A Single Arm Phase II Study Evaluating the Efficacy and Safety of MEDI4736 in Combination With Tremelimumab in Patients With Metastatic Her2 Negative Breast Cancer
Phase: PHASE2
Conditions: Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, Recurrent Breast Carcinoma, Stage IV Breast Cancer
Sponsor: Northwestern University

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
A SINGLE ARM PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF 
DURVALUMAB (MEDI4736) IN COMBINATION WITH TREMELIMUMAB IN PATIENTS WITH 
METASTATIC HER2 NEGATIVE BREAST CANCER: TNBC EXPANSION COHORT
Principal Investigator:
Massimo Cristofanilli, MD
Professor of Medicine
Associate Director of Translational Research and Precision Medicine
Department of Medicine-Hematology and Oncology
Robert H Lurie Comprehensive Cancer Center
Feinberg School of Medicine
710 N Fairbanks Court, Olson Building, Suite 8-250A
Chicago, IL 60611
Tel: 312-503-5488
Email: Massimo.cristofanilli@nm.org
Sub-Investigator(s):                        Northwestern University
                                                          Ami Shah, MD
                                                         Lisa Flaum, MD
                                                        Claudia Tellez, MD                                                    
                                                        William J. Gradishar, MD 
    Luis Blanco, MD
                              
Biostatistician:
  Borko Jovanovic, PhD
                                                         borko@northwestern.edu
Study Intervention(s):
Durvalumab (MEDI4736), Tremelimumab
IND Number:
127042
IND Holder:
  Massimo Cristofanilli, MD
Funding Source:
  Northwestern University 
Medimmune [Drug source]
Avon Breast Cancer Foundation
Version Date:
8.31.2020 
Amendment:
12 
Coordinating Center:
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL 60611 
http://cancer.northwestern.edu/cro/index.cfm
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NU Study Number: NU 15B01
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NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
LIST OF ABBREVIATIONS..............................................................................................................................3
STUDY SUMMARY ..........................................................................................................................................5
1.0
INTRODUCTION – BACKGROUND & RATIONALE.....................................................................7
2.0
OBJECTIVES & ENDPOINTS......................................................................................................13
3.0
PATIENT ELIGIBILITY .................................................................................................................14
4.0
TREATMENT PLAN.....................................................................................................................18
5.0
STUDY PROCEDURES ...............................................................................................................48
6.0
ENDPOINT ASSESSMENT..........................................................................................................53
7.0
ADVERSE EVENTS .....................................................................................................................54
8.0
DRUG INFORMATION.................................................................................................................66
9.0
CORRELATIVES/SPECIAL STUDIES .........................................................................................73
10.0
STATISTICAL CONSIDERATIONS..............................................................................................74
11.0
STUDY MANAGEMENT...............................................................................................................76
APPENDICES ................................................................................................................................................79
REFERENCES: ............................................................................................................................................123
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
H&PE
History & Physical Exam
IV (or iv)
Intravenously
ID
Infectious disease identifying data
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
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STUDY SCHEMA (General cohort)
Stage IV (metastatic) HER 2 Negative Breast Cancer
Combination therapy of Durvalumab 1500mg IV every 4 weeks 
for 4 doses and Tremelimumab 75mg  IV every 4 weeks for 4 
doses.1 After completion of the 4 doses of combination therapy, 
durvalumab will be continued at a dose of 750mg every 2 weeks 
for up to 18 additional doses. The first 750mg dose of 
durvalumab will be 4 weeks after the last combination dose.
Response Assessment every 2 cycles*
Patients may continue on therapy after progression or after 
initial 52 week treatment period (as specified in Sections 4.1.1 
and 4.1.2).
Once off treatment continue follow up at 3, 6, 9, 12 months, 
then every 6 months up to 3 years or until time of death
*Scans are to be completed every 8 weeks, regardless of drug holds or treatment delays
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STUDY SCHEMA (Expansion cohort)
Stage IV (metastatic) TripleNegative Breast Cancer
Combination therapy of Durvalumab 1500mg IV every 4 weeks 
for 4 doses and Tremelimumab 75mg  IV every 4 weeks for 4 
doses.1 After completion of the 4 doses of combination therapy, 
durvalumab will be continued at a dose of 750mg every 2 weeks 
for up to 18 additional doses. The first 750mg dose of 
durvalumab will be 4 weeks after the last combination dose.
Response Assessment every 2 cycles*
Patients may continue on therapy after progression or after 
initial 52 week treatment period (as specified in Sections 4.1.1 
and 4.1.2).
Once off treatment continue follow up at 3, 6, 9, 12 months, 
then every 6 months up to 3 years or until time of death
*Scans are to be completed every 8 weeks, regardless of drug holds or treatment delays.
STUDY SUMMARY
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Title
A Single Arm Phase II Study Evaluating the Efficacy and Safety of 
Durvalumab (MEDI4736) In Combination With Tremelimumab In Patients 
with Metastatic HER2 Negative Breast Cancer: TNBC expansion cohort  
Short Title
Durvalumab and Tremelimumab in Metastatic Breast Cancer
Version
Amendment 12 dated 8.31.2020
Study Design
Phase II
Study Center
Northwestern University
Objectives
Primary Objective:
To evaluate overall response rate (ORR) in patients with metastatic 
HER2 negative breast cancer treated with durvalumab in combination 
with tremelimumab.
Expansion Cohort Objective: To evaluate overall response rate (ORR) in 
patients with metastatic triple negative breast cancer treated with 
durvalumab in combination with tremelimumab.
Secondary Objectives:
To evaluate PFS and OS in patients with metastatic HER2 negative breast 
cancer treated with durvalumab in combination with tremelimumab.
To evaluate clinical benefit rate in this population.
To evaluate safety and tolerability. 
Exploratory:
To evaluate if serum and tissue-based immune-related biomarkers are 
modulated by therapy and predict response. (see Section 2.3 for details)
To assess response rates to next line therapy after progression
Sample Size
A total of 30 patients (15 ER+, 15 ER-) with metastatic breast cancer 
which is HER2 negative will be enrolled into this study and receive 
durvalumab in combination with tremelimumab in order to get 28 
evaluable (14 ER+,14ER-) for response. Expansion cohort based will 
enroll 20 additional patients with TNBC to determine the posterior 
Bayesian probability that the response rate exceeds 30%.
Diagnosis & 
Key 
Eligibility 
Criteria
Patients must have a histologically documented (either primary or metastatic 
site) diagnosis of breast cancer that is HER2 negative (expansion cohort only 
TNBC allowed). Patients must have stage IV disease and must have completed 
at least one line of chemotherapy. Only TNBC patients will be enrolled in the 
expansion cohort. Also, only PD-L1 negative patients in the front line setting will 
be enrolled. Beyond frontline setting, any PD-L1 status is acceptable. . Patients 
must be ECOG performance status of 2 or less and have normal organ 
function. Patients treated with previous immunotherapies are excluded.
Treatment Plan
Patients will be treated with durvalumab 1500mg intravenously (IV) every 4 
weeks for a total of 4 doses, and tremelimumab 75mg IV every 4 weeks for a 
total of 4 doses. After completion of the 4 doses of combination therapy, 
durvalumab will be continued at a dose of 750mg every 2 weeks for up to 18 
additional doses, or until progressive disease or unacceptable toxicity. The first 
750mg dose of durvalumab will be 4 weeks after the last combination dose. 
Patients will be followed for 3 years for survival and progression of disease.
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Breast Cancer: All Subtypes Not Equal
Breast cancer is the most common non-dermatological malignancy in women with an 
estimated 232, 670 new diagnoses in 2014, and the second leading cause of cancer 
death in women with an estimated 40, 000 women in the United States succumbing to 
the disease in 2014 [1]. Breast cancer is a heterogeneous disease comprising of several 
molecular subtypes, which are commonly extrapolated into clinical subtypes, with 
significant prognostic implications [2, 3]. Significant advances have been made in certain 
subtypes of breast cancer, for example human epidermal growth factor 2-neu (HER2) 
receptor positive disease. In this subtype targeted therapies have changed the nature of 
the disease from an aggressive subtype to one which is highly curable in early stages, 
and in some patients with advanced metastatic disease treatable for many years [4]. The 
estrogen receptor (ER) and progesterone receptor (PR) positive subtypes also have 
several targeted therapies using hormonal manipulation, however, when the disease 
becomes metastatic all patients will eventually develop endocrine resistance and often 
require cytotoxic chemotherapy [5]. Similarly, patients with ER, PR, and HER2 negative, 
the so-called triple negative breast cancers (TNBC), biologically tend to display an 
aggressive phenotype, currently do not have targeted therapy options as a standard of 
care, and only have a limited amount of cytotoxic agents available to treat their disease 
[ 6 ] . Patients with metastatic ER positive breast cancer who have used all hormonal 
options, and those with TNBC, experience a poor prognosis with only a few treatment 
options.
1.2
Breast Cancer Immunology
The breast tumor microenvironment is often infiltrated by immune cells. The adaptive 
immune system can identify tumor antigens through immunosurveillence [7]. In this 
process, antigen-presenting cells present non-self antigens to T cells, which allow them 
to recognize and destroy cells expressing such antigens. A hallmark of oncogenesis is 
that tumor cells can develop mechanisms to evade such immune recognition [8, 9].
The presence of tumor infiltrating lymphocytes (TILs) has been associated with more 
favorable prognosis in breast cancer [10]. Paradoxically, TILs have been closely 
associated with ER negative subtypes, tumors with an aggressive biological behavior. 
However, this discrepancy may be due to the fact TILs are associated with better survival 
in basal-like rather than non-basal-like TNBC [11, 12]. Nevertheless, these results 
highlight the importance of immune regulatory mechanisms in the pathogenesis of breast 
cancer.
1.3
Immune Checkpoint Blockade in Breast Cancer
The success of immune checkpoint blockade in certain cancers has served as proof-of- 
concept that immune therapy is a viable therapeutic strategy. Cytotoxic T lymphocyte 
antigen 4 (CTLA-4) inhibitors have shown significant and sustained anti-tumor activity in 
melanoma [12]. While clinical data regarding CTLA-4 inhibition in breast cancer is limited, 
preclinical studies using mammary murine models using poorly immunogenic breast 
cancer cell lines failed to show single agent activity, however, in combination with 
radiation therapy improved survival related to a decrease in lung metastases [13].
Another study demonstrated significant tumor regression with the combination of a 
granulocyte-macrophage colony stimulating factor vaccine and CTLA-4 blockade [14]. A 
phase I clinical trial of 26 patients with hormone receptor positive metastatic breast 
cancer found that treatment with the a humanized immunoglobulin (Ig) IgG2 monoclonal 
antibody (mAb), tremelimumab and exemestane found that this treatment could illicit a 
robust immune response as measured by systemic immune effectors, and 42% of 
patients experienced disease stability for at least 3 months, thus demonstrating possible 
biological and clinical activity [15].
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling
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T-cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated
T-cells[16]. It has 2 known ligands: PD-L1 (B7 H1; CD274) and PD-L2 (B7 DC; CD273) 
[17]. 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. PD-L1 is constitutively expressed by B cells, dendritic cells, and macrophages 
[18].Importantly, PD-L1 is commonly over expressed on tumor cells or on non-transformed 
cells in the tumor microenvironment [19]. 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 tumour 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. In contrast, cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4) is constitutively expressed by regulatory T-cells and 
upregulated on activated T cells. Binding of CTLA-4 to CD80 or CD86 on IC leads to 
inhibition of T-cell activation [20]. 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 ICs. This activity overcomes PD-L1-mediated 
inhibition of antitumour 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.
When this study was designed and launched (2015), the clinical scenario was that, 
blockade of the programmed cell death 1 (PD-1) and its ligand (PD-L1) had been found 
to have anti-tumor activity in certain cancers, with 6-17% overall response rates [ 2 1 ] . 
Approximately 20% of TNBC expresses PD-L1, suggesting that targeting the PD- 1/PD-
L1 checkpoint may be an effective treatment strategy in this subtype [22, 23].
Expression of PD-L1 is known to be associated with poor prognosis in patients with breast 
cancer, particularly those with luminal B and basal-like subtypes [24], thus making 
aggressive phenotype ER positive and triple negative breast cancers attractive subtypes 
in which to investigate PD-L1 blockade. A subsequent  phase 1B study presented at the 
2014 San Antonio Breast Cancer Symposium demonstrated that in patients with heavily 
pretreated metastatic triple negative breast cancer (TNBC) treated with the humanized 
IgG4κ isotype mAb against PD-1, pembrolizumab, 16.1% had a partial response (PR), 
and 9.7% had stable disease (SD) [25].
Through the years, the clinical landscape has evolved. Original study (Santa-Maria et al 
Oncotarget 2018) found that patients who responded had only had 1 line of prior therapy. 
We thus want to limit to no more than 1 line of previous therapy in the metastatic setting. 
Indeed several studies have now shown that responses to immune checkpoint inhibition 
are mostly restricted to earlier lines settings (Santa-Maria et al JNCCN 2019). 
Currently, atezolizumab in combination with nab-paclitaxel is FDA-approved for patients 
with no prior treatment for metastatic TNBC who are PD-L1 immune cell-positive. The 
ImPassion130 study (Schmid et al NEJM 2018) suggests that these patients benefit from 
the addition of atezolizumab to nab-paclitaxel in the front line setting. Therefore, now we 
wish to exclude patients who are PD-L1-positive in the front line setting. Patients who are 
PD-L1-negative are eligible for this protocol in the front line setting, if patients are enrolled 
in the second line setting, PDL1 status is not needed for enrollment.
Although effects of single agent checkpoint blockade are modest, with only a small 
fraction of patients having significant responses, recently combination checkpoint 
blockade with CTLA-4 and PD-1 inhibitors has demonstrated synergistic activity with an 
overall response rate of 40%, and 31% of patients achieving >80% reduction in their 
tumors by 12 weeks [26]. A recently presented phase 1 open-label study evaluating the 
anti-PDL1 inhibitor, durvalumab, in combination with tremelimumab in patients with 
advanced non-small cell lung cancer, revealed that the combination was well tolerated 
with 75% of reported adverse events (AEs) being low grade, and only 3/24 patients 
discontinuing therapy due to treatment-related AEs. Furthermore, patients experienced an 
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overall response rate (ORR) of 30% in the subset of patients that were PD-L1 negative 
[ 2 7 ] . These results suggest that combination immune therapy may improve anti- tumor 
responses.
1.4
Durvalumab (MEDI4736)
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab Investigator’s Brochure (IB).  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 
kappa subclass that inhibits binding of PD-L1 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer.  (MedImmune is a wholly 
owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as 
AstraZeneca throughout this document.)  As durvalumab is an engineered mAb, it does 
not induce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity.  
The proposed mechanism of action for durvalumab is interference of the interaction of PD-
L1.
Durvalumab (MEDI4736) is a human IgG1κ monoclonal antibody directed against 
human PD-L1. Two monotherapy studies (NCT01693562 and NCT01938612), and one 
combination study (NCT02261220) investigating this drug are currently underway. 
NCT01693562 is a first- time-in-human, dose-escalation and dose-expansion study in 
adults with advanced solid tumors. NCT01938612 is a Phase 1, dose-escalation and 
dose-expansion study in Japanese adults with advanced solid tumors. NCT02261220, is 
a Phase 1 study investigating durvalumab in combination with MEDI6469, as well as 
other immune therapies, in patients with advanced malignancies.
1.5
Tremelimumab
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s Brochure (IB).
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-
lymphocyte- associated protein 4 (CTLA-4) also known as CD152 (cluster of 
differentiation 152)  This is an immunomodulatory therapy (IMT) that is being developed 
by AstraZeneca for use in the treatment of cancer. As described above, tremelimumab 
has been safely administered in patients with metastatic breast cancer and, in 
combination with hormone therapy, associated with significant clinical benefit in terms of 
disease stability [15].
Tremelimumab has been administered as monotherapy to subjects participating in 10 
clinical studies, with over 1,000 subjects in a variety of tumor types. Across the clinical 
development program for tremelimumab and that of the related anti-CTLA-4 antibody 
ipilimumab, a pattern of efficacy has emerged that appears to be consistent across tumor 
types for this mechanism of action. Response rates to anti-CTLA-4 antibody monotherapy 
are generally low, approximately 10%. However, in subjects who respond, the responses 
are generally durable, lasting months to years even in subjects with aggressive tumors, 
such as refractory metastatic melanoma. The most common treatment-related toxicity is 
diarrhea (41.2%), rash (27.2%), pruritus (25.1%), fatigue (23.8%), nausea (21.9%), 
vomiting (13.5%), decreased appetite (11.3%), headache (7.2%), pyrexia (7.0%), 
abdominal pain (6.7%), and colitis resulting in hypokalemia (5.5%).
1.6
Durvalumab in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity [19] 
because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination 
therapy for the treatment of cancer.
1.7
Rationale for the Current Study
The association of the PD-1/PD-L1 axis in breast cancer, and early success of inhibitors 
of the PD1/PD-L1 axis in breast cancer, provides background rationale for the use of 
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durvalumab in patients with metastatic breast cancer. Recent studies published in 
melanoma suggest that the combination of the PD-1 inhibitor, nivolumab, in combination 
with the CTLA-4 inhibitor, ipilimumab, have improved progression free survival compared 
to single agent ipilimumab (11.5 months versus 2.9 months, respectively)[28]. 
Furthermore, a recent phase 1 study presented at the European Society for Medical 
Oncology (ESMO) found that in patients with metastatic lung cancer, the combination of 
durvalumab and tremelimumab found this combination was tolerable and associated with 
overall response rates of 28% [27]. The significant synergy in response rates observed 
with inhibition of CTLA-4 and the PD-1/PD-L1 axis in other malignancies supports the 
investigation of this combination in metastatic breast cancer.
1.7.1
Rationale for fixed dosing for durvalumab and tremelimumab
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). Population PK analysis indicated only minor impact of 
body weight (WT) on PK of durvalumab (coefficient of ≤ 0.5). The impact of body 
WT-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 WT of ~75 kg). A total of 
1000 patients were simulated using body WT distribution of 40–120 kg..  Simulation 
results demonstrate that body weight-based (10 mg/kg Q2W) and fixed dosing (750 
mg Q2W) regimens yield similar median steady-state exposures and associated
variability, supporting the potential switch of durvalumab from weight-based to fixed 
dose. Similar considerations hold for the Q4W dosing regimens (20 mg/kg Q4W 
versus 1500 mg Q4W).
A population PK model was developed for durvalumab using monotherapy data as 
detailed in Section 5.1.2 of the IB. 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 or 20 mg/kg Q4W) and fixed dosing (750 mg 
Q2W or 1500 mg Q4W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations exposures (AUCss,0-28, Cmax,ss, and Cmin,ss5th, 
median and 95th percentiles) using the population PK model.
A fixed dose of 750 mg Q2W was selected to approximate 10 mg/kg Q2W and a 
fixed dose of 1500 mg Q4W was selected to approximate 20 mg/kg Q4W (based on 
median body weight of ~75 kg). A total of 1000 patients were simulated using body 
weight distribution of 40 to 120 110 kg. Simulation results demonstrate that body 
weight-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) regimens yield 
similar median steady-state exposures and associated variability, supporting the 
potential switch of durvalumab from weight-based to fixed dose.
Similar considerations hold for the Q4W dosing regimens (20 mg/kg Q4W versus 
1500 mg Q4W).
Similar findings have been reported by others [29-32]. Wang and colleagues 
investigated 12 monoclonal antibodies and found that fixed and body size-based 
dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies. 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 [31]. 
A fixed dosing approach is preferred by the prescribing community due to ease of 
use and reduced dosing errors. Given expectation of similar pharmacokinetic 
exposure and variability, we considered it feasible to switch to fixed dosing 
regimens. Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W 
MEDI4736 (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is 
included in the current study. 
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Fixed dosing of durvalumab and tremelimumab is recommend only for subjects with 
> 30kg body weight due to endotoxin exposure.  Patients with a body weight less 
than or equal to 30 kg will be excluded. 
1.7.2
Rationale for dose and regimen selection
The dose levels selected for this combination of Durvalumab and Tremelimumab 
were based on a recent phase 1 study (Antonio et al. ESMO 2014, poster 
attached), which determined the maximal tolerated dose (MTD) of the 
combination. The combination was found to be safe and tolerable. Based on the 
phase 1 study of this combination (Antonio et al. ESMO 2014), we aim to treat 
for a total of 12 months of therapy. This regimen was associated with continued 
disease control at over 32 weeks (Figure 3 of abstract), and overall response 
rate of 28%. In light of this information, our treatment plan includes an induction 
period of 4 weeks of combination therapy, followed by maintenance 
monotherapy with durvalumab up to 12 months total (or approximately 18 
doses). 
The rationale for maintenance therapy with single-agent durvalumab is based on 
previous experience with immunotherapies. Response to immunotherapy may 
be delayed compared to conventional cytotoxic chemotherapy, and even appear 
as pseudoprogression (radiographic increase in the size of lesion due to T 
lymphocyte infiltration) before patients experience durable responses; to capture 
these delayed responses, the immune-related RECIST criteria have been 
developed (PMID 19934295). Because of the delayed response to 
immunotherapy, this study includes additional therapy using maintenance 
durvalumab after the 4 cycles of combination tremelimumab with durvalumab. 
Furthermore, in the phase 1 study where durvalumab was investigated with 
tremelimumab using various schedules (Antonio et al. ESMO meeting 2014), the 
regimen where there was least toxicity and greatest efficacy seen was when 
there was an induction of durvalumab with trememlimumab for 4 cycles, 
followed by durvalumab maintenance to complete 12 months of therapy. 
Continuing tremelimumab additionally for 12 months was associated with 
increased toxicity, therefore, we do not propose adding trememlimumab to 
durvalumab to the maintenance regimen in this study.  
Pseudoprogression has been well-described in various studies in investigating 
checkpoint inhibitors, and refers to the inflammatory response that looks like 
progression of disease. This phenomenon is actually seen in the phase 1 study 
this proposal is based on (Figure 4 on abstract), but has also been observed in 
numerous other trials (PMID: 21785048). It crucial for drug development of 
immunotherapy to capture pseudoprogression in a safe manner, therefore this 
proposal has been designed to anticipate pseudoprogression and allow for 
continued treatment provided that very specific criteria are met. 
1.7.3 Rationale for Expansion Cohort
Based on initial portion of the study where the first 18 evaluable patients were 
investigated, a striking difference between overall response rates in ER-positive 
and TNBC was observed (Table 1). The ORR in ER-positive was 0%, and in 
TNBC it was 42.9%. Furthermore, the TNBC group had 2 patients with SD 
(clinical benefit rate of 71.4%), and one of the patients listed as PD, in fact had 
pseudoprogression (after 2 months had sub-centimeter LNs enlarge to >15mm, 
captured as PD per RECIST, but afterwards experience stability in these 
lesions, and a PR in target lesions). While the numbers are small, there is a 
clear signal in the TNBC cohort since essentially 6 out of 7 patient experienced 
clinically relevant benefit. Immunotherapy is rapidly evolving in breast cancer, 
and these initial results show promise in this cohort of patients, and the rationale 
of the expansion cohort is to capitalize on this initial experience. 
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Table: Summary of responses by entire cohort and subtype of breast cancer   
All patients
(n=18)
TNBC
(n=7)
ER+
(n=11)
PR
3
3
0
SD≥2 
months
4
2
2
PD
11
2*
9
ORR
16.7%
42.9%
0%
CBR
38.9%
71.4%
18.2%
 *Includes one patient with pseudoprogression (enlargement of a LN with 
subsequent stability), while PD by RECIST, has otherwise experienced a PR based 
on target lesions and has been on study for 10 months (status post cycle 15)
1.8
Rationale for Exploratory Objectives
Immune-related biomarkers
Predictive biomarkers are needed to identify which patients are more likely to experience 
clinical benefit. A critical barrier in the development of immunotherapies for the treatment 
of cancer is the identification of predictive biomarkers to therapy since to date only a small 
proportion of patients derive benefit to immunotherapies. While some studies have shown 
PD-L1 overexpression by immunohistochemistry is associated with response, other 
studies have shown that patients with PD-L1 negative tumors may also exhibit significant 
response suggesting that PD-L1 expression alone may not fully predict response to 
therapy [33, 34]. Therefore, more accurate biomarkers predictive of response or urgently 
needed [35]. 
Immune cells identify cancer cells by detecting antigens, termed neoantigens, expressed 
on cancer cells. Higher mutational burden may correlate with more diverse neoantigen 
landscapes and predict responses to immunotherapy in patients with melanoma and lung 
cancer [36, 37]. Mutational burden may also be assessed on circulating tumor DNA. 
Similarly, patients with mismatch repair-deficient cancers have a higher number of somatic 
mutations compared to those who are mismatch repair-proficient, but furthermore, they 
have better responses to immune checkpoint blockade [11]. Diverse neoantigen 
landscapes are more likely to stimulate neoantigen-specific T cells, which can be 
measured through T cell receptor sequencing to quantify the clonality of the T cell receptor 
repertoire. Preliminary studies in patients with melanoma and lung cancer suggest that 
patients with oligoclonal T cell receptor repertoires are more likely to respond to 
immunotherapy [37, 38]. These immunopharmacogenomic biomarkers may, therefore, 
help identify patients with breast cancer more likely to benefit from immunotherapies. 
The relationship between clonal expansion of the T cell receptor repertoire has been 
studied in patients receiving neoadjuvant therapy in early stage breast cancer. Matched 
samples of patients with early stage breast cancer of various subtypes and assessed the T 
cell receptor populations at baseline and after various chemotherapy regimens. Using the 
diversity index, which assesses T cell beta-receptor clonal diversity, clonal expansion was 
found to be associated with complete and partial responses [39]. In addition, gene 
expression profiling of immune relevant genes can be modulated by immunotherapy and 
be associated with outcomes, including CD8, granzyme A, and perforins (Santa-Maria, 
unpublished).
We therefore, plan to assess the various molecular and immunogenomic markers 
including: circulating tumor DNA, whole exome sequeincing to assess mutational and neoantigen 
burde, T cell receptor sequencing to assess T cell receptor repertoires, and immune-related gene 
expression analysis. 
Response to next line therapy
We are adding a third exploratory objective in order to capture response and duration of 
response to next line therapy. This is based on the fact that significant responses have 
been recently documented, after progression when patients are started on next line of 
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chemotherapy.
Objective will be to determine the response rate (RR) and duration of    response (DoR) of 
next line therapy after progression on durvalumab/ tremelimumab study regimen, for those 
patients who are able to submit detailed follow up data about subsequent treatment and 
response. 
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
To evaluate Overall Response Rate (ORR) in patients with metastatic HER2 negative 
breast cancer treated with durvalumab in combination with tremelimumab
The primary endpoint is ORR, defined as the number(%) of patients with one visit 
response orpartial response (PR) or a complete response (CR) in patients with metastatic 
HER2 negative breast cancer (TNBC in expansion cohort) treated with durvalumab in 
combination with tremelimumab using the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 (23).
Expansion cohort
To evaluate Overall Response Rate (ORR) in patients with metastatic TNBC treated with 
durvalumab in combination with tremelimumab.
The primary endpoint is ORR, defined as the number of patients exhibiting partial 
response (PR) or a complete response (CR) using Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 
2.2
Secondary Objectives & Endpoints
2.2.1
To evaluate PFS and OS in patients with metastatic HER2 negative breast 
cancer treated with durvalumab in combination with tremelimumab.
Secondary endpoints include PFS and OS, where PFS is defined as the time 
from date of treatment initiation to date of documented disease progression or 
death (by any cause in the absence of progression), and OS is defined as the 
time from date of treatment initiation until death due to any cause.
2.2.2
To evaluate safety and tolerability.
The endpoints will be the number, frequency, and severity of adverse events (as 
defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE 
version 4.03) will be recorded.
2.2.3
To evaluate clinical benefit rate in this population.
Clinical benefit rate is defined as stable disease (SD) for ≥ 12 weeks + PR + CR.
2.3
Exploratory Objectives & Endpoints
2.3.1
To evaluate if serum and tissue-based biomarkers including: circulating tumor DNA, 
immunohistochemical expression of PD-L1; tumor infiltrating lymphocytes (TILs); 
changes in tissue and peripheral T cell receptor genotype; mutational and 
neoantigen burden; and immune-related candidate gene expression signatures 
predict response to durvalumab in combination with tremelimumab.
2.3.2.    To determine the response rate (RR) and duration of response(DoR) of 
subsequent next line therapy after progression on durvalumab/ tremelimumab 
study regimen, for those patients who are able to submit detailed follow up data 
about subsequent treatment and response. 
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with stage IV (metastatic) HER2 negative breast 
cancer (both male and female patients are eligible). This will be a single-center trial conducted at 
Northwestern University. The expansion cohort will only include metastatic TNBC.
Eighteen patients will be added in the first stage. If 4 or more respond, then an additional 10 
patients will be added for a total of 28. A total of 30 subjects (15 ER+, 15 ER) will be needed to 
obtain a total of 28 evaluable patients (14ER+ and 14ER-) for this trial. The expansion cohort will 
include 20 evaluable patients with TNBC. Approximately 5 potentially eligible patients are seen per 
month, and it is anticipated that at least 2 per month will be accrued. Potential patients may be 
referred to the Principal Investigator (PI) at Northwestern University, Dr. Massimo Cristofanilli at 
(312) 695-0990.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
For the expansion cohort: Only metastatic TNBC patients will be enrolled.
[Please note: the General cohort had enrolled patients with the following criteria: 
Patients must have a histologically documented (either primary or metastatic 
site) diagnosis of breast cancer that is HER2 non-overexpressing by 
immunohistochemistry, namely 0 or 1. If they have an equivocal 
immunohistochemistry, 2, the tumor must be non-gene amplified by FISH 
performed upon the primary tumor or metastatic lesion (ratio <2 and HER2 copy 
number <4). ER positivity is defined as 1% or greater (29). PR positivity will be 
defined as a result of greater than 10%.Documentation of ER and PR status 
should be available at registration.]
. 
3.1.2
Patients must have measurable disease by RECIST 1.1 criteria.
3.1.3
Patients must be one of the following :

