Conditions: Non-Small Cell Lung Cancer NSCLC
Keywords: PD-L1 (programmed cell death ligand 1)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

Brief summary:
This is a single-arm phase II clinical trial evaluating the safety and efficacy of the PD-L1 inhibitor durvalumab as first-line therapy in 47 patients with advanced NSCLC and ECOG Performance Status 2 (PS2).

Detailed description:
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 mg/mL for intravenous (IV) administration. Durvalumab will be administered at 1500 mg (fixed dose) every 4 weeks until disease progression, death, unacceptable toxicity or withdrawal of consent for a maximum of 12 months of therapy.

Arms:
arm 1: 1500 mg of durvalumab will be administered intravenously (IV) on day 1 of every 28 day cycle.

Interventions: intervention 1: durvalumab
Intervention descriptions: intervention 1: A human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against programmed cell death ligand 1 (PD-L1)

Protocol document:
Prot_SAP_000.pdf: 
 
 
1 
 
TITLE: A phase II clinical trial evaluating the safety and efficacy of durvalumab (MEDI4736) 
as 1st line therapy in advanced non-small cell lung cancer (NSCLC) patients with Eastern 
Cooperative Oncology Group (ECOG) performance status of 2 
 
HCC#: 
16-054 
IND#: 
131552 
Phase: 
II  
 
 
Version: 
12.1 
Version Date: 
08-11-2020 
Investigational Agent: 
Durvalumab (MEDI4736) 
Commercial Agent: 
N/A 
 
Sponsor-Investigator: 
Liza C. Villaruz, MD  
 
5150 Centre Avenue, 5th Floor 
 
T 412-648-6577 
 
F 412-648-6579 
 
Email: villaruzl@upmc.edu 
 
Biostatistician: 
Hong Wang, PhD 
 
UPMC Hillman Cancer Center Biostatistics Shared Resource 
 
UPMC Cancer Pavilion, POB 2, Suite 4 
 
5150 Centre Avenue 
 
Pittsburgh, PA  15232 
 
Email: how8@pitt.edu 
 
 
Source(s) of Support: 
AstraZeneca 
 
Study Monitor: 
Education and Compliance Office for Human Subject 
Research 
Research Conduct and Compliance Office 
University of Pittsburgh 
3500 Fifth Avenue 
Pittsburgh, PA 15213 
 
 
 


 
 
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SYNOPSIS 
 
Rationale 
 
Modulation of the immune checkpoints has permanently altered the therapeutic landscape of 
previously treated advanced NSCLC.  PD1 inhibition with nivolumab is associated with overall 
response rates (ORRs) of about 20% in patients with advanced previously treated squamous and 
non-squamous NSCLC and, importantly, improves overall survival (OS) compared with 
docetaxel (Brahmer et al. 2015; Paz-Ares et al. 2015).  Nivolumab is associated with less 
frequent treatment-related adverse events compared with docetaxel.  In non-squamous NSCLC, 
69% vs.88% of patients had events of any grade, and 10% vs. 54% had events of grade ≥ 3, 
respectively.  Similarly, in squamous NSCLC, 58% vs. 86% had events of any grade, and 7% vs. 
55% had events of grade ≥ 3, respectively (2% of docetaxel treated patients had events of grade 
5).  In advanced NSCLC patients, PD1 blockade with pembrolizumab is associated with an ORR 
of 19%, and a median duration of response (DOR) of 12.5 months. In patients with PD-L1 
positive tumors (PD-L1 expression in ≥ 50% of cells in tumor nests or PD-L1+ bands in stroma 
as assessed by immunohistochemistry utilizing the Merck 22C3 antibody clone), the response 
rate is 45% (Garon et al. 2015).   
 
In an ongoing Phase 1/2, multicenter, open-label study evaluating the safety and clinical efficacy 
of the PD-L1 monoclonal antibody durvalumab 10 mg/kg IV every 2 weeks in patients with 
multiple solid tumor types including NSCLC, the ORR in NSCLC was 14% (23% in patients 
with PD-L1+ tumors by the SP263Ventana PD-L1 immunohistochemistry test), and the disease 
control rate (DCR) at 24 weeks was 24% (Rizvi et al. 2015). ORR was higher in squamous 
(21%) than in non-squamous patients (10%), and responses were durable. Drug-related adverse 
events (AEs) were reported in 48% of patients and were most frequently fatigue (14%), 
decreased appetite (9%), and nausea (8%). Grade ≥ 3 drug-related AEs were reported in 6% of 
patients.  Recently, several phase I/II clinical trials have evaluated the clinical activity of 
monotherapy with PD1 and PD-L1 blocking antibodies in the 1st line treatment of advanced 
NSCLC.  These clinical trials indicate early evidence of durable antitumor activity with response 
rates of 23-29% and tolerable toxicity profiles similar to what has been previously demonstrated 
with PD1 and PD-L1 checkpoint inhibition.  There are currently several ongoing randomized 
phase III clinical trials evaluating PD1 and PD-L1 blocking antibodies in the 1st line treatment of 
advanced NSCLC.  MYSTIC is a phase III open-label study of 1st line durvalumab (20 mg/kg IV 
every 4 weeks) with or without a monoclonal antibody to CTLA-4, tremelimumab (1 mg/kg IV 
every 4 weeks for up to 4 doses), vs. standard of care chemotherapy in advanced NSCLC 
(NCT02453282.)  Notably, this clinical trial is being conducted in patients with an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
 
An ECOG performance status of 2 (PS2) is defined as being “ambulatory and capable of all self-
care but unable to carry out any work activities; up and about more than 50% of waking hours” 
(Oken et al. 1982). Up to 30 to 40% lung cancer patients present with an ECOG PS2 (Buccheri et 
al. 1996; Lilenbaum 2006).  Performance status has long been recognized as an independent 
prognostic factor for survival, thus patients with a PS2 have typically been excluded from 
clinical trials in lung cancer (Stanley 1980; Brundage et al. 2002).  More recent phase II and III 
clinical studies dedicated to defining the optimal therapeutic strategy in PS2 patients have 


 
 
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demonstrated a significant survival advantage with platinum-based doublet chemotherapy over 
single agent therapy with pemetrexed, paclitaxel or erlotinib in the 1st line treatment of advanced 
NSCLC (Lilenbaum et al. 2005; Lilenbaum et al. 2008; Zukin et al. 2013).  Despite these data, 
platinum-based therapy in NSCLC patients with marginal performance status has not been 
universally adopted due to the perceived burden of excess toxicity associated with therapy (West 
2013).    
 
Study Design 
 
This is a single-arm phase II clinical trial evaluating the safety and efficacy of the PD-L1 
inhibitor durvalumab as first-line therapy in 50 patients with advanced NSCLC and ECOG PS2.  
 
Hypothesis 
 
We hypothesize that PD-L1 inhibition with durvalumab is a tolerable regimen with clinical 
activity in PS2 patients with advanced NSCLC. 
 
Primary Objectives 
 
 To estimate overall survival (OS) with durvalumab in advanced NSCLC patients with an 
ECOG PS2.  
 To estimate the safety of durvalumab in NSCLC patients with PS2 as determined by 
grade ≥ 3treatment related adverse events. 
 
Secondary Objectives 
 
 To estimate the progression-free survival (PFS) with durvalumab in advanced NSCLC 
patients with PS2.   
 To estimate overall response rate (ORR). 
 To estimate the rate of 12-month survival (OS12). 
 To estimate OS, PFS, and ORR by PD-L1 expression status 
 To estimate the health related quality of life (HRQL) associated with durvalumab therapy 
in advanced NSCLC patients with PS 2. 
 
Treatment Regimen   
 
Stage IIIB or IV NSCLC with no 
prior therapy and ECOG PS of 2*
N = 50 
*Patients may have received prior adjuvant or
neoadjuvant chemotherapy or chemotherapy given
as part of a curative intent chemoradiotherapy
approach for NSCLC, if the last administration of
the prior regimens occurred at least 1 year prior to
study entry.
Durvalumab 1500 mg (fixed dose)
Day 1 of each 28-day cycle


 
 
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Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous (IV) administration.  Durvalumab will be 
administered at 1500 mg (fixed dose) q 4 weeks until disease progression, death, unacceptable 
toxicity or withdrawal of consent for a maximum of 12 months of therapy. 
 
Statistical Methods 
 
 Primary Objectives: 
 
o The OS curve and a 90% confidence interval for the median OS will be estimated 
by standard methods (the Kaplan-Meier method for survival, and the Greenwood 
variance formula applied to log-transformed survival).  Prior phase II/III clinical 
trials have demonstrated a median OS of about 5 months with single agent 
therapy in PS2 patients with advanced NSCLC (Lilenbaum et al. 2005; Lilenbaum 
et al. 2008; Zukin et al. 2013).   A median OS of 9 months with durvalumab 
would demonstrate a clinically meaningful improvement over the historical 
control median OS of 5 months with single agent therapy.  Assuming 18 months 
of accrual with 6 months of follow-up, N=50 patients would be required to have 
85% power for a 90% confidence interval for median survival to exclude 5 
months (and 78% power for a 95% confidence interval).   
 
o Safety will be summarized for all patients who receive at least one dose of study 
drug.  All adverse events that are determined to be possibly, probably or definitely 
related to treatment will be tabulated according to grade and type, in order of 
frequency. Each adverse event will be counted only once per patient, with the 
highest grade recorded. Serious adverse events and adverse events of special 
interest (ASEI, defined in section 8.1.3) will also be tabulated by frequency. 
Listings will be provided for all on-study deaths and adverse events that lead to 
withdrawal from study.    A rate of grade ≥3 treatment related adverse events of 
30% or less would suggest that durvalumab is more tolerable than a platinum 
doublet in this population [Lilenbaum et al. 2008]. 
 
 Secondary Objectives: 
 
o PFS will be evaluated using the same methodology as for OS.  PFS and OS will 
be evaluated for all patients and for subgroups by PD-L1 status.  The ORR and 
OS12 will be estimated with a 90% Wilson Score confidence interval, for all 
patients and based on PD-L1 status. HRQL at baseline, the end of each 4-week 
cycle, and at the end of therapy will be assessed using the FACT-L v4 
questionnaire (Cella, 2007).  Total scores and subscales will be summarized for 
each patient, and analyzed using standard linear mixed models methods and 
generalized estimating equations.   The primary analysis will summarize baseline 
QOL, average change over the first two cycles of treatment, and average QOL in 
survivors at approximately 6 months and 12 months. 
 


 
 
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TABLE OF CONTENTS 
 
Synopsis 
2 
TABLE OF CONTENTS 
5 
abbreviations and definition of terms 
7 
1. 
OBJECTIVES 11 
1.1 
Primary Objectives .................................................................................................11 
1.2 
Secondary Objectives .............................................................................................11 
2. 
BACKGROUND 
11 
2.1 
Non-Small Cell Lung Cancer.................................................................................11 
2.2 
Durvalumab............................................................................................................12 
2.3 
Rationale ................................................................................................................17 
3. 
PATIENT SELECTION 
18 
3.1 
Inclusion Criteria ...................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................20 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES 
21 
4.1 
General Guidelines .................................................................................................22 
4.2 
Registration Process ...............................................................................................22 
5. 
STUDY PROCEDURES 
22 
5.1 
Screening Phase .....................................................................................................22 
5.2 
Treatment Phase .....................................................................................................23 
5.3 
End of Treatment ...................................................................................................23 
5.4 
Description of procedures ......................................................................................23 
6. 
TREATMENT PLAN 
25 
6.1 
Durvalumab Administration ..................................................................................25 
6.2 
General Concomitant Medication and Supportive Care Guidelines ......................27 
6.3 
Patient Reported Outcomes for FACT-L ...............................................................29 
6.4 
Duration of Therapy ...............................................................................................30 
6.5 
Duration of Follow Up ...........................................................................................31 
6.6 
Criteria for Removal from Study Therapy .............................................................31 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
31 
8. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
32 
8.1 
Safety parameters ...................................................................................................32 
8.2 
Assessment of safety parameters ...........................................................................37 
8.3 
Recording of adverse and serious adverse events ..................................................38 


 
 
