An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Phase: PHASE3
Conditions: Advanced Solid Malignancies
Sponsor: AstraZeneca

• Protocol number: D4191C00068 
• Document title: An Open-Label, Multi-Centre, Safety Study of Fixed-
Dose Durvalumab + Tremelimumab Combination Therapy or 
Durvalumab Monotherapy in Advanced Solid Malignancies (STRONG) 
• NCT number: NCT03084471 
• Version number: 5.0 
• Date of the document: 13 December 2019 

Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736) and 
Tremelimumab
Study Code
D4191C00068
Version
5.0
Date
13 December 2019 
EudraCT Number
2016-005068-33
An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + 
Tremelimumab Combination Therapy or Durvalumab Monotherapy in 
Advanced Solid Malignancies (STRONG)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
2(143)
VERSION HISTORY
Version 1, 20 December 2016
Initial creation
Version 2, 01 March 2017
Changes to the protocol are summarized below.
Section 3.9 Discontinuation of investigational product
In bullet 3, the following additional details were added regarding adverse events (AEs) that 
meet criteria for discontinuation as defined in the Toxicity Management Guidelines 
(Appendix E)
Permanent discontinuation of study drug/study regimen should occur for any 
Grade ≥3 immune-mediated AE, that does not downgrade to Grade ≤1 or baseline 
status (for patients who entered the study with an existing laboratory abnormality) 
within 14 days despite maximum supportive care (ie, use of steroids or potent 
immunosuppressive medication).  Certain exceptions are enumerated below for 
specific immune-mediated AEs:

Pneumonitis / interstitial lung disease (ILD) – For any Grade >3 event 
promptly discontinue study drug/study regimen.

Diarrhea/Enterocolitis - For any Grade >3 event promptly discontinue 
study drug/study regimen.

Nephritis (Serum Creatinine > 3.0 X baseline; >3.0 to 6.0 X ULN) - For 
any Grade >3 event promptly discontinue study drug/study regimen.

Hypothyroidism – Isolated hypothyroidism may be treated with 
replacement therapy without treatment interruption.

Other toxicities may have slightly different time to resolution for any 
Grade >3 event (ie skin rash, peripheral neuropathy), please refer to 
Appendix E, Table 7.  Immune-mediated Reactions, in core protocol for 
details.
For full guidance on these and other toxicities, please reference Appendix E, Table 7 
Immunemediated Reactions, in core protocol.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Version 3, 19 April 2017 
Changes to the protocol are summarized below.
Section 3.1 Inclusion criteria

Criterion 7 changed from “adequate organ and marrow function 
independent of transfusion for at least 7 days prior to screening and 
independent of growth factor support for at least 14 days prior to 
screening” to “adequate organ and marrow function”
Section 4 STUDY PLAN AND TIMING OF PROCEDURES and Section 5 STUDY 
ASSESSMENTS

Collection of tobacco and alcohol use at screening was added.

Clarifications on the collection of vital signs and physical examination 
information (including body weight, and height) were added: vital signs 
should be measured and recorded at all visits from screening to the last 
treatment visit; physical examination information should only be reported 
in the case report form (CRF) if abnormalities are reported as AEs.

In Table 2, urinalysis during treatment visits was changed from “as 
clinically indicated” to mandatory for consistency with other sections and 
urinalysis at the safety follow up visit should be done “per institutional 
care”.

Collection of fresh tumor tissues was described, in case an archival tissue 
sample was not available.

Inconsistencies regarding thyroid stimulating hormone (TSH) evaluations 
were corrected (TSH should be measured at all visits).

Information was added that autoimmune antibody testing (in case of AEs 
of possible autoimmune nature) should be performed by a local 
laboratory.
Section 6.9.1 Data Monitoring Committee

Independent Data Monitoring Committee (IDMC) comprised of 
independent experts changed to Data Monitoring Committee (DMC) 
comprised of internal experts independent from the study team.
Section 7 Investigational product and other treatments

Provision of Standard-of-Care treatment centrally by AstraZeneca under 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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certain circumstances when local sourcing is not feasible was removed.
Appendix E Dose Modification and Toxicity Management Guidelines for 
Immune-mediated, Infusion-related, and Non Immune-mediated Reactions

Definition of Grade 1 hepatitis according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Event (CTCAE) 
version 4.03 was corrected to aspartate transaminase (AST) or alanine 
transaminase (ALT) > upper limit of normal (ULN) to 3 × ULN and/or 
total bilirubin (TB) >ULN to 1.5 × ULN)
Appendix H Tumor Specific Modules
Appendix H was created to include tumor specific modules into the protocol and Module A 
was revised as follows:
Section 1 Introduction:  Minor updates in the introduction.
Section 3.11 Discontinuation of the study:

Number of patients to be enrolled changed from “1200” to “up to 1200” 
(also in Sections 8 and 9.3). 

Regions where the sub-study will be initially open updated to North 
America, Europe and Asia.

Section 6.8.1 Data Monitoring Committee: “Independent Data Monitoring Committee 
(IDMC) comprised of independent experts” was changed to “Data Monitoring Committee 
(DMC) comprised of internal experts independent from the study team”.
Minor editing
Spelling and format errors were corrected.
Version 4.0, 08 February 2018
Changes to the protocol are summarized below.
SYNOPSIS

Duration of the enrolment period was clarified as “2 to 3 years”.

Title of Module A was updated to indicate that durvalumab monotherapy 
is at a fixed dose.

A new appendix, Appendix I, was introduced to describe ancillary studies 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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and the ancillary study in France was listed.

Primary study objective was updated to remove ‘to collect additional 
data’.

Primary study objective on adverse events of special interest was updated 
to include other inflammatory responses.

Secondary study objective of overall survival (OS) text was updated.

Procedures for follow up of patients were clarified.

Frequency of Data Monitoring Committee meetings was updated to 
“every 6 months”. 
Section 1.1 Background and rationale for conducting this study

Sections were updated to be consistent with the current Investigator 
Brochure (IB), Edition 12 dated 03 November 2017. 
Section 1.2 Rationale for study design, doses and control groups

Study 1108 study number was corrected.

Text on dose and treatment regimen justification was added.
Section 1.3 Benefit/risk and ethical assessment

Section 1.3.1 Potential benefits: Text was added.

Section 1.3.2 Overall risks: Information on risks of treatment with 
durvalumab and tremelimumab monotherapies and combined therapy 
was updated per the current IB, Edition 12 dated 03 November 2017.
Section 1.4 Study design

Requirement of a confirmatory scan for patients with progressive disease 
was added.

Procedures for follow up of patients were clarified to inform that there 
will be additional tumor assessment, if clinically possible, and a 
followup for AEs for 90 days and for survival thereafter. 
Section 2 STUDY OBJECTIVES

Primary study objective was updated to remove ‘to collect additional 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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data’ 

Primary study objective on adverse events of special interest was updated 
to include other inflammatory responses

Secondary study objective of overall survival (OS) text was updated.
Section 3.1 Inclusion Criteria

Inclusion criteria were updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017. 
Section 3.2 Exclusion criteria

Exclusion criteria were updated to align with the current Durvalumab 
plus Tremelimumab Protocol template Edition 2.1, dated 
15 November 2017.
Section 3.8 Restrictions

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 3.9 Discontinuation of investigational product

Procedure for a confirmatory scan for patients who discontinue due to 
progressive disease was clarified. 

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 3.10 Criteria for withdrawal

The text “patients will not be withdrawal of consent to the use of their 
study generated data” was removed.
Section 3.11 Discontinuation of the study

The sentence "The study may also be terminated early at the Sponsor’s 
discretion for reasons other than patient safety" was added.
Section 4 STUDY PLAN AND TIMING OF PROCEDURES

Table 2 (footnote b), Section 4.1, and Section 4.2.1: Correction was 
made to inform that height is collected at screening only.

Table 2 (footnote i), Section 5.3.1: Procedure for urinalysis of bilirubin 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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and urobilinogen was clarified.

Table 2 (footnote j), Section 4.1, and Section 5.7: Procedure for 
collection of tumor biopsies was clarified.

Section 4.2.1: Clarification was added that if the blood and urine samples 
were taken at screening within 72 hours prior to first dose, they do not 
need to be repeated on Day 1 (with the exception of urine pregnancy 
test).
Section 5.2.4 Prior and concomitant medication and cancer treatment history

Text was added to clarify procedure for collecting data on prior 
medication.
Section 5.3 Safety assessments

Table 3 was presented in an alternative format to align with Sponsor 
template. 
Section 5.7 Biomarker analysis

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 6.3 Recording of adverse events

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 6.4 Reporting of serious adverse events

Reference to the Safety Handling Plan was added. 
Section 6.5 Adverse events of special interest

Additional inflammatory responses were included. 
Section 6.7 Pregnancy

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 6.8 Medication Error

This section was added to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.

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Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Section 6.9 Study governance and oversight

Section 6.9.1: Specific toxicity management and dose modification 
information: Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 7.1 Identity of investigational product(s)

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 7.2 Dose and treatment regimens 

Text was updated to align with the current Durvalumab plus 
Tremelimumab Protocol template Edition 2.1, dated 15 November 2017.
Section 7.7 Concomitant medications and other treatments

Table 4: Prohibited concomitant medications: Rows “For all treatment 
arms” were deleted as this is a single arm study. 
Section 10.2 Patient data protection

Text was added to clarify disclosure of genotype results.
Section 11 LIST OF REFERENCES

List was updated.
Appendix E: Dose Modification and Toxicity Management Guidelines for 
Immunemediated, Infusion-related, and Non Immune-mediated Reactions
Toxicology management guidelines were replaced with guidelines dated 01 November 2017.
Appendix G: Categories of Adverse Events of Special Interest - List of Preferred Terms
This appendix was deleted.  Consequently, numbering of the subsequent appendices was 
updated.
Appendix G: Signature Page
The signature page that was previously given as Appendix H is now Appendix G. The name 
and contact details of the signatory were updated.
Appendix H: Tumor Specific Modules – Module A

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Title of Module A was updated to indicate that durvalumab monotherapy is at a fixed dose
Appendix I: Country-Specific Ancillary Studies
This appendix was added and the ancillary study in France was listed: Predictive Markers of 
Immune-Mediated Adverse Events and of Treatment Response in Patients Treated with 
Durvalumab Monotherapy or in Combination with Tremelimumab.
All sections

The document was updated to be consistent with the current Durvalumab 
plus Tremelimumab Protocol template Edition 2.1, dated 
15 November 2017.

Minor language and format corrections were made throughout the
document.
Version 5.0, 13 December 2019
Changes to the protocol are summarized below.
Synopsis

The synopsis was aligned to revisions made in Section 1.4 (Study design), Section 2.1
(Primary objective), Section 4.3 (Follow up period), Section 9.3 (Study timetable and end
of study) and Section 9.3 (Study timetable and end of study).

Study dates and duration were updated.
Previous text (revised/deleted text in bold):
It is anticipated that the total enrollment period for the overall study will be approximately 
2 to 3 years, with an overall duration of approximately 5 years.
Study design
Study Duration
Phase of Development
Estimated date of first patient enrolled (United States)
Q1 2017
Phase IIIb
Estimated date of last patient follow up (Global)
Q1 2022
Revised text (revised/added text in bold):
It is anticipated that the total enrollment period for the overall study will be approximately 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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2 to 3 years, with an overall duration of 4 to 5 years.
Study design
Study Duration
Phase of Development
Estimated date of first patient enrolled (United States)
Q1 2017
Phase IIIb
Estimated date of final data cut-off (Global)
Q2 2020
Estimated date of last patient follow up (Global)
Q2 2021
Section 1.3.2 Overall risks
The overall risk section was updated to reflect the safety information available in the latest
version of the IBs of durvalumab and tremelimumab (data cut-off [DCO] 12 July 2019).
Section 1.3.2.1 Durvalumab
Previous text (revised/deleted text in bold):
Risks with durvalumab include, but are not limited to diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I 
diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and 
lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less 
frequent inflammatory events including neurotoxicities, infusion-related reactions, 
hypersensitivity reactions and infections/serious infections.
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies AEs (all grades) reported very commonly (≥10% of 
patients) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, 
vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, 
rash, and pruritus. Approximately 9% of patients experienced an AE that resulted in 
permanent discontinuation of durvalumab and approximately 6% of patients 
experienced an SAE that was considered to be related to durvalumab by the study 
investigator.
Revised text (revised/added text in bold):
Risks with durvalumab include, but are not limited to diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism, type I diabetes mellitus and diabetes insipidus),
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis, 
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions,
pancreatitis, serious infections, and other rare or less frequent inflammatory events 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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including neuromuscular toxicities (eg, Guillain Barré syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of ≥20% include events such as 
fatigue, cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients 
discontinued the drug due to an AE. Please see the current version of the IB for a 
detailed summary of the monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 
events reported across the durvalumab program.
Section 1.3.2.2 Tremelimumab
Previous text (revised/deleted text in bold):
Risks with tremelimumab monotherapy include, but are not limited to GI effects (colitis, 
diarrhea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, other GI events 
eg, ulcerative colitis, dehydration, nausea and vomiting; hepatic events including hepatitis,
and liver enzyme elevations; pneumonitis and ILD; nervous system events including 
encephalitis, peripheral motor and sensory neuropathies, Guillain-Barré and proximal muscle 
weakness; cytopenias including thrombocytopenia, anemia and neutropenia; infusion-related 
reactions, anaphylaxis, and allergic reactions; renal events including renal failure, acute
kidney injury, nephritis, nephrotic syndrome, autoimmune nephritis and electrolyte 
abnormalities such as hypokalemia; autoimmune diseases including autoimmune arthritis, 
Sjogren's syndrome and giant cell temporal arteritis; hyperglycemia and diabetes mellitus;
and pyrexia. 
For information on all identified and potential risks with tremelimumab, please always refer to 
the current version of the tremelimumab IB.
Using pooled data from monotherapy clinical studies AEs (all grades) reported very 
commonly (≥10% of patients) were diarrhea, nausea, fatigue, pruritus, decreased
appetite, rash, vomiting, dyspnea, constipation, cough, pyrexia, abdominal pain, 
decreased weight, headache, asthenia, and anemia. Approximately 16% of patients 
experienced an AE that resulted in permanent discontinuation of tremelimumab and 
approximately 45% of patients experienced an SAE.
Revised text (revised/added text in bold):
Risks with tremelimumab monotherapy include, but are not limited to GI effects (colitis, 
diarrhea, enterocolitis and intestinal perforation), endocrine disorders (hypo- and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash and pruritus),
elevations in lipase and amylase and clinical manifestations of pancreatitis, hepatic events 
(including immune-mediated hepatitis and liver enzyme elevations); pneumonitis and ILD;