Have been treated with at least one prior chemotherapy regimen in 
the metastatic setting 

Within 12 months of their last adjuvant systemic treatment and are felt 
to be chemotherapy refractory.

PD-L1-negative in the front line setting.  
[Note: Beyond frontline, any PD-L1 status is acceptable]
Note: please submit the PD-L1 test with the pathology report at 
registration.
3.1.4
Completion of prior chemotherapy systemic anticancer therapy at least 2 weeks 
prior to study entry.
3.1.5
Radiation therapy must be completed at least 2 weeks prior to study entry. 
Radiated lesions may not serve as measurable disease unless they have been 
radiated ≥12 months prior to enrollment.
3.1.6
Patients may have parenchymal brain metastases if stable (no evidence of 
progression) for at least 1 month after local therapy (radiation or surgery). 
Leptomeningeal disease is excluded. Must have completed any prescribed 
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steroid taper prior to registration
3.1.7
Patients may have had a prior diagnosis of cancer if it has been > 3 years since 
their last treatment.(with the exception of squamous cell carcinoma or basal cell 
carcinoma of the skin or cervical intraepithelial neoplasia) 
3.1.8
Patients must be age ≥ 18 years; both male and female are eligible.
3.1.9
Patients must exhibit an ECOG performance status of ≤2.
3.1.10
Patients must weigh greater than 30 kg.
3.1.11
Patients must have adequate organ and bone marrow function (transfusion 
permitted but not GCSF) within 14 days of first dose of study drug 
administration, as defined below:
Hemoglobin
≥9.0g/dl
absolute neutrophil count
≥ 1,500/mcL (1.5 x 109/L)
platelets
≥ 100,000/mcl
total bilirubin
≤1.5 times the institutional upper limit of 
normal (ULN) (or ≤3 times ULN in case of 
liver metastasis)
AST(SGOT)/ALT(SPGT)
≤ 2.5 X institutional ULN (or ≤5 times ULN in 
case of liver metastasis)
Serum creatinine
CL>40 mL/min by the Cockcroft-Gault 
formula (see appendix) or by 24-hour urine 
collection for determination of creatinine 
clearance
3.1.12
Female subjects must either be of non-reproductive potential (see definition 
below) or must have a negative serum pregnancy test within 7 days prior to 
registration on study.
Evidence of post-menopausal status or negative urinary or serum pregnancy test 
for female pre-menopausal patients. Women will be considered post-menopausal 
if they have been amenorrheic for 12 months without an alternative medical cause. 
The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if 
they have been amenorrheic for 12 months or more following 
cessation of all exogenous hormonal treatments, had radiation-
induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
3.1.13
Female and male patients of reproductive potential must agree to use effective 
birth control from screening to 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 180 days after the last dose of 
durvalumab monotherapy, whichever is the longer time period.[Refer Section 
4.5.1] 
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Should a female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately 
Refer to section 4.5.1 for details.
3.1.14
Willingness to provide a fresh biopsy prior to study enrollment and after 2 cycles 
of treatment as clinically appropriate per PI discretion
3.1.15
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study. Written informed consent and 
HIPAA authorization will be obtained from the subject prior to performing any 
protocol-related procedures, including screening evaluations 
3.1.16
Subject is willing and able to comply with the protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations 
including follow up.
3.2
Exclusion Criteria
3.2.1
Patients with documented HER2-positive metastatic disease based on most 
recent biopsy.
3.2.2
Patients with definite liver metastasis >1cm or signs of visceral crisis or impending 
visceral crisis at the clinical discretion of the treating physician. 
3.2.3
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy 
with the exception of alopecia, vitiligo, and the laboratory values defined in the 
inclusion criteria 

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case 
basis after consultation with the treating physician and/or PI.

Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab or tremelimumab may be 
included only after consultation with the treating physician and/or PI.
3.2.4
Patients who have had chemotherapy or radiotherapy within 2 weeks prior to 
entering the study.
3.2.5
Current or prior use of immunosuppressive therapy within 14 days before the 
first dose of durvalumab or tremelimumab, with the exceptions of intranasal and 
inhaled corticosteroids or systemic corticosteroids at physiological doses, which 
are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
3.2.6
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 2 
electrocardiograms (ECGs) using Bazett’s formula.  Two EKGs 5 minutes (+/-2 
min) apart are mandatory.
 
3.2.7
Receipt of live attenuated vaccination within 30 days prior to registration.
NOTE: patients should also not receive such vaccination within 30 days of 
receiving durvalumab or tremelimumab.
3.2.8
Patients who are taking any herbal (alternative) medicines are NOT eligible for 
participation. Patients must be off any such medications by the time of registration 
for at least 2 weeks.
NOTE: Vitamin supplements are acceptable.
 3.2.9 Patients may not have received any other investigational agents within 2 weeks or 5 
half lifes prior to registration, whichever is shorter.
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3.2 10Prior treatment with immune therapy (including but not limited to CD137, OX40, 
PD-1, PD-L1 or CTLA4 inhibitors such as durvalumab and tremelimumab).
Prior severe infusion reaction to a monoclonal antibody.
3.2.11 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, 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 (eg, 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 and/or PI.

Patients with celiac disease controlled by diet alone
3.2.12 Known  active infection including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and positive TB 
test (PPD, Quantiferon)), 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.
3.2.13History of allogeneic organ transplant.
  3.2.14 History of hypersensitivity to durvalumab or tremelimumab or any excipient.
3.2.15 Major medical conditions that might affect study participation (uncontrolled 
pulmonary, renal, or hepatic dysfunction, uncontrolled infection) are not 
eligible. Other significant comorbid condition which the investigator feels 
might compromise effective and safe participation in the study.
3.2.16 Patients who have an uncontrolled intercurrent illness including, but not limited 
to any of the following, are not eligible:

Symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia

Interstitial lung disease, serious gastrointestinal conditions associated with 
diarrhea

Uncontrolled pulmonary, renal, or hepatic dysfunction

Ongoing or active infection requiring systemic treatment

Psychiatric illness/social situations that would limit compliance with study 
requirements, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed 
consent

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s 
safety or study endpoints
3.2.17 Female patients who are pregnant or nursing are not eligible.
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3.2.18 Patients who are involved in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). Previous enrollment or randomization 
in the present study.
4.0
TREATMENT PLAN
4.1
Overview
Non-randomized, open-label, pilot phase II clinical trial of durvalumab in combination 
with tremelimumab in patients with stage IV HER2 negative breast cancer, with an 
expansion cohort of TNBC.
Patients will be treated durvalumab 1500mg intravenously (IV) every 4 weeks for a total of 
4 doses, and tremelimumab 75mg IV every 4 weeks for a total of 4 doses. After 
completion of the 4 doses of combination therapy (induction phase), durvalumab will be 
continued at a dose of 750mg every 2 weeks for up to 18 additional doses (maintenance 
phase), or until progressive disease (see 4.1.1) or unacceptable toxicity. The first 750mg 
dose of durvalumab will be 4 weeks after the last combination dose. Patients may 
continue on therapy after progression or after initial 52 week treatment period as 
specified in Sections 4.1.1 and 4.1.2. Patients will be followed for 3 years or until time of 
death. Overall response rate (ORR), clinical benefit rate, PFS, and OS will be 
determined. In addition, patient’s next line of therapy will be monitored for response rates 
and duration of clinical benefit to next line therapy. 
Patients will undergo a fresh tissue biopsy prior to study enrollment and two months after 
treatment, unless deemed to be clinically inappropriate per PI or co-investigator, to 
evaluate pharmacodynamic changes in immune-related biomarkers. Correlatives will be 
assessed.
4.1.1
Continuation of Investigational Therapy after Radiographic Progression 
(Pseudoprogression)
Treatment may be continued in the setting of pseudoprogression (radiographic 
increase or new lesions felt to be due to inflammation/immune response) as 
long as all of the following criteria are met:

Absence of clinical symptoms or signs indicating clinically 
significant PD. 

No significant decline in Eastern Cooperative Oncology Group 
(ECOG) performance status (PS >2 or as deemed by treating 
investigator).

Absence of rapid PD or threat to vital organs/critical anatomical sites (e.g., 
spinal cord compression) requiring urgent alternative medical intervention

Patients are made aware of the potential benefits and risks of continuing study 
therapy in the setting of Pseudo-Progression. Patients continuing therapy in the 
setting of suspected pseudoprogression should continue with treatment 
according to whether they in the induction phase (durvalumab 1500mg 
intravenously (IV) every 4 weeks for a total of 4 doses, and tremelimumab 75mg 
IV every 4 weeks for a total of 4 doses) or maintenance phase (durvalumab 
750mg every 2 weeks). For example, a patient with suspected 
pseudoprogression after cycle 2 of durvalumab and tremelimumab would 
continue onto cycle 3 of durvaluamb and trememlimumab rather than 
durvalumab single agent portion of the regimen (maintenance phase).
4.1.2
Continuation of Investigational Therapy after 52 Weeks

Patients who achieve clinical benefit (CR, PR, or SD) until the end of the 52 
week period may enter a follow up phase or continue durvalumab as shown 
in table 5.1 for up to 52 more weeks as long as they are felt to be deriving 
clinical benefit. 

Patients who enter follow up phase will continue to be monitored.  If during the 
first 6 months of follow-up, patients developing PD may be re-treated with 
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durvalumab as shown in table 5.1. Only one 52 week retreatment period will 
be allowed. Patients who are restarted on durvalumab after the initial 52 
week period must meet the following criteria:
o
Patients must have measurable disease by RECIST criteria.
o
Have not received any additional anticancer therapy, radiation, or 
surgery since initially stopping immunotherapy
o
No evidence or clinical concern of development or progression of CNS 
metastasis
o
No secondary cancer
o
Patients must exhibit an ECOG performance status of ≤2.
o
Patients must have adequate organ and bone marrow function 
per section 3.1.10
o
Meet eligibility criteria 3.1.11-3.1.15 as applicable
o
None of the exclusionary criteria with the exception of 3.2.8 only for 
exposure to Durvalumab, as well as 3.2.18
4.2
Treatment Administration
Agent
Dose
Route
Schedule
Cycle 
Length
Durvalumab
1500mg (during 
combination 
therapy), 750 mg 
(during 
monotherapy)
IV
Day 1 of each cycle for 4 
cycles (during combination 
therapy), then every 2 weeks 
for up to 18 additional doses of 
monotherapy. The first 
monotherapy dose of MEDI 
4736 will be 4 weeks after the 
last combination dose.*
4 weeks
(28 days)
Tremelimumab
75mg
IV
Day 1 of each cycle for a total 
of 4 doses
*Patients may continue on therapy after progression or after initial 52 week treatment period as specified 
in Sections 4.1.1 and 4.1.2.
**On each treatment day, hematology and serum chemistry are to be resulted before treatment can begin
4.2.1
Monitoring of Dose Administration
On infusion days, patients receiving durvalumab + tremelimumab treatment will be 
monitored during and after infusion of IP as presented in the bulleted list below.  
Supine BP will be measured using a BP recording device with an appropriate cuff 
size, after the patient has rested for at least 5 minutes.  BP and pulse will be 
collected from patients receiving durvalumab + tremelimumab treatment before, 
during, and after each infusion at the following times (based on a 60-minute 
infusion):  

Prior to the beginning of the infusion (measured once from approximately 
30 minutes before up to 0 minutes [ie, the beginning of the infusion]).  

Approximately 30 minutes during the infusion (halfway through infusion).  

At the end of the infusion (approximately 60 minutes ±5 minutes).  

A 1-hour observation period is recommended after the first infusion of 
durvalumab and tremelimumab. 
If no clinically significant infusion reactions are observed during or after the first 
cycle, subsequent infusion observation periods can 

be at the Investigator’s discretion (suggested 30 minutes after each durvalumab 
and tremelimumab infusion).  

If the infusion takes longer than 60 minutes, then BP and pulse measurements 
should follow the principles as described above or be taken more frequently if 
clinically indicated.  
The date and time of collection and measurement will be recorded on the 
appropriate eCRF.  Additional monitoring with assessment of vital signs is at the 
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discretion of the Investigator per standard clinical practice or as clinically indicated.  
Body weight is also recorded along with vital signs.  A complete physical 
examination will be performed and will include an assessment of the following (as 
clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculo-skeletal (including spine and extremities), genital/rectal, and neurological 
systems and at screening only, height. 
In the event of a Grade ≤ 2 infusion-related reaction, the infusion rate of 
durvalumab or tremelimumab 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. In subjects experiencing Grade ≤ 2 infusion- 
related reaction, subsequent infusions may be administered at 50% of the initial 
rate. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) may be 
administered at the discretion of the investigator. If the infusion-related reaction is 
severe or prolonged (≥Grade 3), methylprednisolone 100 mg (or the equivalent) 
should be administered as well. Investigators may administer steroids per 
protocol guidelines (see Section 4.3) or at their discretion as clinically indicated in 
consultation with the study team. 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions 
must be immediately available, and study personnel must be trained to recognize 
and treat anaphylaxis.
4.3
Toxicity Management & Dose Delays/Modifications
Each patient will be assessed for the development of toxicity according to the timeframe 
referenced in the Schedule of Events table). Toxicity will be assessed according to the 
NCI CTCAE V4.03.
Since the mechanism of action of both durvalumab and tremelimumab leads to T-cell 
activation and proliferation, immune related adverse events (irAE) may be observed, and 
be similar to that of other PD-1/PD-L1 checkpoint inhibitors, and may include immune- 
mediated pneumonitis, enterocolitis, dermatitis, hepatitis, and endocrinopathies (12, 16).
Subjects should be monitored for signs and symptoms of irAEs. In the absence of an 
alternate etiology (i.e. infection or PD), an immune-mediated etiology should be 
considered for signs or symptoms of pneumonitis, enterocolitis, dermatitis, hepatitis, and 
endocrinopathy. In addition to the dose modifications shown in Table 2, it is 
recommended that management of irAEs follow the guidelines outlined for other immune 
checkpoint inhibitors (31). These guidelines recommend the following:

Subjects should be evaluated to identify any alternative etiology

In the absence of clear alternative etiology, all events of an inflammatory nature 
should be considered to be 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 (i.e. infliximab, mycophenolate mofetil, etc.) 
should be considered for events not responding to systemic steroids
If the investigator has any question in regard to an AE being an irAE, the investigator 
should immediately contact the principal investigator. Treatment modifications will not be 
required for AEs that are clearly not attributed to investigational drugs (such as an accident) 
or for laboratory abnormalities that are not deemed to be clinically significant.
Treatment modifications may be required in the event of treatment-related toxicity. General 
guidelines regarding treatment modification are provided in Table 2. Doses may be held 
according to Table 2, there are no dose adjustments. Toxicities are attributed to 
respective drugs (durvalumab or tremelimumab). All toxicities will be graded according 
to NCI CTCAE V4.03 (Appendix B).
IRB #: STU00200984-MOD0045 Approved by NU IRB for use on or after 10/13/2020 through 5/10/2021.

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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)
General Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03 (unless indicated otherwise).
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 of the start of the immune-mediated 
adverse event (imAE)

Grade 3 recurrence of a previously experienced treatment-related imAE 
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.
Grade 4
Permanently discontinue study drug/study regimen.
Note: For asymptomatic amylase or lipase levels of >2.0×ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
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., 
myocarditis, 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 
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.

