8.1 and 8.2). Screening procedures performed within 7 days 
of C1D1 do not need to be repeated on C1D1. 
On the first day of each cycle: 
 Physical examination, including assessment of palpable tumor, ECOG 
performance status, vital signs (including infusion monitoring as described in 
section 9.4.4), and weight.  
 Assessment of adverse events and collection of concomitant medications. A 12-
lead ECG within 1 hour pre-infusion and 0-3 hours post end of infusion on C1D1 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
41 
 
only; and single ECG as clinically indicated. In case of a clinically significant 
ECG abnormality, including QTcF value > 470 ms, two additional ECGs 
collected 2-5 minutes apart should be obtained to confirm the findings. In this 
case, the final QTcF value will be the mean QTcF value calculated from all 3 
ECGs.  
 Hematology. 
 Clinical chemistry. 
o Results from the liver panel must be received prior to dosing. 
o GGT is only due on C1D1 and as clinically indicated. 
 Endocrine functions tests: TSH, free T3 and free T4 (only if TSH is abnormal or 
if there is clinical suspicion of an adverse event related to the endocrine system), 
ACTH and cortisol (if indicated). 
 Urinalysis. 
 Coagulation parameters as clinically indicated.  
 Correlative blood samples per Schedule of Events. 
 Administration of study treatments with an AI and durvalumab (on C1D1, 
patients are to take AI prior to infusion of durvalumab).  
 Tumor biopsy at the end of cycle 1 prior to C2D1 (within 7 days). May be omitted 
at the discretion of the PI. 
9.3 
End of Treatment Visit (28 +/- 7 days after last dose of durvalumab) 
End of treatment is defined as the end of cycle 6 (28 +/- 7 days from C6D1). For subjects 
who discontinue durvalumab prior to 6 months, end of treatment is considered the last 
visit where the decision is made to discontinue treatment. All required procedures may be 
completed within ± 7 days of the end of treatment visit. Repeat imaging disease 
assessment is not required if performed within 28 days prior to the end of treatment visit.  
 Physical examination, including assessment of palpable tumor, ECOG 
performance status, vital signs (including infusion monitoring as described in 
section 9.4.4), and weight.  
 Assessment of adverse events and collection of concomitant medications. 
 Hematology.  
 Clinical chemistry.  
 Endocrine functions tests. 
 Correlative blood samples per Schedule of Events. 
 Administration of study treatments with an AI and durvalumab (if applicable) 
 Breast imaging for disease assessment for all patients. Ipsilateral breast 
mammogram, ultrasound and/or breast MRI are acceptable, provided that the 
same method is used throughput for an individual patient. 
 If clinically indicated: urinalysis, coagulation parameters, 12-lead ECG.  


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Version Date: January 30, 2019 
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All subjects will be followed for recurrence free survival until the end of the study, or 
until the sponsor ends the study. 
9.4 
Description of Study Procedures 
9.4.1 Medical history 
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. 
9.4.2 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.  
9.4.3 Vital signs 
Vital signs (blood pressure, pulse, temperature, and respiration rate) and body weight will 
be evaluated according to the assessment schedules.  
Supine 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 treatment before, during, and after each 
infusion at the following times (based on a 60-minute infusion):  
1. Prior to the beginning of the infusion (measured once from approximately 30 
minutes before up to the beginning of the infusion which is t = 0 minutes).  
2. Approximately 30 minutes into the infusion (halfway through infusion).  
3. At the end of the infusion (approximately 60 minutes ± 5 minutes).  
4. A 1-hour observation period is required after the first infusion of durvalumab. 
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 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 eCRF. Additional monitoring with assessment of vital signs is at the 
discretion of the Investigator per standard clinical practice or as clinically indicated.  
9.4.4 Clinical laboratory tests 


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Principal Investigator: Hung T. Khong, MD 
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43 
 
The following clinical laboratory tests will be performed per the Schedule of 
Assessments: 
 Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential (total neutrophil count including lymphocyte, monocyte, 
eosinophil and basophil counts), platelet count, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration. 
 Clinical chemistry: sodium, potassium, chloride, carbon dioxide, alkaline 
phosphatase, AST, ALT, BUN, glucose, creatinine, calcium, total protein, 
albumin, total bilirubin (direct and indirect bilirubin will be measured if total 
bilirubin is ≥ 2 x ULN with no evidence of Gilbert’s syndrome), lactate 
dehydrogenase (LDH), magnesium, uric acid, amylase, lipase, GGT. 
 