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9. 
PHARMACEUTICAL INFORMATION 
43 
9.1 
Durvalumab............................................................................................................43 
10. 
BIOMARKER STUDIES 
43 
10.1 
Biomarker Studies ..................................................................................................43 
11. 
STUDY CALENDAR 
44 
12. 
MEASUREMENT OF EFFECT 
47 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................47 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS 
53 
13.1 
Data Safety Monitoring Plan .................................................................................53 
13.2 
Quality Control and Quality Assurance .................................................................54 
13.3 
Data Handling and Record-Keeping ......................................................................54 
13.4 
Institutional Review Board (IRB) Approval ..........................................................54 
13.5 
Ethical and Scientific Conduct of the Clinical Study ............................................55 
13.6 
Informed Consent...................................................................................................55 
14. 
STATISTICAL CONSIDERATIONS 
56 
14.1 
Rationale for study design and sample size ...........................................................56 
14.2 
Analysis cohorts .....................................................................................................56 
14.3 
Analysis plan ..........................................................................................................57 
REFERENCES………………………………………………………………………………….. 59 
APPENDIX A 
PERFORMANCE STATUS CRITERIA……………………………….. 62 
APPENDIX B: FACT-L (Version 4)……………………………………………………………. 63 
APPENDIX C: DURVALUMAB DOSE CALCULATIONS………………………………….. 71 
APPENDIX D:  
DOSING DELAYS/DOSE MODIFICATIONS………………………... 72 
 
 
 


 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation or 
special term 
Explanation 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
CDC 
Complement dependent cytotoxicity 
CI 
confidence interval 
CL 
clearance 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
 
 


 
 
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Abbreviation or 
special term 
Explanation 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
FACT-L 
Functional Assessment of Cancer Therapy – Lung 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 
IgG2 
immunoglobulin G2 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  
IL 
interleukin 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
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Abbreviation or 
special term 
Explanation 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
QoL 
quality of life 


 
 
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Abbreviation or 
special term 
Explanation 
QTc 
the time between the start of the Q wave and the end of the T wave 
corrected for heart rate 
 
 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
SOCS3 
suppressor of cytokine signaling 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocyte 
Tmax 
time to peak concentration 
Tmax,ss 
time to peak concentration at steady state 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 


 
 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
 To estimate overall survival (OS) with durvalumab in advanced NSCLC patients with an 
ECOG PS2.  
 To estimate the safety of durvalumab in NSCLC patients with PS2 as determined by 
grade ≥ 3treatment related adverse events. 
 
1.2 
Secondary Objectives 
 
 To estimate the progression-free survival (PFS) with durvalumab in advanced NSCLC 
patients with PS2.   
 To estimate overall response rate (ORR). 
 To estimate the rate of 12-month survival (OS12). 
 To estimate OS, PFS, and ORR by PD-L1 expression status 
 To estimate the health related quality of life (HRQL) associated with durvalumab therapy 
in advanced NSCLC patients with PS 2. 
 
2. BACKGROUND 
 
2.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer mortality in the United States and worldwide (Siegel 
et al. 2015). An estimated 221,200 new lung cancer cases will be diagnosed in 2015 in the 
United States alone, and 158,040 lung cancer deaths are estimated to occur (Siegel et al. 2015). 
A series of large randomized controlled phase III clinical trials established platinum-based 
doublets as the standard of care in the treatment of metastatic NSCLC with response rates of 20-
30% and a median survival of 8-11 months (Fossella et al. 2003; Kelly et al. 2001; Scagliotti et 
al. 2002; Schiller et al. 2002; Zatloukal et al. 2203). In patients with newly diagnosed advanced 
NSCLC, cisplatin/pemetrexed and cisplatin/gemcitabine were associated with similar efficacy, 
though a histology specific survival benefit was noted in patients with non-squamous histology 
with pemetrexed-based therapy, while a survival detriment was noted in patients with squamous 
histology (Scagliotti et al. 2008). Bevacizumab, a monoclonal antibody to VEGF has been 
associated with a survival advantage in combination with carboplatin/paclitaxel compared with 
carboplatin/paclitaxel alone in patients with non-squamous NSCLC (Sandler et al. 2006).   
 
Recent advances in the treatment of metastatic NSCLC have come from recognition that NSCLC 
is not a single disease entity, but rather a collection of distinct molecularly-driven neoplasms.  
Lynch et al. and Paez et al. first described a subset of patients with NSCLC harboring activating 
mutations in the EGFR gene who responded to treatment with EGFR tyrosine kinase inhibitors 
(TKIs) (Lynch  et al. 2004; Paez et al. 2004). This discovery permanently shifted the landscape 
of NSCLC therapy to a personalized approach based on the molecular alterations of a patient’s 
tumor; a paradigm typified not only by targeted therapies in EGFR mutant lung 
adenocarcinomas, but also in ALK translocation driven adenocarcinomas of the lung and more 


 
 
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recently, the therapeutic advances in lung adenocarcinomas harboring ROS1 gene 
rearrangements (Kwak et al. 2010; Bergethon et al. 2012; Shaw et al. 2014). 
 
In the treatment of the majority of patients without an actionable oncogenic driver, modulation of 
the immune checkpoints has altered the therapeutic landscape of previously treated advanced 
NSCLC.  PD1 inhibition with nivolumab is associated with overall response rates (ORRs) of 
about 20% in patients with advanced previously treated squamous and non-squamous NSCLC 
and, importantly, improves overall survival (OS) compared with docetaxel (Brahmer et al. 2015; 
Paz-Ares et al. 2015).  Nivolumab is associated with less frequent treatment-related adverse 
events compared with docetaxel.  In non-squamous NSCLC, 69% vs.88% of patients had events 
of any grade, and 10% vs. 54% had events of grade ≥ 3, respectively.  Similarly, in squamous 
NSCLC, 58% vs. 86% had events of any grade, and 7% vs. 55% had events of grade ≥ 3, 
respectively (2% of docetaxel treated patients had events of grade 5).  In advanced NSCLC 
patients, PD1 blockade with pembrolizumab is associated with an ORR of 19%, and a median 
duration of response (DOR) of 12.5 months. In patients with PD-L1 positive tumors (PD-L1 
expression in ≥ 50% of cells in tumor nests or PD-L1+ bands in stroma as assessed by 
immunohistochemistry utilizing the Merck 22C3 antibody clone), the response rate is 45% 
(Garon et al. 2015).   
 
2.2 
Durvalumab 
 
Investigators should be familiar with the current durvalumab Investigator Brochure (IB Version 
9.0) 
 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. Durvalumab is a human monoclonal antibody (Mab) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 
1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and 
CD80 (B7-1). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, 
with an overall molecular weight of approximately 149 kDa. Durvalumab contains a triple 
mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding 
to complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved in 
triggering effector function. 
 
2.2.1 Summary of non-clinical experience 
 
The non-clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure (IB Version 9.0)    
 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release of 
interferon gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent 
cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. In vivo studies show that durvalumab inhibits tumor growth in a xenograft 
model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 


 
 
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antibody demonstrated improved survival in a syngeneic tumor model when given as 
monotherapy and resulted in complete tumor regression in > 50% of treated mice when given in 
combination with chemotherapy. Combination therapy (dual targeting of PD-L1 and cytotoxic T-
lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression in a mouse model of 
colorectal cancer.  
 
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics and potential toxicity of durvalumab. Following 
intravenous (IV) administration, the PK of durvalumab in cynomolgus monkeys was nonlinear. 
Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing 
doses, suggesting saturable target binding-mediated clearance of durvalumab. No apparent 
gender differences in PK profiles were observed for durvalumab.  
 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab-related adverse effects that were considered to be of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) PK/pharmacodynamics and dose range-
finding study, and a GLP 4-week repeat-dose toxicity study were consistent with antidrug 
antibody (ADA)-associated morbidity and mortality in individual animals. The death of a single 
animal in the non-GLP, PK/pharmacodynamics, and dose range-finding study was consistent 
with an ADA-associated acute anaphylactic reaction. The spectrum of findings, especially the 
clinical signs and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose 
study was also consistent with ADA immune complex deposition, and ADA: durvalumab 
immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry study. Similar observations were reported in cynomolgus monkeys 
administered human mAbs unrelated to durvalumab. Given that immunogenicity of human mAbs 
in nonclinical species is generally not predictive of responses in humans, the ADA-associated 
morbidity and mortality were not considered for the determination of the no-observed-adverse-
effect level (NOAEL) of durvalumab.  
 
Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus 
monkeys showed that subchronic dosing of durvalumab was not associated with any adverse 
effects. Therefore, the NOAEL of durvalumab in all the general toxicity studies was considered 
to be 100 mg/kg, the highest dose tested in these studies. In addition to the in vivo toxicology 
data, no unexpected membrane binding of durvalumab to human or cynomolgus monkey tissues 
was observed in GLP tissue cross-reactivity studies using normal human and cynomolgus 
monkey tissues. 
 
2.2.2 Summary of clinical experience 
 
Clinical experience with durvalumab is fully described in the current version of the durvalumab 
Investigator’s Brochure (Version 9.0). 
 
As of the DCO dates (15Apr2015 to 12Jul2015, Durvalumab IB Version 8.0), a total of 1,883 
subjects have been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 
sponsored and 10 collaborative studies. Of the 1,883 subjects, 1,279 received durvalumab 
monotherapy, 440 received durvalumab in combination with tremelimumab or other anticancer 


 
 
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agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 150 have been treated with 
blinded investigational product. No studies have been completed or terminated prematurely due 
to toxicity. 
 
Pharmacokinetics and Product Metabolism  
 
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 378 subjects 
in the dose-escalation and dose-expansion phases of Study CD-ON-durvalumab-1108 following 
treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks 
(Q3W). The maximum observed concentration (Cmax) increased in an approximately dose-
proportional manner over the dose range of 0.1 to 15 mg/kg. The area under the concentration-
time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-proportional manner 
over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. These 
results suggest durvalumab exhibits nonlinear PK likely due to saturable target-mediated CL at 
doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete target saturation 
(soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) is expected with 
durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses showed accumulation consistent 
with PK parameters estimated from the first dose. In addition, PK simulations indicate that 
following durvalumab 10 mg/kg Q2W dosing, > 90% of subjects are expected to maintain PK 
exposure ≥ 40 µg/mL throughout the dosing interval. 
 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 
subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) 
were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg cohort. 
 
Safety  
 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important 
potential risk particularly with durvalumab and tremelimumab combination therapy. These 
events are manageable by available/established treatment guidelines as described in the study 
protocols. 
 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
 
 


 
 
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Adverse Event Profile of Durvalumab Monotherapy 
 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 
694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 1,279 subjects 
who have received durvalumab monotherapy (not including subjects treated with blinded 
investigational product) across the clinical development program. The majority of treatment-
related AEs were manageable with dose delays, symptomatic treatment, and in the case of events 
suspected to have an immune basis, the use of established treatment guidelines for immune-
mediated toxicity. As of 07 May2015, among the 694 subjects treated with durvalumab 10 mg/kg 
Q2W in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) experienced a 
treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue 
(17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 
in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 
events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased 
aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase 
(GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and 
colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had 
treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 
event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in ≥ 2 
subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related SAEs 
were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that resulted in permanent 
discontinuation of durvalumab were considered as treatment related in 18 subjects (2.6%), with 
colitis being the most frequent treatment-related AE resulting in discontinuation (3 subjects). A 
majority of the treatment-related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 
in severity and resolved with or without sequelae.  
 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in 
Study CD-ON-durvalumab-1108 is generally consistent with that of 
Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-cell 
lung cancer (NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 05May2015, 264 of 
303 subjects (87.1%) reported any AE in Study D4191C00003/ATLANTIC. Overall, events 
reported in ≥ 10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite 
(17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-
thirds of the subjects experienced AEs that were Grade 1 or 2 in severity and manageable by 
general treatment guidelines as described in the current durvalumab study protocols. Grade 3 or 
higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) 
reported AEs that were considered by the investigator as related to investigational product. 
Treatment-related AEs (all grades) reported in ≥ 2% of subjects were decreased appetite (6.6%); 
fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting 
(2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) 
and increased GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four 
of 303 subjects (31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of subjects were 


 
 
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dyspnea (6.6%); pleural effusion, general physical health deterioration (2.3% each); pneumonia 
(2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, respiratory failure, 
disease progression (1.0% each). Nine subjects had an SAE considered by the investigator as 
related to durvalumab. Each treatment-related SAE occurred in 1 subject each with the exception 
of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an 
AE (pneumonia [3 subjects]; general physical health deterioration, disease progression, 
hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary 
arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None of these events 
was considered related to durvalumab. Twenty-three of 303 subjects (7.6%) permanently 
discontinued durvalumab treatment due to AEs. Events that led to discontinuation of durvalumab 
in ≥ 2 subjects were dyspnea, general physical health deterioration, and pneumonia. Treatment-
related AEs that led to discontinuation were increased ALT and increased hepatic enzyme, which 
occurred in 1 subject each. 
 