NU Study Number: NU 15B01
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and 
Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With Tremelimumab or 
Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)
General Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
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). 
−
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 4.03)
Dose Modifications
Toxicity Management
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 consults.
Pneumonitis/Interstitial 
Lung Disease (ILD)
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 
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 

NU Study Number: NU 15B01
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treatment of cancer-related infections)a
−
Consider Pulmonary and Infectious Disease consults.
−
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 consults; 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).a
Diarrhea/Colitis
Large intestine 
perforation/Intestine 
perforation
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).
−
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal surgery 
immediately without any delay.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc.
−
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event, including 
perforation.
−
Use analgesics carefully; they can mask symptoms of 

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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)
(Perforation: 
symptomatic; medical 
intervention indicated*)
* “medical 
intervention” is not 
invasive
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 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a
Grade 3 or 4
(Grade 3 Diarrhea: 
stool frequency of ≥7 
over baseline per day;
Grade 3
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
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 

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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 Perforation: 
severe symptoms, 
elective* operative 
intervention indicated; 
Grade 4 Perforation: 
life-threatening 
consequences, urgent 
intervention indicated)
*This guidance 
anticipates that Grade 3 
operative interventions  
of perforations are 
usually not elective
study drug/study regimen can be resumed 
after completion of steroid taper.
Grade 4
Permanently discontinue 
study drug/study regimen. 
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. If perforation is suspected, 
consult a surgeon experienced in abdominal surgery 
immediately without any delay.
−
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).a
Any Elevations in 
AST, ALT or TB  as 
Described Below
General Guidance
For Any Elevations Described:
−
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
−
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications).
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
 AST or ALT >ULN 
and ≤3.0×ULN if 

No dose modifications.

If it worsens, then treat as described 
−
Continue LFT monitoring per protocol.

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baseline normal, 1.5-
3.0×baseline if 
baseline abnormal; 
and/or TB > ULN and  
≤1.5×ULN  if baseline 
normal, >1.0-
1.5×baseline if 
baseline abnormal
for elevations in  the row below.
AST or 
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or 
TB >1.5×ULN and  
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if 
baseline abnormal

Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal.

If toxicity worsens, then treat as  
described for elevation in the row 
below.

If toxicity improves to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
resume study drug/study regimen 
after completion of steroid taper.
−
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 AST or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or to AST or ALT ≤3.0×baseline 
and/or TB ≤1.5×baseline if baseline abnormal, 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).a
AST or 
ALT >5.0×ULN if 
baseline normal, 
>5×baseline if baseline 
abnormal; and/or 
TB >3.0×ULN if 
baseline normal; 
For elevations in transaminases ≤8×ULN 
and/or in TB ≤5×ULN if baseline normal, 
or for elevations in transaminases 
≤8×baseline and/or TB ≤5×baseline if 
baseline abnormal:

Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
−
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.
−
Request Hepatology consult, and perform abdominal workup 
and imaging as appropriate.

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>3.0×baseline if 
baseline abnormal
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal

Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
within 14 days and after completion 
of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade as described in 
bullet above within 14 days
For elevations in transaminases >8×ULN 
or elevations in TB >5×ULN if baseline 
normal, or for elevations in transaminases 
>8×baseline and/or TB >5×baseline if 
baseline abnormal, permanently 
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
−
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).a

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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.

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Grade 1
(Serum creatinine > 1 
to 1.5×baseline; 
> ULN to 1.5×ULN)
No dose modifications.
For Grade 1:
−
Monitor serum creatinine weekly and any accompanying 
symptoms.

If creatinine returns to baseline, resume its regular 
monitoring per study protocol.

If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4.
−
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).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 

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
31
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).a
Any Grade
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:
−
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
−
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC EPIDERMAL 
NECROLYSIS.
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).
Rash or Dermatitis
(including Pemphigoid)
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
32
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).a
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
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 
v4.03 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 asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, corticosteroid treatment is not indicated 
as long as there are no other signs or symptoms of pancreatic 
inflammation.
−
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 

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
33
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.
1.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
2.
Doses of prednisone are ≤10 mg/day 
or equivalent.
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).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 
For Grade 3 or 4:

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
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Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
34
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.
1.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
2.
Doses of prednisone are ≤10 mg/day 
or equivalent.
−
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).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre)
Any Grade
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications).
−
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations).
−
Perform symptomatic treatment with Neurology consult as 
appropriate.
−

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
35
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.
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
36
−
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 Neurology 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 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability.
For Grade 2:
−
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
−
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 

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
37
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 
autonomic instability.
For Grade 4:
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4 (severe or life-threatening events):
−
Consider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain Neurology consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
38
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 
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
39
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).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 
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
40
−
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 
insufficiency.
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 
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.

NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
NU Study Number: NU 15B01
Other Study Number: MedImmune # ESR-14-10694 (D4190C00030)
Version Date: 8.31.2020 – Amendment12
41
aASCOEd
ucational 
Book 
2015 
“Managin
g Immune 
Checkpoi
nt 
Blocking 
Antibody 
Side 
Effects” 
by 
Michael 
Postow 
MD.
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.
−
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).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).a

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Infusion-Related Reactions
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Manage per institutional standard at the discretion of investigator.
−
Monitor patients for signs and symptoms of infusion-related 
reactions (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.

NU Study Number: NU 15B01
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43
Non–Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (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.

NU Study Number: NU 15B01
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4.4
Concomitant Medications/Treatments
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the appropriate eCRF. Restricted, prohibited, and permitted concomitant 
medications are described in the following tables.  Refer to Table 2 for guidance on 
management of IP-related toxicities.
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy 
for cancer treatment other than those under 
investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment. (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy])
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The following 
are allowed exceptions:

Use of immunosuppressive medications for 
the management of IP-related AEs, 

short-term premedication for patients 
receiving combination agent where the 
prescribing information for the agent requires 
the use of steroids for documented 
hypersensitivity reactions

Use in patients with contrast allergies. 

In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc).
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 90 days after 
the last dose of tremelimumab during the study
Sunitinib
Should not be given concomitantly or through 90 days 
after the last dose of tremelimumab (acute renal failure 
has been reported with combination therapy of 
tremelimumab and sunitinib)
EGFR TKIs 
Should not be given concomitantly.
Should be used with caution in the 90 days post last 
dose of durvalumab.
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
Live attenuated vaccines
Should not be given through 30 days after the last dose 
of IP (including SoC)
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Rescue Medications
Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary by the Investigator to provide adequate 
prophylactic or supportive care, except for those 
medications identified as “prohibited” as listed above
To be administered as prescribed by 
the Investigator
Best supportive care (including antibiotics, nutritional 
support, growth factor support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy, etc])
Should be used when necessary for 
all patients
4.5
Other Restrictions During the Study
4.5.1
Birth control
The following restrictions apply while the patient is receiving study treatment and for 
the specified times before and after:
Female patient of child-bearing potential

Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception 
(Table 1) from the time of screening and must agree to continue using such 
precautions for 180 days after the last dose of durvalumab  + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy. 
Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period. Cessation of birth control after this point 
should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period 
is an acceptable practice; however, periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of birth control. Female 
patients should also refrain from breastfeeding throughout this period.
Male patients with a female partner of childbearing potential

Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from screening 
through 180 days after receipt of the final dose of durvalumab  + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab 
monotherapy. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. Male patients should 
refrain from sperm donation throughout this period.

Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 1). 
N.B Females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) 
or post-menopausal. 
Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific 
requirements apply: 

Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year 
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46
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
Highly effective methods of contraception, defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly are described 
in Table 1. Note that some contraception methods are not considered highly effective 
(eg. male or female condom with or without spermicide; female cap, diaphragm, or 
sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not 
the primary mode of action [excluding Cerazette/desogestrel which is considered 
highly effective]; and triphasic combined oral contraceptive pills).
Table 1. Highly effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal Methods

Copper T intrauterine device

Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a

Etonogestrel implants: eg, Implanon or 
Norplan

Intravaginal device: eg, ethinylestradiol and 
etonogestrel

Medroxyprogesterone injection: eg, Depo-
Provera 

Normal and low dose combined oral 
contraceptive pill

Norelgestromin/ethinylestradiol 
transdermal system

Cerazette (desogestrel)
a
This is also considered a hormonal method
4.5.2
Blood donation
Subjects should not donate blood while participating in this study, or for at least 90 
days following the last infusion of durvalumab or tremelimumab.
4.6
Duration of Therapy
Patients may continue for 12 months of treatment or until any of the following occur:

Disease progression

Development of an inter-current illness that prevents further administration of 
treatment

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the as a whole study

The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures)
4.7
Duration of Follow Up
After patients come off treatment they will be followed up at 3, 6, 9, 12 months and then 
every 6 months for 3 years for survival and progression of disease.
4.8
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF. In general, patients who are permanently 
discontinued from receiving investigational product will be followed for disease 
progression, survival, and safety, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or administered 
subsequent therapy (see below). Subjects who decline to return to the site for evaluations 
will be offered follow-up by phone every 3 months as an alternative.
Patients will be permanently discontinued from study treatment and will not receive any 
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further investigational product if any of the following occurs for the subject in question:

Patient voluntarily withdraws from treatment (follow-up observation is permitted)

Patient is unable to comply with protocol requirements

Patient experiences Grade ≥ 3 infusion reaction

Patient experiences an adverse event that, in the opinion of the investigator or the 
sponsor, contraindicates further dosing

Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant or intends to become pregnant

Patient develops a second malignancy that requires treatment which would interfere 
with this study
Patients will not receive any further investigational product or further study observation 
if any of the following occurs for the subject in question:

Patient becomes lost to follow-up (LTF)

Patient withdraws consent 

Patient initiates an alternative anticancer therapy including another investigational 
agent
4.9
Patient Replacement
If a patient is enrolled in the study but comes off study before cycle 1 day 1 of treatment, 
the patient may be replaced.
A patient who does not reach the first imaging assessment at 2 months for reasons other 
than clinical progression will not be used toward assessment of the primary clinical 
endpoint (ORR), PFS or OS. However, they will be included in the final safety analysis.  
Additional patients may be added if needed for assessment of response.
                    
       .
IRB #: STU00200984-MOD0045 Approved by NU IRB for use on or after 10/13/2020 through 5/10/2021.

Version Date: 8.31.2020 – Amendment12
48
5.0
STUDY PROCEDURES
Visit Number
1
2
3
4
5
6
7
8
9
10
11
x
x + 1
 x + 2 x + 3
x + 4
Procedure/Study Day
SV9
D1
D14 
(±3D)
W4 
(±3D)
W8 
(±3D)
W12 
(±3D)
W16 
(±3D)
W18 
(±3D)
W20
** 
(±3D)
W22
(±3D)
W24
(±3D)
Off 
Treatm
ent8
3M 
(±1 
month)
6M 
±1 
month)
9M 
(±1 
month
12M +
q6M (±1 
month)
Informed consent
X
Durvalumab 1500mg
X
X
X
X
Durvalumab 750mg
X
X
X
X
X
Tremelimumab 75mg
X
X
X
X
CT chest, abdomen, pelvis; 
nuclear bone scan
1, 9
X
X
X
X
X
Assessment of AEs/SAEs15 
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
(including next line therapy 
after off treatment, response)
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination10, weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Height (prior to dosing)
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
X
12-lead Electrocardiogram11
X
Vital signs12
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
2
X
Hepatitis serologies13
X
HIV antibody
X
Pregnancy test
3
X
Serum chemistry4 
X
X
X
X
X
X
X
X
X
X
X
X
X
lactate dehydrogenase, GGT, 
lipase, uric acid and 
amylase 4
X
X
X
X
X
X
X
X
Hematology
5
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation parameters
6
X
X
X
X
Thyroid function tests
7
X
X
X
X 
X
X
X
Research blood samples14
X
X
X18
Tumor biopsy16
X
X
X

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** Visits 8 through 11 will repeat for a total of up to 18 doses of durvalumab, or until progressive disease (see 4.1.1) or unacceptable toxicity, 
with CTs and bone scan done every 8 weeks. Scans are to be completed every 8 weeks, regardless of drug holds or treatment delays. (Note: Bone 
scans will be done only if the patient has bone disease. PET-CT is acceptable in place of bone scan, if a bone scan is contra-indicated for a 
patient’s disease. The same modality used at baseline should be used throughout). Patients may continue on therapy after progression or after 
initial 52 week treatment period as specified in Sections 4.1.1 and 4.1.2.  Abbreviations: SV (screening visit) 
1 The same modality used at baseline should be used throughout. CT must have contrast, MRI with contrast is acceptable alternative if the patient is allergic 
to CT contrast. Scans are required to be completed every 8 weeks, regardless of drug holds or treatment delays.
 (Note: Bone scans will be done only if the patient has bone disease. PET-CT is acceptable in place of bone scan, if a bone scan is contra-indicated for a 
patient’s disease. The same modality used at baseline should be used throughout.) For patients with skin lesions, photographs may be taken on study-
provided camera by study staff on a white background (wall of patient room) using a ruler measurement on a study supplied digital camera. Photographs 
should not include any identifying characteristics. (Please refer to section 6.1.1 for details)
2 Urinalysis will include color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin, and microscopy including WBC/high power field 
(HPF), RBC/HPF.
3 Serum beta-human chorionic gonadotropin (at screening only) for females of child-bearing potential (as indicated) within 7 days of registration.
4 Serum Chemistry Panel will include calcium, chloride, magnesium, creatinine, sodium, potassium, blood urea nitrogen, bicarbonate, glucose, total 
bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, total protein and creatinine clearance. . 
If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin.  Additional chemistry labs will include: 
lactate dehydrogenase (LDH), GGT, lipase, uric acid and amylase. During combination therapy, these labs should be monitored prior to each dose; during 
maintenance monotherapy, labs should be monitored every 8 weeks. 
5 Hematology will include basophils, eosinophils, lymphocytes, platelet count, monocytes, neutrophils, red blood cell count, total white cell count, hematocrit, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, and hemoglobin.
6 Coagulation parameters will include prothrombin time, partial thromboplastin time, and fibrinogen.
7 Thyroid function tests will include thyroid stimulating hormone, free T3, and free T4. During combination therapy, these labs should be monitored prior to 
each dose; during maintenance monotherapy, labs should be monitored every 8 weeks.
8 Patients will be followed by routine clinic visit or phone call at 3, 6, 9, 12 months and then every 6 months for 3 years total from the end of treatment to 
document survival and disease progression.
9 The maximum time interval between Screening Visit/ baseline study procedures and the first dose of study drug will be 14 days. Systemic imaging (CTs, 
bone scan or PET-CT) and consent may be performed up to 28 days prior. Note: Bone scans will be done only if the patient has bone disease.  PET-CT is 
acceptable in place of bone scan, if a bone scan is contra-indicated for a patient’s disease. The same modality used at baseline should be used 
throughout.
10 Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at screening only.  Targeted 
physical examinations are to be utilized by the Investigator on the basis of clinical observations and symptomatology. Situations in which physical 
examination results should be reported as AEs are described in Section 10  
11 Resting 12-lead ECGs (x2, 5 minutes [+/-2 min] apart) will be recorded at screening and as clinically indicated throughout the study. ECGs should be 
obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains in that position. At Screening, 2 ECG’s will be 
obtained on which QTcF must be <470 ms. In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs 
should be obtained over a brief period (eg, 30 minutes) to confirm the finding.  

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12  Vital signs (blood pressure [BP], pulse, temperature) will be evaluated according to the assessment schedules outlined in Section 4.2.1). 
13  Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody
14  80 mL of whole blood should be collected in eight 10 mL plastic lavender top tubes (K2EDTA)
15 AE/SAE will be recorded from time of signature of informed consent, throughout treatment period, including the follow-up period (90 days after the last 
dose of durvalumab/tremelimumab)
16 tumor biopsy is mandatory prior to study enrollment and after 2 cycles of treatment (as clinically appropriate by PI discretion). At progression patients will 
be offered an optional biopsy. (Note: If it is felt to be clinically inappropriate to biopsy the patient, then this should be clearly documented in the patient’s chart 
and CRF. This documentation should also be printed and flagged in the patient’s research chart).
17 On each treatment day, hematology and serum chemistry are to be resulted before treatment can begin.

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5.1 Study Procedures After 52 Weeks of study treatment
                      (For patients who are continuing treatment or re-starting treatment after progression of disease after 52 weeks, this table should not be used 
for patients who stay on therapy due to pseudoprogression)
Visit Number
1
2
3
4
5
6
Procedure/Study Day
Re-
Evaluation 
before re-
treatment
D1
**
D14 
(±3D)
W4 
(±3D)
W6 
(±3D)
W8
***
(±3D)
Durvalumab 750mg*
X
X
X
X
X
CT chest, abdomen, pelvis; 
nuclear bone scan
1, 6
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Physical examination7, weight
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
Vital signs8
X
X
X
X
X
X
Serum chemistry2
X
X
X
X
lactate dehydrogenase, GGT, 
lipase, uric acid and 
amylase 2
X
X
X
Hematology
3
X
X
X
X
Coagulation parameters
4
X
X
X
Thyroid function tests
5
X
X
X
* Treatment for this patient population will be Durvalumab monotherapy. On each treatment day, hematology, serum chemistry are to be resulted before 
treatment can begin.
** The maximum time interval between re-evaluation study procedures and the first dose of study drug will be 14 days
*** Visits 2 through 6 will repeat for a total of up to 26 doses of durvalumab (52 weeks of therapy total), or until progressive disease (see 4.1.1) or 
unacceptable toxicity, with CTs and bone scans done every 8 weeks. Scans are to be completed every 8 weeks, regardless of drug holds or treatment 
delays.
1 The same modality used at initial baseline should be used. Scans to be completed every 8 weeks, regardless of drug holds or treatment delays.
Note: Bone scans will be done only if the patient has bone disease. PET-CT is acceptable in place of bone scan, if a bone scan is contra-indicated for a 

Version Date: 8.31.2020 – Amendment12
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patient’s disease. The same modality used at baseline should be used throughout. For patients with skin lesions, photographs may be taken on study-
provided camera by study staff on a white background (wall of patient room) using a ruler measurement on a study supplied digital camera.  Photographs 
should not include any identifying characteristics
2 Serum Chemistry Panel will include calcium, chloride, magnesium, creatinine, sodium, potassium, blood urea nitrogen, bicarbonate, glucose, total 
bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, total protein and creatinine clearance. If 
Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin.  Additional chemistry labs will include: 
lactate dehydrogenase, GGT, lipase, uric acid and amylase. During maintenance monotherapy, labs should be monitored every 8 weeks.
3 Hematology will include basophils, eosinophils, lymphocytes, platelet count, monocytes, neutrophils, red blood cell count, total white cell count, hematocrit, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, and hemoglobin.
4 Coagulation parameters will include prothrombin time, partial thromboplastin time, and fibrinogen.
5Thyroid function tests will include thyroid stimulating hormone, free T3, and free T4.
6Systemic imaging (CTs, bone scan or PET-CT) may be performed up to 28 days prior to D1. Refer to footnote 1 for instructions regarding bone scan, PET-
CT and skin lesions. 
  7Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at screening only.  Targeted 
physical examinations are to be utilized by the Investigator on the basis of clinical observations and symptomatology. Situations in which physical 
examination results should be reported as AEs are described in Section 10  
8  Vital signs (blood pressure [BP], pulse, temperature) will be evaluated according to the assessment schedules outlined in Section 4.2.1.

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6.0
ENDPOINT ASSESSMENT
6.1
Definitions
6.1.1
Measurable Lesions
Must be accurately measured in at least one dimension (greatest diameter) with a 
minimum size of 10mm by CT scan (cuts of 5mm or less), MRI, or physical exam 
(ideally using calipers). Bone only disease is allowed, however, must have an 
osteoblastic component that can be easily measured.
Note: In case of skin lesions, patients will have standardized digital photography 
of their disease site for disease assessment.  Photographs will be taken at the 
same time points as the CT scans (as indicated in the study procedures table in 
Section 5).  Frontal and lateral photographs will be taken by study staff on a white 
background (wall or curtain in patient room) using a ruler measurement on a study 
supplied digital camera.  Photographs should not include any identifying 
characteristics.
6.1.2
Non-measurable Lesions
Defined as all other lesions less than 10mm. Examples of non-measurable lesions 
include leptomeningeal disease, ascities, pleural/pericardial effusions, 
inflammatory breast disease, lymphangitic involvement of skin or lung.
6.1.3
Response criteria
Complete Response - Disappearance of all lesions.
Partial Response - At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease - At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression.)
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of diameters while 
on study.
6.1.4
Immune-related RECIST
In addition to above, tumor response will be assessed by the irRECIST for 
investigational purposes, not assessment of primary objective (25). Tumor 
response by irRECIST is defined as an immune-related PR (irPR) or CR (irCR) 
over a period of at least 4 weeks. We will define immune-related clinical benefit 
rate as immune-related stable disease (irSD), irPR, or irCR.
6.2
Primary Endpoint
The primary endpoint is Overall Response Rate (ORR), defined as number (%) of patients 
with one visit response of partial response (PR) or a complete response (CR) in patients with 
metastatic HER2 negative breast cancer (TNBC in expansion cohort) treated with 
durvalumab in combination with tremelimumab using the Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 (23). Patients who experience pseudoprogression and 
have subsequent response may count toward ORR. Evaluable patients must have had 
received 2 cycles of therapy and had 2 month scans. 
6.3
Secondary Endpoints
Secondary endpoints include PFS and OS, where PFS is defined as the time from date 
of treatment initiation until date of documented disease progression or death (by any cause 
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in the absence of progression), and OS is defined as the time from date of treatment 
initiation until death due to any cause.
Clinical benefit rate will be assessed and defined as SD (for ≥ 12 weeks) + PR + CR. Any 
patient who has completed two months of study therapy is evaluable for this end point
The number, frequency, and severity of adverse events (as defined by the NCI 
Common Terminology Criteria for Adverse Events or CTCAE version 4.03) will be 
recorded.  Any patient treated with minimum 1 dose of either study drug will be evaluable for 
toxicity.
6.4
Exploratory Endpoints
Biomarkers predictive of response include assessment of serum or tissue-based markers 
including but not limited to: circulating tumor DNA, immunohistochemical expression of PD-
L1; TILs; changes in tissue and peripheral T cell receptor sequencing, mutational and 
neoantigen burden, and immune-related candidate gene signatures at baseline.
To determine the response rate (RR) and duration of response(DoR) of next line therapy after 
progression on durvalumab/ tremelimumab study regimen, for those patients who are able to 
submit detailed follow up data about subsequent treatment and response. 
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires high level 
monitoring, as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial (see Section 5 for time points). In addition, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;

any abnormal laboratory values have returned to baseline;

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
Adverse events and serious adverse events will be recorded from time of signature of 
informed consent, throughout the treatment period and including the follow-up period (90 
days after the last dose of durvalumab + tremelimumab, or until resolution of AEs.
During the course of the study all AEs and SAEs should be proactively followed up 
for each subject. Every effort should be made to obtain a resolution for all events, 
even if the events continue after discontinuation/study completion.
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments.
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The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation.
AstraZeneca/MedImmune retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary
7.2
Definitions & Descriptions
7.2.1
Adverse Event
The International Conference on Harmonization (ICH) Guideline for Good Clinical 
Practice (GCP) E6 (R1) defines an adverse event (AE) as any untoward medical 
occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the medicinal product.
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. 
An AE includes but is not limited to any clinically significant worsening of a 
subject’s pre-existing condition. An abnormal laboratory finding (including ECG 
finding) that requires an action or intervention by the investigator, or a finding 
judged by the investigator to represent a change beyond the range of normal 
physiologic fluctuation, should be reported as an AE.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is 
any new sign or symptom, disease, or other untoward medical event that begins 
after written informed consent has been obtained but before the subject has 
received investigational product. 
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 
(serious or nonserious). An untoward medical event occurring during the 
prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE 
v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
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7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is immediately life-threatening.
The patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition of “Serious Adverse 
Event“.
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to AstraZeneca.
7.2.4
Exceptions to AE and SAE definitions
Generally speaking, any adverse event that results in hospitalization or prolonged 
hospitalization should be documented and reported as an SAE, as described 
above. Likewise, any condition responsible for surgery should be documented as an 
AE if the condition meets the criteria for an AE. However, for the purposes of this 
study, neither the condition, hospitalization, prolonged hospitalization, nor surgery 
are reported as AEs or SAEs under the following circumstances:

Hospitalization or prolonged hospitalization is for a diagnostic or elective 
surgical procedure for a preexisting condition. Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization is required to allow efficacy 
measurement for the study.