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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neurotoxicity (including encephalitis, peripheral motor and sensory neuropathies, 
Guillain-Barré syndrome); thrombocytopenia, anemia and neutropenia; infusion-related 
reactions and hypersensitivity/anaphylactic reactions; renal events (including 
nephritis/autoimmune nephritis and acute kidney injury, autoimmune arthritis, Sjogren's 
syndrome, giant cell temporal arteritis and ulcerative colitis); hyperglycemia and diabetes 
mellitus. 
For information on all identified and potential risks with tremelimumab, please always refer to 
the current version of the tremelimumab IB.
In monotherapy clinical studies, AEs reported at an incidence of ≥20% include events 
such as diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting and 
dyspnea. Approximately 16% of patients experienced an AE that resulted in permanent 
discontinuation of tremelimumab and approximately 45% of patients experienced an SAE.
Please see the current version of the IB for a detailed summary of monotherapy data, 
including AEs, SAEs, and CTC Grade 3 to 5 events reported across the tremelimumab 
program.
Section 1.3.2.3 Durvalumab + Tremelimumab
Previous text (revised/deleted text in bold):
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20 mg/kg and
tremelimumab 1 mg/kg AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, diarrhea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism,
asthenia, decreased weight, peripheral edema, hyponatremia, and rash.
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation
of study drug and approximately 15% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study investigator.
Revised text (revised/added text in bold):
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20 mg/kg and
tremelimumab 1 mg/kg, AEs reported at an incidence of ≥20% included events such as 
fatigue, diarrhea, nausea, decreased appetite, pruritus, dyspnea, constipation and 
anemia. Please see the current version of the durvalumab IB for a detailed summary of 
combination therapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported 
across the durvalumab program, including durvalumab in combination with 
tremelimumab.
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation
of study drug and approximately 16% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study Investigator.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Section 1.4 Study Design
Specific instructions for imAE follow-up were deleted and estimated study duration was
updated.
Previous text (revised/deleted text in bold):
The protocol (and each tumor specific module in APPENDIX H) consists of a screening 
period, a treatment period, a safety follow up period (90 days post treatment discontinuation
for non-imAEs; 12 months post onset for imAEs)*, and a survival follow up period.
*Any imAEs that are unresolved at the patient’s last visit in the study are followed up by the Investigator 
for as long as medically indicated and up to 12 months post onset. Non-imAEs are followed up 90 day visit 
post treatment discontinuation.
Patients will attend a safety follow up visit 90 days after study treatment discontinuation. 
Thereafter, patients will be contacted by phone or electronic communication every 3 months 
for survival status. Patients will be followed for up to 5 years from date of first patient 
treatment initiation. Patients will be followed for survival for a minimum of 6 months 
following enrollment of last patient.
[…]
Figure 1
Study flow chart
Tumor specific modules (APPENDIX H) detail which treatment regimen, combination therapy or monotherapy, 
will be used. 
Patients will continue to receive study treatment as long as they are receiving clinical benefit in the opinion of the 
Investigator unless any of the criteria for treatment discontinuation are met first.
Any imAEs that are unresolved at the patient’s last visit in the study are followed up by the Investigator 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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for as long as medically indicated and up to 12 months post onset. Non-imAEs are followed up 90 days
post treatment discontinuation.
Study is expected to run for approximately 5 years from first patient treatment initiation. Follow up will 
continue for study duration and for minimum follow up to 6 months after last patient enrolled.
Revised text (revised/added text in bold):
The protocol (and each tumor specific module in APPENDIX F) consists of a screening 
period, a treatment period, a safety follow up period (90 days post treatment discontinuation), 
and a survival follow up period.
Patients will attend a safety follow up visit 90 days after study treatment discontinuation.
Thereafter, patients will be contacted by phone or electronic communication every 3 months 
for survival status until the final data cut-off (DCO).
[…]
Figure 1
Study flow chart
Tumor specific modules (APPENDIX F) detail which treatment regimen, combination therapy or monotherapy, 
will be used.
Patients will continue to receive study treatment as long as they are receiving clinical benefit in the opinion of the
Investigator unless any of the criteria for treatment discontinuation are met first.
Survival follow up will continue until the final DCO.
Section 2.1 Primary objective
The description of adverse events of special interest (AESIs) was revised in alignment with
Section 6.5 (Adverse events of special interest) to reflect the safety information available in
the latest version of the IBs of durvalumab and tremelimumab.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Previous text (revised/deleted text in bold):
AESIs observed with durvalumab or tremelimumab to date include: diarrhea / colitis and 
intestinal perforation, pneumonitis / ILD, hepatitis / transaminase increases,), 
endocrinopathies (ie, events of hypophysitis/ hypopituitarism, adrenal insufficiency,
hyper- and hypothyroidism and type I diabetes mellitus), rash / dermatitis, nephritis / 
blood creatinine increases, pancreatitis / serum lipase and amylase increases,
myocarditis, polymyositis, and neuropathy / neuromuscular toxicity (eg, Guillain-Barré, 
and myasthenia gravis). Other inflammatory responses that are rare / less frequent with a 
potential immune-mediated etiology include, but are not limited to pericarditis, sarcoidosis, 
uveitis and other events involving the eye, skin, hematological and rheumatological events. In 
addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different
underlying pharmacological etiology are also considered AESIs.
Revised text (revised/added text in bold):
AESIs observed with durvalumab or tremelimumab include pneumonitis, hepatitis,
diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyperthyroidism,
adrenal insufficiency, hypophysitis/hypopituitarism and type I diabetes mellitus), 
nephritis, rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis, and rare/less
frequent imAEs including neuromuscular toxicities such myasthenia gravis and
Guillain-Barré syndrome. Other inflammatory responses that are rare/less frequent with a 
potential immune-mediated etiology include, but are not limited to pericarditis, sarcoidosis, 
uveitis and other events involving the eye, skin, hematological and rheumatological events,
vasculitis, non-infectious meningitis and non-infectious encephalitis. It is possible that 
events with an inflammatory or immune mediated mechanism could occur in nearly all 
organs. In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions 
with a different underlying pharmacological etiology are also considered AESIs.
Section 3.2 Exclusion criteria (applicable to all modules)
An error in the exclusion criteria related to prior treatment with investigational products or
investigational anticancer therapy was corrected.
Previous text (revised/deleted text in bold):
Exclusion criterion 4:
Participation in another clinical study with an investigational product during the last 28 days 
or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
Exclusion criterion 7:
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is 
shorter, prior to the first dose of study treatment.  

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Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
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Revised text (revised/added text in bold):
Exclusion criterion 4:
Participation in another clinical study with an investigational product during the last 28 days 
or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
Exclusion criterion 7:
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is 
longer, prior to the first dose of study treatment.  
Section 3.9 Discontinuation of investigational product
Duration of survival follow-up was updated.
Previous text (revised/deleted text in bold):
Unless they withdraw consent for further follow up, patients who discontinue study therapy 
will continue on study for acquisition of safety information through 90 days after the last dose 
of study treatment, and for further collection of information regarding survival up to 5 years 
following date of first patient treatment initiation.  All patients will be followed for a 
minimum of 6 months following enrollment of the last patient to the study. 
Revised text (revised/added text in bold):
Unless they withdraw consent for further follow up, patients who discontinue study therapy 
will continue on study for acquisition of safety information through 90 days after the last dose 
of study treatment, and for further collection of information regarding survival until the final
DCO.
Section 3.9.1 Procedures for discontinuation of a patient from investigational product
Duration of survival follow-up was updated.
Previous text (revised/deleted text in bold):
All patients will be followed for survival up to 5 years following date of first patient 
treatment initiation.  All patients will be followed for a minimum of 6 months following 
enrollment of the last patient to the study.
Revised text (revised/added text in bold):
All patients will be followed for survival until the final DCO.
Section 3.10.2 Withdrawal of the informed consent
Duration of survival follow-up was updated.

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Previous text (revised/deleted text in bold):
Patients who withdraw consent for further participation in the study will not receive any 
further durvalumab + tremelimumab or further study observation, with the exception of follow 
up for survival, which will continue until the end of study unless the patient has expressly 
withdrawn their consent to survival follow up.  Note that the patient may be offered additional 
tests or tapering of treatment to withdraw safely.
[…]
Providing consent allows, survival status will be followed up by phone or electronic 
communication every 3 months up to 5 years following date of first patient treatment
initiation.  All patients should be followed for a minimum of 6 months following 
enrollment of the last patient to the study (see Section 4.3).
Revised text (revised/added text in bold):
Patients who withdraw consent for further participation in the study will not receive any 
further durvalumab + tremelimumab or further study observation, with the exception of follow 
up for survival, which will continue until the final DCO unless the patient has expressly 
withdrawn their consent to survival follow up.  Note that the patient may be offered additional 
tests or tapering of treatment to withdraw safely.
[…]
Providing consent allows, survival status will be followed up by phone or electronic 
communication every 3 months until the final DCO (see Section 4.3).
Section 3.11 Discontinuation of the study
Time when the study will be closed to accrual was deleted. Further details were provided
regarding the reasons (other than patient safety) why the Sponsor may terminate the study.
Deleted text:
It is expected that the overall study will close to accrual in third quarter 2021.
[…]
The study may also be terminated early at the Sponsor’s discretion for reasons other than 
patient safety.
Added text:
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 

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have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of patients by the Investigator

Discontinuation of further study drug development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research
organization(s) used in the study of the reason for termination or suspension, as specified by
the applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow up.
4.3
Follow up period
Specific instructions for imAE follow-up were deleted, duration of survival follow up was
updated, and clarification was added regarding patients who do not discontinue treatment
before the final DCO is reached.
Previous text (revised/deleted text in bold):
After this safety follow up visit, patients will be contacted by phone or email every 3 months 
up to 5 years from date of first patient treatment initiation to check survival status until 
death, whichever occurs first. 
Any imAEs that are unresolved at the patient’s last visit in the study are followed up by 
the Investigator for as long as medically indicated and up to 12 months post onset.
Non-imAEs are followed up until the 90-day post-treatment discontinuation visit.
Revised text (revised/added text in bold):
After this safety follow up visit, patients will be contacted by phone or email every 3 months 
to check survival status until death or final DCO, whichever occurs first. 
Patients who do not discontinue treatment before the final data cut-off (DCO) is reached 
will continue to be followed as indicated in Section 6.3.12.
Section 5.1 Survival assessments

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Duration of survival follow-up was updated
Previous text (revised/deleted text in bold):
The survival status of the patient will be collected during the study. After their safety follow 
up visit (90 days), patients will continue to be followed for survival via phone calls or email 
every 3 months up to 5 years following date of first patient treatment initiation.  All 
patients will be followed for a minimum of 6 months following enrollment of the last 
patient to the study.
Revised text (revised/added text in bold):
The survival status of the patient will be collected during the study. After their safety follow 
up visit (90 days), patients will continue to be followed for survival via phone calls or email 
every 3 months until the final DCO, with a final check that should generally occur within 
7 days of the final DCO.
Section 5.3.1 Laboratory safety assessments
The requirement to collect local reference ranges in the CRF was removed.
Previous text (revised/deleted text in bold):
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) 
will be recorded on the appropriate CRF.
Revised text (revised/added text in bold):
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values and units) will be recorded on 
the appropriate CRF.
Table 3 Laboratory safety variables
The row for additional laboratory tests was updated.
Previous text (revised/deleted text in bold):
Additional laboratory 
tests (where clinically
indicated only) a
Free tri-iodothyronine (T3) and free thyroxine (T4)c, creatinine d, 
alkaline phosphatase (ALP), autoimmune antibody test e
(d)
Creatinine Clearance will be calculated by data management using Cockcroft-Gault 
(using actual body weight).
(e)
If a patient experiences an AE that is thought to be possibly of autoimmune nature (eg
thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the Investigator should collect 
a blood sample for appropriate autoimmune antibody testing by a local laboratory.

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Revised text (revised/added text in bold):
Additional laboratory 
tests (where clinically
indicated only)
Free tri-iodothyronine (T3) and free thyroxine (T4)c, creatinine
clearance, alkaline phosphatase (ALP), autoimmune antibody test d
(d)
If a patient experiences an AE that is thought to be possibly of autoimmune nature (eg
thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the Investigator should collect 
a blood sample for appropriate autoimmune antibody testing by a local laboratory.
Section 6.2 Definitions of serious adverse event
New malignant tumors were added as a category of SAEs.
Added text:

AEs for new malignant tumors (ie, not the tumor for which entry into the study is a 
criterion and that is being treated by the IP under study and is not the development of 
new or progression of existing metastasis to the tumor under study) reported during a 
study should generally be assessed as SAEs. If no other seriousness criteria apply, the 
‘Important Medical Event’ criterion should be used.
In certain situations, however, medical judgement on an individual event basis should 
be applied to clarify that the malignant tumor event should be assessed and reported as 
a non-serious AE. For example, if the tumor is included as medical history and
progression occurs during the study, but the progression does not change treatment 
and/or prognosis of the malignant tumor, the AE may not fulfill the attributes for being 
assessed as serious, although reporting of the progression of the malignant tumor as an 
AE is valid and should occur. Also, some types of malignant tumors, which do not 
spread remotely after a routine treatment that does not require hospitalization, may be 
assessed as non-serious; examples include Stage 1 basal cell carcinoma and Stage 1A1 
cervical cancer removed via cone biopsy.
Malignant tumors that – as part of normal, if rare, progression – undergo 
transformation (eg, Richter's transformation of B cell chronic lymphocytic leukemia 
into diffuse large B cell lymphoma) should not be considered a new malignant tumor.
Section 6.3.12 Safety data to be collected following the final DCO of the study
This section was added to clarify how safety data will be collected for patients who continue
receiving treatment of the final DCO is reached.
Added text:

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For patients continuing to receive durvalumab treatment after final DCO and database closure, 
it is recommended that the patients continue the scheduled site visits and Investigators monitor 
the patient’s safety laboratory results prior to and periodically during treatment with 
durvalumab in order to manage AEs in accordance with the durvalumab Dose Modification
and Toxicity Management Guidelines (see Section 6.9.1). All data post the final DCO and 
database closure will be recorded in the patient notes but, with the exception of SAEs, will not 
otherwise be reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure 
must be reported as detailed in Section 6.4.
6.4
Reporting of serious adverse events
Clarification was added regarding the reporting of SAEs occurring after the final DCO is
reached.
Previous text (revised/deleted text in bold):
All SAEs have to be reported, whether or not considered causally related to durvalumab ± 
tremelimumab, or to the study procedure(s). All SAEs will be recorded in the CRF.
Revised text (revised/added text in bold):
All SAEs have to be reported, whether or not considered causally related to durvalumab ± 
tremelimumab, or to the study procedure(s). All SAEs will be recorded in the CRF, except
SAEs occurring after the DCO and database closure. After the DCO, SAEs will be
reported via paper SAE forms and recorded in AstraZeneca database.
Section 6.5 Adverse events of special interest
The description of AESIs was revised to reflect the safety information available in the latest
version of the IBs of durvalumab and tremelimumab.
Previous text (revised/deleted text in bold):
AESIs observed with durvalumab ± tremelimumab include:

Diarrhea / colitis and intestinal perforation

Pneumonitis / ILD

Hepatitis / transaminase increases

Endocrinopathies (ie, events of hypophysitis, hypopituitarism adrenal insufficiency,
hyper- and hypothyroidism and type I diabetes mellitus)

Rash / dermatitis

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
Nephritis / blood creatinine increases

Pancreatitis / serum lipase and amylase increases

Myocarditis

Myositis / polymyositis

Neuropathy / neuromuscular toxicity (eg, Guillain-Barré, and myasthenia gravis)
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosisuveitis, and other events 
involving the eye, skin, hematological and rheumatological events.
Revised text (revised/added text in bold):
AESIs/imAEs observed with durvalumab ± tremelimumab include pneumonitis, hepatitis, 
diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus),
nephritis, rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis and rare/less 
frequent imAEs including neuromuscular toxicities such as myasthenia gravis and
Guillain-Barré syndrome.
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an
inflammatory or immune mediated mechanism could occur in nearly all organs.
Section 6.9.1 Specific toxicity management and dose modification information-
Durvalumab and durvalumab + tremelimumab
The Dosing Modification and Toxicity Management Guidelines (TMGs) were explained in
further details, as the TMGs were removed from the protocol appendices and are provided as a
separate document.
Deleted text:
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and
non-immune-mediated reactions for durvalumab monotherapy and durvalumab + 
tremelimumab are provided in the Dosing Modification and Toxicity Management Guidelines 
(TMGs). The most current version of the TMGs is also available through the following link: 
https://tmg.azirae.com/. In addition, a version of current TMGs is maintained within the Site 
Master File. Please contact your clinical trial associate for information on how to gain access 
to this website.
Added text:

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Comprehensive toxicity management guidelines (TMG) have been developed to assist 
Investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) and tremelimumab
(CTLA-4 inhibitor).  Given the similar underlying mechanisms of toxicities observed with 
these 2 compounds, these guidelines are applicable to the management of patients receiving 
either drug as monotherapy or in combination. Additionally, these guidelines are applicable
when either drug is used alone or in combination and is administered concurrently or 
sequentially with other anti-cancer drugs (ie, antineoplastic chemotherapy, targeted agents), as 
part of a protocol specific treatment regimen.  The TMGs provide information for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune 
mediated reactions that may be observed with checkpoint inhibitor monotherapy or 
combination checkpoint inhibitor regimens, with specific instructions for dose modifications 
(including discontinuations) and treatment interventions. Investigators are advised however to 
use local practice guidelines and consult local references for the management of toxicities 
observed with other cancer treatment. The most current version of the TMGs entitled “Dosing 
Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, 
and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or Combination Therapy
with Tremelimumab or Tremelimumab Monotherapy” is provided to the investigative site as 
an Annex document and is maintained within the Site Master File. In addition, a version of the 
current Dosing Modification and Toxicity Management Guidelines is available through the 
following link: https://tmg.azirae.com/. Please contact your clinical trial associate for 
information on how to gain access to this website.
Section 7.1.1 Durvalumab
Previous text (revised/deleted text in bold):
Drug product should be kept in secondary packaging until use to prevent excessive light 
exposure.
[…]
A dose of 1500 mg (only patients >30 kg in weight are eligible) will be administered using an
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, 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. Add 30.0 mL of durvalumab (ie, 1500 mg of durvalumab 
[MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
If weight falls to ≤30 kg weight-based dosing at 20 mg/kg will be administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, 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. See the study specific drug handling plan for an example of a 