Efficacy  
 
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab 
10 mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in bladder cancer 
(n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative 
breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status 
was known for 383 of the 456 response evaluable subjects. Across the PD-L1-positive tumors, 
ORR was highest for bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma 
(HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the 
head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-positive subset, DCR-24w was highest in 
advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 36.0%), HCC and bladder 
cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
 
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in 
Study D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among these 
subjects, the best overall responses were marrow complete remission (mCR) in 4 subjects 
(19.0%); stable disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 subjects 
(23.8%). The remaining 8 subjects (38.1%) did not meet the criteria for complete remission 
(CR), mCR, partial remission (PR), SD, or PD at the date of assessment. 
 
Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or unresectable melanoma 
treated with the combination of durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK 
inhibitor (MEKi; trametinib), 63 subjects were evaluable for response. A total of 35 subjects 
(55.6%) had a best overall response of confirmed or unconfirmed PR. The disease control rate 
(DCR; CR + PR [regardless of confirmation] + SD ≥ 12 weeks) was 79.4%.  
 
Fixed Dosing  
 


 
 
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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 WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.   
 
Similar findings have been reported by others (Ng et al. 2006; Wang et al. 2009; Zhang et al. 
2012; Narwal et al. 2013). Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies. In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-subject 
variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al. 2012].  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the 
current study. Fixed dosing of durvalumab is recommended only for subjects with > 30kg body 
weight due to endotoxin exposure.  Patients with a body weight less than or equal to 30 kg 
should be dosed using a weight-based dosing schedule (Appendix C).  
 
2.3 
Rationale 
 
In an ongoing Phase 1/2, multicenter, open-label study evaluating the safety and clinical efficacy 
of the PD-L1 monoclonal antibody durvalumab 10 mg/kg IV every 2 weeks in patients with 
multiple solid tumor types including NSCLC, the ORR in NSCLC was 14% (23% in patients 
with PD-L1+ tumors by the SP263Ventana PD-L1 immunohistochemistry test), and the disease 
control rate (DCR) at 24 weeks was 24% (Rizvi et al. 2015). ORR was higher in squamous 
(21%) than in non-squamous patients (10%), and responses were durable. Drug-related adverse 
events (AEs) were reported in 48% of patients and were most frequently fatigue (14%), 
decreased appetite (9%), and nausea (8%). Grade ≥ 3 drug-related AEs were reported in 6% of 
patients.  Recently, several phase I/II clinical trials have evaluated the clinical activity of 
monotherapy with PD1 and PD-L1 blocking antibodies in the 1st line treatment of advanced 
NSCLC.  These clinical trials indicate early evidence of durable antitumor activity with response 
rates of 23-29% and tolerable toxicity profiles similar to what has been previously demonstrated.  
There are currently several ongoing randomized phase III clinical trials evaluating PD1 and PD-
L1 blocking antibodies in the 1st line treatment of advanced NSCLC.  MYSTIC is a phase III 
open-label study of 1st line durvalumab (20 mg/kg IV every 4 weeks) with or without a 
monoclonal antibody to CTLA-4, tremelimumab (1 mg/kg IV every 4 weeks for up to 4 doses), 
vs. standard of care chemotherapy in advanced NSCLC (NCT02453282.)  Notably, this clinical 


 
 
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trial is being conducted in patients with an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
 
An ECOG performance status of 2 (PS2) is defined as being “ambulatory and capable of all self-
care but unable to carry out any work activities; up and about more than 50% of waking hours” 
(Oken et al. 1982). Up to 30 to 40% lung cancer patients present with an ECOG PS2 (Buccheri et 
al. 1996; Lilenbaum 2006).  Performance status has long been recognized as an independent 
prognostic factor for survival, thus patients with a PS2 have typically been excluded from 
clinical trials in lung cancer (Stanley 1980; Brundage et al. 2002).  More recent phase II and III 
clinical studies dedicated to defining the optimal therapeutic strategy in PS2 patients have 
demonstrated a significant survival advantage with platinum-based doublet chemotherapy over 
single agent therapy with pemetrexed, paclitaxel or erlotinib in the 1st line treatment of advanced 
NSCLC (Lilenbaum et al. 2005; Lilenbaum et al. 2008; Zukin et al. 2013).  Despite these data, 
platinum-based therapy in NSCLC patients with marginal performance status has not been 
universally adopted due to the perceived burden of excess toxicity associated with therapy (West 
2013).    
 
This is a single-arm phase II clinical trial evaluating the safety and efficacy of the PD-L1 
inhibitor durvalumab as first-line therapy in 50 patients with advanced NSCLC and ECOG PS2. 
We hypothesize that PD-L1 inhibition with durvalumab is a safe and tolerable regimen and 
associated with a survival advantage in PS2 patients with advanced NSCLC.  The results of this 
clinical study may reframe the treatment paradigm of advanced NSCLC patients with a PS2 to 
focus on immune modulation.   
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Written informed consent  and any locally-required authorization (e.g., HIPAA) obtained 
from the subject prior to performing any protocol-related procedures, including screening 
evaluations  
 
2. Patients must have histologically or cytologically confirmed Stage IIIB or IV (American 
Joint Committee on Cancer, 7th edition; AJCC 7) non-small cell lung cancer. 
 
3. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques 
or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 12 for 
the evaluation of measurable disease. 
 


 
 
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4. Patients must have not have received any prior therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) for the treatment of stage IV NSCLC.  Patients 
may have received prior adjuvant or neoadjuvant chemotherapy or chemotherapy given 
as part of a curative intent chemoradiotherapy approach for NSCLC, if the last 
administration of the prior regimens occurred at least 1 year prior to study entry.  
 
5. Age ≥ 18 years at time of study entry. 
 
Because no dosing or adverse event data are currently available on the use of durvalumab 
in patients <18 years of age, children are excluded from this study. 
 
6. ECOG performance status of 2 (Appendix A). 
 
7. Life expectancy of greater than 12 weeks. 
 
8. Tissue available (archived or fresh tumor biopsy) for the PD-L1 assay. 
 
9. Patients must have normal organ and marrow function as defined below: 
 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
 
Hemoglobin ≥ 9.0 g/dL 
 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not 
apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or 
hepatic pathology), who will be allowed only in consultation with their physician. 
 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN  
 
Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: 
 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        
x 0.85 
72 x serum creatinine (mg/dL) 
 


 
 
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10. Female subjects must either be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for ≥ 1 year without an alternative medical cause; 
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral 
oophorectomy) OR must have a negative serum pregnancy test upon study entry.   
 
11. The effects of durvalumab on the developing human fetus are unknown. For this reason 
and because immunomodulatory agents are potentially teratogenic, sexually active 
women of child-bearing potential and men must agree to use adequate contraception (2 
methods of effective contraception from screening) from screening, for the duration of 
study participation, and for at least 90 days following the last infusion of durvalumab 
(Section 6.2); cessation of contraception after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control.  Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately.  
 
12. 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 
 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). Previous enrollment in the present study. 
 
2. Participation in another clinical study with an investigational product for cancer during 
the last 12 months. 
 
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab. 
 
4. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive 
of but not limited to surgery, radiation and/or corticosteroids, in excess of prednisone 10 
mg/d or equivalent.  
 
5. Sensitizing mutations in EGFR or rearrangements in ALK or ROS1.  
 
6. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to durvalumab. 
 
 
7. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids.  
Patients may be on systemic corticosteroids provided the dose does not exceed 
prednisone 10 mg/d or equivalent for 1 week prior to study drug administration. 
 


 
 
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8. Active autoimmune disease requiring systemic treatment within the past 2 years. 
NOTE: Subjects with autoimmune disease, such as vitiligo, Grave’s disease, or psoriasis 
not requiring systemic treatment (within the past 2 years) are not excluded. 
9. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis). 
10. History of primary immunodeficiency. 
11. History of allogeneic organ transplant. 
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding 
diatheses including any subject known to have evidence of acute or chronic hepatitis B, 
hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social 
situations that would limit compliance with study requirements or compromise the ability 
of the subject to give written informed consent. 
13. Known history of previous clinical diagnosis of tuberculosis. 
14. History of leptomeningeal carcinomatosis. 
15. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab. 
16. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
17. Subjects with uncontrolled seizures. 
18. Pregnant women are excluded from this study because durvalumab is associated with the 
potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with durvalumab, breastfeeding should be discontinued if the mother is treated with 
durvalumab.  
 
19. Prior history of radiation pneumonitis. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 


 
 
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4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally by the Study Coordinator.  
Following registration, patients should begin protocol treatment within 5 days.   
Issues that would cause treatment delays should be discussed with the Investigator. The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
Once the signed informed consent has been obtained, all pretreatment evaluations have been 
performed, and patient’s eligibility has been confirmed by the coordination team and the treating 
physician investigator, a patient will be entered on study. To register a patient, the research nurse 
or data manager must complete the eligibility/registration form and review the signed Informed 
Consent, and HIPAA authorization form. 
To complete the registration process, the research nurse or data manager will: 
 Verify the eligibility 
 Register the patient on study 
 Assign a patient accession number 
 
5. STUDY PROCEDURES 
 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.  The 
Schedules of Assessments during the screening and treatment period is provided following the 
Protocol Synopsis and Section 11. 
 
5.1 
Screening Phase  
 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified.  
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed.  After signing the ICF, completing all 
screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study.  
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the 28-day screening window.  
 
The following procedures will be performed during the Screening Visit: 
 
 Verification of Informed Consent 
 Review of eligibility criteria 
 Medical and surgical, oncologic history and demographics, tobacco and alcohol use 
 Complete physical exam  
 ECOG Performance Status 


 
 
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 Vitals signs (temperature, blood pressure, pulse rate, respiratory rate), weight, pulse 
oximetry 
 Verification of tumor biopsy 
 Review of prior/concomitant medications  
 Imaging by CT/MRI 
 Adverse event/Serious adverse event assessment  
 Clinical laboratory tests for: 
o Hematology (see Table below) 
o Clinical chemistry (see Table below) 
o TSH 
o Coagulation (PT, PTT, INR) 
o Creatinine Clearance 
o Serum pregnancy test (for women of childbearing potential only) 
o , Hepatitis B surface antigen, hepatitis C antibody and HIV serologies 
o Urinalysis (see Table below) 
 
5.2 
Treatment Phase 
 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments, section 11.  Pre-menopausal female subjects of childbearing potential must have 
a negative   urine hCG or serum βhCG checked within 24 hours of 1st durvalumab 
administration. 
   
5.3 
End of Treatment 
 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab prior to 12 months, end of treatment is considered the 
last visit where the decision is made to discontinue treatment. All required procedures may be 
completed within ± 7 days of the end of treatment visit. Repeat disease assessment is not 
required if performed within 28 days prior to the end of treatment visit. 
 
Assessments for subjects who have completed durvalumab treatment and achieved disease 
control, or have discontinued durvalumab due to toxicity in the absence of confirmed progressive 
disease are provided in APPENDIX E. 
    
Assessments for subjects who have discontinued durvalumab treatment due to confirmed PD are 
presented in APPENDIX F.  
 
5.4 
Description of procedures 
 
5.4.1 Medical history and physical examination, weight and vital signs 
 
Findings from medical history (obtained at screening) and physical examination shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
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Physical examinations will be performed on study days noted in the Schedule of Assessments. 
 
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.   
 
 
Vital signs (temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry) will be 
measured per institutional standard of care or as clinically indicated, as noted in the Schedule of 
Assessments.  
 
 
5.4.2 Clinical Laboratory Tests 
 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Appendix E and Appendix F for the timepoints of each test): 
 
 Coagulation parameters: Prothrombin time, activated partial thromboplastin time and 
International normalized ratio to be assessed at baseline and as clinically indicated  
 Pregnancy test (female subjects of childbearing potential only) 
o Serum beta-human chorionic gonadotropin (at screening and as clinically 
indicated during treatment) 
 Thyroid Stimulating Hormone (TSH) 
o free T3 and free T4 only if TSH is abnormal 
 Other laboratory tests 
o Hepatitis B surface antigen, hepatitis C antibody 
o HIV antibody 
 
Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin 
concentration 
 
 
 
 
Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 


 
 
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Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local 
practice 
Gamma glutamyltransferaseb 
Uric acid 
a   If Total bilirubin is ≥2x ULN (and no evidence of Gilbert’s syndrome) then fractionate into 
direct and indirect  bilirubin 
b At baseline and as clinically indicated 
 
 
 
Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells with use of the high 
power field for red blood cells 
 
6. TREATMENT PLAN 
 
6.1 
Durvalumab Administration 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
 
Regimen Description 
Agent 
Premedications 
/ Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Durvalumab 
N/A 
 
**  in 500 
cc NS 
IV over 60 
minutes (±5 
minutes) 
Day 1 
28 days  
(4 weeks) 
 
 
 
** Dose calculation is based in patient weight at the time of each treatment. See section 6.1.1 for fixed dose 
information for subjects weighing greater than or equal to 30 kg and Appendix C for calculation of dose for subjects 
with weight of less than 30 kg. 