Hospitalization or prolonged hospitalization is required for study-directed 
therapy of the target disease of the study, unless it is a worsening or 
increase in frequency of hospital admissions as judged by the principal 
investigator.

Hospitalization or prolonged hospitalization is due to social reasons (i.e. 
awaiting transport home).

Pregnancy is not considered a serious adverse event, any patients who 
become pregnant during the study should discontinue the study 
immediately. Patients should be instructed to notify the investigator if it is 
determined after completion of the study that they become pregnant either 
during the treatment phase of the study or within 30 days or five half-lives 
after the treatment period, whichever is longer.
7.2.5
Durvalumab & Tremelimumab Adverse Events of Special Interest (AESI)
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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 ± tremelimumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants 
and/or hormone replacement therapy. These AESIs are being closely monitored in 
clinical studies with durvalumab monotherapy and combination therapy. An immune-
mediated adverse event (imAE) is defined as an AESI 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 imAE diagnosis. Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the imAE. 
If the Investigator has any questions in regards to an event being an imAE, the 
Investigator should promptly contact the Study Physician.
AESIs observed with durvalumab ± tremelimumab include but are not limited to:

Diarrhea/Colitis

Intestinal perforation

Pneumonitis

ALT/AST increases/hepatitis/hepatotoxicity

Neuropathy/neuromuscular 
toxicity 
(eg. 
Guillain-Barré 
syndrome, 
and 
myasthenia gravis)

Myositis/polymyositis

Endocrinopathies 
(ie, 
events 
of 
hypophysitis/hypopituitarism, 
adrenal 
insufficiency, and hyper- and hypothyroidism, Type I diabetes mellitus)

Rash/Dermatitis

Myocarditis

Nephritis

Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, 
increased serum amylase) 
Other inflammatory responses that are rare with a potential immune-mediated 
etiology are also considered as AESIs and include, but are not limited to, 
pericarditis, sarcoidosis, and uveitis and other events involving the eye, skin, 
hematological and rheumatological events. It is possible that events with an 
inflammatory or immune mediated mechanism could occur in nearly all organs.
The following are more details on specific AESIs:
7.2.5.1Pneumonitis
Across the durvalumab monotherapy pooled dataset pneumonitis events 
observed (pneumonitis, ILD, acute interstitial pneumonitis and pulmonary 
fibrosis) were reported at a frequency rate of Common (98/1889; 5.2%). 
Adverse events of pneumonitis are also of interest for AstraZeneca, as 
pneumonitis has been observed with anti-PD-1 and anti-PD-L1 mAbs (but 
not with anti-PD-L1 mAbs). Initial work-up should include high-resolution CT 
scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. Presentations of pneumonitis can range from asymptomatic 
lung infiltrates to those that mimic
severe bacterial pneumonia [40]. Early consideration of pneumonitis should 
be realised when patients present with new onset or worsening of respiratory 
symptoms such as dyspnea or cough. Prompt treatment with steroids is 
important as per current established toxicity management guidelines. 
Guidelines for the management of patients with immune-related AEs (irAEs) 
including pneumonitis are provided in Table 1.
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7.2.5.2Infusion reactions
AEs of infusion reactions (also termed infusion-related reactions) are of 
special interest to AstraZeneca and are defined, for the purpose of this 
protocol, as all AEs occurring from the start of IP infusion up to 48 hours after 
the infusion start time.  For all infusion reactions, SAEs should be reported to 
AstraZeneca Patient safety as described in Section 10.3.  
7.2.5.3Hypersensitivity reactions
Hypersensitivity reactions as well as infusion-related reactions have been 
reported with anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012).  As 
with the administration of any foreign protein and/or other biologic agents, 
reactions following the infusion of mAbs can be caused by various 
mechanisms, including acute anaphylactic (IgE-mediated) and anaphylactoid 
reactions against the mAbs and serum sickness.  Acute allergic reactions 
may occur, may be severe, and may result in death.  Acute allergic reactions 
may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, 
pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension, myalgia, vomiting, and 
unresponsiveness.  Guidelines for the management of patients with 
hypersensitivity (including anaphylactic reaction) and infusion-related 
reactions are provided in Table 1.   
7.2.5.4Hepatic Function Abnormality
Hepatic function abnormality is defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater 
than 2 × ULN. Examples of hepatitis abnormality are autoimmune hepatitis, 
hepatitis toxic, hepatocellular injury, hepatoxicity resulting in 
hyperbilirubinemia. Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each 
other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or 
whether there is objective evidence that clearly supports causation by a 
disease (eg, cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the investigational product. Guidelines for 
management of patients with hepatic function abnormality are provided in 
Table 1.
7.2.5.5Gastrointestinal disorders
Diarrhea/colitis: is the most commonly observed treatment emergent SAE 
when tremelimumab is used as monotherapy, but may also be related to 
durvalumab.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  There 
were no CTC Grade 4 or 5 events from the pooled dataset, however, fatal 
events of colitis have been reported with durvalumab in combination with 
tremelimumab. Guidelines on management of diarrhea and colitis in patients 
receiving tremelimumab are provided in Table 1.

Intestinal perforation
Across the durvalumab monotherapy pool of studies, intestinal 
perforation was reported at a frequency rate of Uncommon (2/1889; 
0.1%); CTCAE Grades 2 and 4. There were no Grade 5
events.
In the durvalumab + tremelimumab combination pooled dataset, 
intestinal perforation was reported in 3/1088 patients (0.3%; 
Uncommon) and large intestine perforation was reported in
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4 patients (0.4%; Uncommon). All events were CTCAE Grade 4 or 5 
in severity. One patient from study D4190C00010 died due to the 
event of intestinal perforation and had concurrent
peritonitis/Grade 4 sepsis; autopsy was not performed. Another 
patient died due to the event of large intestine perforation and 
disease progression (Study D4190C00006). Both cases were not
considered as treatment-related by the Investigator.
Monitor for symptoms that may be related to bowel perforation such 
as sepsis, peritoneal signs, and ileus (refer to the Toxicity 
Management Guidelines for diarrhoea/colitis). Investigators
should adhere to the overall management for immune-mediated 
toxicities by performing a thorough evaluation to rule out alternative 
aetiologies and by initiating prompt treatment including steroids.
7.2.5.6Endocrine 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 Table 1.
7.2.5.7Pancreatic disorders
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase 
and amylase elevation. Pancreatitis is an inflammatory condition of the 
pancreas that typically manifests initially as asymptomatic elevations of 
amylase and lipase in patients treated with immune checkpoint
inhibitors. Across the 1889 patients in the monotherapy program, events of 
pancreatitis were Uncommon to rare. Four patients (0.2%) experienced 
pancreatitis (CTC Grade 2, Grade 3 and Grade 4 in severity) and 1 patient 
(<0.1%) with CTC Grade 3 acute pancreatitis. Elevations in amylase
and lipase were reported at a frequency rate of Uncommon (0.6% and 0.5%, 
respectively). In ongoing sponsored studies with durvalumab + 
tremelimumab therapy in 1088 patients, events of pancreatitis were 
Uncommon; pancreatitis was reported in 10 patients (0.9%) with 5 of these
CTC Grade 3 in severity. Elevations in amylase and lipase were reported at a 
frequency of Common (91 patients; 8.4% and 101 patients; 9.3%, 
respectively). Most events of amylase increased were Grades 1 and 2 in 
severity while events of lipase increased tended to be more
severe (Grade 3 and Grade 4) with the combination.
Patients should be monitored for signs and symptoms of pancreatitis 
including Grade 3 or 4
elevations in lipase and/or amylase. Close monitoring, early detection and 
prompt treatment of these events are important. 
 Guidelines for the management of patients with immune-mediated 
pancreatic disorders are provided in Table 1.
7.2.5.8Neurotoxicity
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 Table 1.
Myositis/polymyositis
In the durvalumab pool of studies as of the DCO, 3 patients (0.2%) reported 
the event of myositis, including 1 CTCAE Grade 3 in severity. Outside of the 
pooled dataset, there were 2 fatal events of polymyositis considered as 
treatment-related by the Investigator.
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In the durvalumab + tremelimumab combination pool, Grade 3 myositis event 
were reported in 1 patient (<0.1%). In addition, there were 4 SAEs of 
myositis reported from studies outside of the pooled dataset. Grade 2 
polymyositis was reported in 1 patient (<0.1%) from the
combination pooled dataset and 2 additional patients (1 each retrieved from 
the global safety database and a study outside of the pooled dataset). The 
severity of these events were Grade 3 and Grade 5 with the latter patient 
having died due to the event of polymyositis which was
considered related by the Investigator. Autopsy showed polymyositis 
involving the diaphragm and chest wall muscles.
Investigators should adhere to the Toxicity Management Guidelines by 
performing a thorough evaluation to rule out alternative aetiologies and 
initiating prompt treatment with steroids and modification of study drug dose 
regimen depending on the severity of the event. Refer to the Toxicity 
Management Guidelines.
7.2.5.9 Nephritis
Immune-mediated renal events include nephritis. Management of patients 
with immune-related nephritis are provided in Table 1.
7.2.5.10 Dermatitis
Immune-mediated rashes can occur such as dermatitis. Management guidelines 
of immune-related dermatitis are reviewed in Table 1.
Myocarditis
Across the durvalumab monotherapy pool of studies, as of the DCO of 12 
July 2017 there has been 1 serious report of CTC Grade 3 myocarditis and 2 
additional cases (Grade 3 and Grade 4) outside of the pooled dataset. In all 
cases the patients recovered or were improving with
corticosteroid therapy.
Across the durvalumab plus tremelimumab combination pool of studies as of 
12 July 2017 there has been 1 report of myocarditis. In addition myocarditis 
has been reported in 4 patients from clinical studies outside of the pooled 
dataset: 3 patients receiving durvalumab plus
tremelimumab (1 of which resulted in a fatal outcome not considered related 
by the Investigator) and 1 patient receiving durvalumab plus tremelimumab in 
combination with cytotoxic chemotherapy agents, etoposide and carboplatin 
(which resulted in a fatal outcome).
Investigators should be aware of such rare, but severe immune-mediated 
adverse events including myocarditis with its presenting signs/symptoms (eg, 
decreased ejection fraction, arrhythmias, in particular occurrences of 
atrioventricular block).
For patients with suspected myocarditis, investigators should obtain a 
cardiology consult and
institute full diagnostic work-up (that includes exclusion of other alternate 
causes such as infection) and the appropriate management that includes 
discontinuing drug (permanently if event progresses to Grade 3 or 4) and the 
prompt use of steroids or other immunsosuppressives.
For rapid recovery of Grade 1 and 2 events, re-expose with treatment is 
possible. Patients with pre-existing cardiac disorders should be closely 
monitored for deterioration in their cardiac condition, which could suggest 
new onset myocarditis.
7.2.5.11Immune-related adverse events
Based on the mechanism of action of durvalumab and tremelimumab leading 
to T-cell activation and proliferation, there is a possibility of observing irAEs 
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during the conduct of this study.  Potential irAEs may be similar to those 
seen with the use of ipilimumab, BMS-936558 (anti-PD-1 mAb), and BMS-
936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies 
(Hodi et al 2010, Brahmer et al 2012, Topalian et al 2012). These AEs are 
inflammatory in nature and can affect any organ.  With anti-PD-L1 and anti-
CTLA-4 combination therapy, the occurrence of overlapping or increasing 
cumulative toxicities that include irAEs could potentially occur at higher 
frequencies than with either durvalumab or tremelimumab monotherapy.  
Patients should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (eg, infection or PD), an immune-related 
etiology should be considered for signs or symptoms of enterocolitis, 
dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition to the 
dose modification guidelines provided in Table 1, it is recommended that 
irAEs are managed according to the general treatment guidelines outlined for 
ipilimumab (Weber et al 2012). These guidelines recommend the following:

Patients should be evaluated to identify any alternative etiology.

In the absence of a clear alternative etiology, all events of an 
inflammatory nature should be considered immune related.

Symptomatic and topical therapy should be considered for low-grade 
events.

Systemic corticosteroids should be considered for a persistent low-grade 
event or for a severe event.

More potent immunosuppressives should be considered for events not 
responding to systemic steroids (eg, infliximab or mycophenolate).

If the Investigator has any questions in regards to an AE being an irAE, 
the Investigator should immediately contact the treating physician.  
7.2.5.12 Other rare or less frequent AESIs and immune-mediated adverse 
events
Events with an inflammatory or immune mediated mechanism could 
occur in nearly all organs.
Inflammatory events that are less frequent with a potential immune-
mediated aetiology are also considered as AESIs and include, but are 
not limited to, pericarditis, sarcoidosis, uveitis, and other events involving 
the eye (eg, keratitis and optic neuritis), skin (eg, scleroderma and 
vitiligo), haematological (eg, haemolytic anaemia and, immune 
thrombocytopenic purpura) and rheumatological events (polymyalgia 
rheumatic and autoimmune arthritis).
7.2.6
Other events requiring immediate reporting 
7.2.6.1Overdose
An overdose is defined as a patient receiving a dose of durvalumab + 
tremelimumab in excess of that specified in the Investigator’s Brochure, 
unless otherwise specified in this protocol.
Any overdose of a study patient with the durvalumab + tremelimumab, with 
or without associated AEs/SAEs, is required to be reported within 24 hours 
of knowledge of the event to the sponsor and AstraZeneca/MedImmune 
Patient Safety or designee using the designated Safety e-mailbox (refer 
section 7.3.3.4). If the overdose results in an AE, the AE must also be 
recorded on the AE eCRF. 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 reported 
as an SAE. There is currently no specific treatment in the event of an 
overdose of durvalumab or tremelimumab. 
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7.2.6.2Pregnancy
Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should 
be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the 
IP under study may have interfered with the effectiveness of a contraceptive 
medication.  Congenital abnormalities or birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs.  The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up 
and documented even if the patient was discontinued from the study.  
If any pregnancy occurs in the course of the study, then the Investigator or 
other site personnel should inform the appropriate AstraZeneca 
representatives within 1 day, ie, immediately, but no later than 24 hours of 
when he or she becomes aware of it. The designated AstraZeneca 
representative will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site 
within 1 to 5 calendar days for SAEs and within 30 days for all other 
pregnancies. The same timelines apply when outcome information is 
available.(refer section 7.3.3.4).  
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during 
the study and for 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab 
monotherapy, whichever is the longer time period.  
Pregnancy of the patient’s partner is not considered to be an AE.  However, 
the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) 
occurring from 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab 
monotherapy, whichever is the longer time period if possible, be followed up 
and documented.  
Where a report of pregnancy is received, prior to obtaining information about 
the pregnancy, the Investigator must obtain the consent of the patient’s 
partner.  Therefore, the local study team should adopt the generic ICF 
template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
7.2.6.3Hepatic Function Abnormality
Hy’s Law: Cases where a patient shows elevations in liver biochemistry may 
require further evaluation and occurrences of AST or ALT ≥3 × ULN together 
with total bilirubin ≥2 × ULN may need to be reported as SAEs. 
Hepatic function abnormality (as defined in Section 10.1.3.) in a study 
subject, with or without associated clinical manifestations, is required to be 
reported as “hepatic function abnormal” within 24 hours of knowledge of 
the event to the sponsor and AstraZeneca/MedImmune Patient Safety using 
the designated Safety e-mailbox (refer section 7.3.3.4), unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct 
obstruction) that is unrelated to investigational product has been confirmed.
If the definitive underlying diagnosis for the abnormality has been established 
and is unrelated to investigational product, the decision to continue dosing of 
the study subject will be based on the clinical judgment of the investigator. If 
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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 sponsor and 
AstraZeneca/MedImmune
7.2.8
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy. 
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned Quality Assurance Monitor 
(QAM) within 24 hours of becoming aware of the event. Completion of 
the NU CRO SAE Form is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

AE (verbatim)

A description of the event, severity, treatment, and outcome (if 
known)

The date when the AE started and stopped
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
Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
The following variables will be collected for SAEs as applicable:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

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>>
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs (if applicable).

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.

Any death of an NU subject while on treatment regardless of 
expectedness or relationship to study drug will be promptly reported 
to the NU IRB within 24 hours of notification.

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification.

All other deaths of NU subjects not previously reported, other non- 
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review.
7.3.3.3 Reporting to the FDA (completed by the NU QAM)
The NU QAM will handle all FDA reporting in accordance with the 
following:
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to Medimmune
All deaths that occur during the study, or within the protocol-defined 30-day 
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post-last dose of durvalumab + tremelimumab safety follow-up period must be 
reported to AstraZeneca as follows:

Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to AstraZeneca 
as a SAE within 24 hours (see Section Error! Reference source not 
found. for further details). The report should contain a comment regarding 
the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death. 

Deaths with an unknown cause should always be reported as a SAE.
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 + 
tremelimumab 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 and/or sponsor must inform the FDA (as outlined above), of 
any serious or unexpected adverse events that occur in accordance with the 
reporting obligations of 21 CFR 312.32, and will concurrently forward all 
such reports to AstraZeneca.  A copy of the MedWatch report must be 
faxed to AstraZeneca at the time the event is reported to the FDA. It is the 
responsibility of the sponsor to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time.
A cover page should accompany the MedWatch form indicating the 
following:

“Notification from an Investigator Sponsored Study”