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weightbased dose calculation.  
Standard infusion time is 1 hour.  In the event that there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.
Revised text (revised/added text in bold):
Drug product should be kept in original packaging until use to prevent prolonged light 
exposure.
[…]
A dose of 1500 mg (only patients >30 kg in weight are eligible) will be administered using an
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22 μm filter. Add 30.0 mL of durvalumab (ie, 1500 mg of durvalumab 
[MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using 
an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter. See the study specific drug handling plan for an example of a 
weightbased dose calculation.  
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered.
Section 7.1.2 Tremelimumab
Previous text (revised/deleted text in bold):

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Version 5.0
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Drug product should be kept in secondary container until use to prevent excessive light 
exposure.
[…]
A dose of 75 mg (for patients >30 kg in weight; patients ≤30 kg are not eligible for entry to 
the study) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final tremelimumab concentration ranging from 1 to 10 mg/mL, and delivered 
through an IV administration set with a 0.2- or 0.22 μm in-line filter. Add 3.8 mL (ie, 75 mg 
of tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV bag. The 
IV bag size should be selected such that the final concentration is within 1 to 10 mg/mL. Mix 
the bag by gently inverting to ensure homogeneity of the dose in the bag.
If weight falls to ≤30 kg weight-based dosing at 1 mg/kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration 
ranging from 1 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm in-line filter. See the study specific drug handling plan for an example of a 
weightbased dose calculation.  
Standard infusion time is 1 hour.  In the event that there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.
Revised text (revised/added text in bold):
Drug product should be kept in original container until use to prevent prolonged light 
exposure.
[…]
A dose of 75 mg (for patients >30 kg in weight; patients ≤30 kg are not eligible for entry to 
the study) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 3.8 mL (ie,
75 mg of tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV bag. 
The IV bag size should be selected such that the final concentration is within 0.10 to
10 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
If patient weight falls to ≤30 kg, weight-based dosing at 1 mg/kg will be a administered using 
an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab 

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concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter. See the study specific drug handling plan for an example of a 
weight-based dose calculation.
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered.
Section 7.2 Dose and treatment regimens – Durvalumab monotherapy
Deleted text:
Standard infusion time is 1 hour. Less than 55 minutes is considered a deviation. In the event 
that there are interruptions during infusion, the total allowed time should not exceed 8 hours at 
room temperature.

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Section 7.2.1 Duration of treatment and criteria for treatment through progression and
for retreatment
Previous text (revised/deleted text in bold):
All treatment will be administered beginning on Day 1 for durvalumab monotherapy or 
durvalumab + tremelimumab combination therapy until progression unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
[…]
Patients receiving durvalumab + tremelimumab combination therapy may undergo retreatment 
as described below:

Patients who complete the 4 dosing cycles of the combination of 
durvalumab and tremelimumab portion of the regimen (with clinical 
benefit per Investigator judgement), but subsequently have evidence of 
PD during the durvalumab monotherapy portion of the combination 
regimen, with or without confirmation according to RECIST 1.1, may 
restart treatment with the combination.
[…]
Patients who AstraZeneca and the Investigator determine may not continue treatment after PD 
will be followed up for survival.  Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until confirmed disease progression and for survival.
Revised text (revised/added text in bold):
All treatment will be administered beginning on Day 1 for durvalumab monotherapy or 
durvalumab + tremelimumab combination therapy until RECIST 1.1-defined radiological
progression unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.
During the treatment period, patients may continue receiving therapy in the setting of 
unconfirmed radiologic progressive disease (PD) according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until 
progression is confirmed*. A confirmatory scan is required following a RECIST 1.1 
overall time point assessment of progression (PD), preferably at the next scheduled visit 
and no earlier than 4 weeks after the previous assessment of PD.
footnote: *Where treatment is discontinued due to progressive disease, it is 
recommended that a confirmatory scan be performed prior to discontinuation to verify 
progression. According to RECIST 1.1 modified for confirmation of progression, a 
confirmatory scan is required following an overall time point assessment of progression 

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(PD), no earlier than 4 weeks after the previous assessment of PD.
[…]
Patients receiving durvalumab + tremelimumab combination therapy may undergo retreatment 
as described below:

Patients who complete the 4 dosing cycles of the combination of 
durvalumab and tremelimumab portion of the regimen (with clinical 
benefit per Investigator judgement), but subsequently have evidence of
RECIST 1.1 (or other tumor assessment method)-defined PD during 
the durvalumab monotherapy portion of the combination regimen, with or 
without confirmation according to RECIST 1.1, may restart treatment 
with the combination.
[…]
Patients who AstraZeneca and the Investigator determine may not continue treatment after 
RECIST 1.1-defined PD will be followed up for survival.  Patients who have discontinued 
treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent 
anticancer therapy, will be followed up until confirmed RECIST 1.1-defined PD and for 
survival.
Post final data cut off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO 
and database closure may continue to receive their assigned treatment for as long as they 
and their physician considers they are gaining clinical benefit. For patients continuing to 
receive durvalumab treatment following the final DCO and database closure, it is 
recommended that the patients continue the scheduled site visits and Investigators 
monitor the patients’ safety laboratory results prior to and periodically during 
treatment with durvalumab in order to manage AEs in accordance with the durvalumab 
Dosing Modification and Toxicity Management Guidelines (see Section 6.9.1). 
In the event that a roll-over or safety extension study is available at the time of, or
subsequent to, the final DCO and database closure, patients receiving treatment with 
durvalumab may be transitioned to such a study, and the study would reach its end. The 
roll-over or safety extension study would ensure treatment continuation with visit 
assessments per its protocol. Any patient who would be proposed to move to such a study 
would be given a new Informed Consent.
Section 7.8 Post study access to study treatment
Reference to modules for additional information regarding the possible transition to a
long-term extension or an early access program was deleted, as further information was

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included in Section 7.2.1 and Section 9.3.
Deleted text:
If applicable, timelines for transition will be agreed with local bodies, which may include 
regulatory agencies, ECs, and participating institutions.  Details will be provided for each 
tumor-specific cohort and country in individual modules, as applicable.
Section 9.3 Study timetable and end of study
The definition and estimated date of study end was updated.
Previous text (revised/deleted text in bold):
The end of the study is defined as the last visit of the last patient undergoing the study.
The overall study is expected to start in Q1 2017 and end by Q1 2022.
See individual modules for end of study information.
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with durvalumab or tremelimumab.
Revised text (revised/added text in bold):
The end of the study is defined as the last visit of the last patient undergoing the study.
The overall study is expected to start in Q1 2017 and end by Q2 2021.
See individual modules for the definition of final DCO. 
The study may be terminated at individual centers if the study procedures are not being
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with durvalumab or tremelimumab.
In the event that a roll-over or safety extension study is available at the time of or
subsequent to the final DCO and database closure, patients receiving treatment with 
durvalumab may be transitioned to such a study, and the study would reach its end. The 
roll-over or safety extension study would ensure treatment continuation with visit 
assessments per its protocol. Any patient who would be proposed to move to such a study 
would be given a new Informed Consent.

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10.2
Patient data protection
Further information regarding patient data protection was included.
Added text:
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Appendix D: Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law
Appendix D was updated to include current AstraZeneca processes for the reporting of
potential Hy’s law (PHL) and Hy’s law cases (HL).
1. Introduction
Added text:
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
4. Follow up
4.1. Potential Hy’s Law criteria not met
Added text:

Perform follow-up on subsequent laboratory results according to the 
guidance provided in the Clinical Study Protocol.

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4.2. Potential Hy’s Law criteria met
Previous text (revised/deleted text in bold):
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to 
starting study treatment (See section below on Actions required when 
potential Hy’s Law criteria are met before and after starting study
treatment)

Notify the AstraZeneca representative who will then inform the central 
Study Team

The Study Physician contacts the Investigator, to provide guidance, 
discuss and agree an approach for the study patients’ follow up and the 
continuous review of data.  Subsequent to this contact the Investigator 
will:

Monitor the patient until liver biochemistry parameters and 
appropriate clinical symptoms and signs return to normal or baseline 
levels, or as long as medically indicated

Investigate the etiology of the event and perform diagnostic
investigations as discussed with the Study Physician

Complete the three Liver CRF Modules as information becomes 
available

If at any time (in consultation with the Study Physician) the PHL 
case meets serious criteria, report it as an SAE using standard
reporting procedures
Revised text (revised/added text in bold):
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to 
starting study treatment (See section 6. Actions required when potential 
Hy’s Law criteria are met before and after starting study treatment)

Notify the AstraZeneca representative who will then inform the central 
Study Team 

Within 1 day of PHL criteria being met, the Investigator will report
the case as an SAE of Potential Hy’s Law; serious criteria ‘Important 

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medical event’ and causality assessment ‘yes/related’ according to 
protocol process for SAE reporting.

For patients that met PHL criteria prior to starting IMP, the 
Investigator is not required to submit a PHL SAE unless there is a 
significant change # in the patient’s condition

The Study Physician contacts the Investigator, to provide guidance, 
discuss and agree an approach for the study patients’ follow up
(including any further laboratory testing) and the continuous review of 
data.  

Subsequent to this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and 
appropriate clinical symptoms and signs return to normal or baseline 
levels, or as long as medically indicated.

Complete follow up SAE Form as required.

Investigate the etiology of the event and perform diagnostic
investigations as discussed with the Study Physician.

Complete the 3 Liver CRF Modules as information becomes 
available.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The
determination of whether there has been a significant change will be at the discretion of 
the Investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.
5. Review and assessment of potential Hy’s Law cases
Previous text (revised/deleted text in bold):
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP. The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 

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instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative 
explanation on the appropriate CRF.

If the alternative explanation is an AE/SAE, record the AE /SAE in the 
CRF accordingly and follow the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes.

The ‘Medically Important’ serious criterion should be used if no
other serious criteria apply.

As there is no alternative explanation for the HL case, a causality 
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above.

Continue follow up and review according to agreed plan. Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether HL criteria are met. Update the SAE 
report according to the outcome of the review.
Revised text (revised/added text in bold):
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar 
days from date PHL criteria was met. The AstraZeneca Medical Science Director and 
Global Safety Physician will also be involved in this review together with other patient matter

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experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative 
explanation on the appropriate CRF.

If the alternative explanation is an AE/SAE, update the previously 
submitted Potential Hy’s Law SAE and AE CRFs accordingly with 
the new information (reassessing event term; causality and 
seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes.

The ‘Medically Important’ serious criterion should be used if no 
other serious criteria apply.

As there is no alternative explanation for the HL case, a causality
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of 
Potential Hy’s Law, (report term now ‘Hy’s Law case’) ensuring 
causality assessment is related to IMP and seriousness criteria is 
medically important, according to protocol process for SAE 
reporting.

Continue follow up and review according to agreed plan. Once the 
necessary supplementary information is obtained, repeat the review and
assessment to determine whether HL criteria are met. Update the 
previously submitted PHL SAE report following protocol process for 
SAE reporting, according to the outcome of the review and amending 
the reported term if an alternative explanation for the liver

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biochemistry elevations is determined.
References
Previous text (revised/deleted text in bold):
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
Revised text (revised/added text in bold):
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’ Available from: https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation
Appendix E: Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion-Related, and Non-Immune-Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab 
Monotherapy
The appendix was deleted from the protocol. The guidelines will be provided separately from
the protocol as a standalone document.
Appendix E (previously Appendix F): Eastern Cooperative Oncology Group 
Performance Scale
The appendix was renumbered due to the deletion of Appendix E. No changes were made to
the content of the appendix.
Appendix G: Signature Page
The appendix was deleted, as it is no longer needed. The protocol is signed electronically, and
the electronic signature page is added at the end of the protocol.
Appendix F (previously Appendix H): Tumor Specific Modules – Module A
The appendix was renumbered due to the deletion of Appendix E and Appendix G.
Module A was updated to version 4.0, including revisions in the synopsis, Section 2.1
(primary objectives), Section 3.2 (Exclusion Criteria) and Section 9.3 (Study timetable and
end of study).
Refer to the version history of Module A for further information.

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Appendix G (previously Appendix I): Country-Specific Ancillary Studies
The appendix was renumbered due to the deletion of Appendix E and Appendix G.
The IOPREDI ancillary study was updated to version 2.0, including revisions of the synopsis,
Section 1.2 (Rationale for study design), Section 2.1 (Primary objectives), Section 2.2 
(Secondary objectives), Section 3.1 (Inclusion criteria), Section 4 (Study plan and timing of 
procedures), Section 4.1 (Screening/Enrolment Period), Section 4.2 (Treatment Period), 
Section 5 (Study assessments), Section 5.1 (Genetics), Section 5.2 (Biomarker analysis),
Section 6 (Safety reporting and medical management), Section 8.3 (Definitions of analysis
sets), Section 10.4 (Informed consent) and Section 11 (List of references).
Refer to the version history of IOPREDI ancillary study for further information.
Minor editorial changes were made to correct typos, style, or formatting, and to update
cross-references to protocol sections and appendices (and in particular to the Dosing 
Modification and Toxicity Management Guidelines, which are no longer appended to the
protocol).
This Protocol has been subject to a peer review according to AstraZeneca Standard 
procedures.  The Clinical Study Protocol is publicly registered and the results are disclosed 
and/or published according to the AstraZeneca Global Policy on Bioethics and in compliance
with prevailing laws and regulations.

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CLINICAL STUDY PROTOCOL SYNOPSIS
An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + 
Tremelimumab Combination Therapy or Durvalumab Monotherapy in 
Advanced Solid Malignancies (STRONG)
Study site(s) and number of patients planned
Patients will be enrolled in different tumor specific cohorts (Modules; APPENDIX F) and 
country-specific ancillary studies (APPENDIX G).  Additional tumor specific or exploratory
modules may be added in the study. 
The following module and country-specific ancillary study were opened:

Module A: Post-Chemotherapy Urothelial and NonUrothelial Carcinoma 
of the Urinary Tract With Fixed-dose Durvalumab Monotherapy.

IOPREDI, French STRONG ancillary study: Predictive Markers of 
Immune-Mediated Adverse Events and of Treatment Response in 
Patients Treated with Durvalumab Monotherapy or in Combination with 
Tremelimumab.
The total number of patients to be enrolled overall and in each module will depend on the 
types and number of tumor modules added to the main study and country-specific ancillary 
studies. The number of patients and sites to be involved in individual countries will be 
dependent on each module or ancillary study.
It is anticipated that the total enrollment period for the overall study will be approximately 
2 to 3 years, with an overall duration of 4 to 5 years.
Study design
Study Duration
Phase of Development
Estimated date of first patient enrolled (United States)
Q1 2017
Phase IIIb
Estimated date of final data cut-off (Global)
Q2 2020
Estimated date of last patient follow up (Global)
Q2 2021

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Study Flow chart
Tumor specific modules detail which treatment regimen, combination therapy or monotherapy will be used. 
Patients will continue to receive study treatment as long as they are receiving clinical benefit in the opinion of the 
Investigator unless any of the criteria for treatment discontinuation are met first.
Survival follow up will continue until the final data cut-off (DCO).
Study design
This is an open-label, multi-center, study to determine the short and long-term safety of fixed 
doses of durvalumab 1500 mg + tremelimumab 75 mg combination therapy or durvalumab 
1500 mg monotherapy in patients with advanced solid malignancies.
This study is modular in design, each tumor specific Module allowing evaluation of the safety,
tolerability, and antitumor activity of the combination of durvalumab + tremelimumab or 
durvalumab alone in different solid tumors.
The modules are developed as separate components appended to this protocol. Additional 
modules may be added as part of this protocol as decisions on additional tumor types and/or 
exploratory sub-studies are made.
One or more of these modules will be opened in a given country / region based on local 
patient population prevalence, and results of feasibility studies.
The protocol (and each tumor specific module) consists of a screening period, a treatment 
period, a 90day safety follow up period, and a survival follow up period. 
Patients will attend a safety follow up visit 90 days after study treatment discontinuation. 
Thereafter, patients will be contacted by phone or electronic communication every 3 months 
for survival status until the final data cut-off (DCO). 