 
 
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Study drug preparation 
 
For patients weighing ≥ 30 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 
mg/kg Q4W) (based on an average body WT of 75 kg) should be prepared. For subjects <30 kg 
body weight, dose is determined using body mass, calculating the stock volume of durvalumab to 
achieve the accurate dose according to Appendix C. 
   
Preparation of durvalumab doses for administration with an IV bag 
 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration.  
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v)dextrose for IV infusion with a final durvalumab 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm in-line filter.  
 
Remove a volume of IV solution from the IV bag equal to the calculated volume of durvalumab 
to be added to the IV bag prior to addition of durvalumab.  Next, the volume of durvalumab (i.e., 
30.0 mL for 1500 mg of durvalumab) is added to the IV bag such that final concentration is 
within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag. 
 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless there 
is a ≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.   
 
For patients <30kg, Calculate the dose volume of durvalumab and number of vials needed for the 
subject to achieve the accurate dose according to Appendix C. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab,  the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation. 
 


 
 
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The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed. 
 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes time 
allowances and temperatures. 
 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start 
of administration 
4 hours at room temperature, 24 hours at 2°C to 
8°C 
Maximum time for IV bag infusion, 
including interruptions 
8 hours at room temperature 
 
In the event that either preparation time or infusion time exceeds the time limits outlined above, 
a new dose must be prepared from new vials.  Durvalumab does not contain preservatives, and 
any unused portion must be discarded. 
 
Monitoring of dose administration 
 
Subjects will be monitored before, during and after the infusion with assessment of vital signs 
per institutional standard of care or as clinically indicated, as noted in the Schedule of 
Assessment. Subjects are monitored (pulse rate, blood pressure) every 30 minutes during the 
infusion period (including times where infusion rate is slowed or temporarily stopped). 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion.  For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.  
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.  If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The 
standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 4 hours at room 
temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise 
requires new infusion preparation).   
 
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 subjects to an intensive care unit if necessary. 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 


 
 
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Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed below. 
 
Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapy. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for non-cancer related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.  NOTE: Local treatment of isolated lesions for 
palliative intent is acceptable (e.g., by local surgery or radiotherapy). 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. A temporary period of 
steroids will be allowed for different indications, at the discretion of the principal 
investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc). 
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the 
first dose, during treatment with durvalumab and for 30 days post discontinuation of 
durvalumab.  Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 
 
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 
 
Contraception 
 
Females of childbearing potential who are sexually active with a nonsterilised male partner must 
use 2 methods of effective contraception (see below)  from screening, and  for at least 90 days 
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discussed with a responsible physician.  Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. 
 
 Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical cause). 
 Nonsterilised males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception (see below) from screening and for 
90 days after receipt of the final dose of investigational product. 
 
 
 
 
Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or 
injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill 
Minipill 
Patch 
a 
This is also considered a hormonal method. 
 
Blood donation 
 
Subjects should not donate blood while participating in this study and for at least 90 days 
following the last infusion of durvalumab. 
 
6.3 
Patient Reported Outcomes for FACT-L 
 
To ensure completion of the FACT-L questionnaires at the appropriate time-points, assigned 
research staff must adhere to the instructions in this section. The patient should complete the 
FACT-L questionnaires in clinic at the following times: at baseline, prior to the start of each 
cycle, and at the end of therapy.  
 
Research staff should instruct the patient how to properly fill in the FACT-L questionnaire per 
the following instructions: 
 


 
 
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 
All questionnaires must be completed prior to any other study procedures (baseline 
following informed consent) and before discussion of current disease status to avoid 
biasing the patient’s responses to the questions. 
 
Provide a private environment for the patient to answer the questions. 
 
Provide sufficient time for the patient to complete the questionnaire at their own pace. 
 
Avoid assistance from relatives, friends or clinic staff to help the patient answer the 
questionnaires. However, if the patient is unable to read the questionnaire (due to 
vision impairment such as blindness or uncorrected vision, illiteracy), the 
questionnaires may be read out loud by trained clinic staff and responses recorded. 
 
When the patient completes the questionnaire, it should be handed back to the person 
responsible for the questionnaires, checking for completeness prior to initiating any 
other procedures. 
 
Only one answer should be recorded for each question. 
 
6.4 
Duration of Therapy 
 
Treatment may continue for up to 12 months (maximum 12 doses) or until one of the criteria for 
durvalumab discontinuation is met. 
 
Permanent discontinuation of durvalumab 
  
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 
 Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab  
 
 
 Withdrawal of consent or lost to follow-up 
 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 
 Pregnancy or intent to become pregnant 
 Any AE that meets criteria for discontinuation as defined in Appendix D. 
 Grade ≥ 3 infusion reaction 
 Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
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 Initiation of alternative anticancer therapy including another investigational agent 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Appendix E or F, unless consent is withdrawn or the subject is lost to 
follow-up or enrolled in another clinical study.  All subjects will be followed for survival.  
Subjects who decline to return to the site for evaluations will be offered follow-up by phone at 
months 2, 3, 4, 6, 8, 10, 12 after stopping treatment, and then every 2 months after that as an 
alternative. 
 
 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation.  
6.5 
Duration of Follow Up 
 
Patients will be followed for 12 months after discontinuation of study therapy or until death, 
whichever occurs first. Patients discontinuing study therapy for unacceptable adverse event(s) 
will be followed at least until resolution or stabilization of the adverse event (Appendix E). 
 
At the discretion of the sponsor-investigator (or sponsor/investigator) the study may be closed 
prematurely. 
 
6.6 
Criteria for Removal from Study Therapy 
 
Patients will be discontinued from study therapy when any of the criteria listed in Section 6.4 
applies. The reason for study therapy discontinuation and the date of discontinuation must be 
documented in the Case Report Form. 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab, 
the following dose adjustment guidance may be applied: 
 
 Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
 If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive 
care.  If medically appropriate, dose modifications are permitted for durvalumab (see 


 
 
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below). 
 All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 
 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (Appendix D).   
 
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the conduct 
of this study.   
 
Immune-mediated reactions/irAEs, also considered to be AESIs, are important risks of immune 
checkpoint inhibitors, and are being closely monitored in clinical studies with durvalumab 
monotherapy and combination therapy. irAEs observed with durvalumab include colitis, 
pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, 
dermatitis, and nephritis. In addition, pancreatitis is an important potential risk, particularly with 
durvalumab and tremelimumab combination therapy. 
 
Other inflammatory responses with potential immune-mediated etiology reported with 
durvalumab and similar molecules include, but are not limited to, myocarditis, pericarditis, and 
uveitis. Subjects should be monitored for signs and symptoms of irAEs.  In the absence of an 
alternate etiology (e.g., infection or PD) signs or symptoms of the above events of interests 
should be considered to be immune-related.   
 
 Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions 
are detailed in Tables 1, 2, and 3 of Appendix D, respectively.   
 
In addition, management guidelines for adverse events of special interest (AESIs) are 
detailed in the IB version 9.0. All toxicities will be graded according to NCI CTCAE v4.03. 
 
8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
 
8.1 
Safety parameters 
 
8.1.1 Definition of adverse events 
 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 


 
 
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Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding 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 (i.e., 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. 
8.1.2 Definition of serious adverse events 
 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization  
 Results in persistent or significant disability or incapacity  
 Is a congenital abnormality or birth defect in offspring of the subject 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
o Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events 
are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalizations; or development of drug dependency or drug abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 


 
 
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8.1.3 Definition of adverse events of special interest (ASEI) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate etiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
 Colitis 
 Pneumonitis 
 ALT/AST increases / hepatitis / hepatotoxicity  
 Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
 Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
 Dermatitis 
 Nephritis 
 Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase)   
 Pemphigoid 


 
 
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Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator Brochure. More specific guidelines for their evaluation and 
treatment are described in detail in Appendix D. 
8.1.4 Pneumonitis 
 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has 
been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). Initial work-up should include 
high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is 
highly recommended.  
Guidelines for the management of subjects with immune-mediated events including pneumonitis 
are outlined in Appendix D. 
8.1.5 Hypersensitivity reactions 
 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-
L1 and anti-PD-1 therapy (Brahmer et al 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of MAbs can be caused by various 
mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid 
reactions against the MAb, 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 management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Appendix D. 
8.1.6 Hepatic function abnormalities (hepatotoxicity) 
 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al 2012).  Inflammatory hepatitis has been reported in 3% to 9% of 
subjects treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, nausea and/or 
mild fever and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or 
total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 
Guidelines for management of subjects with hepatic function abnormality are outlined in 
Appendix D. 


 
 
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Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to 
be reported as SAEs. These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
8.1.7 Gastrointestinal disorders 
 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on management 
of diarrhea and colitis in patients receiving durvalumab are provided in Appendix D. 
 
8.1.8 Endocrine disorders 
 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Appendix D. 
 
8.1.9 Pancreatic disorders 
 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Appendix D. 
 
8.1.10 Neurotoxicity 
 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Appendix D. 
 
8.1.11 Nephritis 
 
Consult with Nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc).  Patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, infections 
etc.) 
 
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event.   Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided in Appendix 
D. 
Criteria for Hy’s Law (FDA Guidance 2009) 
 The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 


 
 
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greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo  
 Among trial subjects showing such aminotransferase elevations, often with aminotransferases 
much greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x 
ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase)  
 No other reason can be found to explain the combination of increased aminotransferases and 
total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury. 
 
 
8.2 
Assessment of safety parameters 
 
8.2.1 Assessment of severity 
 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below. 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities that affect 
or limit the ability of the subject to perform activities of daily living 
(eating, ambulation, toileting, etc). 
 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 8.1.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 


 
 
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nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
 
8.3 
Recording of adverse and serious adverse events 
 
Adverse events will be recorded using the Adverse Event form using a recognized medical term 
or diagnosis that accurately reflects the event. Adverse events will be assessed by the 
investigator for severity, relationship to the investigational product, possible etiologies, and 
whether the event meets criteria of an SAE and therefore requires immediate notification to 
AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected for each AE: 
AE (verbatim) 
The date and time when the AE started and stopped 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
Whether the AE is serious or not 
Investigator causality rating against durvalumab (yes or no)  
Action taken with regard to durvalumab  
Outcome 
 
In addition, 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 <<criteria>> 
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) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
8.3.1 Study recording period and follow-up for adverse events and serious adverse event 
 
Adverse events and serious adverse events will be recorded from administration of the first dose 
of durvalumab, throughout the treatment period and including the follow-up period (90 days after 
the last dose of durvalumab) or until the initiation of alternative anticancer therapy. 


 
 
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During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety. 
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. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study 
subjects after the 90-day safety follow-up period for patients treated with durvalumab.  However, 
if an investigator learns of any SAEs, including death, at any time after the subject has been 
permanently withdrawn from study, and he/she considers there is a reasonable possibility that the 
event is related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Drug Safety. 
 