The investigator IND number assigned by the FDA

The investigator’s name and address

The trial name/title and AstraZeneca ISS reference number (ESR-14-
10694 (D4190C00030)
Sponsor must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is 
related to disease progression, as determined by the principal 
investigator.
Send SAE report and accompanying cover page by way of email to 
AstraZeneca’s designated mailbox:    
AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided to AstraZeneca 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.
7.3.3.5 Study recording period and follow-up for adverse events and serious 
adverse events
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Adverse events and serious adverse events will be recorded from time of 
signature of informed consent, throughout the treatment period and including 
the follow-up period (90 days after the last dose of durvalumab  
+ 
tremelimumab). 
During the course of the study all AEs and SAEs should be proactively followed 
up for each subject. Every effort should be made to obtain a resolution for all 
events, even if the events continue after discontinuation/study completion.
If a subject discontinues from treatment for reasons other than disease 
progression, and therefore continues to have tumor assessments, drug or 
procedure-related SAEs must be captured until the patient is considered to have 
confirmed PD and will have no further tumor assessments.
The investigator is responsible for following all SAEs until resolution, until 
the subject returns to baseline status, or until the condition has stabilized 
with the expectation that it will remain chronic, even if this extends beyond 
study participation.
8.0
DRUG INFORMATION
8.1
Durvalumab 
8.1.1
Other names
MEDI4736
8.1.2
Classification - type of agent
Durvalumab is a human IgG1κ mAb.
8.1.3
Mode of action
Durvalumab, a human IgG1κ mAb directed against PD-L1, and with reduced 
binding to C1q and the Fcγ receptors
8.1.4
Storage and stability
All investigational products should be kept in a secure and dry place. Vials should 
be stored at 2°C to 8°C (refrigerated) and not be frozen.
8.1.5
Protocol dose specifics
Doses of 1500mg for patients (>30 kg) will be administered using an intravenous 
(IV) bag containing 0.9% (weight/volume) saline or 5% (w/v) dextrose, with a final 
durvalumab (MEDI4736) concentration ranging from 1 to 20 mg/mL and delivered 
through an IV administration set with a 0.2- or 0.22-μm in-line filter.  
If a patient’s weight falls to 30kg or below the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab Q4W until the weight improves to >30 
kg, at which point the patient should start receiving the fixed dosing of durvalumab 
1500mg Q4W. The appendix includes an example of a weight-based dose 
calculation. (Appendix C).
For 1500mg durvalumab dose (patients > 30kg), 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 20 mg/mL, and the 
bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag.  
For the 750mg durvalumab maintenance dose, add 15.0 mL of durvalumab 
(MEDI4736) (ie, 750mg of durvalumab [MEDI4736]) to the IV bag. The IV bag 
size should be selected such that the final concentration is within 1 to 20 mg/mL, 
and the bag is mixed by gentle inversion to ensure homogeneity of the dose in the 
bag. Weight based dosing is not required for the 750mg durvalumab dose.
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Patients will be treated with durvalumab 1500mg intravenously (IV) every 4 weeks 
for a total of 4 doses (along with tremelimumab 75mg IV every 4 weeks for a total 
of 4 doses). After completion of the 4 doses of combination therapy, durvalumab 
will be continued at a dose of 750mg every 2 weeks for up to 18 additional doses. 
8.1.6
Preparation
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the investigator as a 500-mg vial solution for infusion after dilution. 
The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 
0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 
10.0 mL. 
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique. Total in-use 
storage time from needle puncture of durvalumab vial to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 
46°F).  If in-use storage time exceeds these limits, a new dose must be prepared 
from new vials. Infusion solutions must be allowed to equilibrate to room 
temperature prior to commencement of administration. 
8.1.7
Route of administration for this study
The liquid product is to be diluted with 0.9% (w/v) saline or 5% (w/v) dextrose for 
IV infusion.
8.1.8
Incompatibilities
No formal drug-drug interaction studies have been conducted with durvalumab. 
There are no known clinically significant interactions of durvalumab with other 
medicinal products.
8.1.9
Availability & Supply
Durvalumab will be supplied by AstraZeneca as a 500-mg vial concentrate 
solution for infusion. Investigational products will be supplied by Medimmune in 
containers with identical appearances in coded kits for each product respectively. 
Each investigational product kit has a unique number that is printed on all labels 
within the kit (ie, the outer carton label and the label of each container within the 
carton). Each carton and vial is labeled with the same unique sequence number 
range. MEDI4736 will be supplied in liquid form. 
Durvalumab will be provided to Northwestern University by MedImmune, 
Northwestern University will request durvalumab submitted via email indicating the 
amount of bottles required to the contact below:
Linda M. Hall
Sr. Clinical Project Manager 
HallL@medimmune.com
P: 301-398-5419| F: 301-398-9435
Please allow approximately 10 days for drug delivery.
8.1.10
Side effects
Below safety data from 393 subjects with various types of cancer who received 
Durvalumab alone is provided. Related side effects reported in subjects receiving 
durvalumab alone were:
Frequent - Expected to occur in 10% to 25% of people (10 to 25 out of 100 
people): Fatigue (13.5%)
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Not Frequent – Expected to occur in 2% to less than 10% of people (2 to less 
than 10 out of 100 people): Nausea (8.4%), Diarrhea (5.3%), Decreased appetite
(5.3%), Rash (5.3%), Vomiting (4.8%), Itchiness (4.1%), Difficulty breathing
(3.8%), Fever (3.1%), Low thyroid (2.8%), Increased liver enzymes (2.5%),
Cough (2.5%), Muscle pain (2.3%), Stomach pain (2.0%), Dizziness (2.0%). In 
addition, productive cough,dysphonia, abdominal pain, blood TSH 
increase/decrease, hypophysitis, dysuria, night sweats, pyrexia, oedema peripheral, 
upper respiratory tract infections, pneumonia, oral candidiasis,dental and oral soft 
tissue infections, influenza, myalgia, myositis and polymyositis have been identified 
as adverse drug reactions.
Related and serious side effects reported in subjects receiving durvalumab alone 
were:
•
Blockage in the urinary tract
•
Fluid in the space surrounding the lung and inflammation of the lung
•
Increase in calcium in the blood
•
Joint pain
•
Worsening of cancer
•
Increase in liver enzymes and blockage of the tract between the liver and 
small intestine
•
Spinal cord swelling
•
Irregular heart beat or rhythm
•
Chest pain and fluid in the abdomen
•
Dehydration
•
Disorder in the blood vessels of the organs
•
Swelling of the tumor
•
Lack of muscle control during walking or picking up objects
There was one death felt to be related to durvalumab when administered alone. 
The subject who had a prior history of cardiac illness including a prior heart attack 
died due to a disorder of the blood vessels. The Study Doctor also indicated 
possible other causes of the fatal event.
8.1.11
Nursing implications
Durvalumab will be administered as an IV infusion over approximately 1 hour in 
duration (± 5 minutes). If the infusion is less than 55 minutes or more than 65 it is 
considered a deviation. 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.
Durvalumab infusion will start approximately 1 hour after the end of tremelimumab 
infusion.  The duration will be approximately 1 hour (± 5 minutes) for each 
infusion.  Refer to Section 4.2.1 for monitoring of vitals.
Since the compatibility of durvalumab with other IV medications and solutions, 
other than normal saline (0.9% [w/v] sodium chloride for injection) and 5% (w/v) 
dextrose, is not known, the durvalumab solution should not be infused through 
an IV line in which other solutions or medications are being administered. No 
incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. The date, start time, interruption, and completion time of 
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durvalumab administration must be recorded in the source documents.
In the event that there are interruptions during infusion, the total allowed time 
should not exceed 8 hours at room temperature. 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.
8.1.12
Return and Retention of Study Drug
All unused investigational products will be returned to a MedImmune-authorized 
depot or disposed of upon authorization by MedImmune according to the 
investigational site policy.
8.2
Tremelimumab
8.2.1
Other names
n/a
8.2.2
Classification - type of agent
Tremelimumab is being developed as an immunotherapeutic agent for various 
cancers.
8.2.3
Mode of action
Tremelimumab is a human IgG2 anti-CTLA-4 mAb.
8.2.4
Storage and stability
Investigational product must be stored at 2 to 8 degrees Celsius and must not be 
frozen.
8.2.5
Protocol dose specifics
Tremelimumab 75mg IV every 4 weeks for a total of 4 doses for patients > 30kg.
A dose of 75 mg (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 tremelimumab 
concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm in-line filter.  Add 3.8 mL (ie,75 mg of 
tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV 
bag. The IV bag size should be selected such that the final concentration is within 
0.10 to 10 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the 
dose in the bag.  
If a patient’s weight falls to 30kg or below the patient should receive weight-based 
dosing equivalent to 1mg/kg tremelimumab Q4W until the weight improves to >30 
kg, at which point the patient should start receiving the fixed dosing of 
tremelimumab 75 mg Q4W. The appendix includes an example of a weight-based 
dose calculation. (Appendix D)
8.2.6
Preparation
The dose of 75 mg of tremelimumab for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique.  Total in-use 
storage time from needle puncture of tremelimumab vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2ºC-8°C (36ºF-46°F). 
If storage time exceeds these limits, a new dose must be prepared from new vials. 
The infusion solution in the prepared final IV bag should be equilibrated to room 
temperature prior to administration. Tremelimumab does not contain preservatives 
and any unused portion must be discarded.
8.2.7
Route of administration for this study
IV
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8.2.8
Incompatibilities
No formal drug-drug interaction studies have been conducted with 
tremelimumab. However, in RCC studies, acute renal failure has been 
reported with the combination of tremelimumab and sunitinib. It is unknown 
whether a similar reaction will be observed when tremelimumab is combined 
with other tyrosine kinase inhibitors.
8.2.9
Availability & Supply
Tremelimumab will be supplied by AstraZeneca either as a 400-mg or a 25-mg 
vial solution for infusion after dilution.  The solution contains 20 mg/mL 
tremelimumab, 20 mM histidine/histidine hydrochloride, 222 mM trehalose 
dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL.  The nominal fill 
volume is 20.0 mL for the 400-mg vial and 1.25 mL for the 25-mg vial.  
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 original container until use to prevent 
prolonged light exposure.
.
Tremelimumab will be provided to Northwestern University by MedImmune., 
Northwestern University will request tremelimumab submitted via email indicating 
the amount of bottles required to the contact below:
Linda M. Hall
Sr. Clinical Project Manager 
HallL@medimmune.com
P: 301-398-5419 F: 301-398-9435
Please allow approximately 10 days for drug delivery.
8.2.10
Side effects
Below are safety data from 973 subjects with various types of cancer who 
received tremelimumab alone. Related side effects reported in subjects receiving 
tremelimumab alone were:
Very Frequent – Expected to occur in more than 25% of people (more than 25 
out of 100 people): Diarrhea (41.2%), Rash (27.2%), Itching (25.1%)
Frequent - Expected to occur in 10% to 25% of people (10 to 25 out of 100 
people): Fatigue (23.8%), Nausea (21.9%), Vomiting (13.5%), Decreased
appetite (11.3%)
Not Frequent – Expected to occur in more than 5% to less than 10% of people 
(more than 5 to less than 10 out of 100 people): Headache (7.2%), Fever (7.0%), 
Stomach pain (6.7%), Inflammation of the large intestine (5.5%)
Related and serious side effects reported in more than 1% of people (more than 1 out 
of 100 people) receiving tremelimumab alone were: Diarrhea (9.2%), Inflammation 
of the large intestine (3.6%), Vomiting (2.3%), Nausea (1.8%), Dehydration (1.8%)
Deaths thought to be related to tremelimumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people). There 
were five deaths reported that were thought to be related to side effects caused by 
tremelimumab. The deaths per subject are summarized with the causes noted 
(where known):
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•
Sudden death in a subject with advanced skin cancer who had a history 
of smoking. The subject had a family history of sudden cardiac death 
and had recently changed antidepressant medications. While on 
tremelimumab treatment, the subject had symptoms that might be 
consistent with decreased blood flow to the heart. However, the exact 
cause of death was not confirmed.
•
Lack of oxygen to the brain due to sudden and unexpected loss of heart 
function in a subject whose skin cancer had spread to the lungs. The 
subject had a history of medical conditions that could increase the risk for 
heart problems including diabetes, increased blood pressure, elevated 
levels of fat in the blood and diarrhea. One week before loss of heart 
function, the subject experienced kidney failure, dehydration, fever and 
increased creatinine (a compound in the blood removed by the kidney that 
when high can indicate poor kidney function). The study doctor thought 
there was a possibility that the side effects and loss of heart function could 
be related to tremelimumab.
•
Imbalance of essential minerals necessary for body function due to long 
lasting diarrhea in a subject with advanced skin cancer.
•
Blood clot in the lungs in a subject with advanced skin cancer that had 
worsened.
•
In a subject with advanced skin cancer, respiratory failure in relation to an 
infection that occurred after complications from surgery performed to treat 
inflammation and bleeding of the large intestine was the immediate cause 
of death. The study doctor thought the large intestine inflammation and 
complications that followed after surgery were related to tremelimumab.
8.2.11
Nursing implications
The first day of dosing is considered Day 1. Infusion duration for tremelimumab will 
be approximately 1 hour (± 5 minutes). If the infusion is less than 55 minutes or 
more than 65 it is considered a deviation. Tremelimumab will be administered first; 
followed by Durvalumab approximately 1 hour after the end of the tremelimumab 
infusion.
Each dose of investigational product should be administered using the following 
guidelines:
1.
Investigational product must be administered at room temperature by 
controlled infusion into a peripheral vein or central line. Prior to the start of 
the infusion, ensure that the bag contents are at room temperature to 
avoid an infusion-related reaction due to the administration of the solution 
at low temperatures.
2.
A physician must be present at the site or immediately available to respond 
to emergencies during all administrations of investigational product. Fully 
functional resuscitation facilities should be available. Investigational product 
must not be administered via IV push or bolus but as a slow IV infusion. 
The entire content of each IV bag will be infused using an infusion pump.
3.
The infusion lines should be attached only at time of use. Lines used for 
infusion during dose administration will need to be equipped with 0.22- or 
0.2-µm in-line filters.
4.
The duration of the investigational product administration will be 
recorded.
Tremelimumab will be administered as an IV infusion over approximately 1 hour 
(± 5 minutes). 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 (unless prohibited by institutional practice).
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In the event that there are interruptions during infusion, the total allowed time 
should not exceed 8 hours at room temperature. If either preparation time or 
infusion time exceeds the time limits a new dose must be prepared from new 
vials.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin 
have been observed. Tremelimumab solution should not be infused with other 
solutions or medications.
8.2.12
Return and Retention of Study Drug
All unused investigational products will be returned to a MedImmune-authorized 
depot or disposed of upon authorization by MedImmune according to the 
investigational site policy.
8.3
Combination of Durvalumab and Tremelimumab regimens
Patients in the durvalumab + tremelimumab combination therapy phase will receive 1500 
mg durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 750 mg durvalumab q2w starting 
on Week 16 for up to 8 months (18 doses) (see Figure 2). Fixed dosing is only for subjects 
with > 30kg body weight.  Patients with a body weight ≤ to 30 kg will be excluded. If a patient 
becomes <30kg on study, please see additional dosing instructions per each agent
Tremelimumab will be administered first, followed by durvalumab.  The duration for each will 
be approximately 1 hour (± 5 minutes).  A 1-hour observation period is recommended after 
the first infusion of durvalumab and tremelimumab.  If no clinically significant infusion 
reactions are observed during or after the first cycle, subsequent infusion observation 
periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab 
and tremelimumab infusion).  
8.3.1
Study drug preparation durvalumab and tremelimumab
Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W durvalumab 
(equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 20 mg/kg 
Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the 
current study. 
8.3.2
Monitoring of dose administration
Patients will be monitored during and after the infusion with assessment of vital signs 
at the times specified in the Study Protocol.
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 (eg, 
diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator.  If the infusion-related reaction is 
≥Grade 3 or higher in severity, study drug will be discontinued (even during 
durvalumab monotherapy).
As with any antibody, allergic reactions to dose administration are possible.  
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.  The study site must have immediate access to emergency resuscitation 
teams and equipment in addition to the ability to admit patients to an intensive care 
unit if necessary
8.3.3
Side Effects when durvalumab and tremelimumab are given together (see 
current IB for full details)
Below are safety data from 61 subjects with lung cancer who received durvalumab 
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in combination with tremelimumab. Related side effects reported in subjects 
receiving the combination were:
Very Frequent – Expected to occur in more than 25% of people (more than 25 
out of 100 people): Fatigue (26.2%)
Frequent – Expected to occur in 10% to 25% of people (10 to 25 out of 100 
people): Diarrhea (21.3%), High level of amylase (increased amylase in your 
blood may indicate poor function of your pancreas; 13.1%)
Not Frequent – Expected to occur in 5% to less than 10% of people (5 to less than 
10 out of 100 people): High level of alanine aminotransferase (ALT is a substance 
that is found in the blood and when high can indicate damage to the liver; 9.8%), 
Itching (9.8%), Decreased appetite (8.2%), High level of aspartate 
aminotransferase (AST is a substance that is found in the blood and when high 
can indicate damage to the liver; 8.2%), Inflammation of large intestine (8.2%), 
Rash (8.2%), Low level of blood thyroid stimulating hormone decreased (this may 
indicate that your thyroid is releasing too much thyroid hormone; 6.6%), High  level 
of lipase (lipase is a substance that is found in the blood and when high can 
indicate damage to the pancreas; 6.6%). Intestinal perforation has been seen to 
occur in more increased frequency and severity when durvalumab and 
tremelimumab are used in combination.
Related and serious side effects reported in at least 2 subjects receiving the 
durvalumab and tremelimumab combination were: Diarrhea (8.2%), Inflammation 
of the large intestine (6.6%), Inflammation of the lung (3.3%), High level of AST 
(3.3%), High level of ALT (3.3%), High level of amylase (3.3%)
Related and serious side effects reported in at least 2 subjects receiving the 
durvalumab and tremelimumab combination were:
There was one death thought to be related to the durvalumab and tremelimumab 
combination treatment. The subject experienced myasthenia gravis and 
polymyositis. Myasthenia gravis and polymyositis are rare conditions that cause 
weakened muscles. They also cause swelling and tenderness. In this subject’s 
case, the muscles responsible for swallowing and breathing as well as other 
muscles were affected. The subject declined treatment for the events. The 
polymyositis led to the subject’s death approximately 2 months after receiving the 
first treatment with durvalumab and tremelimumab.
9.0
CORRELATIVES/SPECIAL STUDIES
              Please refer to laboratory manual for additional details
9.1 
Tissue sample collection guidelines 
A fresh tissue biopsy of the primary tumor or a metastatic site at baseline and after 2 
cycles of treatment will be collected. Re-biopsy after cycle 2 must be of the original biopsy 
site. In case of complete response, a biopsy of the original site will be re-biopsied, if 
feasible (i.e. chest wall metastasis), or another metastatic site may be used. The tumor 
lesion planned for biopsy must not be used as index lesion for assessment of disease 
unless there are no other lesions suitable for biopsy or the lesion used for biopsy is ≥ 2 cm 
in its longest diameter. 
Fresh tissue biopsies will be performed using an image-guided core needle at the 
aforementioned time points (pretreatment, after 2 cycles) according to institutional practice. 
If clinically practical, subjects will undergo 4 core biopsies at each scheduled biopsy time 
point, ideally at least 3 core biopsies. Skin punch biopsies are acceptable, however, at least 2 
punch biopsies that are at least 8mm in shortest diameter are necessary. All tissue samples will 
be immediately frozen in liquid nitrogen and then stored at -80°C, full details are provided 
in the lab manual. Collected tissues at baseline will undergo a touch prep to be sent to 
pathology for standard of care testing.
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Tumor samples will be stored and may be used for additional correlative studies at a later 
date such as, but not limited to, immunohistochemistry, tumor mutation analysis and 
proteomic analysis.
9.2
Blood sample Collection Guidelines
Research blood samples will be collected at baseline and 2 months, and at end of study or 
time of discontinuation)..
80 mL of whole blood should be collected per lab manual instructions. Please ensure that 
tubes are completely filled at time of collection.
9.3
Sample Processing, Storage, and Shipment
Refer to the lab manual for sample processing, storage, and shipment information.
9.4
Assay Methodology
See lab manual for details.
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
This will be a single-arm, open-label, pilot phase II study to assess the efficacy and safety 
of durvalumab in combination with tremelimumab in patients with stage IV breast cancer 
which is HER2 negative. Patients who have completed the week 16 CT or nuclear bone 
scan will be evaluable for response endpoints. (Note: Bone scans will be done only if the 
patient has bone disease. PET-CT is acceptable in place of bone scan, if a  bone scan is 
contra-indicated for a patient’s disease. The same modality used at baseline should be 
used throughout.)
The primary endpoint is ORR, defined as number (%) of patients with at least one visit 
response of partial response (PR) plus complete response (CR) in patients with metastatic 
HER2 negative breast cancer treated with durvalumab in combination with tremelimumab 
using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (23).Any 
patient who has completed two months of study therapy is evaluable for this end point.
Secondary endpoints include PFS and OS, where PFS is defined as the time from date 
of treatment initiation until date of documented disease progression or death (by any 
cause in the absence of progression), and OS is defined as the time from date of 
treatment initiation until death due to any cause. Clinical benefit rate (SD for ≥ 12 weeks 
+ PR + CR) will be assessed. Any patient who has completed two months of study 
therapy is evaluable for this end point.
The safety endpoints will be the number, frequency, and severity of adverse events (as 
defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE version 
4.03) will be recorded. Any patient treated with minimum 1 dose of either study drug will 
be evaluable for toxicity. 
The expansion cohort will follow a similar design but only include patients with metastatic 
TNBC. Responses will be captured by RECIST v1.1.
Exploratory endpoints include serum and tissue-based biomarkers including: circulating 
tumor DNA, immunohistochemical expression of PD-L1; TILs; changes in tissue and 
peripheral T cell receptor sequencing, mutational and neoantigen burden, and immune-related 
candidate gene signatures at baseline.
Based on the fact that significant responses have been recently documented after 
progression when patients are started on next line of chemotherapy; a third exploratory 
objective is being added in order to capture response and duration of response to next line 
therapy.
Objective: To determine the response rate (RR) and duration of response(DoR) of next line 
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therapy after progression on durvalumab/ tremelimumab study regimen, for those patients 
who are able to submit detailed follow up data about subsequent treatment and response. 
10.2
Sample Size and Accrual
A total of 35 patients (as needed)with metastatic breast cancer which is HER2 negative will 
be enrolled into this study and receive durvalumab in combination with tremelimumab, in 
order to get 28 evaluable for response. 15 patients with ER-positive disease and 15 patients 
with ER-negative disease will be enrolled (i.e. 2 cohorts with 14 evaluable each). Patients who 
have completed the week 8 CT or nuclear bone scan will be evaluable for response 
endpoints. Bone scans will be done only if the patient has bone disease. PET-CT is 
acceptable in place of bone scan, if a  bone scan is contra-indicated for a patient’s 
disease. The same modality used at baseline should be used throughout.
Using a Simon’s two-stage design, we assume the undesirable overall response rate (null 
hypothesis) to be approximately 10%, and the alternate hypothesis to be approximately 
30% based on previously published and presented data. Eleven patients will be added in 
the first stage. If 2 or more respond, then an additional 16 patients will be added for a total 
of 27. If 6 or more respond, then the hypothesis that the response rate is at least 30% is 
supported. This design has a Type I error rate of 4% and 80% power, and has a  70% 
chance of stopping early for futility after the first stage if the true response rate is 10%. The 
design is based on the complete sample and is not stratified by estrogen receptor status.
ORR will also be calculated separately by receptor status, but the study is not powered 
for analyses within these subgroups.
For the expansion cohort we expect the ORR based on RECIST v1.1 to exceed 30% 
given our preliminary data.  Using a Bayesian design assuming a prior beta distribution 
with parameters 0.3 and 0.7, there is a posterior probability of 0.81 that the ORR 
exceeds 30% if 8 or more responses out of 20 evaluable patients are observed.
10.3
Data Analyses Plans
The primary analysis will be on the intent-to-treat (ITT) population, including all evaluable 
patients. Best ORR defined as will be defined as number (%) of patients with at least one visit 
response of complete or partial response by the Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1). Best objective response prior to disease progression will be used. 
The overall response rate will be estimated by the proportion of overall response, and its 
80% confidence interval (CI) and 95% CI will be estimated using the exact binomial 
distribution.
Additionally, we will evaluate clinical benefit rate, defined as stable disease for ≥ 12 
weeks complete or partial response using RECIST 1.1 guidelines in a similar manner. We 
will also perform similar analyses using Immune Related RECIST (irRECIST). 
PFS is defined as the time from date of treatment initiation until date of documented disease 
progression or death (by any cause in the absence of progression). OS is defined as the 
time from the date of start of treatment until death due to any cause. For patients alive at 
the time of data cut-off, PFS and OS will be censored as of the last tumor assessment 
date or known to be alive, respectively. The PFS and OS will be estimated using the 
Kaplan-Meier method. The number, frequency, and severity of adverse events (as defined 
by the NCI Common Terminology Criteria for Adverse Events or CTCAE version 4.03) will 
be recorded.
Baseline percent PDL1 expression, TILs (sTILs, iTILs, and their ratio), and changes in T 
cell subpopulations will be used as a continuous variable to predict clinical benefit or 
overall response rates using appropriate statistical summaries. Cox proportional hazards 
regression will be used to compare how these biomarkers are associated with PFS and 
OS as well.
Changes from baseline in these biomarkers will also be analyzed to assess for 
pharmacodynamic effects of treatment. Continuous variables will be analyzed using 
either paired t-tests, signed rank tests or repeated measures analysis of variance.
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For analysis of each T cell receptor clonotype, we will apply a newly-developed algorithm 
Bowtie2 aligner (Ref; Nature methods 2012; 9:357-9), in collaboration with Profs. Miyano 
and Yamaguchi in Human Genome Center, The University of Tokyo. We will assign each 
of V, (D), J and C segments in the TCRA and TCRB reference sequences provided by 
IMGT/GENE-DB (Ref; Nucleic acids research 2005; 33:D256-61). By our approach, we will 
also identify novel exons that are not deposited in the reference sequence database. After 
decomposition of T cell receptor sequencing reads into V, (D), J and C segments, we will 
determine amino acid sequences of CDR3 (complementarity determining region 3), which 
plays a critical role in recognition of antigen. We will also calculate the diversity index 
(inverse Simpson’s index) in CDR3 sequences to assess overall diversity and clonality in 
the T cell receptor clonotyes. Descriptive statistics will be used to assess differences from 
baseline to two months, and their relationship with clinical endpoints.
Determination of response rate to subsequent next line therapy will be determined in a 
similar manner as to the primary objective when feasible, where ORR is defined as number 
(%) of patients with at least one visit response of PR or CR. In instances where data for this post-
hoc analysis cannot be obtained and only clinical responses can be obtained (ie patient followed 
up at an outside institution and only clinical radiograph reports are available), these will be 
used. Best objective response prior to disease progression will be used. Response rates will 
calculated using proportions and the 80% and 95% confidence intervals will be estimated using 
the exact binomial distribution. Duration of response to next line therapy will be defined as date 
from next line therapy until date of last dose of next line therapy. The Kaplan-Meier method will be 
used to assess duration of response to next line therapy. 
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
MedImmune Scientific Affairs. In the event that external participating sites are added, 
amendments will be distributed by the lead institution (Northwestern) to all external sites 
upon approval by the Northwestern University IRB.
11.3
Registration Procedures
For potential patients for phase II studies, study teams are asked to inform the assigned 
QAM (croqualityassurance@northwestern.edu) of the date and time that the patient will 
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need to be registered.  
BEFORE a patient can be treated on study, the following items must be completed and 
submitted to confirm eligibility and receive a subject identification number: 