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Investigational product, dosage and mode of administration
Durvalumab + tremelimumab combination therapy 

Durvalumab 1,500 mg plus tremelimumab 75 mg via intravenous (IV)
infusion once every 4 weeks (Q4W), starting on Week 0, for up to a 
maximum of 4 doses (or cycles) followed by:

Durvalumab monotherapy 1,500 mg via IV infusion Q4W, starting 
4 weeks after the last infusion of the combination or discontinuation of 
tremelimumab. 
OR
Durvalumab monotherapy 

Durvalumab 1,500 mg via IV infusion Q4W, starting on Week 0. 
Each tumor specific module will specify combination therapy or monotherapy, and will 
provide details of infusion duration.
Study Objectives
Primary Objective
The common primary objective of all tumor sub-studies is:
1.
To assess the incidence, severity, nature, seriousness, intervention/treatment, 
outcome, and causality, including immune-relatedness, of adverse events (AEs) of 
special interest (AESIs) in patients with advanced solid malignancies treated with
fixed doses of durvalumab and tremelimumab combination therapy or durvalumab
monotherapy.
An AESI is one of scientific and medical interest specific to understanding of the 
Investigational Product. AESIs for durvalumab ± tremelimumab include but are not limited to 
events with a potential inflammatory or immune-mediated mechanism and which may require
more frequent monitoring and/or interventions such as steroids, immunosuppressants and/or
hormone replacement therapy. An immune-mediated adverse event (imAE) is defined as an 
AESI that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate etiology.  
AESIs observed with durvalumab or tremelimumab include pneumonitis, hepatitis,
diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyperthyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism and type I diabetes mellitus), nephritis,
rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis, and rare/less frequent imAEs
including neuromuscular toxicities such myasthenia gravis and Guillain-Barré syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, hematological and rheumatological events, vasculitis, non-infectious 

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meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs. In addition, infusion-related
reactions and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological etiology are also considered AESIs.
The specific safety objective will be further defined in each tumor specific module. 
Secondary Objectives 
The common secondary objectives of all tumor sub-studies are:
1.
To assess the incidence, severity, nature, seriousness, intervention/treatment,
outcome, and causality of AEs (including serious adverse events [SAEs]).
2.
To assess the incidence and frequency of durvalumab and tremelimumab (as 
applicable to each tumor Module) interruption and discontinuation due to 
treatmentemergent AEs (including SAEs).
3.
To assess overall survival (OS).
Additional secondary objectives and exploratory objectives may be added to tumor sub-
studies in each country / region.  Additional sub-studies / exploratory studies may be added to 
the protocol, in modular fashion.
Exploratory Objective
1.
To assess overall response rate (ORR) and disease control rate (DCR) based on 
Investigator assessed response to treatment (RECIST 1.1).
Target patient population
The target patient population of the protocol includes patients with advanced solid tumors who 
meet the overall and tumor specific inclusion and exclusion criteria as outlined in each
Module.
Duration of treatment
Patients may continue receiving therapy as long as they are continuing to demonstrate clinical
benefit, as judged by the Investigator, and in the absence of initiation of alternative cancer 
treatment, unacceptable toxicity, withdrawal of consent, or other reason for treatment 
discontinuation. 
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
disease progression.
Progression during treatment
During the treatment period, patients may continue receiving therapy in the setting of 
unconfirmed radiologic progressive disease (PD) according to Response Evaluation Criteria in 

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Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until progression is 
confirmed*. A confirmatory scan is required following a RECIST 1.1 overall time point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 
4 weeks after the previous assessment of PD.
Patients with PD by RECIST 1.1 (unconfirmed and confirmed) who, in the Investigator’s 
opinion, continue to receive benefit from their treatment and who meet the criteria for 
treatment in the setting of PD may continue to receive their treatment for as long as they are 
gaining clinical benefit.  
However, patients will not be permitted to continue immunotherapy if progression occurs after 
confirmed response (complete response [CR] or partial response [PR] as defined by 
RECIST 1.1) to immunotherapy treatment in target lesions (regardless of the appearance of 
new lesions) ie, the response and progression events both occurred in the target lesions while 
receiving immunotherapy during the same treatment period. 
Patients in Modules with combination durvalumab + tremelimumab may restart treatment with 
the combination if they complete the 4 dosing cycles with durvalumab + tremelimumab (with 
clinical benefit per Investigator judgement) but subsequently have PD during treatment with 
durvalumab alone and provided they meet eligibility criteria for retreatment.
See Section 7.8 for post-study access to treatment information.
Follow up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, withdrawal from treatment, or patients who have started a subsequent 
anticancer therapy, will be followed up for AEs for 90 days, and thereafter followed up to 
record disease progression and survival (described in the next section).  These patients are not 
eligible for re-treatment at any time.
Survival
All patients in the study should be followed up for survival until the final DCO. 
Data Monitoring Committee
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with AstraZeneca Patient Safety.  Issues identified 
in this study or in other studies but deemed relevant for this study will be addressed promptly, 
                                               
*Where treatment is discontinued due to progressive disease, it is recommended that a confirmatory scan be 
performed prior to discontinuation to verify progression. According to RECIST 1.1 modified for confirmation of 
progression, a confirmatory scan is required following an overall time point assessment of progression (PD), no 
earlier than 4 weeks after the previous assessment of PD.

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which could involve amendments to the study protocol and letters to Investigators, as 
appropriate.
In addition to the ongoing AstraZeneca overall safety monitoring, a Data Monitoring 
Committee (DMC) comprised of internal experts independent from the study team will be 
convened and will meet approximately every 6 months after the study has started to review 
safety assessments and make recommendations to continue, amend, or stop the study based on 
safety findings. Full details of the DMC remit, procedures, processes, meeting frequency, and 
interim analyses can be found in the DMC Charter.
Steering Committee
A Steering Committee (SC) will be assembled by AstraZeneca for the executive oversight and 
supervision of the study. The committee of oncology experts will serve this role through 
regular scheduled meetings or teleconferences and, if necessary, additional ad hoc meetings.  
Details of the SC remit, procedures, processes, and meeting frequency, will be outlined in an 
SC Charter. 
Statistical methods
The primary analysis set is the safety analysis set which will include all enrolled patients who 
received at least 1 dose of durvalumab or tremelimumab. 
The safety analysis set will be used for all analyses.
The primary outcome measure for the study is the number and proportion of patients with 
AESI. Pre-defined MedDRA preferred terms groupings will be used to identify AESI. For 
each AESI ‘grouped’ term, the number (%) of patients experiencing any of the specified terms 
will be presented overall, by seriousness, by causality and by maximum NCI CTCAE grade. 
The exact 95% CIs around the incidence estimates will also be reported for each AESI type.
While the precise sample size and number of AESIs that will be included in the study overall 
and in each module is not known a priori, sample sizes are included that would allow the
collection of additional data on the incidence, severity, nature, seriousness, 
intervention/treatment, and causality, including immune-relatedness, of AESIs. See each 
Module for details.
A detailed description of statistical methods is found in the tumor specific modules.

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS .................................................. 37
TABLE OF CONTENTS................................................................................... 43
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 48
1.
INTRODUCTION ............................................................................................. 53
1.1
Background and rationale for conducting this study ........................................... 53
1.1.1
Immunotherapies ............................................................................................... 53
1.1.2
Durvalumab ....................................................................................................... 54
1.1.3
Tremelimumab................................................................................................... 55
1.1.4
Durvalumab in combination with tremelimumab................................................ 55
1.2
Rationale for study design, doses and control groups.......................................... 56
1.2.1
Dose and treatment regimen justification............................................................ 56
1.2.2
Rationale for fixed dosing .................................................................................. 57
1.3
Benefit/risk and ethical assessment .................................................................... 57
1.3.1
Potential benefits................................................................................................ 58
1.3.2
Overall risks....................................................................................................... 58
1.3.2.1
Durvalumab ....................................................................................................... 58
1.3.2.2
Tremelimumab................................................................................................... 59
1.3.2.3
Durvalumab + Tremelimumab ........................................................................... 59
1.3.3
Overall benefit risk ............................................................................................ 60
1.4
Study Design...................................................................................................... 61
2.
STUDY OBJECTIVES...................................................................................... 64
2.1
Primary objective............................................................................................... 64
2.2
Secondary objectives.......................................................................................... 64
2.3
Exploratory objective......................................................................................... 65
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 65
3.1
Inclusion criteria ................................................................................................ 65
3.2
Exclusion criteria (applicable to all modules) ..................................................... 67
3.3
Patient enrollment and randomization ................................................................ 70
3.4
Procedures for handling incorrectly enrolled patients ......................................... 71
3.5
Methods for assigning treatment groups (not applicable).................................... 71
3.6
Methods for ensuring blinding (not applicable) .................................................. 71

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3.7
Methods for unblinding (not applicable)............................................................. 71
3.8
Restrictions........................................................................................................ 71
3.9
Discontinuation of investigational product ......................................................... 73
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 74
3.10
Criteria for withdrawal....................................................................................... 75
3.10.1
Screen failures ................................................................................................... 75
3.10.2
Withdrawal of the informed consent................................................................... 75
3.10.2.1
Survival status for withdrawn consent and lost to follow up patients .................. 75
3.11
Discontinuation of the study............................................................................... 76
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 77
4.1
Screening/Enrollment period.............................................................................. 84
4.2
Treatment period................................................................................................ 85
4.2.1
Baseline visit (Day 1)......................................................................................... 85
4.2.2
Treatment period................................................................................................ 86
4.3
Follow up period................................................................................................ 87
5.
STUDY ASSESSMENTS.................................................................................. 88
5.1
Survival assessments.......................................................................................... 88
5.2
Demographics/Medical, medication, surgical history.......................................... 88
5.2.1
Demographics.................................................................................................... 88
5.2.2
Physical examination, vital signs and medical history ........................................ 88
5.2.3
Disease characteristics and ECOG...................................................................... 89
5.2.4
Prior and concomitant medication and cancer treatment history.......................... 89
5.3
Safety assessments............................................................................................. 89
5.3.1
Laboratory safety assessments............................................................................ 89
5.3.1.1
Thyroid stimulating hormone ............................................................................. 91
5.3.1.2
Coagulation........................................................................................................ 91
5.3.1.3
Other lab tests .................................................................................................... 91
5.3.2
ECOG................................................................................................................ 91
5.3.3
ECG................................................................................................................... 91
5.3.4
Physical exam, vital signs .................................................................................. 91
5.3.5
Other safety assessments.................................................................................... 92
5.3.5.1
Immune-mediated adverse events....................................................................... 92
5.3.5.2
Autoimmune antibody test ................................................................................. 92
5.4
Other assessments (not applicable)..................................................................... 92
5.5
Pharmacokinetics (not applicable)...................................................................... 92
5.6
Pharmacodynamics (not applicable) ................................................................... 92
5.7
Biomarker analysis............................................................................................. 92
5.7.1
Storage, re-use and destruction of biological samples......................................... 93
5.7.2
Labeling and shipment of biological samples ..................................................... 94

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5.7.3
Chain of custody of biological samples .............................................................. 94
5.7.4
Withdrawal of Informed Consent for donated biological samples....................... 94
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 95
6.1
Definition of adverse events............................................................................... 95
6.2
Definitions of serious adverse event ................................................................... 95
6.3
Recording of adverse events............................................................................... 96
6.3.1
Time period for collection of adverse events ...................................................... 96
6.3.2
Follow up of unresolved adverse events ............................................................. 96
6.3.3
Variables............................................................................................................ 97
6.3.4
Causality collection............................................................................................ 98
6.3.5
Relationship to protocol procedures ................................................................... 98
6.3.6
Adverse events based on signs and symptoms .................................................... 99
6.3.7
Adverse events based on examinations and tests ................................................ 99
6.3.8
Hy’s Law ........................................................................................................... 99
6.3.9
Disease progression............................................................................................ 99
6.3.10
New cancers..................................................................................................... 100
6.3.11
Deaths.............................................................................................................. 100
6.3.12
Safety data to be collected following the final DCO of the study...................... 100
6.4
Reporting of serious adverse events ................................................................. 101
6.5
Adverse events of special interest..................................................................... 101
6.6
Overdose.......................................................................................................... 103
6.6.1
Durvalumab or tremelimumab.......................................................................... 103
6.7
Pregnancy ........................................................................................................ 103
6.7.1
Maternal exposure............................................................................................ 103
6.7.2
Paternal exposure............................................................................................. 104
6.8
Medication Error.............................................................................................. 104
6.9
Management Durvalumab ± Tremelimumab related toxicities.......................... 106
6.9.1
Specific toxicity management and dose modification information-
Durvalumab and durvalumab + tremelimumab................................................. 106
6.10
Study governance and oversight....................................................................... 107
6.10.1
Data Monitoring Committee............................................................................. 107
6.10.2
Steering Committee.......................................................................................... 107
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 108
7.1
Identity of investigational product(s)................................................................ 108
7.1.1
Durvalumab ..................................................................................................... 108
7.1.2
Tremelimumab................................................................................................. 109
7.2
Dose and treatment regimens ........................................................................... 110
7.2.1
Duration of treatment and criteria for treatment through progression and 
for retreatment ................................................................................................. 111

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7.3
Labeling........................................................................................................... 113
7.4
Storage............................................................................................................. 114
7.5
Compliance...................................................................................................... 114
7.6
Accountability.................................................................................................. 114
7.7
Concomitant medications and other treatments................................................. 115
7.7.1
Other concomitant treatment ............................................................................ 117
7.8
Post-study access to study treatment................................................................. 117
8.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 117
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 117
9.1
Training of study site staff................................................................................ 118
9.2
Monitoring of the study.................................................................................... 118
9.2.1
Source data ...................................................................................................... 119
9.2.2
Study agreements............................................................................................. 119
9.2.3
Archiving of study documents.......................................................................... 119
9.3
Study timetable and end of study...................................................................... 119
9.4
Data management by AstraZeneca or delegate ................................................. 119
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 120
10.1
Ethical conduct of the study ............................................................................. 120
10.2
Patient data protection...................................................................................... 120
10.3
Ethics and regulatory review ............................................................................ 121
10.4
Informed consent ............................................................................................. 122
10.5
Changes to the clinical study protocol and informed consent form ................... 123
10.6
Audits and inspections ..................................................................................... 123
11.
LIST OF REFERENCES ................................................................................. 124
LIST OF TABLES
Table 1
Highly Effective methods of contraception (<1% failure rate)...............73
Table 2
Study Plan detailing the procedures.......................................................79
Table 3
Laboratory safety variables ...................................................................90
Table 4
Prohibited concomitant medications.................................................... 116
Table 5
Supportive medications ....................................................................... 117

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LIST OF FIGURES
Figure 1
Study flow chart....................................................................................63
Figure 2
Durvalumab dosing regimen ............................................................... 110
Figure 3
Durvalumab + tremelimumab dosing regimen..................................... 111
LIST OF APPENDICES
APPENDIX A
Additional Safety Information............................................................. 128
APPENDIX B
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................ 130
APPENDIX C
Genetic Research ................................................................................ 132
APPENDIX D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 135
APPENDIX E
Eastern Cooperative Oncology Group Performance Scale ................... 141
APPENDIX F
Tumor Specific Modules..................................................................... 142
APPENDIX G
Country-Specific Ancillary Studies ..................................................... 143

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation  
AChE
Acetylcholine esterase
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine transaminase
APTT
Activated partial thromboplastin time
AST
Aspartate transaminase
AUC
Area under the concentration-time curve
BUN
Blood urea nitrogen
CD
Cluster of differentiation
CI
Confidence interval
CL
Clearance
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form (electronic/paper)
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Event

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Abbreviation or 
special term
Explanation  
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4 (also known as CD152)
DCO
Data cut-off
DCR
Disease control rate
DMC
Data Monitoring Committee
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR TKI
Epidermal growth factor receptor tyrosine kinase inhibitors
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HL
Hy’s Law
HNSCC
Head and neck squamous cell carcinoma
HPF
high power field
IB
Investigator’s brochure

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Abbreviation or 
special term
Explanation  
IC
Immune cells
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IgG
Immunoglobulin G
imAE
immune-mediated adverse event
IL
Interleukin
ILD
Interstitial lung disease
IMP
Investigational Medicinal Product
INR
International normalized ratio
International 
Co-ordinating
Investigator
If a study is conducted in several countries the International
Co-ordinating Investigator is the Investigator co-ordinating the 
Investigators and/or activities internationally
IP
Investigational product 
IRB
Institutional Review Board
IV
Intravenous
IVRS/IWRS
Interactive Voice/Web Response System
LDH
Lactate dehydrogenase
LFT
Liver function test
mAb
Monoclonal antibody
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities

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Abbreviation or 
special term
Explanation  
MEDI4736
Durvalumab
MOA
Mechanism of action
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PCP
Pneumocystis pneumonia
PD
Progressive disease
PD1
Programmed cell death-1
PD-L1
Programmed death ligand 1
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PO
Oral, per os
PR
Partial response
Q12W
Every 12 weeks
Q2W
Every 2 weeks
Q4W
Every 4 weeks
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red Blood Cell

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Abbreviation or 
special term
Explanation  
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event 
SC
Steering Committee
T3
Tri-iodothyronine 
T4
Thyroxine 
TB / TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TMG
Toxicity Management Guidelines
TNF
Tumor necrosis factor
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WT
Weight

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
See tumor specific modules (APPENDIX F) for tumor specific background and rationales.
1.1.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn et al 
2004).  
Programmed death ligand 1 (PD-L1) is part of a complex system of receptors and ligands that 
are involved in controlling T-cell activation. The PD-1 receptor (CD279) is expressed on the 
surface of activated T-cells (Keir et al 2008).  It has 2 known ligands: PD- L1 (B7 H1; 
CD274) and PD-L2 (B7 DC; CD273) (Okazaki and Honjo 2007). The PD-1 and PD-L1/PD 
L2 belong to the family of immune checkpoint proteins that act as co inhibitory factors, which 
can halt or limit the development of T-cell response.  When PD-L1 binds to PD-1, an 
inhibitory signal is transmitted into the T cell, which reduces cytokine production and 
suppresses T cell proliferation. Tumor cells exploit this immune checkpoint pathway as a 
mechanism to evade detection and inhibit immune response.
PD-L1 is constitutively expressed by B cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly over expressed on tumor cells or on non-transformed
cells in the tumor microenvironment (Pardoll 2012).  PD-L1 expressed on the tumor cells 
binds to PD-1 receptors on the activated T-cells leading to the inhibition of cytotoxic T-cells.  
These deactivated T-cells remain inhibited in the tumor microenvironment.  The PD-1/PD-L1 
pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in
response to endogenous anti-tumor activity.  
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the 
PDL1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors
expressed on immune cells (ICs). This activity overcomes PD-L1-mediated inhibition of
antitumor immunity. While functional blockade of PD-L1 results in T-cell reactivation, this 
mechanism of action (MOA) is different from direct agonism of a stimulatory receptor such as 
CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients
with cancer. Results of non-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance antitumor immune response in cancer patients (Brahmer et al 2012; 
Hirano et al 2005; Iwai et al 2002; Okudaira et al 2009; Topalian et al 2012; Zhang et al 2008) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 

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(Powles et al 2014; Rizvi et al 2015; Segal et al 2015). In addition high mutational burden,
eg, in bladder carcinoma (Alexandrov et al 2013) may contribute to the responses seen with 
immune therapy.
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T-cells and upregulated on activated T-cells.  CTLA-4 delivers a
negative regulatory signal to T-cells upon binding of CD80(B7.1) or CD86(B7.2) ligands on
antigen-presenting cells (Fife and Bluestone 2008). Blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor 
activity in animal models, including killing of established murine solid tumors and induction 
of protective antitumor immunity.  Therefore, it is expected that treatment with an anti CTLA-
4 antibody will lead to increased activation of the human immune system, increasing 
antitumor activity in patients with solid tumors.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade 
of negative regulatory signals to T-cells such as CTLA-4 and PD-L1 has promising clinical 
activity.  Ipilimumab was granted United States (US) Food and Drug Administration (FDA) 
approval for the treatment of metastatic melanoma and is currently under investigation for 
several other malignancies whilst nivolumab and pembrolizumab, two anti-PD-1 agents and 
atezolizumab, an anti-PD-L1 agent have been granted approvals by agencies such as the US
FDA and the European Medicines Agency approval for the treatment of a number of 
malignancies including metastatic melanoma, squamous and non-squamous cell non-small-
cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial carcinoma. In 
addition, there is data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a 
wide range of tumor types.
1.1.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T-cells and 
CD80 (B7.1) on ICs. Durvalumab is being developed by AstraZeneca/MedImmune for use in 
the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.)  The 
proposed MOA for durvalumab is interference in the interaction of PD-L1 with PD 1 and 
CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition 
of immune responses, including those that may result in tumor elimination.  In vitro studies 
demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T-
cells resulting in the restored proliferation of IFN-γ (Stewart et al 2015).  In vivo studies have 
shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism (Stewart et al 2015).  Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  
To date durvalumab has been given to more than 6000 patients as part of ongoing studies
either as monotherapy or in combination with other anticancer agents.  Details on the safety 

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profile of durvalumab monotherapy are summarized in Section 1.3.2.1.  Refer to the current 
durvalumab Investigator’s Brochure (IB) for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics.
1.1.3
Tremelimumab
Tremelimumab is a IgG2 mAb that is directed against CTLA-4; cluster of differentiation 
[CD]152), a cell surface receptor that is expressed primarily on activated T-cells and acts to 
inhibit their activation. Tremelimumab completely blocks the interaction of human CTLA-4 
with CD80 and CD86, resulting in increased release of cytokines (interleukin [IL]-2 and 
IFNγ) from human T-cells, peripheral blood mononuclear cells and whole blood (Tarhini and 
Kirkwood 2008). Tremelimumab is being developed by AstraZeneca for use in the treatment 
of cancer.
To date tremelimumab has been given to more than 1500 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of tremelimumab monotherapy are summarized in Section 1.3.2.2.  
Refer to the current tremelimumab IB for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics.
1.1.4
Durvalumab in combination with tremelimumab
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both 
PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); 
therefore, in addition to evaluating both agents in the monotherapy setting in a number of
cancer indications AstraZeneca is also investigating the use of durvalumab + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose escalation study to establish the safety, 
pharmacokinetics (PK)/pharmacodynamics, and preliminary antitumor activity of durvalumab 
+ tremelimumab combination therapy in patients with advanced non-small cell lung cancer 
(NSCLC).  The dosing schedule utilized is durvalumab every 2 or 4 weeks (Q2W, Q4W) up to 
12 months, combined with tremelimumab Q4W up to Week 24 for 7 doses then every 
12 weeks (Q12W) for 2 additional doses for up to 12 months.  The study is ongoing and 
continues to accrue.  In addition, other clinical studies have since started looking at the 
combination in both NSCLC and other oncology indications.
To date more than 3000 patients have received the combination using a number of doses and 
dosing schedules. Details on the safety profile of durvalumab + tremelimumab combination 
therapy are summarized in Section 1.3.2.3.  Refer to the current editions of the durvalumab 
and tremelimumab IBs for a complete summary of non-clinical and clinical information 
including safety, PK and efficacy.

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1.2
Rationale for study design, doses and control groups
This study is designed to further evaluate the safety and overall survival (OS) of durvalumab + 
tremelimumab combination therapy or durvalumab monotherapy using fixed dosing in 
advanced solid tumor patients. 
This study is designed to complement and expand the safety databases from the ongoing 
Phase III pivotal combination trials – D419AC00001 (MYSTIC), D419AC00003 
(NEPTUNE), D419LC00001 (KESTREL), D4193C00002 (EAGLE) and D419BC00001 
(DANUBE), and potentially the durvalumab monotherapy studies – D4191C00001 (PACIFIC) 
and Study D4190C00001 (Study 1108).  As most of these studies were initiated using weight-
based dosing (mg/kg), expanding data on the safety profile of the fixed-dose combination is 
warranted, particularly with rare events.  
The study will assess short and long-term safety including evaluation of nature of toxicities 
(adverse events [AEs], serious adverse events [SAEs], immune-mediated adverse events 
[imAEs]), interventions / treatment, and outcomes of treatment of these.
The study will also yield in depth understanding of rare events, or new imAEs that may occur 
through long-term administration of study drug.
1.2.1
Dose and treatment regimen justification
In the original studies with durvalumab, the schedule of 10 mg/kg Q2W has been tested. This 
was then amended to 20 mg/kg Q4W, which represents the same dose with a different 
schedule. As for tremelimumab, doses tested included 1 mg/kg Q4W, 3 mg/kg Q4W and 
10 mg/kg Q4W. The selection of a combination dose and schedule for the combination of
durvalumab and tremelimumab for taking forward into the wider program consisted of 
optimizing durvalumab at a dose that would allow for maximum target suppression, optimize 
synergy, and balance safety following combination with tremelimumab. 
Based on PK/pharmacodynamic (monotherapy and combination) and preliminary efficacy 
data from the combination in Study D4190C000061, durvalumab doses of 3 and 10 mg/kg 
Q4W combination cohorts were excluded from further development.  The 10 mg/kg Q2W and 
20 mg/kg Q4W regimens are expected to have similar AUC at steady state based on PK 
simulations. Cohorts were therefore narrowed to 15 mg/kg Q4W and 20 mg/kg Q4W of 
durvalumab. Monotonic increases in pharmacodynamic activity with the combination 
(increased activation/proliferation markers on CD4 and CD8 T-cells in periphery) were 
observed with increasing doses of tremelimumab (1, 3, 10 mg/kg) in comparison to 
durvalumab monotherapy. Safety data from the 15 and 20 mg/kg durvalumab Q4W cohorts 
demonstrated numerical increases in the frequency of treatment-related AEs and AEs leading 
to discontinuation of investigational product with increasing doses (>1 mg/kg) of 
tremelimumab. In addition, clinical activity of the durvalumab and tremelimumab 
combination did not appear to provide qualitative changes of deeper or more rapid responses 
with increasing doses of tremelimumab. As a result, the selected dose and schedule of the 
combination based on data from Study D4190C00006 was 20 mg/kg durvalumab and 1 mg/kg 
tremelimumab Q4W for 4 doses, followed by 20 mg/kg durvalumab monotherapy Q4W.

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1.2.2
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from a Phase 
I 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 the 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-patient variability with fixed 
dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) 
(Wang et al 2014). Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤0.5). The WT-based (1 mg/kg Q4W) and fixed dosing 
(75 mg/kg Q4W; based on median body WT of ~75 kg) regimens were compared using 
predicted PK concentrations (5th, median and 95th percentiles) using population PK model in a 
simulated population of 1000 patients with body weight distribution of 40 to 120 kg. Similar 
to durvalumab, simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less 
betweenpatient 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 mAbs and found that fixed 
and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in pharmacokinetic/pharmacodynamics parameters (Zhang et al 
2012). 
A fixed dosing approach is preferred by the prescribing community because of the 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) 
and a fixed dose of 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in 
the current study.
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
durvalumab monotherapy, tremelimumab monotherapy, and durvalumab + tremelimumab 
combination therapy, respectively, prior to the overall benefit/risk assessment.

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1.3.1
Potential benefits
There remains a significant unmet medical need for additional treatment options for advanced 
solid tumors, including bladder, lung, and head and neck. 
Treatment with agents targeting PD-1/PD-L1 (such as durvalumab) or CTLA-4 (such as 
tremelimumab) has shown activity in several tumor types in a subset of patients deriving 
meaningful and durable benefit.  Efficacy data for patients treated with durvalumab 
monotherapy in the bladder cancer, lung cancer, and head and neck squamous cell carcinoma 
(HNSCC) cohorts have shown some clinical activity.  Preliminary data generated from 
patients with NSCLC treated with durvalumab + tremelimumab combination therapy have 
shown early signs of clinical activity, and data from competitors indicate that the combination 
may act synergistically (Wolchok et al 2013).  Thus, these agents may potentially offer benefit 
to this patient population.  The study design aims to minimize potential risks and intensive 
monitoring, including early safety assessment, is in place for those risks deemed to be most 
likely based on prior experience with the investigational products (IPs; including durvalumab 
and tremelimumab).
See tumor specific modules (APPENDIX F) for description of potential benefits.
1.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the 
potential for adverse effects on other tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immunemediated effects, can occur in 
nearly any organ system, and are most commonly seen as gastrointestinal (GI) AEs such as 
colitis and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis 
and liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies 
including hypo- and hyper-thyroidism.
1.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper-
and hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), hepatitis/increases in 
transaminases, nephritis/increases in creatinine, rash/dermatitis, myocarditis, 
myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, pancreatitis, 
serious infections, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (eg, Guillain Barré syndrome, myasthenia gravis).

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For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of ≥20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab 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 (Section 6.9.1).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
1.3.2.2
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to GI effects (colitis, 
diarrhea, enterocolitis and intestinal perforation), endocrine disorders (hypo- and 
hyper-thyroidism, hypophysitis and adrenal insufficiency), skin effects (rash and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, hepatic events 
(including immune-mediated hepatitis and liver enzyme elevations); pneumonitis and ILD;
neurotoxicity (including encephalitis, peripheral motor and sensory neuropathies,
Guillain-Barré syndrome); thrombocytopenia, anemia and neutropenia; infusion-related 
reactions and hypersensitivity/anaphylactic reactions; renal events (including 
nephritis/autoimmune nephritis and acute kidney injury, autoimmune arthritis, Sjogren's 
syndrome, giant cell temporal arteritis and ulcerative colitis); hyperglycemia and diabetes 
mellitus. 
For information on all identified and potential risks with tremelimumab, please always refer to 
the current version of the tremelimumab IB.
In monotherapy clinical studies, AEs reported at an incidence of ≥20% include events such as 
diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting and dyspnea.
Approximately 16% of patients experienced an AE that resulted in permanent discontinuation 
of tremelimumab and approximately 45% of patients experienced an SAE. Please see the 
current version of the IB for a detailed summary of monotherapy data, including AEs, SAEs, 
and CTC Grade 3 to 5 events reported across the tremelimumab program.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB.
1.3.2.3
Durvalumab + Tremelimumab
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study D4190C00006, in patients with NSCLC, 

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and is being studied in a number of other ongoing clinical trials in a number of different 
indications, and has to date shown a manageable safety and tolerability profile.
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20 mg/kg and a tremelimumab dose of 1 mg/kg) are similar to 
those for durvalumab and tremelimumab monotherapy. Emerging data from Study 
D4190C00006, other studies evaluating the combination, and from combinations of other 
agents in the same class indicate an increased frequency and/or severity of some of these 
immune-mediated toxicities.
For information on all identified and potential risks with the durvalumab + tremelimumab 
combination please always refer to the current version of the durvalumab IB. 
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20 mg/kg and
tremelimumab 1 mg/kg, AEs reported at an incidence of ≥20% included events such as 
fatigue, diarrhea, nausea, decreased appetite, pruritus, dyspnea, constipation and anemia.
Please see the current version of the durvalumab IB for a detailed summary of combination 
therapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program, including durvalumab in combination with tremelimumab.
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation
of study drug and approximately 16% of patients experienced an SAE that was considered to 
be related to durvalumab and tremelimumab by the study Investigator.
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB.
1.3.3
Overall benefit risk
The toxicity profile of the combination of durvalumab and tremelimumab included fatigue, 
colitis, diarrhea, aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
increases, amylase and lipase increases, rash and pruritus, and other immune-mediated 
reactions, which were mostly reversible and manageable by the available protocol treatment 
guidelines.  Increased toxicities have been seen when these agents are used in combination. 
In particular, based on the specific MOA of durvalumab and tremelimumab leading to T-cell 
activation and proliferation, there is the possibility of observing imAEs during the conduct of 
this study.  Potential imAEs may be similar to those seen with the use of ipilimumab, BMS-
936558, and BMS-936559 and may include immune-mediated enterocolitis, dermatitis, 
hepatitis, and endocrinopathies (Brahmer et al 2012, Hodi et al 2010, Topalian et al 2012).  
Patients should be monitored for signs and symptoms of imAEs.  In the absence of an 
alternate etiology (eg, infection or PD), an immune-related etiology should be considered for 
signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy.  It is 
recommended that management of imAEs follow the Dosing Modification and Toxicity 
Management Guidelines outlined in Section 6.9.1.