 Coagulation parameters: prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR).  
 Endocrine function tests: TSH, free T3, free T4, cortisol, adrenocorticotropic 
hormone (ACTH). 
 Urinalysis: color and appearance, pH, specific gravity, bilirubin, blood protein, 
glucose, ketones. Microscopy should be used as appropriate to investigate white 
blood cells and use the high power field for red blood cells.  
9.4.5 Correlative samples 
Correlative blood samples 
Blood samples for correlative studies will be collected for the following tests as well as 
stored for future research:  
 Cytokine level measurement (before C1D1, C2D1, C4D1 and end of C6 or EOT). 
Additional details about correlative blood samples are provided in section 14.4. 
Archival tumor samples and fresh tumor biopsies 
Tumor tissue samples will be collected before the first study treatment, at the end of cycle 
1 (within 7 days), and from the definitive surgical specimens. Collection of fresh tissue 
samples may be omitted at the discretion of the PI. 
Archival tissue is acceptable for enrollment after confirmation that stored tissue blocks 
are of adequate quality and can yield a minimum of 10 sections each 4 to 5 microns thick. 
A fresh biopsy is mandatory if the amount of archival tissue is insufficient.  
Fresh tumor tissue collection via ultrasound-guided core biopsy is mandatory once a 
patient has completed one cycle of treatment (collection to be within 7 days of the end of 
a cycle). However, this may be omitted at the discretion of the PI. 
Tumor tissue samples will be analyzed for changes in PD-L1 expression, changes in 
subtypes of immune infiltrates, cytokine patterns, and levels of Ki-67 expression.  
Further details about sample collection, storage, and testing are provided in the laboratory 
manual and in sections 14.1 and 14.2. 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
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10 
CRITERIA FOR EVALUATION AND ENDPOINT 
10.1 
Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical 
laboratory test results. More frequent safety evaluations may be performed if clinically 
indicated or at the discretion of the investigator. 
The type, incidence, severity, timing, seriousness, and relatedness of adverse events and 
laboratory abnormalities will be assessed and recorded. 
10.2 
Efficacy 
Tumor response will be assessed by clinical breast examination (CBE), which includes 
examination of the breast, axilla, and supraclavicular fossa. Tumor assessment by 
imaging is required prior to surgery. 
Evaluation by Clinical Exam or Imaging 
The following definition of response will be used for objective clinical response rate: 
Clinical complete response (CR): Palpable lesion(s) identified at baseline are no longer 
palpable and there are no new lesion(s) or other signs of disease progression.  
Clinical partial response (PR): A reduction in the product of the two largest perpendicular 
diameters of the primary tumor by 50% or more. 
Clinical progression of disease (PD): An increase in the product of the two largest 
perpendicular diameters of the primary tumor by 25% or more or the presence of a new 
lesion. 
Clinical stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
Evaluation by pathologic Assessment: 
All patients will be followed through their post-treatment standard of care surgery to 
evaluate pathologic response per local pathologist’s assessment. Pathologic complete 
response is defined as no histologic evidence of invasive tumor cells in the surgical breast 
specimen, axillary nodes, or non-axillary sentinel nodes (SNs) identified after 
neoadjuvant therapy. 
10.3 
Stopping Rules 
Safety run-in phase: Refer to section 4.2 for definition and evaluation of Dose Limiting 
Toxicities. 
Extension phase: Based on a Simon’s two stage Optimum design (see statistical details 
in section 11.3), an initial analysis will be done on the first 14 evaluable patients (this 
includes the 6 patients in the safety run-in phase). Recruitment will be terminated if an 
mPEPI 0 is achieved in 0 or 1 patients. If 2 or more patients achieve an mPEPI 0 the 