8.3.2 Reporting of serious adverse events 
 
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 the first dose of durvalumab is taken through 90 days after the last dose of 
durvalumab or until the initiation of alternative anticancer therapy.  The investigator and/or 
Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of 
the SAE as per local requirements. 
The investigator and/or sponsor must inform the FDA, via a  departmental SAE form, of any 
serious and 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 
departmental SAE form 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 


 
 
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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. 
All events meeting the definition of a serious adverse event should be reported according to the 
internal departmental SAE checklist and SAE form. Copies should be sent to: 
1. Investigator and Sponsor* 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
 
* A cover page should accompany the departmental SAE 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-15-11317) 
* 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:    
 
1.  Contact info. and reporting guidelines for any supporting entities per contract 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Sections B and C of the departmental SAE form: 
 
 CTCAE term(s) and grade(s)  
 current status of study drug 
 all interventions to address the AE (testing and result, treatment and response) 
 hospitalization and/or discharge dates 
 event relationship to study drug 
 
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.  
8.3.3 Reporting of deaths 
 
All deaths that occur during the study or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period must be reported as follows: 


 
 
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Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to as a SAE within 
24 hours (see Section 8.3.2 for further details).  The report should 
contain a comment regarding the co-involvement of progression of 
disease, if appropriate, and should assign main and contributory causes 
of death.   
Deaths with an unknown cause should always be reported as a SAE.   
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented as events for survival analysis, but will not be reported as 
an SAE. 
8.3.4 Other events requiring reporting 
 
8.3.4.1 
Overdose 
 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified in 
the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox (see 
Section 8.3.2 for contact information). If the overdose results in an AE, the AE must also be 
recorded as an AE (see Section 8.3). Overdose does not automatically make an AE serious, but if 
the consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be recorded and reported as an SAE (See Section 8.3). There is currently no 
specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
8.3.4.2 
Hepatic function abnormality 
 
Hepatic function abnormality (as defined in Section 8.1.6 in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient 
Safety using the designated Safety e-mailbox (see Section 8.3.2 for contact information), unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) 
that is unrelated to investigational product has been confirmed. 
 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study subject will be based on the 
clinical judgment of the investigator. 


 
 
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 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be initiated 
by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
 
8.3.4.3 
Pregnancy 
 
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.   
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner.  Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   


 
 
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9. PHARMACEUTICAL INFORMATION 
 
9.1 
Durvalumab 
 
The Pharmaceutical Development R & D Supply Chain Management section of  
AstraZeneca/MedImmune will supply  durvalumab to the investigator as a 500-mg vial solution 
for infusion after dilution. 
 
9.1.1 Formulation/packaging/storage 
 
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 
275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The 
nominal fill volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Durvalumab must be used within the individually assigned expiry 
date on the label. 
 
9.1.2 Disposition of unused investigational study drug 
 
The site will account for all investigational study drug dispensed and also for appropriate 
destruction.  Certificates of delivery and destruction must be signed. 
 
 
10. BIOMARKER STUDIES 
 
10.1 
Biomarker Studies 
 
10.1.1 PD-L1 Testing 
 
PD-L1 testing will be performed per standard of care analysis methods in a CLIA certified lab. 
 
Tumor tissue sample collection for PD-L1 testing 
 
 Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy.  Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) to 
allow for adequate PD-L1 immunohistochemistry analyses.   
 When the collection of a new sample is not clinically appropriate, archival samples may 
be utilized provided the specimen obtained is less than 3 years old.  When archival 
samples are used to assess PD-L1 status, the age of the sample / date of collection should 
be captured.   
 Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for PD-
L1 analysis. Samples taken from malignant pleural effusions or other appropriate 


 
 
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cytological specimens are acceptable for interpretation of PD-L1 status, and if sufficient 
tumor cells are present to complete the analysis. 
 
 
 
 
11. STUDY CALENDAR 
 
Schedule of study assessments: Screening and Treatment Period (up to 12 months: 
maximum of 12 doses) 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of the subject. 
Pre- 
screening   Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline  
Every 4 weeks 
Every 8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
 
4, 8, 12, 16, 20,  etc 
8, 16, 24, 32, 40 
and 48 
12, 24, 36, 48 
(±3 days) 
(±7 days) 
Written informed 
consent/assignment of  
subject identification 
number 
X 
 
 
 
 
 
Physical examinationa 
 
X 
X 
X 
 
 
ECOG performance status 
 
X 
X 
X 
 
 
Medical and surgical 
history; review previous 
treatments for NSCLC 
 
X 
 
 
 
 
Demography and history of 
tobacco and alcohol use  
 
X 
 
 
 
 
Vital signs  
 Per institutional standard of care or as clinically indicated  
Weight 
 
X 
X 
X 
 
 
Formal verification of 
eligibility criteria 
 
X 
 
 
 
 
Obtain archived or fresh 
tumour biopsy for PD-L1 
assay (Section 10 further 
detail) 
 
X 
 
 
 
 
Hematologyd 
 
X 
X 
X 
 
 
Liver enzyme paneld 
 
 
 
X  
 
 


 
 
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Schedule of study assessments: Screening and Treatment Period (up to 12 months: 
maximum of 12 doses) 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of the subject. 
Pre- 
screening   Screening 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline  
Every 4 weeks 
Every 8 Weeks 
Every 
12 weeks 
Day 
-42 to -1 
-28 to -1 
1 
Day 1 of the week 
Week 
-6 to -1 
-4 to -1 
0 
 
4, 8, 12, 16, 20,  etc 
8, 16, 24, 32, 40 
and 48 
12, 24, 36, 48 
(±3 days) 
(±7 days) 
Serum Chemistry 
(Comprehensive metabolic 
panel plus Mg, LDH, uric 
acid)d 
 
X 
X 
X 
 
 
Amylase/Lipased 
 
X 
X 
X 
 
 
Creatinine clearance 
(calculated)d 
 
X 
X 
As clinically indicated 
Thyroid function tests 
(TSH and fT3 and fT4)e 
 
X 
X 
 
X 
 
 
Serum βhCG (check 
pregnancy status)f  
 
 
X 
As clinically indicated 
Urinalysisg  
 
X 
X 
 
X 
 
 
Coagulation parametersh 
 
X 
As clinically indicted 
Hepatitis B, and C; HIVi  
 
X 
 
 
 
 
 
Adverse event/serious 
adverse event assessment 
 
X 
X 
All visits 
Concomitant medications 
 
X 
X 
All visits 
Palliative radiotherapy 
 
As clinically indicated 
Durvalumab administration 
(monotherapy) 
 
X 
X 
 
X 
 
 
FACT-Lj 
 
 
X 
 
X 
 
 
Tumor assessment (CT or 
MRI)k  
 
X 
 
 
 
X 
 
a.  Full physical examination at baseline; targeted physical examination at other timepoints 
b.  Vital signs include temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry will be assessed per 
institutional standard of care or as clinically indicated.   
d.  Comprehensive metabolic panel includes the following: Na, K, CL, CO2, urea nitrogen (BUN), creatinine, glucose, calcium, 
total protein, albumin, total bilirubin, AST, ALT, and alkaline phosphatase; and Mg, LDH, uric acid. Calculated creatinine 
clearance to confirm adequate renal function per Cockcroft-Gault formula (see Inclusion Criteria). If screening laboratory 
assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results must be available and 


 
 
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reviewed before commencing an infusion. Gamma glutamyltransferase (GGTP) tested at Screening, Day 1 and as clinically 
indicated.   
e.  Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of 
an adverse event related to the endocrine system. 
f.  Pre-menopausal female subjects of childbearing potential only.  Must be checked within 24 hours of 1st durvalumab 
administration; see section 5.4.2. 
g.  Urinalysis performed at Screening, baseline Day 1, every 4 weeks and as clinically indicated. 
h.  Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
i.   Screening for serum hepatitis B surface antigen, hepatitis C antibody, and HIV antibody. 
j.  See Appendix  B and Section 6.3. 
k.  CT (preferred) or MRI scans of the chest, abdomen, and other sites if clinically indicated, preferably with IV contrast, are 
collected during screening (for baseline) and as close to and prior to initiation of study treatment. Screening brain MRI 
(preferably with IV contrast; or CT head with contrast in patients who are unable to have an MRI) to rule out metastasis requiring 
concurrent treatment. Timing of on-treatment (follow-up) CT/MRI scans is every 8 weeks (± 1 week) for the first 48 weeks and 
then at least every 12 weeks (± 1 week) until PD or off-study. Response according to RECIST 1.1 criteria (CR, PR) requires a 
confirmatory scan preferably at the next regularly scheduled imaging visit and no earlier than 4 weeks after the prior assessment 
of CR, PR, or SD. A confirmation of progression scan is required for patients who are deemed clinically stable by the 
Investigator. The confirmatory scan is acquired preferably at the next regularly scheduled imaging visit and no earlier than 4 
weeks after the prior assessment of PD. 
    
 
 


 
 
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12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with durvalumab. 
 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 


 
 
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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 


 
 
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followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 


 
 
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Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 


 
 
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12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Investigator). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 


 
 
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until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 


 
 
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Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
 
13.1 
Data Safety Monitoring Plan 
 
Sponsor/Investigator, Sub-investigators, regulatory, CRS management, clinical research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
 
 serious adverse events 
 subject safety issues 
 recruitment issues 
 accrual 
 protocol deviations 
 unanticipated problems 
 breaches of confidentiality 
 
Minutes from the DSMB meetings are available to anyone unable to attend the center DSMB. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 4. All study treatment associated adverse events that 
are serious, at least possibly related and unexpected will be reported to the IRB. Any 
modifications necessary to ensure subject safety and decisions to continue, or close the trial to 
accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated. 
 


 
 
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All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPCI DSMC which 
also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
13.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical 
Practice compliance will be conducted periodically (i.e., at a minimum of annually) by qualified 
staff of the Education and Compliance Office – Human Subject Research, Research Conduct and 
Compliance Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
13.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance 
with Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not 
submitted or approved for the investigational drug, until 2 years after investigations under the 
IND have been discontinued and the FDA so notified. 
 
13.4 
Institutional Review Board (IRB) Approval 
 
The investigator (i.e., the study site principal investigator) will obtain, from the University of 


 
 
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Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator will promptly notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of an sponsor’s decision to modify the previously accepted clinical protocol, the sponsor will 
submit (i.e., in advance of implementing the change) a Protocol Amendment to the IND 
describing any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of protocol changes requiring the 
submission of a Protocol Amendment include: 
 
 Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
 Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
 The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 
 
13.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, 
requirements, and regulations of the University of Pittsburgh IRB, University of Pittsburgh and 
University of Pittsburgh Medical Center, Commonwealth of Pennsylvania, and applicable federal 
agencies. 
 
13.6 
Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The 
investigator, or a sub-investigator(s) designated by the sponsor, will obtain the written, signed 


 
 
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informed consent of each subject, or the subject’s authorized representative, prior to performing 
any study-specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the issues discussed 
during the informed consent process will be documented in the subject’s case history. The 
investigator or sub-investigator will retain the original copy of the signed informed consent form, 
and a copy will be provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator will obtain the informed consent of 
enrolled subjects for continued participation in the clinical study.  When a reconsent is required, 
the lead study coordinator will notify all sub-investigators and study coordinators via email that a 
reconsent is needed. The email notification will also list the changes in the new consent and 
specify which patients need to be reconsented. 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Rationale for study design and sample size 
 
Although platinum-based doublet chemotherapy demonstrates a survival advantage over single 
agent therapy with pemetrexed, paclitaxel or erlotinib in the 1st line treatment of advanced 
NSCLC with ECOG PS2 (Lilenbaum et al. 2005; Lilenbaum et al. 2008; Zukin et al. 2013), it 
has not been universally adopted due to the perceived burden of excess toxicity associated with 
therapy (West 2013).   Our study investigates a possible therapy to address the unmet need of an 
effective, tolerable first-line therapy for the large population of advanced NSCLC patients with 
PS2. Durvalumab is in the class of PD-L1 monoclonal antibodies that have yielded durable 
responses in a sizeable minority of patients, without the side effects of a platinum doublet.  A 
single-arm trial is appropriate given the development stage of durvalumab and the incremental 
steps required toward staging a much larger trial, such as to assess noninferiority with a 
platinum-based doublet.  The trials cited above in this patient population establish benchmarks 
for reasonable and unreasonable efficacy and toxicity. 
 
Prior phase II/III clinical trials have demonstrated a median OS of about 5 months with single 
agent therapy in PS2 patients with advanced NSCLC (Lilenbaum et al. 2005; Lilenbaum et al. 
2008; Zukin et al. 2013).   A median OS of 9 months with durvalumab (approximately the level 
achieved by the platinum-based doublets in these trials) would demonstrate a clinically 
meaningful improvement over the historical control median OS of 5 months with single agent 
therapy.  Assuming 18 months of accrual with 6 months of follow-up, N=50 patients are required 
to have 85% power for a 90% confidence interval for median survival to exclude 5 months (and 
78% power for a 95% confidence interval).   
 
14.2 
Analysis cohorts 
 
The safety cohort includes all patients who receive at least one dose of study drug.  (SAEs 


 
 
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occurring following written informed consent but before initiating study therapy will be reported 
as described in Section 8.3.2, but will not be part of study summaries.) 
 