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Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy 
due to malignant disease, the activity seen with durvalumab in this tumor type, and the 
strength of the scientific hypotheses under evaluation, the durvalumab monotherapy and 
durvalumab + tremelimumab combination therapy proposed in this study may have the 
potential to provide meaningful clinical benefit with a manageable safety and tolerability 
profile by generating durable clinical responses, thereby improving quality of life and 
potentially extending survival.  Furthermore, pre-clinical and clinical evidence indicate that 
the combination of PD 1/PD-L1 and CTLA-4 targeting agents may provide antitumor activity, 
with additional synergy from the combination (Wolchok et al 2013).  Therefore, the 
investigation of the potential therapeutic efficacy of durvalumab monotherapy and 
durvalumab + tremelimumab combination therapy in patients with PD-L1-High and PD-L1 
Low/Neg tumors is acceptable, and the overall benefit/risk assessment supports the proposed 
study design.  
1.4
Study Design
This is an open-label, multi-center, study to determine safety of fixed doses of durvalumab 
1500 mg and tremelimumab 75 mg combination therapy or durvalumab 1500 mg 
monotherapy in patients with advanced solid malignancies. 
The protocol (and each tumor specific module in APPENDIX F) consists of a screening 
period, a treatment period, a safety follow up period (90 days post treatment discontinuation), 
and a survival follow up period. 
Patients will attend a safety follow up visit 90 days after study treatment discontinuation. 
Thereafter, patients will be contacted by phone or electronic communication every 3 months 
for survival status until the final data cut-off (DCO).
Investigational product, dosage and mode of administration
Durvalumab + tremelimumab combination therapy 

Durvalumab 1,500 mg plus tremelimumab 75 mg via IV infusion once 
every 4 weeks (Q4W), starting on Week 0, for up to a maximum of 
4 doses (or cycles) followed by:

Durvalumab monotherapy 1,500 mg via IV infusion Q4W, starting 
4 weeks after the last infusion of the combination or discontinuation of 
tremelimumab. 
OR
Durvalumab monotherapy

Durvalumab 1,500 mg via IV infusion Q4W, starting on Week 0. 

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Each tumor specific module (APPENDIX F) will specify combination therapy or 
monotherapy, and will provide details of infusion duration. 
Duration of treatment
Patients may continue receiving therapy as long as they are continuing to demonstrate clinical 
benefit, as judged by the Investigator, and in the absence of initiation of alternative cancer 
treatment, unacceptable toxicity, withdrawal of consent, or other reason for treatment 
discontinuation. 
Unless specific treatment discontinuation criteria are met patients will continue therapy until 
disease progression. 
Progression during treatment
During the treatment period, patients may continue receiving therapy in the setting of 
unconfirmed progressive disease (PD) according to Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until progression is 
confirmed*. A confirmatory scan is required following a RECIST 1.1 overall time point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 
4 weeks after the previous assessment of PD.  
Patients with PD by RECIST 1.1 (unconfirmed and confirmed) who, in the Investigator’s
opinion, continue to receive benefit from their treatment and who meet the criteria for 
treatment in the setting of PD may continue to receive treatment for as long as they are 
gaining clinical benefit.  
However, patients will not be permitted to continue immunotherapy if progression occurs after 
confirmed response (complete response [CR] or partial response [PR] as defined by RECIST 
1.1) to immunotherapy treatment in target lesions (regardless of the appearance of new 
lesions), ie, the response and progression events both occurred in the target lesions while 
receiving immunotherapy during the same treatment period. 
Patients in Modules with combination durvalumab + tremelimumab may restart treatment with 
the combination if they complete the 4 dosing cycles with durvalumab + tremelimumab (with 
clinical benefit per Investigator judgement) but subsequently have PD during treatment with 
durvalumab alone and provided they meet eligibility criteria for retreatment.
See Section 7.8 for post-study access to treatment information.
                                               
* Where treatment is discontinued due to progressive disease, it is recommended that a confirmatory scan be 
performed prior to discontinuation to verify progression. According to RECIST 1.1 modified for confirmation of 
progression, a confirmatory scan is required following an overall time point assessment of progression (PD), no
earlier than 4 weeks after the previous assessment of PD.

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Follow up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, or withdrawal from treatment, or patients who have started a subsequent 
anticancer therapy, will have one additional tumor assessment on a subsequent scan, if 
clinically feasible, will be followed up for AEs for 90 days, and thereafter followed up for 
survival (described in the next section). These patients are not eligible for re-treatment at any 
time.
Follow Up for Safety and Survival
Patients will attend a safety follow up visit 90 days after study treatment discontinuation. 
Thereafter, patients will be contacted by phone or email every 3 months for survival status 
until the final DCO.
Figure 1
Study flow chart
Tumor specific modules (APPENDIX F) detail which treatment regimen, combination therapy or monotherapy, 
will be used. 
Patients will continue to receive study treatment as long as they are receiving clinical benefit in the opinion of the 
Investigator unless any of the criteria for treatment discontinuation are met first.
Survival follow up will continue until the final DCO.

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2.
STUDY OBJECTIVES
2.1
Primary objective
1.
To assess the incidence, severity, nature, seriousness, intervention/treatment, 
outcome, and causality, including immune-relatedness, of adverse events of special 
interest (AESIs) in patients who are treated with durvalumab and tremelimumab 
combination therapy or durvalumab monotherapy, using fixed dosing. 
An AESI is one of scientific and medical interest specific to understanding of the 
Investigational Product. AESIs for durvalumab and tremelimumab include but are not limited 
to events with a potential inflammatory or immune-mediated mechanism and which may 
require more frequent monitoring and/or interventions such as steroids, immunosuppressants 
and/or hormone replacement therapy. An imAE is defined as an AESI that is associated with 
drug exposure and is consistent with an immune-mediated MOA and where there is no clear 
alternate etiology.
AESIs observed with durvalumab or tremelimumab include pneumonitis, hepatitis,
diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism and type I diabetes mellitus), nephritis,
rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis, and rare/less frequent imAEs
including neuromuscular toxicities such myasthenia gravis and Guillain-Barré syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, hematological and rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs. In addition, infusion-related 
reactions and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological etiology are also considered AESIs.
The specific safety objective will be defined in each tumor specific module (APPENDIX F).
2.2
Secondary objectives
The common secondary objectives of all tumor sub-studies are:
1.
To assess the incidence, severity, nature, seriousness, intervention/treatment, 
outcome, and causality of treatment-emergent AEs (including SAEs).
2.
To assess the incidence and frequency of durvalumab ± tremelimumab interruption 
and discontinuation due to treatment-emergent AEs (including SAEs).
3.
To assess OS.

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Additional secondary objectives and exploratory objectives may be added to individual 
modules in each country / region.  Additional sub-studies / exploratory studies may be added 
to the protocol, in modular fashion.
2.3
Exploratory objective
1.
To assess overall response rate (ORR) and disease control rate (DCR) based on 
Investigator assessed response to treatment (RECIST 1.1). 
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. Common criteria are 
included here. For ease of reference, these common criteria have also been incorporated in 
each of the sub-studies.
Tumor specific additional inclusion and exclusion criteria are included within each module
(APPENDIX F). 
3.1
Inclusion criteria
For inclusion in the study patients should fulfill the following criteria:
1.
Must have a life expectancy of at least 12 weeks.
2.
Age ≥18 years at the time of screening. For patients aged <20 years and enrolled in 
Japan, a written informed consent should be obtained from the patient and his or her
legally acceptable representative
3.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization (eg, 
Health Insurance Portability and Accountability Act in the US, European Union 
[EU] Data Privacy Directive in the EU) obtained from the patient/legal 
representative prior to performing any protocol-related procedures, including
screening evaluations. For patients aged <20 years and enrolling in Japan, a written
informed consent should be obtained from the patient and his or her legally 
acceptable representative.
4.
Disease not amenable to curative surgery 
5.
Eastern Cooperative Oncology Group (ECOG) performance status as defined in the 
specific module.
6.
Body weight >30 kg.

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7.
No prior exposure to anti-PD-1 or anti-PD-L1, including on another AstraZeneca 
study.  Exposure to other investigational agents may be permitted after discussion
with the Sponsor.
8.
Adequate organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.0 × 109 /L

Platelet count ≥75 × 109/L

Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert's syndrome, who will be allowed in 
consultation with their physician.

ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST 
≤5 × ULN

Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine 
clearance (CL) >40 mL/min as determined by Cockcroft-Gault (using actual 
body weight)
Males:
Creatinine CL =
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL =
Weight (kg) × (140 - Age) x 0.85
(mL/min)
72 × serum creatinine (mg/dL)
9.
Female patients of childbearing potential (ie, not surgically sterile or 
post-menopausal) who are sexually active with a non-sterilized male partner must 
use at least one highly effective method of contraception from the time of screening 
and must agree to continue using such precautions for 180 days after the last dose
of durvalumab + tremelimumab combination therapy or 90 days after the last dose 
of durvalumab monotherapy (see Section 3.8 and specifically Table 1).
10.
Evidence of post-menopausal status or negative urinary or serum pregnancy test 
(per Section 4) for female pre-menopausal patients.  Women will be considered 
post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause.  The following age-specific requirements apply: 

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
Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses 
>1 year ago, had chemotherapy-induced menopause with last menses >1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
11.
Non-sterilized male patients who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from screening 
through 180 days after receipt of the final dose of durvalumab + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab 
monotherapy (see Section 3.8).
3.2
Exclusion criteria (applicable to all modules)
Please also refer to each specific Module for specific criteria applicable to each module of the 
study. The exclusion criteria, common to all modules in the study are described in this 
section.
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and/or staff at the study site).
2.
Previous IP assignment in the present study.
3.
Concurrent enrollment in another clinical study, or another sub-study of this 
protocol, unless it is an observational (non-interventional) clinical study or during 
the follow up period of an interventional study.
4.
Participation in another clinical study with an investigational product during the last 
28 days or 5 half-lives, whichever is longer, prior to the first dose of study 
treatment.
5.
Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy 
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related 
conditions (eg, hormone replacement therapy) is acceptable.  
6.
Local treatment of isolated lesions for palliative intent is acceptable (eg, local 
surgery or radiotherapy).  

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7.
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, 
whichever is longer, prior to the first dose of study treatment.  
8.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 4 weeks of the first dose of study drug.  Note: Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is acceptable.
9.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
10.
History of allogenic organ transplantation.
11.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated 
with diarrhea, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs or compromise
the ability of the patient to give written informed consent
12.
History of another primary malignancy except for

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of investigational product (durvalumab + 
tremelimumab) and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease
13.
History of leptomeningeal carcinomatosis
14.
Has untreated central nervous system (CNS) metastases and/or carcinomatous 
meningitis identified either on baseline brain imaging (please refer to RECIST for 
details on the imaging modality) obtained during the screening period or identified 
prior to signing the ICF. Patients whose brain metastases have been treated may 
participate provided they show radiographic stability (defined as 2 brain images, 
both of which are obtained after treatment to the brain metastases. These imaging 
scans should both be obtained at least 4 weeks apart and show no evidence of 
intracranial progression). In addition, any neurologic symptoms that developed 
either as a result of the brain metastases or their treatment must have resolved or be 
stable either, without the use of steroids, or are stable on a steroid dose of 
≤10 mg/day of prednisone or its equivalent and anti-convulsants for at least 14 days 
prior to the start of treatment. Brain metastases will not be recorded as RECIST 
Target Lesions at baseline.

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15.
History of active primary immunodeficiency.
16.
Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in 
line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus 
(positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA.
17.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab or tremelimumab.  The following are exceptions to this 
criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra 
articular injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent
18.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc.]).  The following are exceptions to 
this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician

Patients with celiac disease controlled by diet alone
19.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.  Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 
30 days after the last dose of IP.
20.
Known allergy or hypersensitivity to study drug(s) or compounds of similar 
biologic composition to the study drug(s), or any of the study drug excipients.

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21.
Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti-cancer therapy 
with the exception of vitiligo, alopecia, and the laboratory values defined in the 
inclusion criteria. 

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Study Physician. 

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or tremelimumab may be included only after 
consultation with the Study Physician
22.
For women only, currently pregnant (confirmed with positive pregnancy test) or 
breast feeding.  
23.
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 180 days after the last dose of durvalumab + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy.
24.
Prior randomization or treatment in a previous durvalumab and/or tremelimumab 
clinical study regardless of treatment arm assignment. 
Procedures for withdrawal of incorrectly enrolled patients are described in Section 3.4.
3.3
Patient enrollment and randomization
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed that are not part of routine medical care.
2.
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS).  This number 
is the patient’s unique identifier and will be maintained throughout the study.
3.
Determine patient eligibility. See Section 3.
4.
Obtain signed informed consent for genetic research study (optional and where 
applicable)
Patients will begin treatment on Day 1. Treatment should start no more than 3 working days 
after registration.
If a patient does not meet eligibility criteria or withdraws from participation in the study after 
enrollment, then his/her enrollment number cannot be reused.

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Investigator(s) should keep a record / screening log of patients who entered pre-study 
screening.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria (screening failures) must not, under any 
circumstances, be enrolled or receive study treatment. There can be no exceptions to this rule. 
Patients who are enrolled (by error), but subsequently found not to meet all the eligibility 
criteria must not be initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is incorrectly started on treatment, 
the Investigator should inform the AstraZeneca study physician or designee immediately, and 
a discussion should occur between the AstraZeneca study physician (or designee) and the 
Investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca study physician or designee must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups (not applicable)
All Modules under this protocol consist of a single treatment regimen. All enrolled patients in 
a given Module will receive the same treatment.
3.6
Methods for ensuring blinding (not applicable)
The study is not blinded. All modules under this protocol consist of single treatment regimen. 
All enrolled patients in a given module will receive the same treatment.
3.7
Methods for unblinding (not applicable)
The study is not blinded. All modules under this protocol consist of single treatment regimen. 
All enrolled patients in a given module will receive the same treatment.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Female patient of childbearing potential

Female patients of childbearing potential who are not abstinent and intend to be
sexually active with a non-sterilized male partner must use at least 1 highly
effective method of contraception (Table 1) from the time of screening
throughout the total duration of the drug treatment and the drug washout period 
(180 days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after the last dose of durvalumab monotherapy). Non-
sterilized male partners of a female patient of childbearing potential must use 
male condom plus spermicide throughout this period. Cessation of birth 
control after this point should be discussed with a responsible physician.  

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Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control.  Female patients should also refrain from 
breastfeeding throughout this period.
2.
Male patients with a female partner of childbearing potential

Non-sterilized male patients who are not abstinent and intend to be sexually 
active with a female partner of childbearing potential must use a male condom 
plus spermicide from the time of screening throughout the total duration of the 
drug treatment and the drug washout period (180 days after the last dose of 
durvalumab + tremelimumab combination therapy or 90 days after the last dose 
of durvalumab monotherapy). However, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of 
contraception.  Male patients should refrain from sperm donation throughout 
this period.

Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table 1).
Note: Females of childbearing potential are defined as those who are not surgically sterile (ie,
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution.

Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with 
last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago.
Highly effective methods of contraception, defined as one that results in a low failure rate (ie,
less than 1% per year) when used consistently and correctly are described in Table 1.  Note 
that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).

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Table 1
Highly Effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal Methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)a

Implants: Etonogestrel-releasing 
implants: eg, Implanon® or Norplan® 

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: eg, NuvaRing®  

Injection: Medroxyprogesterone 
injection: eg, Depo-Provera®  

Combined Pill: Normal and low dose 
combined oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system: eg, Ortho 
Evra®   

Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill
a
This is also considered a hormonal method
3.
All patients: Patients should not donate blood or blood components while 
participating in this study and through 180 days after receipt of the final dose of 
durvalumab + tremelimumab combination therapy or 90 days after receipt of the 
final dose of durvalumab or until alternate anticancer therapy is started.  
4.
Restrictions relating to concomitant medications are described in Section 7.7.
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP treatment (durvalumab + tremelimumab 
combination therapy, durvalumab monotherapy) if any of the following occur in the patient in 
question:
1.
Withdrawal of consent from further treatment with IP. The patient is, at any time, 
free to discontinue treatment, without prejudice to further treatment.  A patient who 
discontinues treatment is normally expected to continue to participate in the study 
unless they specifically withdraw their consent to further participation in any study 
procedures and assessments (see Section 3.10.2)
2.
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates 
further dosing
3.
Any AE that meets criteria for discontinuation as defined in the Dose Modification 
and Toxicity Management Guidelines (see Section 6.9.1)

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4.
Pregnancy or intent to become pregnant
5.
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits)
6.
Initiation of alternative anticancer therapy including another investigational agent
7.
Clinical progression, ie, Investigator determination that the patient is no longer 
benefiting from treatment with IP, with or without radiological progression by 
RECIST 1.1
8.
Transition to commercial drug supply. Note: If allowed by local regulations, the 
study Sponsor may transition patients from study treatment to commercial drug 
supply when the IP becomes commercially available in the country where the 
patient is living. See Section 7.8 for post-study access to treatment information. 
Unless they withdraw consent for further follow up, patients who discontinue study therapy 
will continue on study for acquisition of safety information through 90 days after the last dose 
of study treatment, and for further collection of information regarding survival until the final
DCO. 
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP without prejudice to further treatment.  A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE.  If possible, they will be seen and assessed by an 
Investigator.  AEs will be followed up (see Section 6).  The Study Physician should be 
notified of any ongoing AE that may delay treatment or necessitate permanent discontinuation 
of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment.  Patients who are 
permanently discontinued will enter follow up (see Table 2).  
All patients will be followed for survival until the final DCO.  
Where treatment is discontinued due to PD, it is recommended that a confirmatory scan be 
performed prior to discontinuation to verify progression.  According to RECIST 1.1 modified 
for confirmation of progression, a confirmatory scan is required following an overall time 
point assessment of PD, no earlier than 4 weeks after the previous assessment of PD.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in Table 2 as an alternative.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.