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45 
 
study will proceed to enroll until a total of 42 evaluable patients have been accrued (for 
an estimated total of 46 patients assuming a 10% nonevaluability).  
11 
STATISTICAL CONSIDERATIONS 
11.1 
Description of analysis sets 
11.1.1 
Safety analysis set 
Safety run-in phase: The safety analysis set will include all subjects who received at 
least 1 dose of AI or durvalumab, and had adverse events recorded at all visits up to and 
including C2D1 (prior to cycle 2 infusion) or had experienced a DLT at one or more 
visits up to and including C2D1 (prior to cycle 2 infusion). 
Extension phase: The safety analysis set will include all subjects who received at least 
one dose of AI or durvalumab.  
11.1.2 
Efficacy analysis set 
The efficacy analysis set will include all subjects in both safety run-in phase and 
extension phase of the study who received at least 1 planned dose of AI and durvalumab. 
11.2 
Methods of statistical analyses 
11.2.1 
Safety Analyses 
Safety data will be summarized for all patients receiving at least 1 dose of study 
treatment. 
All patients who receive any study treatment will be included in the final summaries and 
listings of safety data. Detailed information collected for each AE will include a 
description of the event, duration, severity, relatedness to study drugs, action taken, and 
clinical outcome. Severity of the AEs will be graded according to the CTCAE version 
5.0.  
The DLT analysis will include the 6 DLT evaluable subjects enrolled in the safety run-in 
phase who must have had the opportunity to be on treatment for 1 cycle (4 weeks) from 
the initial dosing of durvalumab and received at least 1 dose of AI and one dose of 
durvalumab. 
11.2.2 
Efficacy Analyses 
Primary Endpoint: A Simon’s two-stage Optimum design will be used in which the drug 
will be determined to be efficacious if 7 or more patients achieve an mPEPI of 0. The 
study will stop after the first 14 patients are enrolled if 1 or fewer patients achieve an 
mPEPI of 0. 
Secondary Endpoints: The best response, including complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD), for each patient will also 
be summarized with 95% confidence intervals. Descriptive statistics will be used to 


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summarize all patient characteristics, treatment administration and compliance.  Kaplan-
Meier curves will be used to estimate the median recurrence free survival time. 
 
11.3 
Determination of sample size 
Sample Size Justification/Statistical Analysis: 
A Simon two-stage Optimum design will be used in phase 2 for the calculation of sample 
size. Achieving mPEPI 0 in less than 10% of the patients is non desirable (response 
probability of poor drug P0 = 0.10) and we aim to achieve mPEPI 0 in at least 25% of the 
patients (response probability of good drug P1 = 0.25). The type I error rate and power 
were set to 0.10 and 85%, respectively. The first stage sample size is 14 evaluable 
patients. If 2 or more patients achieve mPEPI 0 among the first 14 evaluable patients the 
study will continue to enroll until reaching the maximum sample size of 42 (for an 
estimated total of 46 patients assuming a 10% nonevaluability). The treatment would be 
considered worthwhile for further study if 7 or more patients out of the 42 achieve 
mPEPI 0. The probability of early termination is 0.585 and the expected sample is 25.63. 
Note, PEPI score 0 was obtained in approximately 16% of patients with AI alone (5)3. 
However, in this study, clinical T2 N0 stage accounted for approximately three quarters 
of the study population. Knowing our patient population and referral patterns for 
neoadjuvant therapy for ER+ disease, we projected that the vast majority of patients 
referred to this study would be clinically node positive (at least N1) and/or T3, either or 
both of which could and would greatly reduce the rate of PEPI score 0. That was the 
reason for our setting the non-desirable rate at a lower number, 10% instead of 16%.  
12 
REGISTRATION GUIDELINES 
All subjects must personally sign and date the consent form before commencement of 
study-specific procedures (i.e., non-standard of care procedures). 
All subjects who enter into the screening period for the study (defined as the point when 
the subject signs the informed consent) must be registered as screened subjects and will 
receive a unique subject identification number before any study-specific procedures are 
performed. This number will be used to identify the subject throughout the clinical study 
and must be used on all study documentation related to that subject.  
Subjects that are determined to be eligible for study entry will be enrolled in the study. 
Subjects that are determined not eligible must be designated as screen failures, and the 
reason for the screen-failure provided. Subjects who do not meet all eligibility criteria 
may be rescreened once at the discretion of the investigator. If a subject is being 
rescreened, he or she may need to reconsent to the study to ensure that the Institutional 
Review Board (IRB)-approved informed consent form has been signed within 28 days of 
enrollment. Subjects who are determined ineligible after rescreening must be designated 
as screen-failures, and the reason for the screen failure must be provided. 
Subjects who fail to meet the inclusion criteria or who meet the exclusion criteria should 
not, under any circumstances, be enrolled. There can be no exceptions to this rule. Where 