The primary efficacy cohort may exclude patients who withdraw from study therapy prior to the 
second cycle for reasons unrelated to disease progression or toxicity.  Examples include patients 
who withdraw due to concerns about insurance coverage, or reluctance to travel an additional 
distance for study participation.  However, these patients will be followed for overall survival if 
they do not withdraw consent, and will be included in a sensitivity analysis of efficacy endpoints 
for the full safety cohort. 
 
14.3 
Analysis plan 
 
Summary tables describing the patient cohort will be compiled, including: 
 Demographics (age, sex, race, ethnicity, smoking history, recent weight loss) 
 Disease history (current stage, tumor sites, histology) 
 Comorbidities at start of therapy (cardiac, pulmonary, other) 
 PD-L1 expression status 
 
Analysis of primary endpoints: 
 
 The OS curve, median OS, and a 90% confidence interval for the median OS will be 
estimated by standard methods (the Kaplan-Meier method for survival, and the 
Greenwood variance formula applied to log-transformed survival) in the efficacy cohort 
(primary analysis) and safety cohort (sensitivity analysis).  Durvalumab will be 
considered a promising therapy in this population if the estimated median OS is 9 months 
or greater, and/or the lower bound of a 90% confidence interval for the median OS is 
greater than 5 months.  However, these results will be interpreted in the context of safety 
data and the presence of durable responses attributed to study therapy.).   
 All adverse events that are determined to be possibly, probably or definitely related to 
treatment will be tabulated according to grade and type, in order of frequency in the 
safety cohort. Each adverse event will be counted only once per patient, with the highest 
grade recorded. Serious adverse events and adverse events of special interest (ASEI, 
defined in section 8.1.3) will also be tabulated by frequency. Listings will be provided for 
all on-study deaths and adverse events that lead to withdrawal from study.  
 
Lilenbaum et al (2008) observed a rate of grade ≥3 adverse events of 41% (90% CI 31%-
53%) for a platinum-based doublet, and 27% (90% CI 18%-38%) for erlotinib. In this 
context of balancing expected toxicity and efficacy, a rate of grade ≥3 treatment related 
adverse events of 30% or less would be acceptable, especially if associated with efficacy 
in individuals.  In a cohort of n=50, a 30% rate of grade ≥3 adverse events would have a 
90% CI of (21%-41%), demonstrating it is likely more tolerable than the platinum 
doublet. 
 
Secondary Objectives: 
 


 
 
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 PFS will be evaluated using the same methodology as for OS.  PFS and OS will be 
evaluated in the unselected populations and based on PD-L1 status.  The ORR and OS12 
will be estimated with a 90% Wilson Score confidence interval, for the unselected 
population and based on PD-L1 status. HRQL at baseline, the end of each cycle, and at 
the end of therapy will be assessed using the FACT-L questionnaire (David Cella, Ph.D., 
2007).  Total scores and subscales will be summarized for each patient, and analyzed 
using standard linear mixed models methods and generalized estimating equations.   The 
primary analysis will summarize baseline QOL, average changes over the first two cycles 
of treatment, and average QOL in survivors at approximately 6 months and 12 months. 
 
 
 


 
 
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REFERENCES 
 
1. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, 
Siwak-Tapp C, Gonzalez A, Fang R, et al: ROS1 rearrangements define a unique molecular 
class of lung cancers. J Clin Oncol 2012, 30:863-870. 
2. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, 
Felip E, Holgado E, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-
Small-Cell Lung Cancer. N Engl J Med 2015, 373:1627-1639. 
3. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, 
Pluzanski A, Vokes EE, Holgado E, et al: Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015. 
4. Brundage MD, Davies D, Mackillop WJ: Prognostic factors in non-small cell lung cancer: a 
decade of progress. Chest 2002, 122:1037-1057. 
5. Buccheri G, Ferrigno D, Tamburini M: Karnofsky and ECOG performance status scoring in 
lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J 
Cancer 1996, 32A:1135-1141. 
6. Cella D.F., Bonomi A.E., Lloyd S.R., Tulsky D.S., Kaplan E., Bonomi P. Reliability and 
validity of the Functional Assessment of Cancer Therapy - Lung (FACT-L) quality of life 
instrument. Lung Cancer 1995; 12: 199-220. 
7. EuroQol G: EuroQol--a new facility for the measurement of health-related quality of life. 
Health policy (Amsterdam, Netherlands) 1990, 16:199-208. 
8. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, 
Ramlau R, Szczesna A, Fidias P, et al: Randomized, multinational, phase III study of 
docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-
small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003, 21:3016-3024. 
9. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, 
Gubens M, Horn L, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med 2015, 372:2018-2028. 
10. Gettinger S, Hellmann S, Sheperd FA, Antonia S, Brahmer J, Chow LQ, Goldman J, 
Juergens RA, Borghaei H, Ready N, et al: First-line monotherapy with nivolumab (NIVO; 
anti-programmed dealth-1[PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, 
efficacy and correlation of outcomes with PD-1 ligand (PD-L1). J Clin Oncol 2015, 33 
(suppl; abstr 8025). 
11. Kelly K, Crowley J, Bunn PA, Jr., Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, 
Wozniak AJ, Weiss GR, Moore DF, et al: Randomized phase III trial of paclitaxel plus 
carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--
small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001, 19:3210-3218. 
12. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, 
Janne PA, Costa DB, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung 
cancer. N Engl J Med 2010, 363:1693-1703. 
13. Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, Witt K, Botkin D: 
Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced 
non-small-cell lung cancer and a performance status of 2. J Clin Oncol 2008, 26:863-869. 
14. Lilenbaum RC, Cashy J, Hensing TA, Young S, Cella D: Prevalence of poor performance 
status in lung cancer patients: implications for research. J Thorac Oncol 2008, 3:125-129. 


 
 
HCC #:16-054 
Version Date: 008/11/2020 
60 
15. Lilenbaum RC, Herndon JE, 2nd, List MA, Desch C, Watson DM, Miller AA, Graziano SL, 
Perry MC, Saville W, Chahinian P, et al: Single-agent versus combination chemotherapy in 
advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin 
Oncol 2005, 23:190-196. 
16. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris 
PL, Haserlat SM, Supko JG, Haluska FG, et al: Activating mutations in the epidermal growth 
factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J 
Med 2004, 350:2129-2139. 
17. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. American journal 
of clinical oncology 1982, 5:649-655. 
18. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman 
N, Boggon TJ, et al: EGFR mutations in lung cancer: correlation with clinical response to 
gefitinib therapy. Science 2004, 304:1497-1500. 
19. Rizvi N, Barlesi F, Brahmer J, E F, Forde P, Garassino MC, Goldberg SM, J V, Jarkowski A, 
McIntosh S, et al: Phase III, randomized, open-label study of durvalumab (MEDI4736) in 
combination  with tremelimumab or durvalumab alone versus platinim-based chemotherapy 
in first-line treatment of patients with advanced/metastatic NSCLC: MYSTTIC. J for 
Immunotherapy of Cancer 2015, 3 (Suppl 2 ) : P171. 
20. Rizvi N, Brahmer J, Ou I, Segal N, Khleif S, Hwu WJ, Gutierrez M, Schoffski P, Hamid O, 
Weiss J, et al: Safety and clinical activity of MEDI4736, an anti-programmed cell death-
ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J Clin 
Oncol 2015, 33 (suppl; abstr 8032). 
21. Rizvi N, Garon EB, Leighl N, Hellmann MD, Patnaik A, Gandhi L, Eder JP, Rangwala R, 
Lubiniecki GM, Zhang J, et al: Optimizing PD-L1 as a biomarker of response with 
pembrolizumab (pembro; MK-3475) as first-line therapry for PD-L1- positive metastatic 
non-small cell lung cancer (NSCLC): Updated data from KEYNOTE-001,. J Clin Oncol 
2015, 33 (suppl; abstr 8026). 
22. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson 
DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl 
J Med 2006, 355:2542-2550. 
23. Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, Matano E, Boni C, 
Marangolo M, Failla G, et al: Phase III randomized trial comparing three platinum-based 
doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002, 20:4285-4291. 
24. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski 
P, Gatzemeier U, Digumarti R, Zukin M, et al: Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer. J Clin Oncol 2008, 26:3543-3551. 
25. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH: 
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl 
J Med 2002, 346:92-98. 
26. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon 
BJ, Blackhall F, et al: Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung 
Cancer. N Engl J Med 2013:(EPub ahead of print). 
27. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2015. CA: a cancer journal for clinicians 
2015, 65:5-29. 


 
 
HCC #:16-054 
Version Date: 008/11/2020 
61 
28. Spigel D, Chaft JE, Gettinger S, Chao BH, Dirix LY, Schmid P, Chow LQ, Chappey C, 
Kowanetz M, Sandler A, et al: Clinical activity and safety from a phase II study (FIR) of 
MPDL3280A (anti-PDL1)-selected patients with non-small cell lung cancer (NSCLC). J Clin 
Oncol 2015, 33 (suppl; abstr 8028). 
29. Stanley KE: Prognostic factors for survival in patients with inoperable lung cancer. J Natl 
Cancer Inst 1980, 65:25-32. 
30. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M: Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World journal of surgery 2010, 34:1059-1065. 
31. West HJ: Patients with advanced non-small-cell lung cancer and marginal performance 
status: walking the tight rope towards improved survival. J Clin Oncol 2013, 31:2841-2843. 
32. Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, Fojtu H, 
Grygarkova I, Sixtova D, Roubec J, et al: Gemcitabine plus cisplatin vs. gemcitabine plus 
carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. 
Lung Cancer 2003, 41:321-331. 
33. Zukin M, Barrios CH, Pereira JR, Ribeiro Rde A, Beato CA, do Nascimento YN, Murad A, 
Franke FA, Precivale M, Araujo LH, et al: Randomized phase III trial of single-agent 
pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung 
cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol 2013, 
31:2849-2853. 
 
 
 


 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


 
 
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APPENDIX B: FACT-L (VERSION 4) 
 
 
 








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APPENDIX C: DURVALUMAB DOSE CALCULATIONS  
Durvalumab Dosing 
The durvalumab dosing should be done depending on subject weight (if subject is < 30kg): 
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 only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials 
 
 


 
 
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APPENDIX D:  
DOSING DELAYS/DOSE MODIFICATIONS 
 
Table 1- Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Immune-
related 
Adverse 
Events 
(Overall 
Management 
For toxicities 
not noted 
below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Drug administration modifications of 
study drug/study regimen will be made 
to manage potential immune-related 
AEs based on severity of treatment-
emergent toxicities graded per NCI 
CTCAE v4.03. 
 
In addition to the criteria for permanent 
discontinuation of study drug/regimen 
based on CTC grade/severity (table 
below), permanently discontinue study 
drug/study regimen for  the following 
conditions:  
 Inability to reduce corticosteroid 
to a dose of ≤10 mg of 
prednisone per day (or 
equivalent) within 12 weeks 
after last dose of study 
drug/regimen 
 Recurrence of a previously 
experienced Grade 3 treatment-
related AE following resumption 
of dosing. 
It is recommended that management of 
irAEs follow the guidelines presented in this 
table: 
- Patients should be thoroughly evaluated 
to rule out any alternative etiology (e.g., 
disease progression, concomitant 
medications, infections, etc.) 
- In the absence of a clear alternative 
etiology, all events should be considered 
potentially immune related. 
- Symptomatic and topical therapy should 
be considered for low-grade (Grade 1 or 
2, unless otherwise specified) events  
- For persistent  (greater than 3 to 5 days) 
low-grade (Grade 2)  or severe (Grade 
≥3) events  promptly start prednisone 
PO 1-2mg/kg/day or IV equivalent  
- If symptoms recur or worsen during 
corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose 
(prednisone dose  [e.g. up to 2-
4mg/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 immune related adverse event for 
specific type of immunosuppressive) 
should be considered for events not 
responding to systemic steroids.   
- Discontinuation of study drug is not 
mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to 
local tumour response (e.g. 
inflammatory reaction at sites of 
metastatic disease, lymph nodes etc.). 
Continuation of study drug in this 
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 
treatment can be 
resumed once event 
stabilizes to grade ≤1 
after completion of 
steroid taper. 
Patients with 
endocrinopathies who 


 
 
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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, and  
3) doses of prednisone 
are at less than or equal 
to 10mg/day or 
equivalent. 
 
situation should be based upon a 
benefit/risk analysis for that patient  
 
 
  
Grade 3 
Depending on the 
individual toxicity, may 
permanently discontinue 
study drug/study 
regimen. Please refer to 
guidelines below 
 