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Copy of the pathology report (upload to NOTIS)

Signed and dated Eligibility Checklist (upload to NOTIS and keep original hard copy 
in a secure location/study chart)
The assigned QAM will review the registration documents. Once review is complete, he or 
she will register the patient, assign a subject identification number, provide a cohort 
assignment (as applicable) and send a confirmation of registration to involved personnel. 
Registration will then be complete and the patient may begin study treatment. 
11.4
Data Submission
Data collection for this study will be done through NOTIS. Access to the trial in NOTIS is 
granted to appropriate roles identified at the time of participating site activation, or upon 
request. Site users will not be able to access the study in NOTIS until all required and study 
specific trainings are completed. 
Once a patient is confirmed and registered to the study, eCRFs should be submitted 
according to the study procedures table.  Generally, for all phase II patients, data are due 
with 10 days of a visit or end of cycle.  A set amount of data may also be requested for any 
screen failures, as is defined by the study. In most instances, this will include collection of 
adverse events and baseline data from the time of registration to the date of screen failure. 
11.5    Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be provided to 
the Clinical Trials Office at Northwestern University (as applicable):

Completed feasibility assessment(s) to verify site’s capacity to support a 
Northwestern sponsored trial

Signed copy of Northwestern University’s Data Participating Site Acknowledgement 
which details data submission guidelines

Draft consent form for review and approval prior to submission to the local IRB

A copy of the official IRB approval letter for the protocol and informed consent

A copy of the IRB approved informed consent

Pertinent credentials (CVs, MLs, CITI & GCP Training and FDFs) for the local PI and 
any sub-investigators who will be involved in the study at the site

Form FDA 1572 appropriately filled out and signed with appropriate supporting 
certifications
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training, and delegation of authority log). Full requirements will be outlined in the 
study start-up packet upon successful completion of a feasibility assessment. 
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11.6       Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of 
the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer 
to the CTO website for additional information). The level of risk attributed to this study 
requires high level, as outlined in the DSMP. The assigned QAM, with oversight from the 
Data and Safety Monitoring Committee, will monitor this study in accordance with the study 
phase and risk level. In addition, the study will abide by all safety reporting regulations, as 
set forth in the Code of Federal Regulations. 
11.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
11.7.1 Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.
11.7.2   Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s).
A protocol deviation may be considered an instance of Reportable New Information 
(RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.8  Investigator Obligations – Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements Subject data protection. The Principal Investigator is 
responsible for the conduct of the clinical trial at the site in accordance with Title 21 of the 
Code of Federal Regulations and/or the Declaration of Helsinki. The PI is responsible for 
personally overseeing the treatment of all study patients. The PI must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
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the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Clinical Trial Audit Committee (CTAC), as outlined in the DSMP.
11.9  Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches its 
primary completion date, as defined by ClinicalTrials.gov. This is the date that the final 
patient was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three months 
after a study’s primary completion date, the PI must send a written request for data 
approval to the QAM which includes justification. Requests must be made a minimum of 
six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release 
will be provided to the PI. If the request is approved, the QAM will present the data set to 
the DSMC for approval. A final, DSMC-approved dataset, as applicable, will then be 
released 6-8 weeks after the request was made. The investigators are expected to use 
only DSMC-approved data and statistical analyses any time they are disseminating trial 
data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and 
statistical analyses are used appropriately. Once the biostatistician and QAM gives final 
approval, the publication may be submitted to external publisher.
11
 APPENDICES
APPENDIX A- EFFECTIVE METHODS OF CONTRACEPTION
Please refer to section 4.5.1 for details
.
APPENDIX B- COMMON TOXICITY CRITERIA FOR ADVERSE EVENTS
Toxicity will be graded according to the NCI’s Common Toxicity Criteria for Adverse Events 
(CTCAE) version 4.0. The CTCAE version 4.0 can be accessed at the following link:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
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APPENDIX C – Durvalumab weight based dose calculation
For durvalumab dosing done depending on subject weight. Weight-based dosing should be utilized for 
patients whose weight decreased to ≤ 30 kg who would otherwise be receiving the durvalumab 1500mg 
Q4W fixed dose:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag:
Dose (mL) = XY mg / 50 (mg/mL)
Where 50 mg/mL is durvalumab nominal concentration.
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle are only needed for greater than 10% change in weight.
5. The number of vials required for dose preparation is the next greatest whole number of vials from the 
following formula:
Number of vials = Dose (mL) / 10.0 (mL/vial)
Example: 
1. Cohort dose: 20 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 600 mg = 20 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag:
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL
5. The number of vials required for dose preparation: 
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials
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APPENDIX D – Tremelimumab weight based dose calculation
                            [Note: Cohort Dose X = 1 mg/kg]
For Tremelimumab, dosing done depending on subject weight. Weight-based dosing should be utilized for 
patients whose weight decreased to ≤ 30 kg:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 20 (mg/mL) 
where 20 mg/mL is tremelimumab nominal concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle are only needed for greater than 10% change in weight or if patient’s 
weight improves to >30kg. Once a patient’s weight improves to >30kg, patient should start receiving the 
fixed dosing of tremelimumab 75mg Q4W
5. The number of vials required for dose preparation is the next greatest whole number of vials from the 
following formula:
Number of vials = Dose (mL) / 20.0 (mL/vial)
Example: 
1. Cohort dose: 1 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL
5. The number of vials required for dose preparation: 
Number of vials = 1.5 (mL) / 20.0 (mL/vial) = 1 vial
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APPENDIX E – Protocol Summary of Changes
Original Protocol – June 10, 2015
Amendment 1 – July 20, 2015 
Changes Requested During FDA Review of IND
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Face Page (PI address, 
IND number, IND 
holder, version date, 
amendment number)
N/A
PI address corrected, 
IND number and IND 
holder added, 
amendment number 
updated
Administrative
Section 1.6 (Rationale 
for the current study)
N/A
Clarified rationale for the 
study, justification for 
choosing the proposed 
doses and schedule of 
MEDI4736 and 
tremelimumab therapy 
and rationale for 
administering 18 
additional doses of 
MEDI4736
Per FDA reviewer 
recommendations
Sections 3.0 (Patient 
eligibility) & 3.1 
(Inclusion Criteria) 
Target population was 
females with Her2-
negative breast cancer
Modified to include both 
female and male
Per FDA reviewer 
recommendations
Section 3.1 (Inclusion 
criteria)
Stated that ER+ 
patients ositive must 
have progressed 
through standard 
hormone therapy & 
received at least one 
line of chemotherapy in 
the metastatic setting.
Modified to require 
progression through 
prior therapy with 
Palbociclib in addition to 
standard chemotherapy 
and hormone therapy
Per FDA reviewer 
recommendations
Section 3.2 (Exclusion 
criteria)
N/A
Added exclusion criteria 
to exclude patients with 
documented Her2-
positive metatstatic 
breast cancer regardless 
of Her2-negative status 
of primary tumor
Per FDA reviewer 
recommendations
Section 4.1 (Treatment 
plan)
N/A
Added a statement 
regarding continued 
safety monitoring in case 
of decision to continue 
therapy on patients who 
develop disease 
progression while on 
study
Per FDA reviewer 
recommendations
Table 2

Treatment allowed 
to resume for G3 
hepatitis as well as 
for G3 immune-
mediate 
neurotoxicity and 
G3 immune- 
mediated 
peripheral 
Dose modification and 
toxicity management in 
Table 2 modified as 
follows: 

Added statement 
regarding ruling out 
infections etiologies 
for G2 
diarrhea/enterocolitis
Per FDA reviewer 
recommendations
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neuromotor 
syndromes

Stated that 
treatment could 
resume for G3 non-
immune mediate 
AEs that 
downgrade to ≤ G2 
within 7 days or 
resolve to ≤ G1 or 
baseline within 14 
days,

Requires treatment 
discontinuation for 
G3 (or higher) 
hepatotoxicity, 
immune mediated 
neurotoxicity, and 
immune-mediate 
peripheral 
neuromotor 
syndromes.

Requires that G3 
non-immune 
mediated reactions 
downgrade to ≤ G2 
with 7 days AND 
resolve to ≤ G1 or 
baseline within 14 
days.
Section 5.0 (Study 
Procedures)

Imaging for 
RECIST response 
required only at 
baseline, W16, and 
off-study.

No reference was 
made to the time 
between screening 
procedures and 
first dose of study 
drug.

Less frequent 
monitoring of 
thyroid, liver, and 
chemistry tests 
required.

Amended to reflect 
that imaging for 
RECIST response 
will be performed 
every 2 cycles (8 
weeks) while 
patients are 
receiving therapy

Amended to clarify 
that the maximum 
time interval between 
Screening Visit/ 
baseline study 
procedures and the 
first dose of study 
drug will be 14 days.