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subjects who do not meet the selection criteria are incorrectly started on treatment, or 
where subjects subsequently fail to meet the study criteria post initiation, a discussion 
will occur between the Principal Investigator and the Protocol Monitoring Committee 
regarding whether to continue or discontinue the subject from treatment. The PI and the 
PMC are to ensure all such decisions are appropriately documented. In situations where 
an agreement cannot be reached, the subject should have their study therapy stopped. 
Treatment should start within five working days after registration. The registration date 
will be the enrollment date. 
To register eligible patients on study, patients must sign an informed consent prior to 
screening and registration indicating awareness of the investigation nature of the study. 
Eligibility will be centrally reviewed by the Moffitt Monitoring Core following 
completion and investigator certification of a Moffitt approved eligibility checklist. The 
checklist will be emailed to monitoring.core@moffitt.org during regular business hours. 
After monitoring core QA review is complete, patients will be registered into 
Oncore on study and initiate study treatment. 
13 
DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of electronic forms for each patient that 
provides a record of the data generated according to the protocol. CRF’s should be 
created prior to the study being initiated and updated (if applicable) when amendments to 
the protocol are IRB approved. Data capture should be restricted to endpoints and 
relevant patient information required for planned manuscripts. These forms will be 
completed on an on-going basis during the study. The medical records will be source of 
verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility and attention to detail by a member of the Research Compliance 
Office. The CRFs will be completed by the Investigator or a member of the study team as 
listed on the Delegation of Duties Log. The data will be reviewed no less than annually 
by the Protocol Monitoring Committee. The Investigator will allow the Protocol 
Monitoring Committee or Research Compliance Office personnel access to the patient 
source documents, clinical supplies dispensing and storage area, and study documentation 
for the above-mentioned purpose. The Investigator further agrees to assist the site visitors 
in their activities. 
14 
SPECIAL INSTRUCTIONS  
14.1 
Tumor tissue for PD-L1 testing 
Preferred baseline sample for PD-L1 testing are less than or equal to 3 months old. In 
cases where an archived sample less than 3 months old is not available, patients will be 
asked to undergo a new biopsy if considered clinically appropriate by their treating 
physician.  
Fresh samples should be collected via a core needle of 18 gauge or larger or be collected 
by an incisional or excisional tumor biopsy. Where institutional practice uses a smaller 


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gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) 
to allow for adequate PD-L1 immunohistochemistry analyses.  
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin. 
Samples from fine needle aspirates (FNA) are not appropriate for PD-L1 analysis. A 
minimum of 5 slides 4 to 5 microns in thickness is required for testing. 
To ensure comparability of data across all studies of durvalumab and/or tremelimumab 
and to gain real world experience on the performance of this assay, it is encouraged that 
all studies that include PD-L1 testing utilize the Ventana SP263 assay. 
14.2 
Tumor tissue for other testing 
Tumor tissue samples embedded in paraffin will also be analyzed by hematoxylin-eosin 
and immunohistochemical staining for several biomarkers, including biomarkers of 
immune cell response (i.e., CD3, CD4, CD8, CD56), immune cell activation (i.e., 
CD45RO, HLA-DR, CD137), proliferation (Ki67) (Ki67 will be obtained on both tumor 
cells and T cells), Treg phenotype (i.e., CD4/CD25/FOXP3).   
Frozen tumor tissue samples will be stored for future studies (including TCR sequencing 
and the generation of tumor-infiltrating lymphocytes and the characterization of their 
phenotype and function as well as generation of tumor clones and the characterization of 
their phenotypes and mutational status). 
A minimum of 5 slides 4 to 5 microns in thickness is required for the above testing. 
14.3 
Other correlative studies 
Serum and plasma will be collected at baseline, the end of cycle 1, of cycle 3, and of 
cycle 6 or EOT . Serum will be tested for cytokine levels using ELISA. The rest of the 
serum and plasma will be stored for future studies. 
Estimates for total blood volume collections are as follows: 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety: 
Clinical chemistry 
7 
6-12 
42-84 
 
Hematology 
7 
6-12 
42-84 
 
 
 
 
 
 
 
 
Biomarker (serum/plasma) 
60 
4 
240 
Total 
 
 
324-408 


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15 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Informed consent  
Informed consent will be obtained from all research participants prior to performing any 
study procedures using the most recent IRB approved version.  
15.2 
Institutional Review 
Study will be approved by a central Institutional Review Board. 
15.3 
Adverse Events 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
15.3.1 This study will utilize the CTCAE Version 5.0 for AE and SAE reporting. An 
electronic copy of the CTCAE Version 5.0 can be downloaded from 
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspxAdverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. For the purposes of this study, the terms toxicity 
and adverse event are used interchangeably. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. Elective treatment or surgery or preplanned treatment or surgery (that was 
scheduled prior to the subject being enrolled into the study) for a documented pre-
existing condition, that did not worsen from baseline, is not considered an AE. 
The collection of adverse events will begin after first study drug administration and end 
90 days post last dose of study treatment or initiation of a new anticancer therapy, 
whichever comes first.  
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
After 90 days, only subjects with ongoing investigational product-related SAEs will 
continue to be followed for safety. 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or 
other means, will be collected and recorded and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit or phone contact during the study. Adverse events also may be 
detected when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. As far as possible, each 
adverse event should be evaluated to determine: 
 Its severity grade based on CTCAE v. 5.0 (grade 1 to 5). 