Grade 4 
Permanently discontinue 
study drug/study 
regimen  
 
Note:  For Grade 3 and above 
asymptomatic amylase or lipase levels 
hold study drug/regimen and if complete 
work up shows no evidence of 
pancreatitis, may continue or resume 
study drug/regimen 
 
Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
 
Pneumonitis/ 
ILD 
Grade of 
Pneumonitis 
(CTCAE 
version 4.03)  
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 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT 
scan.  
Grade 1  
(Asymptomati
c, clinical or 
diagnostic 
observations 
only, 
intervention 
not indicated) 
No dose 
modification 
required. 
However, 
consider 
holding study 
drug/study 
regimen dosing 
as clinically 
appropriate 
and during 
diagnostic 
work-up for 
other etiologies 
For Grade 1 (Radiographic Changes Only) 
-      Monitor and closely follow up in 2-4 days for 
clinical symptoms, pulse oximetry (resting 
and exertion) and laboratory work-up and 
then as clinically indicated 
-      Consider pulmonary and  infectious disease 
consult 
Grade 2  
(Symptomatic
, medical 
intervention 
indicated, 
limiting 
instrumental 
ADL)  
Hold study 
drug/study 
regimen dose 
until grade 2 
resolution to ≤ 
Grade 1 
 
•If  toxicity 
worsens then 
treat as Grade 
3 or Grade 4  
 
•If toxicity 
improves to 
Grade ≤1, then 
the decision to 
reinitiate study 
drug/regimen 
at next 
For Grade 2 (Mild to Moderate New Symptoms) 
- Monitor symptoms daily and consider 
hospitalization 
- Promptly start systemic steroids (e.g., 
prednisone 1-2mg/kg/day PO or IV 
equivalent) 
- Reimaging as clinically indicated 
- If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2 to 
4mg/kg/day started  
- If still no improvement within 3-5 days 
despite IV methylprednisone at 2-4/g/kg/day, 
promptly start immunosuppressive therapy 
such as TNF inhibitors (e.g. infliximab at 
5mg/kg every 2 weeks). Caution: Important to 
rule out sepsis and refer to infliximab label 
for general guidance before using infliximab  
- Once improving, gradually taper steroids over 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
scheduled 
treatment date 
will be based 
upon treating 
physician’s 
clinical 
judgment and 
after 
completion of 
steroid taper.  
 
≥28 days  and consider prophylactic 
antibiotics, antifungal or anti PCP treatment 
(refer to current  NCCN guidelines for 
treatment of  cancer-related infections 
(Category 2B recommendation) 
- Consider pulmonary and infectious disease 
consult 
- Consider as necessary  discussing with study 
physician 
Grade 3 or 4  
(Grade 3: 
Severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise, 
urgent 
intervention 
indicated [e.g. 
tracheostomy 
or intubation])  
Permanently 
discontinue 
study 
drug/study 
regimen 
 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life threatening  
- Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- Obtain pulmonary and infectious disease  
consult 
- Hospitalize the patient 
- Supportive Care (oxygen, etc.) 
- If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with additional immunosuppressive 
therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks dose) 
started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab  
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and in particular,  anti 
PCP treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections (Category 2B recommendation)1 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
Diarrhea/ 
Enterocolitis 
Grade of 
Diarrhea 
(CTCAE 
version 4.03) 
Any Grade 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in 
stool) or related to bowel perforation (such as 
sepsis, peritoneal signs and ileus) 
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, other medications, infections 
including testing for clostridium difficile 
toxin, etc.) 
- Steroids should be considered  in the absence 
of clear alternative etiology, even for low 
grade events, in order to prevent potential 
progression to higher grade event 
- Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis 
Grade 1 
diarrhea  
(stool 
frequency of 
<4 over 
baseline per 
day)  
No dose 
modification 
For Grade 1 diarrhea :  
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical 
judgment. 
Grade 2 
diarrhea (stool 
frequency of 
4-6 over 
baseline per 
day)  
Hold study 
drug/study 
regimen until 
resolution to ≤ 
Grade 1 
 
•If  toxicity 
worsens then 
treat as Grade 
3 or Grade 4 
 
•If toxicity 
improves to 
Grade ≤1, then 
study 
For Grade 2 diarrhea:  
- 
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 
or IV equivalent  
- 
If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 
mg/kg/day 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 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
drug/study 
regimen can be 
resumed after 
completion of 
steroid taper. 
methylprednisolone 2-4mg/kg/day started.  
- 
If still no improvement within 3-5 days 
despite 2-4mg/kg IV methylprednisolone, 
promptly start immunosuppressives such as 
(infliximab at 5mg/kg once every 2 weeks). 
Caution: Important to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab   
- 
Consult study physician if no resolution to ≤ 
Grade 1 in 3-4 days 
- 
Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Grade 3 or 4 
diarrhea  
 
(Grade 3: 
stool 
frequency of 
≥7 over 
baseline per 
day;  
 
Grade 4: life 
threatening 
consequences) 
Permanently 
discontinue 
study 
drug/study 
regimen 
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent  
- 
Monitor stool frequency and volume and 
maintain hydration   
- 
Urgent GI consult and imaging and/or 
colonoscopy as appropriate 
- 
If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4mg/kg/day or 
equivalent, promptly start further 
immunosuppressives (e.g. infliximab at 
5mg/kg once every 2 weeks).   
- 
Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab.  
- 
Once improving, gradually taper steroids 
over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
Hepatitis 
(Elevated 
LFTs) 
Infliximab 
should not be 
used for 
management 
of Immune 
Related 
Hepatitis 
Grade of 
Liver 
Function Test 
Elevation 
(CTCAE 
version 4.03) 
 
 Any Grade 
- 
Monitor and evaluate liver function test: 
AST, ALT, ALP and total bilirubin (TB)  
- 
Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, 
concomitant medications)  
Grade 1  
(AST or ALT 
> ULN to 3 
times ULN 
and/or TB > 
ULN to 1.5 
times ULN) 
No dose 
modification 
If  it worsens, 
treat as Grade 
2 event 
For Grade 1 AST or ALT and/or TB elevation        
  -     Continue LFT monitoring per protocol   
Grade 2  
(AST or ALT 
> 3 to 5 times 
ULN and/or 
TB >1.5-3.0 
times ULN) 
Hold Study 
drug/study 
regimen dose 
until grade 2 
resolution to ≤ 
Grade 1 
 
•If  toxicity 
worsens then 
treat as Grade 
3 or Grade 4 
 
•If toxicity 
improves to 
grade ≤1 or 
baseline, 
resume study 
drug/study 
regimen after 
For Grade 2 AST or ALT and or TB elevation :  
- Regular and frequent checking of LFTs (e.g. 
every 1-2 days) until elevations of these are 
improving or resolved.   
- If no resolution to ≤ Grade 1 in 1-2 days, 
discuss with study physician. 
- If event is persistent (> 3-5 days) or worsens, 
promptly start prednisone 1-2mg/kg/day or IV 
equivalent.  
- If still no improvement within 3-5 days 
despite 1-2mg/kg/day of prednisone or IV 
equivalent, consider additional workup and 
prompt treatment with IV methylprednisolone 
2-4mg/kg/day started. 
- If still no improvement within 3-5 days 
despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (mycophenolate 
mofetil)1 . Discuss with study physician if 
 
 
 
 
 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
completion of 
steroid taper.    
mycophenolate mofetil is not available.  
Infliximab should NOT be used. 
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Grade 3 
(AST or ALT 
>5-20 times 
ULN and/or 
TB > 3.0-10 
times ULN 
For elevations 
in 
transaminases 
≤ 8 × ULN, or 
elevations in 
bilirubin ≤ 5 × 
ULN  
 
Hold study 
drug/study 
regimen dose 
until resolution 
to ≤ Grade 1 or 
baseline  
 
Resume study 
drug/study 
regimen if 
elevations 
downgrade ≤ 
Grade 1 or 
baseline within 
14 days and 
after 
completion of 
steroid taper.    
 
Permanently 
discontinue 
study 
drug/study 
regimen if the 
For Grade 3 or 4 AST or ALT and/or TB 
elevation: 
- Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or 
equivalent  
- If still no improvement within 3-5 days 
despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent , 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil)  Discuss with 
study physician if mycophenolate is not 
available. Infliximab should NOT be 
used. 
- Hepatology consult, abdominal workup, 
and imaging as appropriate. 
- Once improving, gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B 
recommendation]) 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
elevations do 
not downgrade 
to ≤ Grade 1 or 
baseline within 
14 days  
 
For elevations 
in 
transaminases 
> 8 × ULN or 
elevations in 
bilirubin > 5 × 
ULN, 
discontinue 
study 
drug/study 
regimen 
 
Permanently 
discontinue 
study 
drug/study 
regimen for 
any case 
meeting Hy’s 
law criteria 
(ALT > 3x 
ULN + 
bilirubin > 2x 
ULN without 
initial findings 
of cholestasis 
(i.e. elevated 
alkaline P04) 
and  in the 
absence of any 
alternative 
cause 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
Grade 4  
(AST or ALT 
> 20 times 
ULN and/or 
TB > 10 times 
ULN)  
Permanently 
discontinue 
study 
drug/study 
regimen  
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine)  
Grade of 
Elevated 
Serum 
Creatinine 
(CTCAE 
version 4.03) 
 
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, proteinuria, etc.)  
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
- Steroids should be considered in the absence 
of clear alternative etiology even for low 
grade events (Grade 2) , in order to prevent 
potential progression to higher grade event 
Grade 1 
[Serum 
Creatinine > 
1-1.5X 
baseline;  > 
ULN to 1.5X 
ULN]  
No dose 
modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any 
accompanying symptom 
 If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol. 
 If creatinine worsens, depending 
on the severity , treat as Grade 2 or 
Grade 3 or 4  
-      Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, etc. 
Grade 2 
[Serum 
Creatinine>1.
5-3.0X 
baseline; 
>1.5X-
3.0XULN] 
 
Hold study 
drug/study 
regimen until 
resolution to ≤ 
Grade 1 
 
•If  toxicity 
worsens then 
treat as Grade 
For Grade 2 elevated creatinine:  
- Consider symptomatic treatment including 
hydration, electrolyte replacement, 
diuretics, etc.  
- Carefully monitor serum creatinine  every 
2-3 days and as clinically warranted 
- Consult Nephrologist and consider renal 
biopsy if clinically indicated 
- If event is persistent (> 3-5 days) or 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
3 or Grade 4 
 
•If toxicity 
improves to 
Grade ≤1 or 
baseline, then 
resume study 
drug/study 
regimen after 
completion of 
steroid taper.    
worsens,  promptly start  prednisone 1 to 2 
mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days 
or worsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone at 
2-4mg/kg/day started.  
- Once improving gradually taper steroids 
over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B 
recommendation]).  
- 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 X 
baseline; 
>3.0-6.0 X 
ULN 
 
Grade 4: 
Serum 
Creatinine > 
6.0 X ULN)  
Permanently 
discontinue 
study 
drug/study 
regimen 
- 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 or IV equivalent  
- If event is not responsive within 3-5 days 
or worsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2-
4mg/kg/day started.  
- Once improving,  gradually taper steroids 
over ≥28 days  and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]  
Rash 
(excluding 
Bullous skin 
Grade of Skin 
Rash  
(Please refer 
Any Grade 
Monitor for signs and symptoms of dermatitis 
(rash and pruritus)  
**IF THERE IS ANY BULLOUS 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
formations) 
to 
NCICTCAE 
version 4.03 
for definition 
of 
severity/grade 
depending on  
type of skin 
rash)  
FORMATION, THE STUDY PHYSICIAN 
SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED** 
Grade 1  
No dose 
modification 
For Grade 1: 
- Consider symptomatic treatment including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., urea 
cream) 
 
Grade 2 
For persistent 
(> 1- 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 study 
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 3-5 days or is worsening despite 
symptomatic treatment and/or use of 
moderate strength topical steroid, discuss with 
study physician and promptly start systemic 
steroids prednisone  1-2 mg/kg/day or IV 
equivalent   
- Consider skin biopsy if persistent for >1-2 
weeks or recurs 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
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 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 improving, gradually taper steroids over 
≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- Discuss with Study Physician 
Grade 4 
Permanently 
discontinue 
study 
drug/study 
regimen  
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.) 
Any Grade  
(Depending on 
the type of 
endocrinopath
y, refer to NCI 
CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity)  
 
- Consult Endocrinologist 
- Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms 
include headache, fatigue, behavior changes, 
changed mental status, vertigo, abdominal 
pain, unusual bowel habits, hypotension and 
weakness. 
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression including brain metastases, 
infections, etc.) 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
- Monitor and evaluate thyroid function tests: 
TSH, free T3 and free T4 and other relevant 
endocrine labs depending on suspected 
endocrinopathy.  
- If a patient experiences an AE that is thought 
to be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing.  
Grade 1 
(Depending 
on the type of 
endocrinopath
y, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade 1) 
No dose 
modification 
For Grade 1: (including those with asymptomatic 
TSH elevation) 
- Monitor patient with appropriate endocrine 
function tests 
- If TSH < 0.5X LLN, or TSH >2X ULN or 
consistently out of range in 2 subsequent 
measurements, include FT4 at subsequent 
cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2  
(Depending 
on the type of 
endocrinopath
y, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
2) 
  
For Grade 2 
endocrinopathy 
other than 
hypothyroidis
m, hold study 
drug/study 
regimen dose 
until  subject is 
clinically 
stable 
 
•If  toxicity 
worsens then 
treat as Grade 
3 or Grade 4  
 
Study 
drug/study 
regimen can be 
resumed once 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids 
- Initiate hormone replacement as needed for 
management 
- Evaluate endocrine function, and as clinically 
indicated,  consider pituitary scan 
- For patients with abnormal endocrine work 
up, except for those  with isolated 
hypothyroidism,  consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant 
hormone replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). - 
 
- Once improving, gradually taper steroids over 
≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
event stabilizes 
and after 
completion of 
steroid taper. 
 