Modified to reflect 
that thyroid function, 
liver function, and 
clinical chemistries 
will be done prior to 
each dose during 
combination therapy 
and then every 4 
weeks during 
maintenance 
therapy.  
Per FDA reviewer 
recommendations
Amendment 2 – July 25, 2015 
Changes Requested by IRB
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Section 4.4 
(Concomitant 
medications/treatments)
Stated that herbal 
therapies “should be 
avoided.” 
Modified section to 
clarify concomitant use 
of herbal during therapy 
and make section 
consistent with exclusion 
criteria
Per IRB reviewer 
suggestion
Section 8.0 (Drug 
Information)
Formulation of 
investigational drugs 
referenced both 
Clarified the formulation 
of investigational drugs 
(MEDI4736 and 
Per IRB reviewer 
suggestion
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lyophilized and liquid 
formulations; shipment 
of agents to other sites 
mentioned.
Tremelimumab) supplied 
by MedImmune. 
Clarified that 
Northwestern University 
is the only site for 
shipment purposes 
Original Protocol – June 10, 2015
Amendment 3 – Oct .9. 2015
Changes Requested by Astrazeneca
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
        Title
A single arm 
phase II study 
evaluating the 
efficacy and safety 
of MED14736 in 
combination with 
tremelimubab in 
patients with 
metastatic HER2 
negative breast 
cancer
A single arm phase II 
study evaluating the 
efficacy and safety of 
Durvalumab 
(MED14736) in 
combination with 
tremelimubab in 
patients with metastatic 
HER2 negative breast 
cancer
Per new IB
Signature page
Present 
Removed
New  NU IIT protocol 
template 
Throughout
Drug referred to as 
MEDI4736
MED14736 drug name 
Durvalumab added. 
Per new IB
Study summary; Sec 
2.0,4.1
Primary endpoint was 
defined as Clinical 
Benefit Rate, 
Primary endpoint 
changed to Overall 
Response ate(ORR)
Clinical benefit rate 
added as the secondary 
endpoint
Per sponsor Astrazeneca, 
based on recent study’s
Study summary;
Section3.0 ;
N/A
Accrual: two cohorts of 15 
pts, ER+ and ER-
Ensure equal 
subgroups
Section 3.0 
(patient eligibility)
Stated as ‘Stage IV’
Word ‘metastatic’ added 
For clarification
Section 3.1.7
Exceptions to” prior 
diagnosis of cancer 
not specified.”
Exceptions stated:
squamous cell carcinoma or 
basal cell carcinoma of the 
skin or cervical intraepithelial 
neoplasia
Per PI  
To increase clarity for 
inclusion criteria
Section 3.1.10
(incl. criteria)
N/A
Creatinine ≤2ng/ml
ANC≥1000
Platelets≥50,000/mcl
Laboratory parameters:
Added Hb level ≥9.0g/dl
Serum Creatinine: new 
assessment criteria
ANC≥1500/mcL(1.5x10L)
Platelets≥100,000/mcl
Per new IB 
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Section 3.1.10
Transfusion and GCSF 
detail not included
Added “ transfusion 
permitted but not GCSF” 
for the laboratory values
Per PI. To increase clarity 
of eligibility criteria
Section 3.1.11
(incl.criteria)
Required pregnancy 
test
Required only negative 
pregnancy test 
Requires Serum 
pregnancy test
Added “ females of non-
productive potential” (with 
definition)
OR negative serum 
pregnancy test
For clarification
Per Astrazeneca
Section 3.1.12
(incl. criteria)
Addressed females 
of reproductive 
potential
Methods of birth 
control were stated ; 
duration was ‘study 
participation’
Addressed “ male patients 
of reproductive potential” in 
addition to females
Birth control methods and 
duration changed
Added statement for female 
patients to report new or 
suspected pregnancy during 
study participation
Per Astrazeneca
Section 3.1.14
(incl. criteria)
Section 3.1.15
(incl. criteria)
Requirement of 
consent before 
registration 
N/A
Added statement clarifying 
time-point for consent
Added statement for subject 
willingness for study 
compliance
For clarification
Per revised NUIIT 
protocol template
Sections in Excl. criteria     
             3.2.4
             3.2.5,
             3.2.10
             3.2.11
             3.2.12
             3.2.16
N/A
Added ECG  specifications; 
vaccine prohibitions; 
Inflammatory bowel 
disease; Organ transplant; 
hypersensitivity to 
durvalumab or excipient;
Exclude any study staff 
(who may also be patients) 
to avoid potential conflict of 
interest.
Per Astrazeneca
Section 3.2.3
(Excl.criteria)
Use of 
Immunosuppressive 
therapy 
Timepoint changed; 
exceptions stated 
Clarification-per 
Astrazeneca
Section 3.2.4
Number of EKGs 
required was not 
stated.
Added “ 2 EKGs 5 mins apart 
is mandatory”
Per PI . For clarity and 
confirmation of EKG 
findings
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Study Schema; Study 
summary; Sec 4.2
Only weight based 
dosing 
Change in dosing for 
Durvalumab and 
Tremelimubab:
Fixed dosing regimen and 
weight based dosing
Per new IB
Section 1.4 
(Durvalumab/MEDI4736)
N/A
Information regarding drug  
Durvalumab added to 
existing information
Per new IB
Section 1.5 
(Tremelimumab)
N/A
Information regarding drug 
Tremelimubab added to 
existing information
Per new IB
Section 1.6 (Durvalumab 
in combination with 
Tremelimumab)
N/A
This section is a new addition 
and describes the 
synergistic/additive 
Combination of Durvalumab 
and tremelimubab 
Per Astrazeneca
Section 1.7.1 (Rationale 
for fixed dosing)
N/A
This is a new section 
describing : Rationale for 
fixed dosing for durvalumab 
and tremelimumab
Per Astrazeneca and 
new IB
Section 4.1
Section 4.1.1
Provision for optional 
biopsy at progression
Provision of separate 
ICF at PD
Provision removed
Provision removed
Per PI. 
Per PI
Section 4.2.1 (Monitoring 
of dose administration)
N/A
Details for monitoring of 
subjects for infusion-related 
reactions have been added
For clarity
Section 4.2.1
Grade 3 reaction not 
clarified, even though 
description was there
Description now classified as 
“ ≥Grade 3  reaction” in the 
paragraph about modification 
of infusion rate
Per PI. To increase 
clarity
Section 4.3 (Toxicity 
Management)
Dose reduction 
tables present for 
both drugs.
“Modifications should 
be implemented only 
if toxicities are 
attributed to 
respective drugs”
Dose reductions tables for 
both drugs deleted.
Statement inserted
“Doses may be held 
according to Table 2, there 
are no dose adjustments. 
Toxicities are attributed to 
respective drugs 
(durvalumab or 
tremelimumab)”
Per Astrazeneca and new 
IB
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Table 2 (Immune related 
Adverse Events) 
The term ‘study 
physician’ was used.
The term ‘study physician’ 
was replaced with ‘treating 
physician’
For clarity and logistical 
convenience
Section 4.4 (Concomitatnt 
Medications/Treatment)
List of concomitant 
medications and 
prohibited treatments 
referred to were 
limited.
List of concomitant 
medications and prohibited 
treatments while the patient 
is on the study has been 
expanded.
Per Astrazeneca
Section 4.5 (Other 
Restrictions)
This section number 
was associated with 
‘Duration of therapy 
in the previous’ in the 
previous version. 
New section number 
is 4.6.
New section has been added 
to detail other restrictions 
during the study that includes 
birth control and blood 
donation while on the study
Per Astrazeneca
Section 4.6 (Duration of 
therapy - previously 
section 4.5)
Duration of therapy 
was 14 months
Duration reduced to 12 
months.
Clarification, per 
Astrazeneca
Section 4.8 (Removal of 
subjects - previously 
section 4.7)
N/A
Revised previous 
criteria/added new criteria for 
subject removal from the 
study or stopping treatment. 
Re-defined conditions for 
permanent discontinuation 
vs. stopping of IP 
administration to the subject.
Per Astrazeneca
Section 5.0 (Study 
procedures – Main study 
table)
Previous table had 
descriptions for 
dose/body weight. 
Hepatitis and HIV 
tests were not 
included. 
Updated table to describe 
fixed doses for Durvalumab 
(Medi4736) and 
Tremelimumab. Added new 
screening tests to include 
Hepatitis & HIV. Expanded 
lab tests to add. Footnotes 
updated. 
Per Astrazeneca
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Section 5.0 (Study 
procedures – Main study 
table)
Previous table +/- 7 
days window for visit 
At 3M,6M,9M, 12M 
Tumor biopsy at 12 
wk
Column heading” Off 
study”
Optional biopsy at 
end of treatment
Concomitant 
medications review 
not marked at all 
visits
Assessment of 
AE/SAE s not 
included in 9M and 
12 M visit
Added a window of +/- 1 
month for all said visits
Tumor biopsy at 8 wk.
Column heading “ OFF 
treatment”
Optional biopsy at treatment 
removed 
Concomitant medication 
review marked for all visits
Assessment of AE/SAEs 
included in 9M and 12 M 
visit. Footnotes added” 
AE/SAE to be followed up 
until resolved or patient off 
study”
Per PI and QA . To 
increase scheduling 
flexibility and ensure 
patient compliance
Error correction
Per PI
Per QA 
Per QA
Section 5.1 (Study 
procedures – additional 
study table)
N/A
Additional study table added 
for patients continuing 
treatment/re-starting 
treatment after disease 
progression.
Per suggestions from QA 
team
Section 6.2 (Primary 
endpoint) 
Primary endpoint was 
Clinical benefit rate
N/A
Primary endpoint changed to 
Overall Response Rate 
(ORR). 
Evaluable patient defined
Based on new literature 
reports using this drug 
combination.
Per PI 
Section 6.3 (Secondary 
Endpoints)
N/A
Added Clinical benefit rate as 
a secondary endpoint
Evaluable patient defined
To retain Clinical benefit 
rate as one of the study 
goal.
Per PI
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Section 7.0 (Adverse 
events) 
N/A
1.
7.1 AE monitoring 
section elaborated.
2.
7.2.1 AE definitions 
elaborated.
3.
7.2.3 Added a statement 
about causality 
assessment and 
communication with 
sponsor.
4.
7.2.25 AE of Special 
Interest (AESI) was 
elaborated.
5.
7.2.6 Other events 
requiring immediate 
reporting expanded
6.
7.3.3 Expedited 
Reporting of 
SAEs/Other events 
elaborated
Per Astrazeneca
Section 8.0 (Drug 
information)
N/A
1.
8.1.5 Dose 
specifications for 
Durvalumab to be 
used in the protocol 
elaborated.
2.
8.1.6 – Durvalumab 
preparation and 
reconstitution 
updated.
3.
8.1.9 Durvalumab 
availability and 
supply updated. 
4.
8.2.6 Preparation of 
Tremelimumab 
described. 
5.
8.2.9 – 
Tremelimumab 
availability and 
supply updated. 
6.
8.3 Dose 
specifications for the 
combination of 
Durvalumab plus 
Tremelimumab 
elaborated. New 
sections added to 
detail drug 
preparation for the 
combination, 
monitoring of the 
administered dose.
Updated based on IB v8.0 
dt 09.01.15.
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Section 8.1.11
N/A
Details about infusion 
schedule and monitoring of 
vitals added.
Per QA. For clarity
Section 8.2.9; 8.1.9
N/A
Updated drug availability 
information 
Per new IB
Section 9.0 
(Correlative/Special 
Studies)
1.
N/A
2.
End of study 
biopsy
1.
Reference to lab 
manual for details 
was added
1.
Per QA 
recommendation
2.
Feasibility and 
funding will be 
insufficient for 
end of study 
biopsy
Section 9.2
“Blood samples 
will be collected 
at end of study” 
Added” “Blood samples 
will be collected at end 
of study or time of 
discontinuation”
Per QA.
Section 10.0 (Statistics)
N/A
1.
10.1 – Clinical benefit 
rate added to secondary 
endpoint.
2.
10.2 Sample size 
updated.
3.
10.3 Data analyses plan 
modified to define ORR 
as the primary endpoint
4.
Evaluable patients 
defined.
Based on changes to the 
primary and secondary 
endpoints.
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Section 11.3 (Registration 
Procedures)
This section had 
references to 
eligibility confirmation 
by QAM and to eCRF 
training.
Section related to eligibility 
confirmation by QAM and 
eCRF training deleted.
Per QA
Section 11.7 (Investigator 
obligations)
Statement referring to the 
study being conducted 
under ICG/GCP added.
Per Astrazeneca
Amendment 3 – Oct 9, 2015
Amendment 4 – Dec 8, 2015
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Section 3.1.12 
(Inclusion Criteria)
Previous version 
stated that the use of 
effective birth control 
while on the study to 
be 180 days after the 
last dose of 
combination and 90 
days after the last 
dose of Durvalumab 
monotherapy
Period for use of 
effective birth control 
while on the study 
changed to 180 days 
after the last dose of 
combination therapy 
and 180 days after last 
dose of Durvalumab 
monotherapy
Per updated 
recommendations from 
MedImmune
Section 3.2.4 
(Exclusion criteria)
Previous version 
stated: ‘… calculated 
from 3 ECGs’
Corrected to ‘… 
calculated from 2 
ECGs’
To correct for error.
Section 4.3 (Toxicity 
management and dose 
delays/modifications)
N/A
Dose Modification 
description in Table 2 
updated
To reflect the updated IB 
for Durvalumab
Section 4.4 
(Concomitant 
Medications)
Previous version 
incorrectly stated 
‘Refer to section 5.6’
Corrected to read 
‘Refer to Table 2’
Correction for error
Section 7.2.5 (Adverse 
Events of Special 
Interest)
N/A
Section updated to add 
descriptions related to 
Nephritis and 
Dermatitis
To reflect the updated IB 
for Durvalumab
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Section 8.2.11 
(Nursing implications)
Previous version 
incorrectly indicated 
that Tremelimumab 
will be administered 
after Durvalumab 
Sequence and duration of 
infusion for 
Tremelumumab and 
Durvalumab was clarified
To correct 
discrepancy 
between section 
8.1.11 and 8.2.11
Section 9.0 
(Correlatives/Special 
studies)
Sec 9.1 (Tissue 
sample collection 
guidelines) previously 
specified different 
sample processing 
instructions for 
different biopsies
Sec 9.4 (Assay 
Methodology) had 
detailed methodology 
for various assays to 
be used for correlative 
studies
Sec 9.1 (Tissue sample 
collection guidelines) 
changed to clarify that all 
tissue samples will be 
immediately frozen in 
liquid nitrogen 
Sec 9.4 (Assay 
Methodology) – detailed 
methodology was 
replaced by statement 
‘See lab manual for 
details’
For clarity
For simplicity and 
clarity.
Amendment 5 – Feb 8, 2016
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Section 3.1 (Inclusion 
Criteria)
Sec 3.1.3
Sec 3.1.7
Previous version 
stated prior therapy 
with Palbociclib as an 
inclusion criteria for 
patients with ER 
positive breast 
cancers
Prior diagnosis of 
cancer > 5 years
Removed prior therapy 
with Palbociclib as an 
inclusion criteria for 
patients with ER 
positive breast cancers. 
Replaced with clinical 
resistance and 
progression through  
endocrine therapy as a 
criteria
Replaced with prior 
diagnosis > 3 years
Eligibility changed to 
reflect endocrine 
resistance more 
dynamically, this 
wording reflects biology 
more accurately and will 
enhance accrual.
Will enhance accrual, 
consistent with many 
cancer protocols.
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Section 3.2 (Exclusion 
Criteria)
3.2.1
3.2.7
Previous version 
stated: ‘even if their 
primary breast cancer 
was Her2-negative
Prior treatment with 
investigation agents 4 
weeks before 
registration was a 
criteria for exclusion
Replaced with: ‘based 
on most recent biopsy’
Replaced with prior 
treatment with 
investigational agents 
‘within 2 weeks of 5 half 
lives’
 For clarity
Table 1 (Immune-
mediated reactions) – 
Dose Modifications for 
Hepatitis
 Previous version 
incorrectly stated 
transaminases ≤ 8 x 
ULN or bilirubin ≤ 5 x 
ULN
Corrected to read 
transaminases ≥ 8 x 
ULN or bilirubin ≥ 5 x 
ULN
 Corrections
Section 5.0 (Study 
table)
Thyroid function tests
Footnote 11
Footnote 14
Previous versions were 
missing the required ‘X’ 
for Thyroid function 
tests at W4 and W8
Previous version stated 
‘a single ECG’ will be 
obtained at screening
Previous version stated 
36 ml
Added ‘X’ for W4 and 
W8
Changed to state  ‘2 
ECGs’ will be obtained 
at screening
Changed to 80 ml
Corrections
Corrections
Correlative analysis 
requires additional blood 
testing.
Section 8.3 
(Combination of 
Durvalumab and 
Tremelimumab 
regimens)
Previous dose for 
durvalumab 
monotherapy after 
week 16 was 
incorrectly stated at 
1500 mg 
Dose for durvalumab 
monotherapy starting 
week 16 changed to 
750 mg.
Corrections
Section 9.0 
(Correlatives/Special 
studies)
9.1 Tissue sample 
collection
9.2 Blood sample 
collection guidelines
N/A
Previous version 
stated 40 mL volume 
for research blood 
samples to be 
collected
Skin punch biopsies 
added as an alternative 
to core needle biopsy
Revised to state 80 mL 
will be collected 
Some patients 
may have skin 
disease, offer 
guidance to 
tissue needed.
Correlative 
analysis requires 
additional blood 
testing.
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Amendment 6– July 1st, 2016
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
Cover page
NU Sub-Investigators 
listed
Removed 
B.carneiro,MD;
Y.Chae,MD;
J.Kaplan,MD;
A.Williams,
H.Garrett,
Ellen Dammrich
Megan Sullivan
Added: 
Massimo 
Cristofanilli,MD;
Luis Blanco, MD
Per PI
Section 1.7.3
N/A
Section added: 
Ratiobale for 
Exploratory 
Objectives:
Three exploratory 
objectives have been 
explained. The third 
objective is a new one 
that is being added in 
this amendment.
Section was not 
included earlier in the 
protocol. Inclusion of 
this section will 
increase clarity and 
improve protocol 
structure.
Section 2.3.3
Section 6.4.3
Section 10.1
N/A
Added third exploratory 
endpoint.
“To determine the 
response rate (RR) and 
duration of 
response(DoR) of next 
line therapy after 
progression on 
durvalumab/ 
tremelimumab study 
regimen, for those 
patients who are able to 
submit detailed follow up 
data about subsequent 
treatment and 
response”.
This is based on the 
fact that significant 
responses have been 
recently documented, 
after progression when 
patients are started on 
next line of 
chemotherapy.
Exclusion criteria 
3.1.10
Patients must have 
adequate organ and 
bone marrow function 
(transfusion permitted but 
not GCSF) within 14 
days prior to registration.
Patients must have 
adequate organ and 
bone marrow function 
(transfusion permitted but 
not GCSF) within 14 
days of first dose of 
study drug 
administration.
Modified to be 
consistent with 
instructions in the study 
procedures table
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Section 4.1
Treatment overview
Added terms: “Induction 
phase” and 
“Maintenance Phase”.
Also added: In addition 
patient’s next line of 
therapy will be monitored 
for response rates and 
duration of clinical 
benefit to next line 
therapy.
For clarity
In keeping with the 
addition of the 3rd 
exploratory endpoint.
Section 4.1.1
Section heading: 
Continuation of 
Investigational Therapy 
after Progression.
Section heading 
changed to: 
Continuation of 
Investigational Therapy 
after Radiographic 
Progression (Pseudo-
progression).
Language added stating 
treatment regimen for 
patients continuing 
therapy with suspected 
pseudo-progression. 
Language indicates that 
patients should continue 
with treatment according 
to whether they in the 
induction phase or 
maintenance phase
To separately state the  
treatment regimen for 
pseudo-progression as 
opposed to subjects 
who continue treatment 
beyond 52 weeks , 
which is described in 
section 4.1.2
Section 4.1.2
Continuation of 
Investigational 
Therapy After 52 
Weeks
1.
Patients who 
achieve 
clinical 
benefit (CR, 
PR, or SD) 
until the end 
of the 52 
week period 
may enter a 
follow up 
phase or 
continue 
durvalumab 
as shown in 
table 5.1 for 
up to 52 
more weeks 
as long as 
they are felt 
to be deriving 
clinical 
benefit. 
2.
During follow-
up ,patients 
develop who 
PD may be re-
treated with 
Durvalumab. 
Only 52 week 
1.
Patients who 
achieve 
clinical 
benefit (CR, 
PR, or SD) 
until the end 
of the 52 
week period 
may enter a 
follow up 
phase or 
continue 
durvalumab 
as shown in 
table 5.1 for 
up to 52 more 
weeks as 
long as they 
are felt to be 
deriving 
clinical 
benefit. 
2.
Patients who 
enter follow up 
phase will 
continue to be 
monitored.  If 
during the first 
6 months of 
To clearly state the 
different scenarios and 
course of action for 
subjects who continue 
investigational therapy 
after 52 weeks.
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retreatment 
period will be 
allowed.
follow-up, 
patients 
developing 
PD may be 
re-treated 
with 
durvalumab 
as shown in 
table 5.1. Only 
one 52 week 
retreatment 
period will be 
allowed. 
Patients who 
are restarted 
on 
durvalumab 
after the initial 
52 week 
period must 
meet the 
following 
criteria:
Criteria have 
been listed
Section 5.0
Study procedures
Concomitant medication 
schedule
Footnote 1 regarding 
imaging:
The same modality used 
at baseline should be 
used throughout.
Modified to: 
Concomitant 
medications (including 
next line therapy after off 
treatment, response 
data).Same schedule as 
previously followed for 
concomitant medication
Added to footnote 1
CT must have contrast, 
MRI with contrast is 
acceptable alternative if 
the patient is allergic to 
CT contrast
In order to capture the 
data for next line 
therapy in keeping with 
the 3rd exploratory 
objective.
In order to provide 
patients with a safe 
alternative in case of 
allergy to CT contrast.
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N/A
Added footnote 16:
tumor biopsy is 
mandatory prior to study 
enrollment and after 2 
cycles of treatment (as 
clinically appropriate by 
PI discretion).
For clarity
Section 5.0-Study 
procedures table 
footnote 11;
Eligibility Criteria 3.2.4
2 EkGs 5 mins apart
2 EKGs 5 minutes(+/-2 
mins) apart
Window inserted for 
logistical convenience, 
so that  patients may 
not be deemed 
ineligible for very minor 
time deviations.
Section 5.1 
Section heading:
Study procedures
(For patients who are 
continuing treatment or 
re-starting treatment 
after progression of 
disease.
Section heading 
modified: 
Study Procedures 
After 52 Weeks of 
study treatment
 (For patients who are 
continuing treatment or 
re-starting treatment 
after progression of 
disease after 52 weeks, 
this table should not be 
used for patients who 
stay on therapy due to 
pseudo-progression).
Other  minor edits made
in the footnotes in order 
to increase clarity.
For clarity
Section 10.2
Sample size and 
accrual(statistics 
section)
Patients who have 
completed the week 16 
CT or nuclear bone 
scan will be evaluable 
for response endpoints.
Patients who have 
completed the week 8 
CT or nuclear bone scan 
will be evaluable for 
response endpoints
Error correction.
Week 16 changed to 
week 8 to be consistent 
with the rest of the 
protocol.
Section 10.3
Statistical data 
analyses plans
Data analyses plans 
explained
Added paragraph for 
3rd exploratory 
objective:
Determination of 
response rate to next 
line therapy will be 
determined in a similar 
manner as to the 
primary objective when 
feasible, where ORR 
is defined as  PR or CR. 
In instances where data for 
this post-hoc analysis 
cannot be obtained and 
only clinical responses can 
be obtained (ie patient 
followed up at an outside 
institution and only clinical 
radiograph reports are 
Per PI and statistician, 
in keeping with the 
addition of the 3rd 
exploratory objective.
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available), these will be 
used. Maximum response 
prior to disease 
progression will be used. 
Response rates will be 
calculated using 
proportions and the 80% 
and 95% confidence 
intervals will be estimated 
using the exact binomial 
distribution. Duration of 
response to next line 
therapy will be defined as 
time next line therapy 
begins, and last dose of 
next line therapy. The 
Kaplan-Meier method will 
be used to assess duration 
of response to next line 
therapy. 
Amendment 7 
September 26th ,2016
Section 5.0 
(Study Procedures)
Thyroid function tests 
scheduled every 4 
weeks during 
maintenance. But it was 
marked at W16, W18 
and W20 in the table.
Footnote **(under W20 
in the table)read: 
Visits7 through 9 will 
repeat for a total of up to 
18 doses of durvalumab, 
or until progressive 
disease (see 4.1.1) or 
unacceptable toxicity, 
with CTs and bone 
scan done every 8 
weeks.
Footnote 16 states details 
about tumour biopsy
t 
The ‘X’ indicating the 
W18 thyroid function test 
removed from the table.
The Footnote has been 
modified to indicate that 
Visits 8 through 9 will be 
repeated.
Added a note to footnote 
16:
“Note:
If it is felt to be clinically 
inappropriate to biopsy 
the patient, then this 
should 
be 
clearly 
documented 
in 
the 
patient’s 
chart 
and 
CRF.This documentation 
should also be printed 
and 
flagged 
in 
the 
patient’s 
research 
chart).”
For accuracy, 
consistency and 
clarity
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Section 5.0(Study 
procedures) and 
Section 5.1
(Study Procedures 
After 52 Weeks of 
study treatment)
Respiration rate 
included as part of vital 
signs.
Respiration rate 
removed from vital 
signs.
Respiration rate is not 
routinely done in 
clinic every time as 
part of vital signs. 
Hence, removed to 
prevent protocol 
deviations. 
             Amendment 8  April 26th , 2017(with additional updates after initial SRC approval)
Section(s) Affected
Prior Version
Amendment 8 Changes
Rationale
Protocol title page
and throughout
Original title
PI credentials 
Added: TNBC expansion 
cohort
Updated PI credentials 
by adding MSCI along 
with MD
An expansion cohort 
for TNBC patients has 
been added to this 
study
To be consistent with 
current PI credentials
List of abbreviations
previous list
Added:
ID: Infectious disease 
identifying data
For clarity
Study schema 
Had only one schema 
which illustrated the 
study 
Two schemas: 
1. For general cohort 
with Her2 negative 
breast cancer patients
2. For Expansion cohort-
with Triple negative 
breast cancer patients.
Added footnote that 
scans are to be 
completed every 8 
weeks, regardless of 
drug holds or treatment 
An expansion cohort 
for TNBC patients has 
been added to this 
study
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delays.
 All other details about 
this cohort is similar to 
the general cohort.
Study summary
and Section 2.1 
(Primary objectives 
and endpoints)
Primary, secondary and 
exploratory objectives 
listed.
Added Expansion cohort 
objective to the Primary 
Objective, stating the 
evaluation of ORR in 
TNBC patients with the 
same drug and dose 
combination.
Exploratory objective 
modified as explained in 
section 2.3
In order to 
accommodate and 
analyze the expansion 
cohort of TNBC 
patients
Study schema: 
sample size 
section(statistics)
Details about the 30 
patients in the general 
cohort.
Added language:
“Expansion cohort based 
will enroll 20 additional 
patients with TNBC to 
determine the posterior 
Bayesian probability that 
the response rate 
exceeds 30%.”
In order to 
accommodate and 
analyze the expansion 
cohort of TNBC 
patients
Study schema : 
diagnosis and key 
Eligibility criteria
and Section 4.1 
treatment overview
Criteria listed briefly
Added language:
(expansion cohort only 
TNBC allowed)
In order to 
accommodate the 
expansion cohort of 
TNBC patients
Section 1.7.1 
rationale for fixed 
dosing for durvalumab 
and tremelimumab
Patients with a body 
weight ≤30kg should be 
dosed using a weight 
based dosing schedule. 
Patients with a body 
weight ≤ 30kg will be 
excluded.
Study is for adult 
population, data for 
<30kg patients 
primarily in pediatrics.
Section 1.7.3
Rationale for 
expansion cohort 
N/A
A new section added  
explaining the rationale 
for inclusion of the TNBC 
expansion cohort: 
A striking difference 
between response 
rates in ER-positive 
(0%) and TNBC(42.9%)  
was observed.
Essentially 6 out of 7 
patients in TNBC 
cohort experienced 
clinically relevant 
benefit.
Section 1.8
Rationale for 
Exploratory Objective
N/A 
A new section added to 
explain rationale for 
exploratory objectives
For clarity
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Section 2.2.1
Secondary objective
and Section 6.3
Secondary Endpoints
Statement of objective 
PFS and OS along with 
definitions
PFS definition modified :
“from date of treatment 
initiation to date of 
documented disease 
progression or death(by 
any cause in the 
absence of 
progression).”
OS definition reworded 
for clarity
For increased clarity 
Section 2.1
and 
Section 6.2
Primary Objective and 
Endpoint
ORR listed as primary 
endpoint with definition.
ORR definition updated 
to read;
“ORR defined as 
number (%) of patients 
with one visit response 
of partial response (PR) 
or a complete response 
(CR) in patients with 
metastatic HER2 
negative breast cancer 
(TNBC in expansion 
cohort) treated with 
durvalumab in 
combination with 
tremelimumab using the 
Response Evaluation 
Criteria in Solid Tumors 
(RECIST) Version 1.1”
Language added for 
evaluable patients and 
pseudoprogression.
Clarified how ORR 
determined and 
evaluated
Section 2.3.1
Exploratory endpoint
and 
Sections 6.4.1 
To evaluate if tissue-
based 
immunohistochemical 
expression of PD-L1; 
tumor infiltrating 
lymphocytes (TILs); 
peripheral T cell 
subpopulations; 
changes in tissue and 
peripheral T cell 
receptor genotype; 
human leukocyte 
antigen (HLA) 
genotype; and 
immune-related 
candidate gene 
signatures predict 
response to 
durvalumab in 
combination with 
tremelimumab.
Modified to add: 
serum biomarkers as 
well. Biomarkers will also 
include circulating tumor 
DNA and mutational and 
neoantigen burden
As decided after 
internal review by 
sponsor and PI
To assess response 
rates to next line 
therapy after 
progression
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Section 3.0 
Patient eligibility 
overview
Previous details
Added language that 
states that the expansion 
cohort will include only 
metastatic TNBC 
patients and this cohort 
will include 20 evaluable 
patients with TNBC.
In order to 
accommodate the 
expansion cohort of 
TNBC patients.
Eligibility criteria 
3.1.1
Description of 
histological criteria for 
general cohort.
Added language: 
PR positivity will be 
defined as a result of 
greater than 10%. 
Documentation of ER 
and PR status.
The expansion cohort 
will only include Her-2 
negative, ER and PR-
negative patients.
 