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 Its relationship to each of the study drugs (definite, probable, possible, unlikely, 
and not related). 
 Its duration (start and end dates or if continuing at final exam). 
 Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; hospitalization/prolonged 
hospitalization). 
 Whether it constitutes an SAE. 
All adverse events will be treated appropriately. Such treatment may include changes in 
study drug treatment as listed in the dose interruption and modification section of this 
protocol (see section 7.1 for guidance). Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the study drugs drug are 
described in the drug information section (section 3.1), the most recent investigator 
brochures (for durvalumab), and the FDA-approved product labels (for the three AIs). 
This information will be included in the patient informed consent and will be discussed 
with the patient during the study as needed. 
All adverse events will be recorded in the subject specific AE log.  
15.3.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. Moffitt 
Cancer Center and all participating sites will report SAEs by completing an SAE 
report in ONCORE, the electronic data capture system. 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 Is fatal or life-threatening. 
 Results in persistent or significant disability/incapacity. 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
 Causes congenital anomaly or birth defect. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition (procedures such as central line 
placements, paracentesis, and pain control). 
o Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start 
of study drug. 


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o Treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of a SAE given above and not resulting in hospital 
admission. 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition. 
Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless of whether they are felt to be treatment related or not. Toxicities unrelated to 
treatment that do NOT fall within the definitions above, must simply be documented as 
AEs in the patient research chart 
The collection of serious adverse events will begin after signature of the ICF and end 90 
days post last dose of study treatment or initiation of a new anticancer therapy, whichever 
comes first. If a subject discontinues 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. 
In addition to capturing all information required for an AE, the following information 
will be collected for SAE as applicable: 
 Date AE met criteria for serious AE 
 Date Investigator became aware 
of serious AE 
 Which criterion makes the AE 
serious  
 Date of hospitalization 
 Date of discharge 
 Probable cause of death 
 Date of death 
 Autopsy performed 
 Description of AE 
 Causality assessment in relation 
to Study procedure(s) 
 Causality assessment in relation 
to Additional Study Drug 
15.3.3 Death 
All deaths that occur during the study, or within the protocol-defined 90-day post-last 
dose of durvalumab 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 as an SAE. 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.  
Any death which occurs more than 90 days after protocol treatment has ended but which 
is felt to be treatment related, must be reported. 
15.3.4  Adverse events of special interest 


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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 the sponsor. 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 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 the Principal Investigator. 
AESIs observed with durvalumab include: 
 Diarrhea / Colitis and intestinal perforation 
 Pneumonitis / ILD 
 hepatitis / transaminase increases 
 Endocrinopathies 
(i.e. 
events 
of 
hypophysitis/hypopituitarism, 
adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
 Rash / Dermatitis 
 Nephritis / Blood creatinine increases 
 Pancreatitis  / serum lipase and amylase increases   
 Myocarditis 
 Myositis / Polymyositis 
 Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
 Other inflammatory responses that are rare / less frequent with a potential 
immune-mediated aetiology include, but are not limited to, pericarditis, 
sarcoidosis, uveitis and other events involving the eye, skin, haematological and 
rheumatological events. 


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 In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions 
with a different underlying pharmacological etiology are also considered AESIs. 
 Further information on these risks (e.g. presenting symptoms) can be found in the 
current version of the durvalumab Investigator’s Brochures. More specific 
guidelines for their evaluation and treatment are described in detail in the Dosing 
Modification and Toxicity Management Guidelines (please see Appendix 1). 
These guidelines have been prepared by AstraZeneca to assist the Investigator in 
the exercise of his/her clinical judgment in treating these types of toxicities.  
These guidelines apply to AEs considered causally related to the study drug/study 
regimen by the reporting investigator. 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator Brochure.  
For durvalumab, AESIs will comprise the following: 
Pneumonitis 
AEs of pneumonitis are 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.  
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti PD-L1 and anti-PD-1 therapy (44). 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 


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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 
(e.g., 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.  
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 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. 
15.3.5 Immune-related adverse events 
Based on the mechanism of action of durvalumab 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-