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If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be enrolled. If patients who do not meet eligibility criteria are enrolled in error, these 
patients should have the reason for study withdrawal recorded as ‘Incorrect Enrollment’ (ie,
patient does not meet the required inclusion/exclusion criteria). Patients may be rescreened.
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. It should be confirmed and documented in source notes if the 
patient is withdrawing consent to the study treatment or to all study procedures, including 
survival follow up. Efforts should be made to follow patients until the end of study, but 
particularly to conduct the 90-day safety follow up.
Patients who withdraw consent for further participation in the study will not receive any 
further durvalumab + tremelimumab or further study observation, with the exception of 
follow up for survival, which will continue until the final DCO unless the patient has 
expressly withdrawn their consent to survival follow up.  Note that the patient may be offered 
additional tests or tapering of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study.  If 
possible, they will be seen and assessed by an Investigator(s). AEs will be followed up (See 
Section 6). The Study Physician should be notified of any ongoing AE that may delay 
treatment or necessitate permanent discontinuation of treatment.
Providing consent allows, survival status will be followed up by phone or electronic 
communication every 3 months up until the final DCO (see Section 4.3).
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to:

All further participation in the study including any further follow up (eg,
survival contact telephone calls)

Withdrawal to the use of any samples (see Section 5.7.4)
3.10.2.1
Survival status for withdrawn consent and lost to follow up patients
Patients will be considered lost to follow up only if no contact has been established by the 
time the study is completed (see Section 9.3), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in the
study, including telephone contact, should be documented as “withdrawal of consent” rather 

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than “lost to follow up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow up and evaluations should 
resume according to the protocol.
In order to support key end point of OS analysis, all enrolled patients’ survival status should 
be re-checked, this includes those patients who withdrew consent or are classified as “lost to 
follow up”.
1.
Lost to Follow up – site personnel should check hospital records, the patients’ 
current physician, and a publicly available death registry (if available) to obtain a
current survival status.  
2.
In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available death registries (if available) where it is possible 
to do so under applicable local laws to obtain a current survival status.  
3.11
Discontinuation of the study
Sections 3.9 and 3.10 address individual patient discontinuation from treatment and from 
study. 
The overall study will close to new enrollment once all modules in all countries have 
completed accrual.
Accrual to any given module in any country will close once accrual targets for that module 
and country have been met.
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that meet any of the following criteria:

meet individual stopping criteria or are otherwise considered significant

are assessed as causally related to study treatment

are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow up must be recorded in the case report form (CRF). All reasons for 
discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients' interests.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 

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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of patients by the Investigator

Discontinuation of further study drug development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow up.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Procedures outlined in the table should be performed as indicated.  However not all data will 
be collected on the CRF.  Details regarding reporting of AEs, concomitant medications, and 
test results in the CRFs are provided in Sections 5 and 6.
Additional efficacy and safety procedures may be added to the tumor specific modules as 
deemed necessary for the tumor cohort or for the country.
For durvalumab monotherapy or durvalumab + tremelimumab combination arms
Patients may delay dosing under certain circumstances.

Dosing may be delayed per Toxicity Management Guidelines, due to 
either an immune or a non-immune-mediated AE (see Section 6.9.1).

If dosing must be delayed for reasons other than treatment-related 
toxicity, dosing will resume as soon as feasible

Dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with efficacy or other 
assessments (as applicable by tumor Module).  Subsequent time between 
2 consecutive doses cannot be less than 22 days, based on the half-lives 

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of durvalumab and tremelimumab (see current IBs for durvalumab and 
tremelimumab.  
Additional procedures not forming part of the primary or secondary objectives may be added 
as sub-study modules to the protocol.

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Table 2
Study Plan detailing the procedures 
Visit
Screening
Treatment period
Safety follow 
up visit
Survival 
follow up
phone 
calls/emails
For details 
see Protocol 
Section
Baseline
(Day 1)
Treatment visits
Visit window
Day -28 to 
Day-1
0
±3 days
±5 days
±5 days
±14 days
Week
Weeks -4 to 
Week -1
Week 0
Weeks 4, 8, 
12
Q4W from 
Week 16
90 days
after last 
dose
Every 
3 months
Section
Written informed 
consent
X
4.1
Inclusion/ exclusion 
criteria (main criteria 
and tumor specific 
criteria for each 
Module)
X
X
3.1 & 3.2;
also refer to 
each Module
Demographics and 
tobacco and alcohol 
use
X
5.2.1
Medical history
X
5.2.2
Disease characteristics
X
5.2.3
Cancer treatment 
history
X
5.2.4
ECG recording a
X
As clinically indicated
5.3.3
ECOG performance 
status
X
X
X
X
5.2.3; also 
refer to each 
Module

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Visit
Screening
Treatment period
Safety follow 
up visit
Survival 
follow up
phone 
calls/emails
For details 
see Protocol 
Section
Baseline
(Day 1)
Treatment visits
Visit window
Day -28 to 
Day-1
0
±3 days
±5 days
±5 days
±14 days
Week
Weeks -4 to 
Week -1
Week 0
Weeks 4, 8, 
12
Q4W from 
Week 16
90 days
after last 
dose
Every 
3 months
Section
Physical examination, 
body weight, height 
and vital signs b
X
X
X
X
5.2.2 and 
5.3.4
Laboratory Assessments c
Clinical chemistry d
X
X e
X
X
Per 
institutional 
care
5.3.1
Hematology d
X
X e
X
X
5.3.1
Coagulation
X
As clinically indicated
5.3.1.2
Hepatitis B, C, HIV 
virology
X
Per 
institutional 
care
5.3.1.3
Pregnancy test f
X(serum)
X f
X
X
5.3.1
TSH g, free T3, Free 
T4 h
X
X e
X
X
5.3.1.1
Urinalysis i
X
X e
X
X
5.3.1
Optional Blood 
sample (translational
science/ genomics)
At Screening visit or during first treatment visit (prior to dosing)
5.7
PD-L1 results
X (if 
available)
4.1, 5.7

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Visit
Screening
Treatment period
Safety follow 
up visit
Survival 
follow up
phone 
calls/emails
For details 
see Protocol 
Section
Baseline
(Day 1)
Treatment visits
Visit window
Day -28 to 
Day-1
0
±3 days
±5 days
±5 days
±14 days
Week
Weeks -4 to 
Week -1
Week 0
Weeks 4, 8, 
12
Q4W from 
Week 16
90 days
after last 
dose
Every 
3 months
Section
Archival tumor tissue 
sample provision j
X
5.7
Concomitant 
medications k
X
X
X
X
X
5.2.4
AEs / SAEs l
X
X
X
X
X
6.3
Combination Therapy Modules
Durvalumab m, n
X
X
X
7.2
Tremelimumab m, n
X
X
7.2
Monotherapy Modules
Durvalumab m, n
X
X
X
7.2
Investigator Reported 
Tumor / Response 
Assessment
Per Institution Standard
X
RECIST 1.1
Survival status
X
X
5.1
Reason for withdrawal
If applicable
If applicable
3.10
Note: All assessments listed in the table are to be performed prior to dosing during the treatment period. Inclusion/exclusion criteria are to be verified before 
the first dose of study drug.

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(a)
Any clinically significant abnormalities detected require triplicate ECG results.
(b)
Vital signs are to be measured and recorded at all visits from screening to last treatment visit.  Complete physical examination including body 
weight is recorded at screening and baseline, and height at screening. Targeted physical examination (including body weight) only after baseline 
full assessment. Physical examination information will only be reported in the CRF if abnormalities are reported as AEs.
(c)
Blood and urine samples are to be collected within 72 hours prior to dosing to ensure that the results are available for review on the day of the 
visit. On the day of the visit, the results must be reviewed prior to IP administration. 
(d)
Serum or plasma clinical chemistry (including liver function test [LFT) monitoring) and hematology may be performed more frequently if 
clinically indicated.
(e)
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be 
repeated at Day 1.
(f)
For women of childbearing potential, a serum pregnancy test is to be performed at screening. Urine pregnancy test (dip-stick or at the local 
laboratory) or serum pregnancy test at baseline visit and every treatment visit. Pregnancy test may occur on Day 1, but results must be available 
and reviewed by the treating physician or Investigator prior to commencing an infusion.
(g)
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
(h)
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
(i)
Urinalysis: Tests for urine bilirubin and urobilinogen will be done (per institutional standard method) at baseline only, and repeated only as 
clinically indicated.
(j)
Archival tumor tissue for PD-L1 central testing and for banking and retrospective exploratory testing: This procedure is optional for the patient 
and requires consent.  An archival, formalin-fixed, paraffin-embedded tumor block should be sent to the central laboratory.  If an archival tumor 
block cannot be shipped to the central laboratory, then unstained slides with newly cut sections should be provided as described in the Laboratory 
Manual.  If an archival sample is not available and if the patient provides consent, a sample should be collected via an image-guided core needle 
biopsy (at least 18 gauge or larger core diameter) or an excisional tumor biopsy. This procedure should be followed only if a biopsy is 
technically feasible and not associated with unacceptable clinical risk. 

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(k)
Screening and baseline medications and use of corticosteroid or other immunosuppressive drugs and any other drugs/interventions to manage 
AESIs and AEs/SAEs (including dose, route, duration).
(l)
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
(m)
During the combination portion of treatment, tremelimumab will be administered first; the durvalumab infusion will start approximately 1 hour 
(maximum 2 hours) after the end of the tremelimumab infusion.  If there are no clinically significant infusion reactions with the first cycle, and at 
the discretion of the Investigator, then for all other cycles, the durvalumab can be given immediately after the tremelimumab infusion has 
finished.
(n)
Results for LFTs, electrolyte, full blood count, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by 
the treating physician or Investigator prior to dosing.

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4.1
Screening/Enrollment period
Procedures will be performed according to the Study Plan.
All screening procedures must be performed within 28 days before dosing (Day -28 to 
Day -1). The screening evaluations may be carried out over more than one day. Written 
informed consent and any locally required privacy act document authorization must be 
obtained prior to performing any protocol-specific procedures, including screening 
evaluations. However, if evaluations that have been performed within 28 days prior to the 
date of dosing for other purposes prior to informed consent are otherwise suitable for use as 
screening evaluations, those evaluations need not be repeated if the patient consents to allow 
use.
1.
Obtain written informed consents and appropriate privacy act document 
authorization
2.
Assign enrollment number
3.
Perform complete physical examination including body weight and height
4.
Collect vital signs
5.
Collect urine for urinalysis
6.
Collect blood samples for:

Clinical chemistry

Hematology

Coagulation tests

Hepatitis B and C, HIV virology

Serum pregnancy test

Thyroid stimulating hormone (TSH) and if TSH is abnormal or there is 
clinical suspicion of an AE related to the endocrine system, free T3 and
free T4
7.
Collect demographic characteristics, tobacco and alcohol use, medical history and 
disease characteristics, prior and concomitant medication, and cancer treatment 
history
8.
Assess AEs
9.
Assess ECOG performance status

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10.
Perform electrocardiogram (ECG)
11.
Collect PD-L1 status, expression, and details of sample and testing, if available
12.
Provision of archival tumor tissue sample for PD-L1 testing and for banking and 
retrospective testing.  This procedure is optional for the patient and requires 
consent.  An archival, formalin-fixed, paraffin-embedded tumor block should be 
sent to the central laboratory.  

If a tumor block cannot be shipped to the central laboratory, and if there 
is sufficient sample to allow PD-L1 testing, then unstained slides with 
newly cut tumor sections should be provided as described in the 
Laboratory Manual.  

If an archival sample is not available and if the patient consents, then a 
sample should be collected either by an image-guided core needle biopsy 
(at least 18-gauge or larger core diameter needle) or by an excisional 
tumor biopsy. This procedure is optional for the patient and should be 
done only if the biopsy is technically feasible and is not associated with 
unacceptable clinical risk. 
13.
Collect blood sample for translational science/ genomics (optional)
4.2
Treatment period
Procedures will be performed according to the Study Plan. For Day 1 of treatment, 
pre-dose/dosing/post-dose procedures are shown under the baseline visit (Section 4.2.1).
After Day 1, pre-dose/dosing/post-dose procedures should be performed as shown below in 
Section 4.2.1.
4.2.1
Baseline visit (Day 1)
Pre-Dose
The following assessments are to be completed pre-dose:
1.
Collect blood and urine sample for laboratory evaluation within 72 hours prior to 
dosing (see Table 3 for tests, including pregnancy test, as specified in Section 
5.3.1).  If these samples (with the exception of the urine pregnancy test) were 
collected at the screening visit within 72 hours prior to dosing on Day 1, then these 
samples are not required to be repeated for dosing on Day 1.  Collect blood sample 
for TSH, and free T3 and free T4 (if TSH is abnormal or there is clinical suspicion 
of an AE related to the endocrine system).  Urine pregnancy test can be done using 
dip-stick or at the local laboratory.  Coagulation tests only required if clinically 
indicated.

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2.
Review of results by treating physician or Investigator prior to dosing for at least 
the following tests: Blood urea nitrogen (BUN), serum creatinine, electrolytes, 
hematology, liver function tests, urinalysis (excluding urine microscopy), and 
pregnancy test (for women of childbearing potential). 
3.
Perform complete physical examination including body weight.
4.
Assess AEs and ongoing relevant medical conditions.
5.
Update concomitant medications.
6.
Assess ECOG performance status.
7.
Take vital signs before administration of study treatment.
8.
Assess inclusion/exclusion criteria.
Dosing and post-dose
After the above assessments are completed:
1.
Administer study treatment per Module (durvalumab + tremelimumab combination 
therapy or durvalumab monotherapy).
2.
Take vital signs as per institutional care recommendations for the administration of 
mAbs.
3.
Assess AEs during and subsequent to infusion.
4.2.2
Treatment period
Pre-dose
1.
Collect blood and urine sample for laboratory evaluation within 72 hours prior to 
dosing (see Table 3 for tests, including pregnancy test, if required) as specified in 
Section 5.3.1. Collect blood sample for TSH, and free T3 and free T4 (if TSH is 
abnormal or there is clinical suspicion of an AE related to the endocrine system). 
Urine pregnancy test can be done using dip-stick or at the local laboratory per 
institutional practice.
2.
Review of results by treating physician or Investigator prior to dosing for at least 
the following tests: BUN, serum creatinine, electrolytes, hematology, liver function
tests, urinalysis (excluding urine microscopy), and pregnancy test (for women of 
childbearing potential).
3.
Perform targeted physical examination including body weight.
4.
Assess AEs and ongoing relevant medical conditions.

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5.
Update concomitant medications.
6.
Assess ECOG performance status.
7.
Take vital signs before administration of study treatment (durvalumab +
tremelimumab combination therapy or durvalumab monotherapy as per Module).
8.
Recording of Investigator assessment of treatment response.
Dosing and post-dose
After the above assessments are completed:
1.
Administer study treatment.
2.
Take vital signs as per institutional care recommendations for the administration of 
monoclonal antibodies.
3.
Assess AEs during and subsequent to infusion.
4.3
Follow up period
Procedures will be performed according to the Study Plan.
All patients who discontinue study treatment will attend a safety follow up visit 90 days after 
study treatment discontinuation.
The following procedures will be performed:
1.
Assess AEs.
2.
Update concomitant medications.
3.
Record Investigator assessment of treatment response.
4.
Record subsequent therapy.
5.
Record survival status.
After this safety follow up visit, patients will be contacted by phone or email every 3 months 
to check survival status until death or final DCO, whichever occurs first. 
Patients who do not discontinue treatment before the final DCO will continue to be followed
after the final DCO, as indicated in Section 6.3.12.