For clarity, and in 
order to accommodate 
the expansion cohort 
of TNBC patients.
Section 3.1.10
Inclusion criteria
N/A
New criteria included 
which states that
patients must weigh 
>30kgs for them to be 
included in the study
Study is for adult 
population, data for 
<30kg patients 
primarily in pediatrics.
Section 3.1.12
Inclusion criteria
Details about pregnancy 
test requirements. 
Added language 
regarding age specific 
requirements.
According to updated 
language per sponsor.
Section 3.2.2 
N/A
New exclusion criteria 
added stating that 
patients with visceral 
crisis or impending 
visceral crisis will be 
excluded at the clinical 
discretion of the treating 
physician.
Excludes patients with 
definite liver metastsis 
>1cm
Immunotherapy takes 
several weeks to 
work.So, patients with 
rapidly progressive 
disease unlikely to 
benefit.
This subset of 
patients did 
exceptionally poor in 
the first cohort
Section 3.2.3
Exclusion criteria
N/A
New exclusion criterion 
added with details 
regarding unresolved 
toxicity from previous 
anti-cancer therapy
To avoid compounded 
toxicity with 
investigational drugs.
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Section 3.2.5
Exclusion criteria
Current or prior use of 
immunosuppressive 
therapy within 28 days 
prior to the first dose of  
durvalumab or 
tremelimumab 
Updated from 28 days to 
14 days.
Sufficient time for 
washout. Window 
narrowed to  expedite 
enrollment
Section 3.2.6
Exclusion criteria
Mean QT interval 
corrected for heart rate 
using Bazett’s correction
Changed to:
Mean QT interval 
corrected for heart rate 
using Fridericia’s 
correction.
Current studies have 
used this correction 
model. 
Section 3.2.8
Exclusion criteria
Prior treatment with 
immune therapy 
(including but not limited 
to CD137, OX40, PD-1, 
PD-L1 or CTLA4 
inhibitors)
Updated to :
“Prior treatment with 
immune therapy 
(including but not limited 
to CD137, OX40, PD-1, 
PD-L1 or CTLA4 
inhibitors such as 
durvalumab and 
tremelimumab)
For added clarity
Section 3.2.10 
Exclusion criteria
N/A
New exclusion criteria 
added for prior 
documented 
autoimmune or 
inflammatory disorders 
with some exceptions 
listed. 
Immunotherapy may 
adversely affect 
autoimmune or 
inflammatory disease.
Section 3.2.11
Exclusion criteria
N/A
New criterion added 
which includes TB, HIV, 
HCV and Hep B 
infections and the 
criterion for exclusion of 
patients with these 
infections.
Immunotherapy not 
studied in patients 
with these 
immunodeficient 
states, unclear effects 
on ID or anti-cancer 
effects.
Exclusion criteria 
3.2.13
History of 
hypersensitivity to 
durvalumab or any 
excipient.
Updated to :
Hypersensitivity to 
durvalumab or 
tremelimumab or any 
excipient
Prevent allergic 
reactions
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Exclusion criteria
3.2.15 
Previous list of 
uncontrolled intercurrent 
illness that excluded 
patients from the study.
Added: 
1.
Symptomatic 
congestive heart 
failure, 
uncontrolled 
hypertension, 
unstable angina 
pectoris, cardiac 
arrhythmia
2.
Interstitial lung 
disease, serious 
gastrointestinal 
conditions 
associated with 
diarrhea
3.
Psychiatric 
illness/social 
situations that 
substantially 
increase risk of 
incurring AEs or 
compromise the 
ability of the 
patient to give 
informed 
consent.
For added safety and 
clarity
Section 4.1.1 
(Pseudoprogression)
Pseudoprogression 
defined as: radiographic 
increase felt to be due to 
inflammation/immune 
response.
Criteria for continuation 
of treatment in case of 
pseudoprogression 
included “No decline in 
Eastern Cooperative 
Oncology Group”
Added language to state 
radiographic increase or 
“new lesions” felt to be 
due to 
inflammation/immune 
response.
Modified to 
No ‘significant’ decline 
in Eastern Cooperative 
Oncology Group(PS>2 
or as deemed by treating 
investigator)
Per PI
For clarity and 
specificity
Section 4.2 
Treatment 
administration
Tabular details about 
treatment administration
Added language as 
footnote stating labs 
required to start 
treatment 
“On each treatment 
day, hematology and 
serum chemistry are 
to be  resulted before 
treatment can begin”
For clarity
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Section 4.2.1 
Monitoring of dose 
administration
Investigators may 
administer steroids at 
their discretion as 
clinically indicated and 
per their institutional 
guidelines
Modified to: 
“Investigators may 
administer steroids per 
protocol guidelines (see 
Section 4.3) or at their 
discretion as clinically 
indicated in consultation 
with the study team.”
For safety and 
convenience
Section 4.3 
Table 1-Immune 
mediated reactions
Previous table with 
details of overall 
management of Immune 
–mediated reactions
Updated to current 
instructions for overall 
management of Immune 
–mediated reactions
Based on current IB
Section 4.4
Concomitant 
medications/treatment
s
Previous language 
including table for rescue 
medications
Added table detailing 
“prohibited concomitant 
medications’
As mandated by 
sponsor AstraZeneca
Section 4.5.1
Birth control
Previous language
Added language 
describing various 
scenarios and age 
related restrictions
Some repetitive 
language deleted.
Reference to this section 
added to eligibility 
criteria 3.1.13 as well.
As decided after 
internal review by 
sponsor and current 
Durvalumab IB
Section 4.9
Patient replacement
Previous language:
If a patient is enrolled 
in the study but 
comes off study 
before cycle 1 day 1 
of treatment, the 
patient may be 
replaced.
Added language;
A patient who does not 
reach the first imaging 
assessment at 2 months 
for reasons other than 
clinical progression may 
be replaced. They will 
not be used toward 
assessment of the 
primary clinical endpoint 
(ORR), PFS or OS. 
However, will be 
included in the final 
safety analysis
For clarity
Section 5.0
Study procedures 
table
Tabular listing of study 
procedures with 
footnotes
Modifications done:
1.
Removed Con-
meds and 
general 
chemistry , 
hematology and 
thyroid tests 
review from the 
For safety, clarity and 
convenience 
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6,9 and 12 mths 
follow-up visits
2.
Additional labs 
of 
LDH,GGT,lipase
,uric acid and 
amylase along 
with coagulation 
and thyroid tests 
can be done 
every 2 months 
in the 
monotherapy 
phase
3.
Week 22 column 
created which is 
similar to week 
18.
4.
Week 24 column 
created to 
illustrate tests 
done every 2 
months in the 
monotherapy 
phase.
1.
Footnote with ** 
updated to state 
that visits 8 
through 11 will 
be repeated. 
Alsoa dded 
language to 
state that scans 
are to be done 
every 8 weeks 
regardless of 
treatment dealys 
or drug holds
5.
Footnotes 1 and 
9: language 
added to state 
that bone scans 
will be done only 
if the patient has 
bone disease.
6.
Footnote 4 
updated to move 
creatinine 
clearance from 
additional 
chemistry labs to 
serum chemistry 
panel. Also 
language added 
to state that if 
total bilirubin is 
≥2xULN (no 
evidence of 
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Gilbert’s 
syndrome) then 
fractionate into 
direct and 
indirect bilirubin.
Additional 
chemistry labs to 
be monitored 
every 8 weeks 
instead of 4 
weeks.
7.
Footnote 15 
updated to state 
that AE/SAE 
will now be 
followed up until 
90 days after 
last dose of 
either drug.
8.
Footnote 16 
updated along 
with 
corresponding 
position in the 
tale, to state that 
at progression, 
patients will be 
offered an 
optional biopsy.
9.
Footnote 17 
added to state 
the labs required 
to be resulted to 
start treatment 
on each 
treatment 
day.(this 
matches with 
section 4.2)
10. Footnote 18 
Language added 
for a research 
sample to be 
collected for all 
patients on 
therapy for >12 
months 
(between 12-24 
months).
In order to do 
additional correlatives 
to assess long term 
responders. 
Section 5.1 (table)
Study Procedures 
After 52 Weeks of 
study treatment
Tabular listing of study 
procedures with 
footnotes
Modifications done:
2.
Additional labs 
of 
LDH,GGT,lipase
,uric acid and 
amylase along 
with coagulation 
and thyroid tests 
For clarity, 
convenience
and consistency
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can be done 
every 2 months 
in the 
monotherapy 
phase
3.
Footnotes 1 
:language added 
to state that 
bone scans will 
be done only if 
the patient has 
bone disease.
4.
Footnote*** and 
1:Added 
language to 
state that scans 
are to be done 
every 8 weeks 
regardless of 
treatment dealys 
or drug holds
5.
Footnote *  : 
added language 
to state the labs 
required to be 
resulted to start 
treatment on 
each treatment 
day.(this 
matches with 
section 4.2 and 
5.0)
6.
Footnote 2 
updated to move 
creatinine 
clearance from 
additional 
chemistry labs to 
serum chemistry 
panel. Additional 
chemistry labs to 
be monitored 
every 8 weeks 
instead of 4 
weeks.
7.
Removed ‘X’ 
from the first row 
of the table that 
earlier would 
have indicated 
Informed 
consenting 
again. 
8.
Footnote 9 
Language added 
for a research 
sample to be 
In order to do 
additional correlatives 
to assess long term 
responders. 
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collected for all 
patients on 
therapy for >12 
months(to be 
collected 
between 12-24 
months)
Section 5.0 Footnote 
1,
5.1 Footnote 1 and 6
and  
Section 6.1.1 
Endpoint Assessment
No language regarding 
skin lesion photography 
Language inserted 
regarding photography of 
skin lesions for disease 
assessment.
For convenience and 
to be complaint with 
ethical requirements
Section 6.1.1
Endpoint definitions
Measurable lesions 
definition: 
“Must be accurately 
measured in at least one 
dimension (greatest 
diameter) with a 
minimum size of 
10mmx10mm by CT 
scan (cuts of 5mm or 
less), MRI, or physical 
exam (ideally using 
calipers)”
Updated 10x 10mm to 
10mm
Correction of error
Section 7.2.5
Durvalumab and 
Tremelimumab AESI
Different AESIs listed 
and described 
individually
Added introductory 
language for AESIs
Per sponsor 
AstraZeneca
Section 7.2.6.3
Hepatic Function 
Abnormality(under 
AESIs)
Previous details
Added Hy’s law to this 
for assessment of cases 
and categorizing as 
SAE. 
As decided after 
internal review by 
sponsor and PI
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Section 7.3.3.4
Reporting to 
Medimmune
Previous details
Added language with 
instructions for reporting 
of all deaths that occur 
during the study, or 
within the 
protocol-defined 30-day 
post-last dose of 
durvalumab  + 
tremelimumab safety 
follow-up period, to 
AstraZeneca
As mandated by 
sponsor AstraZeneca.
Section 7.3.3.5 
study recording period 
and follow-up for AEs 
and SAEs
N/A
New section added with 
language describing the 
recording and follow-up 
of AEs and SAEs
As decided after 
internal review by 
sponsor and PI
Section 8.1.5
protocol dose 
specifics
Previous details
New language for 
preparation, dilution and 
weight based dosing 
inserted. Reference to 
appendix c is made, 
which contains more 
details about weight 
based dosing.
Based on current 
Durvalumab IB
Section 8.1.6
Durvalumab drug 
preparation
A concentrate for 
solution will be supplied 
by AstraZeneca
This has been removed.
Now a 500mg vial 
solution for infusion will 
be provided and it has to 
be diluted before use. 
Based on current 
Durvalumab IB
Section 8.1.7
Route of 
administration
For Iv infusion; 
reconstituted solution (for 
lyophilized product) was 
to be diluted with 
0.9%(W/v) saline
Reconstituted solution 
(for lyophilized product) 
has been removed and 
the drug is described as 
‘liquid solution’.
5% (w/v) dextrose can 
also be used for dilution
Based on current 
Durvalumab IB
Section 8.1.9
availability and supply 
of Durvalumab
previous details which 
included description of 
each vial containing drug 
product 
Description of each vial 
removed. Drug product 
will now be supplied as a 
liquid solution that needs 
to be diluted before 
infusion.
Based on current 
Durvalumab IB
Section 8.1.11
Nursing implications 
for Durvalumab
previous language
New details about 
infusion windows, 
incompatibilities and 
maximum time between 
doses have been 
inserted
Based on current 
Durvalumab IB
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Section 8.2.5
protocol dose 
specifics for 
Tremelimumab
Previous language
New language on dose 
preparation and weight 
based dose calculation 
inserted. Reference to 
Appendix D made which 
contains further details
Based on current 
Durvalumab IB
Section 8.2.6
preparation of 
Tremelimumab
Previous storage details
storage details have 
been modified
Based on current 
Durvalumab IB
Section 8.2.9
Availability and supply 
of tremelimumab
Tremelimumab will be 
supplied as a sterile 
solution, packaged in 20-
mL clear glass vials with 
a rubber stopper and 
aluminum seal. Each vial 
contains 20 mg/mL of 
tremelimumab (with a 
nominal fill of 400 mg per 
vial) in 20 mM histidine 
buffer, pH 5.5, with 84 
mg/mL of trehalose 
dihydrate, 0.2 mg/mL 
polysorbate 80, and 0.1 
mg/mL disodium-EDTA 
dihydrate.
Removed this language. 
The standard supply of 
tremelimumab is 
delivered in a white 
carton with 16 vials of 
tremelimumab within 
foam inserts.
Based on current 
Tremelimumab 
IB/procedures
Section 8.2.11
Nursing implications 
for Tremelimumab
Previous information
New details about 
infusion windows 
inserted.
Maximum time 
between infusions 
have been stated.
Incompatibilities of 
Tremelimumab have 
been clarified
For  increased safety 
and clarity
Section 8.3 and 8.3.1
Study drug preparation 
durvalumab and 
tremelimumab
This included instructions 
for dose volume 
calculation for patients 
<30 kgs, for both drugs
Removed the 
instructions for dose 
volume calculation for 
patients ≤30kgs body 
weight.
Patients with a body 
weight ≤ to 30 kg
will be excluded.
Since a new inclusion 
criteria states that 
patients must weigh 
greater than 30kgs
Section 8.3.2
Monitoring of dose 
administration
(instructions apply to 
both drugs-combination 
regimen)
Modified language to 
say that , If the 
infusion-related reaction 
is ≥Grade 3 or higher in 
severity, study drug will 
be discontinued and this 
is will apply  during 
Durvalumab 
monotherapy as well.
For clarity
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Section 8.3.3
Side Effects when 
durvalumab and 
tremelimumab are given 
together
Added language;
(see current IB for full 
details)
For clarity
Section 9.2
Research blood 
sample collection
previous details
Added language:
For a research sample to 
be collected for all 
patients on therapy for 
>12 months(to be 
collected between 12-24 
months)
In order to do 
additional correlatives 
to assess long term 
responders. 
Section 10
Statistics
Details about design, 
sample size and analysis
Added language for 
TNBC expansion cohort 
sating that it will have 
similar design as general 
cohort and responses 
will be captured by 
RECIST 1.1. In addition, 
it states the use of 
Bayesian design for 
analysis. Other language 
modified to align with the 
new updates.
Sample size and accrual 
language modified to 
state: Eleven patients will 
be added in the first 
stage. If 2 or more 
respond, then an 
additional 16 patients 
will be added for a total 
of 27. If 6 or more 
respond, then the 
hypothesis that the 
response rate is at least 
30% is supported. This 
design has a Type I error 
rate of 4% and 80% 
power, and has a 70% 
chance of stopping early 
for futility after the first 
stage if the true 
response rate is 10%.
In order to 
accommodate and 
analyze the expansion 
cohort of TNBC 
patients
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Section 11.8
Publication policy
Previous details 
Added language:
“All clinical data, all 
blood and tissue 
samples, and 
publication/authorship 
rights will be under the 
direct supervision of Dr. 
Massimo Cristofanilli. 
Any use of data or 
resultant publication 
must be approved 
directly by Dr. 
Cristofanilli”
Per PI, for clarity
Appendix A
Table containing 
acceptable methods of 
contraception
Table removed. 
Reference made to 
section 4.5.1 for 
contraception details
Due to repetition of 
information. Section 
4.5.1 contains current 
sponsor approved 
language
Appendix C
N/A
New appendix added 
which describes
“Durvalumab weight 
based dose calculation”
For added clarity and 
convenience
Appendix D
N/A
New appendix added 
which describes 
“tremelimumab weight 
based dose calculation”
For added clarity and 
convenience
Amendment 9  October 20th,  2017(re-submitted to SRC with version date 12.7.17)
Section(s) Affected
Prior Version
Amendment 9 updates
Rationale
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Section 1.3
Section 1.7.1
Referenced outdated 
data for durvalumab and 
tremelimumab dosing.
Deletes old data and 
replaces with new data 
about the PD-L1 
blockade mechanism, 
durvalumab fixed dosing 
(versus weight-based 
dosing), 
Updated per 
durvalumab IB edition 
12
Section 1 
References
n/a
Updates all reference 
numbers and 
bibliography to 
incorporate EndNote 
and correct numbering 
of references in order of 
appearance.
Administrative 
document update and  
to account for new 
data from durvalumab 
IB edition 12 
Study procedure 
tables
Section 5.1
footnote  **, 1 and 9 
 and 
Section 5.2
Footnote 1 and 6
Note: Bone scans will be 
done only if the patient 
has bone disease.
Added language:”PET-
CT is acceptable in 
place of bone scan, if a  
bone scan is contra-
indicated for a patient’s 
disease. The same 
modality used at 
baseline should be used 
throughout.”
For safety and 
flexibility
Section 7.2.5
n/a
Adds new AESI’s related 
to durvalumab +/- 
tremelimumab as well as 
additional data for 
existing AESI’s. New 
AESI’s include:

Intestinal perforation

Myositis/polymyositis

Myocarditis

Other inflammatory 
responses
Updated to align with 
durvalumab IB edition 
12
Section 10
Statistics
Patients who have 
completed the week 8 
CT or nuclear bone 
scan will be evaluable 
for response 
endpoints. 
Added language:
“Bone scans will be 
done only if the patient 
has bone disease. PET-
CT is acceptable in 
place of bone scan, if a  
bone scan is contra-
indicated for a patient’s 
disease. The same 
modality used at 
baseline should be used 
throughout.”
To be in alignment 
with the updates made 
to Section 5
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References
The section heading was 
missing
References heading 
added
Correction of error
Amendment 10– 1.10.19 
Section(s) Affected
Prior Version
Amendment 10 
Changes
Rationale
Section 4.3
Toxicity management  
and dose 
delays/modifications
Previous management 
details based on 
earlier toxicity tables 
received from 
AstraZeneca
Updated with most 
current toxicity 
management and dose 
modifications tables 
received from 
AstraZeneca dated Nov 
2017. In addition, the 
cardiac toxicity details 
have been updated 
based on Durvalumab 
action letter dated 
8.6.18
To be in alignment with 
most current 
specifications from 
AstraZeneca
Section 5
Study procedures table
AEs/SAEs were 
indicated to be 
assessed at the 6, 9 
and 12 month visits 
(after last dose of 
treatment) as well. 
Updated to indicate that 
AEs/SAEs will only be 
followed up till the 3 
month visit (after the last 
dose of treatment)
Correction of 
discrepancy since the 
rest of the protocol 
states that AEs/SAEs 
are to be followed up 
for 90 days after the 
last dose of treatment.
Section 7.2.6.
Other events requiring 
immediate reporting
Incorrect reference to 
section 10.3 for 
contact information
Correct reference to 
section 7.3.34 for 
contact information 
regarding Safety e-
mailbox for AstraZeneca
Correction of error
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Amendment 11– 10.29.19 
Section(s) Affected
Prior Version
Amendment 11 
Changes
Rationale
Title page
Massimo Cristofanilli, 
MD was still listed as 
Sub-I
Alfred Rademaker, 
PhD still listed as 
biostatistician
MedImmune listed as 
funding source
Removed Dr.Cristofanilli 
and added 
Claudia Tellez, MD as 
sub-I
Added affiliate PI:
Cesar A.Santa-Maria, 
MD from Johns Hopkins
Removed Alfred 
Rademaker and added 
Masha Kocherginsky, 
PhD as biostatistician
Specified that  
MedImmune is only drug 
source.
Administrative update
[Dr.Cristofanilli is the PI 
for this study]. 
On boarding of first 
affiliate site for this 
study. 
Change of statistician. 
Alfred Rademaker is no 
longer at NU.
MedImmune is only 
supplying drug for this 
study.
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Section 1.3
Background:
Immune Checkpoint 
Blockade in Breast 
Cancer
Previous language 
regarding immune 
checkpoint blockade
Updated with current 
developments in 
immune checkpoint 
blockade in breast 
cancer.
This language serves as 
rationale for modification 
to the eligibility criteria 
which now facilitates the 
enrollment of PD-L1 
negative patients in the 
front line setting only 
into the trial. It has been 
clarified that beyond 
frontline, any PD-L1 
status is acceptable. this 
will give the study some 
wriggle room for 
enrollment
Updates made based 
on evolving clinical 
landscape. Reference 
provided.
Section 3.1.1
Inclusion criteria
and Study summary
Criteria stated 
requirements for both 
general and expansion 
cohort. 
Expansion cohort 
included. 
The expansion cohort 
will only include HER2-
negative, ER and PR-
negative patients.
The general cohort 
details are now included 
as a note. The 
Expansion cohort will 
now enroll only 
metastatic TNBC 
patients.
Enrollment to general 
cohort is done. Only 
expansion cohort is 
now enrolling patients.
TNBC patients alone 
are being enrolled. 
Rationale explained in 
section 1.7.3 
Section 3.1.3
Inclusion criteria
and Study summary
Along with other 
requirements, patients 
with ER positive 
disease were included.
Patients with ER positive 
disease removed and  
PD-L1 negative patients 
in the front line setting 
are now eligible. A note 
has been inserted to 
clarify that beyond 
frontline, any PD-L1 
status is acceptable
Based on current 
clinical landscape, 
explained in the 
background section.
Section 3.2.6
Exclusion criteria
For ECGs the 
Friderica’s Correction
was listed
Friderica’s correction 
replaced by Bazett’s 
formula. 
To align with standard 
procedures used at NU
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Section 3.1.13
Inclusion criteria
Criteria regarding birth 
control
Inserted Appendix A
For clarity and 
consistency
Section 4.3
Toxicity Management & 
Dose 
Delays/Modifications
Previous version of 
toxicity management 
guidelines
Removed previous 
version.
Inserted : Updated  
toxicity management 
guidelines (dated Oct 
2019) 
Based on information 
received from 
AstraZeneca
Section 4.9
Patient replacement
A patient who does not 
reach the first imaging 
assessment at 2 
months for reasons 
other than clinical 
progression may be 
replaced. They will not 
be used toward 
assessment of the 
primary clinical 
endpoint (ORR), PFS 
or OS. However, they 
will be included in the 
final safety analysis
Previous language has 
been reworded to state:
“A patient who does not 
reach the first imaging 
assessment at 2 months 
for reasons other than 
clinical progression will 
not be used toward 
assessment of the 
primary clinical endpoint 
(ORR), PFS or OS. 
However, they will be 
included in the final 
safety analysis.  
Additional patients may 
be added if needed for 
assessment of 
response.”
For increased clarity 
Section 5.0
Study procedures table
Discrepancy between 
the footnotes and the 
‘X’ in the table for 
Thyroid tests and LDH
, GGT, lipase, uric acid 
and amylase
Research blood 
sample collection had 
a follow-up sample that 
was stated in footnote 
18 and indicated in the 
table
Corrected the 
discrepancy by moving 
the ‘X’s to the right 
columns.
This ‘X’ has been 
removed and footnote 
18 has been removed as 
well.
Correction of 
discrepancy
This sample is no 
longer being collected. 
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Section 5.1
Study Procedures After 
52 Weeks of study 
treatment
Research blood 
sample collection 
indicated in the table 
along with footnote 9
This has been removed
This sample is no 
longer being collected.
Section 8.2.9
Tremelimumab 
Availability and supply
Previous language. 
Tremelimumab was 
being supplied as a 
400mg vial solution. 
Replaced by updated 
language as mandated 
by AstraZeneca. 
Tremelimumab will now 
be supplied as either 
400mg or a 25mg vial 
solution for infusion after 
dilution. 
To add flexibility for 
AstraZeneca to send  
smaller vials of 
tremelimumab.
Section 9.2
Blood sample 
Collection Guidelines
Another research 
sample will be 
collected at 12 months. 
If the sample is not 
collected at 12 months, 
it can be collected 
anytime between 12-24 
months, while the 
patient is in therapy
This has been removed
To align with updates 
made to the rest of the 
protocol. {This sample 
is no longer being 
collected}.
Exclusion criteria
Numbering of criteria 
was wrong. There were 
two 3.2.2
Numbering had been 
corrected
Correction of error
Throughout
N/A
Minor language updates 
made for clarity
For increased clarity 
and consistency 
across the protocol.
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Section 11.3
Study Management
‘Registration 
procedures’
Standard language 
from old protocol 
template
Replaced by standard 
language from current 
protocol template
Administrative update
Section 11.4
Study Management
‘Data submission’
Standard language 
from old protocol 
template
Replaced by standard 
language from current 
protocol template
Administrative update
Section 11.5
Instructions for 
participating sites
N/A
New sub-section added 
Since affiliate sites are 
now joining the study.  
Section 11.6
Study management
‘Data management 
and 
Monitoring/Auditing
This was previously 
section 11.5.
It contained standard 
language from old 
protocol template
This is now section 11.6 
since we have a new 
section 11.5 dedicated 
as described above.
This now contains
standard language from 
current protocol template
Administrative update
Section 11.9
Study Management
‘Publication policy’
This was previously 
section 11.8.
It contained standard 
language from old 
protocol template 
This now contains
standard language from 
current protocol template
Administrative update
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Appendix D
Tremelimumab weight 
based dose calculation
Previous language
Language updated to 
align with Section 8.2.9
For clarity and 
consistency
Amendment 11 dated 10.29.19 [version 11.1]
Section(s) Affected
Prior Version 
Amendment 11.1 
Changes
Rationale
Title page 
Added Masha 
Kocherginsky, PhD, as 
biostatistician replacing 
Alfred Rademaker
Removed 
Masha Kocherginsky, 
PhD, as biostatistician
and added 
Borko Jovanovic, PhD 
as biostatistician
Re-assignment of 
statistician
Amendment 12 dated 8.31.2020
Title page
Inclusion of Johns 
Hopkins as an affiliate 
site with Dr.Cesar 
Santa-maria as PI
Removal of Johns 
Hopkins as an affiliate 
site
Johns Hopkins will no 
longer  join the study 
as an affiliate site. This 
study was closed on 
7.20.2020 due to low 
accrual, as decided by 
PI in agreement with 
SRC sub-committee for 
Accrual Review
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Section 3.1.13
Inclusion criteria 
regarding use of birth 
control
Reference to Appendix 
A made here for details
Reference to Appendix 
A has been replaced 
with reference to 
Section 4.5.1
For convenience.
Section 4.5.1 contains 
the specified 
information. Appendix 
A also refers to this 
section
Exclusion criteria
Numbering was 
incorrect. There was a 
repetition of number 
3.2.7 after 3.2.8 which 
made the rest of the 
numbering incorrect
Numbering has been 
corrected
Correction of error
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