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mediated enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and 
endocrinopathies). Error! Bookmark not defined.,1 These AEs are inflammatory in nature and can 
affect any organ. Patients should be monitored for signs and symptoms of irAEs. In the 
absence of an alternate etiology (e.g., 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 
Appendix 1, it is recommended that irAEs are managed according to the general 
treatment guidelines outlined for ipilimumab. 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 (e.g., infliximab or mycophenolate). 
 If the Investigator has any questions in regards to an AE being an irAE, the 
Investigator should immediately contact the PI. 
15.3.6 Potential drug-induced liver injury 
The combination of increased transaminases plus increased total bilirubin may be 
indicative of drug-induced liver injury (DILI), and should be considered as clinically 
important events. Patients meeting any of the following criteria will require further 
follow-up as outlined below: 
 For patients with normal ALT, AST, and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin >2.0 x ULN. 
 For patients with elevated AST, ALT, or total bilirubin value at baseline: AST or 
ALT > 2 x baseline and > 3.0 x ULN OR AST or ALT > 8.0 x ULN, whichever is 
lower, combined with total bilirubin > 2 x baseline and > 2.0 x ULN.  
Medical review needs to ensure that liver test elevations are not caused by cholestasis, 
defined as an alkaline phosphatase elevation > 2.0 x ULN with R value < 2 in patients 
without bone metastasis, or elevation of alkphos liver fraction in patients with bone 
metastasis. 
Note: The R value is calculated by dividing the ALT by the alkphos, using multiples of 
the ULN for both values [R value = (ALT/ULN)/(alkphos/ULN)]. It denotes the relative 
pattern of ALT and/or alkphos elevation is due to cholesteric or hepatocellular liver 
injury or mixed type injury. 
An R value > 5.0 is used to define hepatocellular injury, R < 2.0 as cholestatic injury, and 
R between 2.0 to 5.0 as mixed hepatocellular-cholestatic injury. 


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In the absence of cholestasis, these patients should be immediately discontinued from 
study drug treatment, and repeat LFT testing as soon as possible, preferably within 48 
hours from the awareness of the abnormal results. The evaluation should include 
laboratory tests, detailed history, physical assessment and the possibility of liver 
metastasis or new liver lesions, obstructions/compressions, etc. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with 
no other alternative cause for LFT abnormalities identified, should be considered as 
“medically significant”, thus met the definition of SAE, and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the 
outcome clearly documented. 
15.4 
SAE Reporting Requirements 
SAEs must be reported concurrently to the IRB according to IRB policy and AstraZeneca 
within 24 hours of learning of the event.   
All SAEs will be reported to the Clinical Trial Office of Moffitt Cancer Center in 24 hours 
via ONCORE. . 
External sites should abide by local IRB requirements for submission of SAEs.  
AstraZeneca Notifications: 
All SAEs will be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). The reporting period for SAEs is the 
period immediately following the time that written informed consent is obtained through 
90 days after the last dose of durvalumab or until the initiation of alternative anticancer 
therapy. The investigator and/or Sponsor are responsible for informing the Ethics 
Committee and/or the Regulatory Authority of the SAE as per local requirements. 
The Investigator (or other designated site personnel) must notify the appropriate 
AstraZeneca representative of an SAE no later than 24 hours after becoming aware of 
the event. 
The designated AstraZeneca representative will work with the Investigator to ensure that 
all necessary information is provided to the AstraZeneca Patient Safety data entry site 
within 1 calendar day of initial receipt for fatal and life threatening events and within 5 
calendar days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site personnel 
inform AstraZeneca representatives of any follow-up information on a previously 
reported SAE no later than 24 hours of becoming aware of it.  
A MedWatch 3500A form must be completed along with a cover page indicating the 
following: 
 “Notification from an Investigator Sponsored Study” 
 The investigator IND number assigned by the FDA 
 The investigator’s name and address 


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 The trial name/title and AstraZeneca ISS reference number (ESR-17-13182) 
The investigator must also ensure that either the SAE report or the cover page detail the 
causality of the event in relation to all study medications and whether the event is related 
to disease progression, as determined by the principal investigator. 
SAE reports and accompanying cover pages will be sent via 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 and the FDA. 
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.  
15.5 
Other events requiring reporting 
15.5.1 Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Principal 
Investigator, the PMC (via the RCO), and AstraZeneca/MedImmune Patient Safety or 
designee using the designated safety e-mailbox (see Section 15.5 for contact 
information).  
If the overdose results in an AE, the AE must also be recorded as such. 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.  
There is currently no specific treatment in the event of an overdose of durvalumab. The 
investigator will use clinical judgment to treat any overdose. 
15.5.2 Hepatic function abnormality 
Hepatic function abnormality (as defined in section 15.4.6) 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 Principal Investigator, the 
PMC (via the RCO), and AstraZeneca/MedImmune Patient Safety using the designated 
Safety e-mailbox (see Section 15.5 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. 