Patients with 
endocrinopathi
es 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, and 
3) doses of 
prednisone are 
at less than or 
equal to 
10mg/day or 
equivalent. 
treatment (please refer to current NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- For patients with normal endocrine work up 
(lab or MRI scans), repeat labs/MRI as 
clinically indicated. 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
Grade 3 or 4 
(Depending 
on the type of 
endocrinopath
y, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
3 or 4)  
For Grade 3 or 
4 
endocrinopathy 
other than 
hypothyroidis
m, hold study 
drug/study 
regimen dose 
until 
endocrinopathy 
symptom(s) 
are controlled. 
Resume study 
drug/study 
regimen     
once event 
stabilizes and 
after 
completion of 
steroid taper    
 
For Grade 3 or 4: 
- Consult endocrinologist 
- Isolated hypothyroidism may be treated with 
replacement therapy without treatment 
interruption and without corticosteroids 
- Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- Administer hormone replacement therapy as 
necessary. 
- For adrenal crisis, severe dehydration, 
hypotension, or shock: immediately initiate 
intravenous corticosteroids with 
mineralocorticoid activity 
- Once improving, gradually taper 
immunosuppressive steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please 
refer to current NCCN guidelines for 
treatment of  cancer-related infections 
[Category 2B recommendation]) 
- Discuss with study physician 
Immune 
mediated  
Neurotoxicity 
(to include but 
not limited to 
limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)   
 
Grade of 
Neurotoxicity  
Depending on 
the type of 
neurotoxicity , 
refer to NCI 
CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
 
Any Grade  
 
 
 
 
 
 
 
- Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes and 
medications, etc.)  
- Monitor patient  for general 
symptoms (headache, nausea, 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
vertigo, behavior change, or 
weakness) 
- Consider appropriate diagnostic 
testing (e.g. electromyogram and 
nerve conduction investigations) 
- Symptomatic treatment with 
neurological consult as appropriate 
 
Grade 1 
 No dose modifications 
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 Grade 4 
 
Study drug/study 
regimen can be resumed 
once event stabilizes to 
grade ≤1 and after 
completion of steroid 
taper    
- Discuss with the study physician  
- Obtain  Neurology Consult  
- Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin, duloxetine, etc.) 
- Promptly start systemic steroids 
prednisone 1-2mg/kg/day or IV 
equivalent  
- If no improvement within 3-5 days 
despite 1-2mg/kg/day prednisone or 
IV equivalent consider additional 
workup and promptly treat with 
additional immunosuppressive 
therapy (e.g. IV IG)  
 
 
Grade 3 
 Hold Study 
drug/study regimen 
dose until resolution 
to ≤ Grade 1 
 Permanently 
discontinue Study 
For Grade 3 or 4: 
- Discuss with study physician 
- Obtain Neurology Consult 
- Consider hospitalization 
- Promptly initiate empiric IV 
methylprednisolone 1 to 2 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
drug/study regimen if 
Grade 3 irAE does not 
resolve to ≤ Grade 1 
within 30 days. 
mg/kg/day or equivalent  
- If no improvement within 3-5 days 
despite IV corticosteroids, consider 
additional workup and promptly 
treat with additional 
immunosuppressants (e.g. IVIG)  
- Once stable, gradually taper steroids 
over ≥28 days 
Grade 4 
 
 Permanently 
discontinue study 
drug/study regimen 
Immune-
mediated 
peripheral 
neuromotor 
syndromes, 
such as 
Guillain-Barre 
and 
Myasthenia 
Gravis 
 
Any Grade 
- The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since 
certain patients may unpredictably 
experience acute decompensations 
which can result in substantial 
morbidity or in the worst case, 
death. Special care should be taken 
for certain sentinel symptoms which 
may predict a more severe outcome, 
such as prominent dysphagia, 
rapidly progressive weakness, and 
signs of respiratory insufficiency or 
autonomic instability 
- Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes and 
medications, etc.). It should be 
noted that the diagnosis of immune-
mediated peripheral neuromotor 
syndromes can be particularly 
challenging in patients with 
underlying cancer, due to the 
multiple potential confounding 
effects of cancer (and its treatments) 
throughout the neuraxis. Given the 
importance of prompt and accurate 
diagnosis, it is essential to have a 
low threshold to obtain a 
neurological consult 
- Neurophysiologic diagnostic testing 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
(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  
 
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 modification 
- Discuss 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 unless 
the symptoms are very minor and 
stable 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
 
Permanently discontinue 
study drug/study 
regimen if it does not 
resolve to ≤ Grade 1 
within 30 days or if there 
are signs of respiratory 
insufficiency or 
autonomic instability 
 
Grade 2  
- 
Discuss 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, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o Steroids may be 
successfully used to treat 
Myasthenia Gravis. 
Important to consider 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
that steroid therapy 
(especially with high 
doses) may result in 
transient worsening of 
myasthenia and should 
typically be administered 
in a monitored setting 
under supervision of a 
consulting neurologist. 
o Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or 
IV IG. Such decisions 
are best made in 
consultation with a 
neurologist, taking into 
account the unique needs 
of each patient. 
o If Myasthenia Gravis-
like neurotoxicity 
present, consider starting 
acetylcholine esterase 
(AChE) inhibitor therapy 
in addition to steroids. 
Such therapy, if 
successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
o Important to consider 
here 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 


 
 
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Table 1- Immune-Mediated Reactions (continued) 
 
 
Dose 
Modifications 
Toxicity Management 
plasmapheresis if not 
responsive to IV IG. 
Grade 3 
Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
 
Permanently discontinue 
Study drug/study 
regimen if Grade 3 irAE 
does not resolve to ≤ 
Grade 1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability 
For severe or life threatening (Grade 3 
or 4) events:  
- Discuss with study physician 
- Recommend hospitalization 
- Monitor symptoms and obtain 
neurological consult 
MYASTHENIA GRAVIS 
o Steroids may be 
successfully used to treat 
Myasthenia Gravis.  It 
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 
acetylcholine esterase 
(AChE) inhibitor therapy 
in addition to steroids. 
Such therapy, if 
successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
Important to consider here 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 4 
Permanently discontinue 
study drug/study 
regimen  


 
 
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Table 2- Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
 
- Management 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, skin rashes etc.) and anaphylaxis 
(e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.) 
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 1 or Grade 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 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. 
Grade 3/4 
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) 
 
 
Table 3- Non-immune Mediated Reactions 
CTC 
Grade/Severity 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for 
adverse events 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  
1 
No dose adjustment  
Treat accordingly as per 
institutional standard  


 
 
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Table 3- Non-immune Mediated Reactions 
CTC 
Grade/Severity 
Dose Modification  
Toxicity Management  
2 
Hold study drug/study regimen until resolution to 
≤ Grade 1 or baseline 
Treat accordingly as per 
institutional standard  
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 at next scheduled dose. Otherwise, 
discontinue study drug/study regimen 
Treat accordingly as per 
institutional standard  
 
 
4 
Discontinue Study drug/study regimen (Note for 
Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms 
and as per Investigator’s clinical judgment and in 
consultation with the sponsor)  
Treat accordingly as per 
institutional standard  
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease 
Service; ILD = interstitial lung disease; IM = intramuscular; irAE = immune-related adverse 
event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid 
stimulating hormone; ULN = upper limit of normal. 
 
 
 


 
 
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APPENDIX E 
Schedule of study procedures: follow-up for subjects who have completed durvalumab 
treatment and achieved disease control (until confirmed progression of disease) and 
subjects who have discontinued durvalumab due to toxicity in the absence of confirmed 
progression of disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months, then Every 
6 Months thereafter  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examinationa 
X 
 
 
 
 
 
 
 
Vital signs (temperature, 
respiratory rate, blood pressure, 
pulse) 
Per institutional standard of care or as clinically indicated 
Weight 
X 
 
 
 
 
 
 
 
Serum βhCG 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated  
ECOG performance status 
X 
X 
X 
 
X (and month 
9) 
 
 
X 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact 
with subjects who refuse to 
return for evaluations and agree 
to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
X 
X 
 
 
 
 
X 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and 
fT3 and fT4)b  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-L questionnaire 
X 
 
X 
For subjects who achieve disease control following 12 months of 
treatment, patient questionnaires should be completed every 12 
weeks relative to the date of enrollment until confirmed PD by 
RECIST 1.1 by investigational site review. 
For subjects who discontinue study drug due to toxicity or a reason 
other than confirmed PD, patient questionnaires should be 
completed relative to the date of enrollment as follows: every 8 
weeks for the first 12 months, then every 12 weeks until confirmed 
PD by RECIST 1.1 by investigational site review. 


 
 
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APPENDIX E 
Schedule of study procedures: follow-up for subjects who have completed durvalumab 
treatment and achieved disease control (until confirmed progression of disease) and 
subjects who have discontinued durvalumab due to toxicity in the absence of confirmed 
progression of disease 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months, then Every 
6 Months thereafter  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Tumor assessment (CT or MRI) 
For subjects who achieve disease control following 12 months of treatment, tumor 
assessments should be performed every 12 weeks (± 1 week) relative to the date of first 
infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review.  Please 
refer to Schedule of Assessments for timings of confirmatory scans.   
For subjects who discontinue durvalumab due to toxicity (or symptomatic deterioration), 
tumor assessments should be performed relative to the date of first infusion as follows: every 
8 weeks (± 1 week) for the first 48 weeks (per Schedule of Assessments ), then every 12 
weeks(± 1 week)  until confirmed PD by RECIST 1.1 by investigational site review.  Please 
refer to Schedule of Assessments for timings of confirmatory scans.   
Upon confirmed PD, scans should be conducted according to local standard clinical practice 
until a new treatment is started (these scans are optional). 
a. 
Full physical exam 
b. 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical 
suspicion of an adverse event related to the endocrine system. 
 
 
 
 


 
 
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APPENDIX F 
Schedule of study procedures: follow-up for subjects who have discontinued durvalumab 
treatment due to confirmed progression of disease at the discretion of the investigator 
Evaluation 
Time Since Last Dose of durvalumab 
Day (±3) 
Months (±1 week) 
12 Months, then Every 
6 Months thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examinationa 
X 
 
 
 
 
 
 
 
Vital signs (temperature, respiratory 
rate, blood pressure, pulse) 
 Per institutional standard of care or as clinically indicated.  
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated 
ECOG performance statusb 
X 
X 
X 
 
 
 
 
 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Serum βhCG 
X 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and fT3 
and fT4)c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-L questionnaire 
X 
 
X 
 
 
 
 
 
Tumor assessment (CT or MRI) 
For subjects who continue on durvalumab post-confirmed progression at the 
investigator’s discretion (following consultation with the sponsor), tumor assessments 
should be performed relative to the date of first infusion per Schedule of Assessments  
until durvalumab is stopped. 
For subjects who discontinue durvalumab following confirmed progression, scans 
should be conducted according to local clinical practice until a new treatment is started 
(these scans are optional). 
a. Full physical exam 
b. PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status 
c. Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an 
adverse event related to the endocrine system. 
 


 
 
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