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 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 Principal Investigator, the PMC, and AstraZeneca/MedImmune. 
15.6 
Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period for 
which the IRB approval has already been given will not be initiated without submission 
of an amendment for IRB review and approval.  
These requirements for approval will in no way prevent any immediate action from being 
taken by the investigator in the interests of preserving the safety of all patients included 
in the trial.  
15.7 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved by 
the IRB. Protocol deviations have the potential to place participants at risk and can also 
undermine the scientific integrity of the study thus jeopardizing the justification for the 
research. Protocol deviations are unplanned and unintentional events. 
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations which 
meet any of the following criteria: 
 Exceptions to eligibility criteria. 
 Intended to eliminate apparent immediate hazard to a research participant.  
 Harmful (caused harm to participants or others, or place them at increased risk. 
harm - including physical, psychological, economic, or social harm). 
 Possible serious or continued noncompliance.  
15.8 
FDA Annual Reporting  
An annual progress report will be submitted to the FDA within 60 days of the anniversary 
of the date that the IND went into effect. [21 Code of Federal Regulations (CFR) 312.33]. 
Content of this report is listed in Appendix III. 
15.9 
Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical 
Trials Reporting Program) by the Clinical Trials Office. 


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16 
DATA MANAGEMENT 
16.1 
Data Collection 
The Clinical Research Coordinators, Data Specialists, and Investigators of each site will be 
responsible for the recording of the site’s data into the electronic data capture system, ONCORE. 
16.2 
Protocol Monitoring Committee 
The Protocol Monitoring Committee (PMC) will be composed of medical and statistical 
independent reviewers and will meet to review the efficacy and safety data and determine a 
risk/benefit analysis in this subject population. The purpose of the PMC is to advise on serious 
safety considerations, lack of efficacy and any other considerations within the charge to the 
Committee. The PMC may request additional meetings or safety reports as deemed necessary 
upon discussion with the principal investigator. The PMC may stop the study following review 
of results from each interim analysis. The PMC meets monthly and reviews accrual, patterns and 
frequencies of all adverse events, protocol violations and when applicable, internal audit results. 
16.3 
Study Monitoring and Auditing 
16.3.1 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
Investigators, or a designated member, must enter study data onto CRFs or other data collection 
system. The Investigator will permit study-related monitoring visits and audits by AstraZeneca 
or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), 
providing direct access to the facilities where the study took place, to source documents, to 
CRFs, and to all other study documents.  
 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during monitoring visits to review data and resolve any queries and to allow direct access to 
the subject’s records (e.g., medical records, office charts, hospital charts, and study related 
charts) for source data verification. The data collection must be completed prior to each visit and 
be made available to the AstraZeneca representative so that the accuracy and completeness may 
be checked.  
16.3.2 Site Responsibilities 
A conference call/study meeting will be held monthly to review patient enrollment and accrual, 
safety and toxicity data, and treatment results, as available.  
16.3.3 Monitoring 
Monitoring will be performed regularly by the MCC Clinical Monitoring Core for accuracy, 
completeness, and source verification of data entry, validation of appropriate informed consent 


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process, reporting of SAEs, and adherence to the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements  
 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. The monitoring will include source data verification, utilizing research subjects’ 
medical records.  
 
The Sponsor maintains a robust pharmacovigilance system comprising a governance framework 
and standard operating procedures supporting a systematic process for review, evaluation, and 
management of accumulating safety data from clinical trials and other sources to identify a 
potential new safety signal and ensure that an investigational product’s risks are adequately 
assessed and communicated to investigators, IRBs/IECs, and regulatory bodies during clinical 
development.  
 
For this study, safety monitoring activities will include but are not limited to review and 
evaluation of single serious adverse event (SAE) occurrences in real-time as reported through the 
SAE reporting process outlined in this section of the protocol, and review and evaluation, in real-
time, of one or more occurrences of an uncommon SAE that is not commonly associated with 
product exposure.  
Findings and/or safety data obtained during this study will provide information for the overall 
review of safety that is conducted by the Sponsor on a routine basis. The Sponsor will report 
expeditiously any findings from clinical trials (ongoing or completed), epidemiological studies, 
pooled analysis of multiple studies, and findings from animal or in vitro testing that suggest a 
significant risk in humans exposed to the study product.  
 
Safety data collection for this study begins at the time of the subject’s receiving the first dose of 
study medication. The investigator is responsible for the detection and documentation of events 
that meet the definition of an unanticipated problem, AE or SAE.  
 


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17 
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Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
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27. 
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Zhang Q, Tang D, Zhao H. Immunological therapies can relieve aromatase inhibitor-
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Chen J, Feng Y, Lu L, et al. Interferon-γ-induced PD-L1 surface expression on human 
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Abiko K, Matsumura N, Hamanishi J, et al. IFN-γ from lymphocytes induces PD-L1 
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Muenst S, Schaerli AR, Gao F, et al. Expression of programmed death ligand 1 (PD-L1) 
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Yardley D, Green N, Papish S, et al. Rheumatologic Evaluation of Adjuvant Letrozole in 
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Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. 
          Pharmacokinetics of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in 
 


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          Patients with advanced solid tumors. Journal of Clinical Oncology 32, no. 15_suppl (May 
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Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size based dosing of 
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activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 
Jun 28;366(26):2455-65. 
 


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18 
APPENDIX  


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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions [Durvalumab (MEDI4736)] 1 November 2017 Version 
General Considerations 
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 v5.0. 
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. 
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. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
 
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. 
 
Some events with high likelihood for morbidity and/or mortality – e.g., myo-
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., 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 (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 


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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions [Durvalumab (MEDI4736)] 1 November 2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
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: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., 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. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (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 (e.g., 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 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 


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general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP 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 study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., 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; consider, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., 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 
(e.g., 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 patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 
2B recommendation]).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
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 (e.g., disease progression, other 
medications, or infections), including testing for clostridium 


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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 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day) 
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
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 (e.g., 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 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. 
− 
Consider, as necessary, discussing with study physician 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 


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anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3 diarrhea: stool 
frequency of ≥7 over 
baseline per day; 
Grade 4 diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: severe 
abdominal pain, change 
in bowel habits, medi-
cal intervention indi-
cated, peritoneal signs; 
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
 
Grade 3 
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper. 
 
Grade 4 
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 (e.g., 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-PJP treatment (refer to current NCCN guidelines for 
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 (e.g., viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and  
≤1.5×ULN) 
 
No dose modifications. 
 
If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 


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Grade 2 
(AST or  
ALT >3.0×ULN and 
≤5.0×ULN and/or  
TB >1.5×ULN and  
≤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 (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider, as 
necessary, discussing with study physician. 
− 
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 work up 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 (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP 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 >5.0×ULN and 
≤20.0×ULN and/or  
TB >3.0×ULN and  
≤10.0×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 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 (i.e., 
mycophenolate mofetil). Discuss with study physician 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-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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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 initial 
findings of cholestasis (i.e., 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 (e.g., 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 (e.g., 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; > 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 


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ULN to 1.5 × ULN) 
 
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. 
− 
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-PJP 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; 
 
Grade 4: serum 
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. 
− 
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 


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creatinine >6.0 × ULN) 
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-PJP 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 5.0 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, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., 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 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., 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, consider, as necessary, 
discussing with study physician 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. 
 
 


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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-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v5.0 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
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, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as there 
are no other signs or symptoms of pancreatic inflammation. 


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− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., 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. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
− 
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 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, 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. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
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 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, consider short-term corticosteroids (e.g., 1 
to 2 mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 


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investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
[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 and Type 1 diabetes 
mellitus, 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. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
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. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v5.0 
for defining the CTC 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 


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excluding Myasthenia 
Gravis and Guillain-
Barre) 
grade/severity) 
− 
Consider appropriate diagnostic testing (e.g., 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: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., 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 
(e.g., 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 imAE does not resolve 
to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
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 (e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 


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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 
(e.g., 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 essential to have a low 
threshold to obtain a neurological consult. 
− 
Neurophysiologic diagnostic testing (e.g., 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: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 


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regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability. 
of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., 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 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 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
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 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
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82 
 
autonomic instability. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
neurologist. 
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. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
83 
 
medications, or infections) 
 
Grade 1 
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion) 
 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or 
exertion; 
intervention indicated) 
 
(Grade 
4: 
Life-
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support)) 
 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
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-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
84 
 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
(moderate 
pain 
associated 
with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
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 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
85 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
insufficiency. 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
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-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Grade 3 or 4 
(pain associated with 
severe 
weakness; 
limiting 
self-care 
ADLs) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
86 
 
bFDA 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; imAE immune-mediated 
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; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
87 
 
Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
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 (e.g., 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 (e.g., 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 (e.g., 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. 
 
 
 


Protocol name: DURVALUMAB TRIAL IN POSTMENOPAUSAL BREAST CANCER 
Version Date: January 30, 2019 
Principal Investigator: Hung T. Khong, MD 
Version number: v5.1 
 
88 
 
Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., 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 Sponsor.). 
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 Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.