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Drug Substance Durvalumab (MEDI4736) and Tremelimumab
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Version 5.0
Date 13 December 2019
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5.
STUDY ASSESSMENTS
The Investigator will ensure that data are recorded on the electronic CRFs (eCRFs) as 
specified in the study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
5.1
Survival assessments
The survival status of the patient will be collected during the study. After their safety follow 
up visit (90 days), patients will continue to be followed for survival via phone calls or email 
every 3 months until the final DCO, with a final check that should generally occur within 
7 days of the final DCO.
The survival status (including cause of death) and the date of death or last follow up date will
be collected.
No further efficacy assessments will be performed during the study. Evaluation of treatment 
benefit will be performed by the Investigator according to standard medical practice before 
each treatment administration.
5.2
Demographics/Medical, medication, surgical history
5.2.1
Demographics
Patient characteristics including age, gender, ethnicity (if available or allowed by local 
regulations), race (if available or allowed by local regulations), and geographic residence will 
be collected. Tobacco and alcohol use will also be collected.
5.2.2
Physical examination, vital signs and medical history
At screening and baseline, a complete physical examination (including body weight and 
height) will be performed and include an assessment of the following: general appearance,
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems.  After baseline, only targeted physical examination (including body 
weight) is necessary. 
Physical examination information will only be reported in the CRF if abnormalities are 
reported as AEs. For information on how AEs based on physical examination should be 
recorded and reported, see Section 6.3.
Findings from medical history and physical examination will be given a baseline grade 
according to the procedure for AEs. Increases in severity of pre-existing conditions during the

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Version 5.0
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study will be considered AEs, with resolution occurring when the grade returns to at or below 
the pre-study baseline.
5.2.3
Disease characteristics and ECOG
Tumor histology (based on medical records), stage at diagnosis, current stage, ECOG
performance status, as well as co-morbidities and relevant medical history, will be collected.
The standard ECOG performance status scale and criteria (Oken et al 1982) will be used (refer 
to APPENDIX E).
5.2.4
Prior and concomitant medication and cancer treatment history
For cohorts that allow prior anticancer therapy (see Modules), therapy type (targeted or non-
targeted) and agents received, start and end-dates, radiation therapy, and surgery received 
prior to study enrollment must be documented.  Additionally, any medication that the patient 
has ingested 30 days prior to study entry, including dose, frequency and the medical condition 
for which it was prescribed, must be documented.
5.3
Safety assessments
5.3.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, coagulation
(only if clinically indicated), and urinalysis will be taken at the times indicated in the 
assessment schedules and as clinically indicated (see Sections 4.1 through 4.3 and Table 2).  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values and units) will be recorded on 
the appropriate CRF.
The laboratory variables to be measured are presented in Table 3.

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Table 3
Laboratory safety variables
Hematology/ 
Hemostasis (whole 
blood) 
White blood cell (WBC) count with differential, platelet count, red blood 
cell (RBC) count, hemoglobin (Hb), hematocrit, mean corpuscular volume 
(MCV), mean corpuscular hemoglobin concentration (MCHC)
Clinical chemistry 
(serum or plasma)
Serum creatinine, total bilirubin, aspartate transaminase (AST), alanine 
transaminase (ALT), thyroid stimulating hormone (TSH), blood urea 
nitrogen (BUN), lipase, amylase, electrolytes (potassium, calcium, sodium),
lactase dehydrogenase
Urinalysis (local 
laboratory or dip-stick 
per institutional 
care) a
Hb, leukocytes, protein, glucose, bilirubin a, urobilinogen a, ketones, specific 
gravity
Urine microscopy
WBC/high power field (HPF), RBC/HPF, epithelial cells, casts, crystals
Pregnancy test for 
women of 
child-bearing potential
Serum pregnancy tests performed for all women of childbearing potential at 
screening. At baseline and each treatment visit, a urine pregnancy test 
(dip-stick or at a local laboratory) or serum pregnancy test will be 
performed
Other safety tests 
(screening only) b
Hepatitis B surface antigen, hepatitis C antibody, HIV antibodies (eg,
HIV-1 and HIV-2)
Additional laboratory 
tests (where clinically
indicated only)
Free tri-iodothyronine (T3) and free thyroxine (T4)c, creatinine clearance, 
alkaline phosphatase (ALP), autoimmune antibody testd
(a)
Tests for urine bilirubin and urobilinogen will be done (per institutional standard method) 
at baseline only, and repeated only as clinically indicated.
(b)
At screening only, for the evaluation of eligibility criteria.
(c)
If TSH is abnormal or there is clinical suspicion of an AE related to the endocrine system 
then free T3 and free T4 testing will be done. 
(d)
If a patient experiences an AE that is thought to be possibly of autoimmune nature (eg
thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the Investigator should collect 
a blood sample for appropriate autoimmune antibody testing by a local laboratory.
The hematology and clinical chemistry should be performed at a local laboratory at or near to 
the Investigator site. Urinalysis should be performed at a local laboratory (at or near to the
Investigator site) or by dip-stick per institutional care. Tests for urine bilirubin and 
urobilinogen will be done (per institutional standard method) at baseline only, and repeated 
only as clinically indicated.
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site. Clinically significant (as assessed by the Investigator) laboratory 
abnormalities will be recorded in the CRF as AEs. Laboratory results relevant to / associated 
with AESIs will be recorded in the CRF.

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Additional safety samples may be collected during the study if clinically indicated at the 
discretion of the Investigator and according to standard medical practice. The Investigator 
should make an assessment of the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed and dated, and retained at center as 
source data for laboratory variables. For information on how AEs based on laboratory tests 
Note: In case a patient shows an AST or ALT ≥3 ULN or total bilirubin ≥2 ULN please refer 
to APPENDIX D for further instructions (also see Section 6.3.8).
5.3.1.1
Thyroid stimulating hormone
Perform TSH at all visits. Free T3 and free T4 will only be measured if TSH is abnormal or if 
there is clinical suspicion of an AE related to the endocrine system.
5.3.1.2
Coagulation
Activated partial thromboplastin time (APTT) will be performed at screening and if clinically 
indicated.
International normalized ratio (INR) will be performed at screening and if clinically indicated.  
Patients taking warfarin may participate in this study; however, it is recommended that INR be 
monitored carefully at least once per week for the first month, then monthly if the INR is 
stable. 
Each coagulation test result will be recorded in the CRF.
5.3.1.3
Other lab tests
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies and HIV antibodies.
5.3.2
ECOG
The standard ECOG performance status scales and criteria (Okazaki and Honjo 2007) will be 
used (refer to APPENDIX E).
5.3.3
ECG
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study.  ECGs should be obtained after the patient has been in a supine position for 5 minutes 
and recorded while the patient remains in that position.
In case of a QTcF value >470 ms or in case of clinically significant ECG abnormalities, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.
5.3.4
Physical exam, vital signs
At screening and baseline, a complete physical examination (including body weight and 
height) will be performed and include an assessment of the following: general appearance, 

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respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and 
neurological systems. After baseline, only targeted physical examination (including body 
weight) is necessary.
Physical examination information will only be reported in the CRF if abnormalities are 
reported as AEs. For information on how AEs based on physical examination should be 
recorded and reported, see Section 6.3.
Vital signs including pulse, blood pressure (systolic and diastolic), and temperature will be 
monitored at screening and at every visit during the study. During durvalumab and 
tremelimumab infusions, vital signs should be monitored as per institutional care 
recommendations for the administration of monoclonal antibodies. Vital signs will be 
measured and recorded at all visits from screening to the last treatment visit.
5.3.5
Other safety assessments
5.3.5.1
Immune-mediated adverse events
Safety findings supporting the monitoring and evaluation of imAEs, including radiographic or 
pathologic findings, or pulmonary function tests (in case of pneumonitis or ILD), should be 
reported in the CRF. Reporting of an imAE will trigger reporting of additional relevant / 
associated safety findings.
For management of imAEs please refer to the Dosing Modification and Toxicity Management 
Guidelines as indicated in Section 6.9.1.
5.3.5.2
Autoimmune antibody test
If a patient experiences an AE that is thought to be possibly of autoimmune nature (eg
thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the Investigator should collect a
blood sample for appropriate autoimmune antibody testing by a local laboratory. For 
management of imAEs please refer to the Dosing Modification and Toxicity Management 
Guidelines as indicated in Section 6.9.1.
5.4
Other assessments (not applicable)
5.5
Pharmacokinetics (not applicable)
5.6
Pharmacodynamics (not applicable)
5.7
Biomarker analysis 
Pre-treatment tumor PD-L1 expression data, if available, will be collected on the CRF for all
patients. 
At the screening visit, an archival tumor block (formalin-fixed paraffin-embedded), if 
available, will be obtained from all patients.  The provision of archival tumor tissue block is 
optional for the patients and requires a patient consent.  If an archival tumor block exists and 

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there is sufficient quantity to allow for PD-L1 analysis, then the tumor tissue block should be 
shipped to the central laboratory.  If a tissue block is unavailable, unstained slides with newly 
cut sections from the tissue block should be provided.  If an archival sample is not available
and if the patient provides consent, a sample should be collected via an image-guided core 
needle biopsy (at least 18-gauge or larger core diameter) or an excisional tumor biopsy 
sample. This procedure should be done only if the biopsy is technically feasible and is not 
associated with unacceptable clinical risk.
Instructions and guidelines for collecting archival tumor sample and for the storage, and 
shipment of biologic samples are given in the Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent or additional research 
(not described in this protocol) but relevant to evaluating biological and/or clinical response to 
immunotherapy, either now or in the future on remaining biological samples (eg blood or 
tumor tissue). The purpose of this additional research is to investigate further the potential 
side effects of the study drugs and the underlying mechanism of the diseases under study.
The results may be pooled with biomarker data from other durvalumab/tremelimumab studies 
to evaluate biological responses across indications and to compare results in monotherapy 
versus combination settings.
Management of biomarker data
The biomarker data will have unknown clinical significance.  AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study Investigator, general physician, or any other third party, unless
required to do so by law.  The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work.  
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
5.7.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.  Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the Clinical Study Report (CSR) in a
separate report. The results of this biomarker research may be pooled with biomarker data 
from other studies involving durvalumab or tremelimumab to generate hypotheses to be tested 
in future research.

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5.7.2
Labeling and shipment of biological samples
The Principal Investigator will ensure that samples are labeled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see APPENDIX B.
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.
5.7.3
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of receipt of arrival.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of, or until further shipment, and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered in the AstraZeneca Biobank during the 
entire life cycle.
5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented.  If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:

Ensure that AstraZeneca is immediately notified of the patients’ 
withdrawal of informed consent to the use of donated samples

Ensure that biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of or destroyed and the action 
documented

Ensure that the organization(s) holding the samples is/are immediately 
informed about the withdrawn consent and that samples are disposed of 
or destroyed, the action is documented, and the signed document is 
returned to the study site

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
Ensure that the patient and AstraZeneca are informed about the sample 
disposal
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product. An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver) or the abnormal results of an investigation (eg,
laboratory findings, ECG). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, and follow 
up), that fulfills 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/incapacity or substantial 
disruption of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above

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
AEs for new malignant tumors (ie, not the tumor for which entry into the 
study is a criterion and that is being treated by the IP under study and is 
not the development of new or progression of existing metastasis to the 
tumor under study) reported during a study should generally be assessed 
as SAEs. If no other seriousness criteria apply, the ‘Important Medical 
Event’ criterion should be used.
In certain situations, however, medical judgement on an individual event 
basis should be applied to clarify that the malignant tumor event should 
be assessed and reported as a non-serious AE. For example, if the tumor 
is included as medical history and progression occurs during the study, 
but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed 
as serious, although reporting of the progression of the malignant tumor 
as an AE is valid and should occur. Also, some types of malignant 
tumors, which do not spread remotely after a routine treatment that does
not require hospitalization, may be assessed as non-serious; examples 
include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.
Malignant tumors that – as part of normal, if rare, progression – undergo 
transformation (eg, Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumor.
For further guidance on the definition of a SAE, see Additional Safety Information in
APPENDIX A.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events and SAEs will be collected from time of the patient signing the ICF until the
follow up period is completed (90 days after the last study treatment administration). If an 
event that starts post the defined safety follow up period noted above is considered to be due 
to a late onset toxicity to study drug then it should be reported as an AE or SAE as applicable.
6.3.2
Follow up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued study drug or the
study has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.

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6.3.3
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a 
calendar day)

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in
Section 6.3.4

Description of the SAE

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The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.  A copy of the CTCAE version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2 and the Additional 
Safety Information in APPENDIX A. An AE of severe intensity need not necessarily be 
considered serious. For example, nausea that persists for several hours may be considered 
severe nausea, but not a SAE unless it meets the criteria shown in Section 6.2 and 
APPENDIX A. On the other hand, a stroke that results in only a limited degree of disability 
may be considered a mild stroke but would be a SAE when it satisfies the criteria shown in 
Section 6.2 and APPENDIX A.
6.3.4
Causality collection
The Investigator will assess causal relationship between durvalumab (monotherapy Modules),
or between durvalumab and tremelimumab (combination therapy Modules) and each AE, and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by durvalumab?’ (monotherapy Modules) or and ‘Do you 
consider that there is a reasonable possibility that the event may have been caused by 
durvalumab or tremelimumab?’ (combination therapy Modules)?’
For SAEs, causal relationship will also be assessed for other medication, study procedures and
alternative etiologies. Note that for SAEs that could be associated with any study procedure 
the causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in APPENDIX A.
6.3.5
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment-emergent (ie,
SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A protocol-
related SAE may occur as a result of a procedure or intervention required during the study (eg,
blood collection).  The following guidelines should be used by Investigators to assess the 
relationship of SAEs to the protocol:

Protocol-related: The event occurred due to a procedure or intervention 
that was described in the protocol for which there is no alternative 
etiology present in the patient’s medical record.

Not protocol-related: The event is related to an etiology other than the 
procedure or intervention that was described in the protocol.  The 
alternative etiology must be documented in the study patient’s medical 
record.

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6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated
laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.  Whenever possible, the reporting 
Investigator should use the clinical rather than the laboratory term (eg, anemia versus low 
hemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 ULN together with total bilirubin ≥2 ULN may need to be 
reported as SAEs. Please refer to APPENDIX D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which durvalumab + tremelimumab combination therapy or durvalumab 
monotherapy is being studied. It may be an increase in the severity of the disease under study 
and/or increases in the symptoms of the disease. The development of new, or progression of 
existing metastasis to the primary cancer under study should be considered as disease 
progression and not an AE. Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study.

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6.3.10
New cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are 
those that are not the primary reason for the administration of durvalumab ± tremelimumab 
and have been identified after the patient’s inclusion in this study.
6.3.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined follow 
up period after the administration of the last dose of study drug, must be reported as follows:

Death clearly resulting from disease progression should be reported to the 
Study Monitor/Physician at the next monitoring visit and should be 
documented in the CRF in the Statement of Death page.  It 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 the Study 
Monitor/Physician as an SAE within 24 hours.  It should also be 
documented in the Statement of Death page in the CRF. The report 
should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE.  It 
should also be documented in the Statement of Death page in the CRF. A 
post mortem may be helpful in the assessment of the cause of death, and 
if performed, a copy of the post mortem results should be forwarded to 
AstraZeneca Patient Safety or its representative within the usual 
timeframes.
Deaths occurring after the protocol-defined safety follow up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurs as a result of an event that started post the defined safety follow up period and the 
event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE.
6.3.12
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, 
it is recommended that the patients continue the scheduled site visits and Investigators monitor 
the patient’s safety laboratory results prior to and periodically during treatment with 
durvalumab in order to manage AEs in accordance with the durvalumab Dose Modification 
and Toxicity Management Guidelines (see Section 6.9.1). All data obtained post the final 
DCO and database closure will be recorded in the patient notes but, with the exception of 
SAEs, will not otherwise be reported for the purposes of this study.

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All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days
following the last dose of durvalumab treatment) post the final DCO and database closure 
must be reported as detailed in Section 6.4.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to durvalumab ± 
tremelimumab, or to the study procedure(s). All SAEs will be recorded in the CRF, except
SAEs occurring after the DCO and database closure. After the DCO, SAEs will be reported
via paper SAE forms and recorded in AstraZeneca database.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca study representatives (or designees) within one day ie,
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca study representative (or designee) works with the Investigator to 
ensure that all the necessary information is provided to the AstraZeneca Patient Safety data 
entry site within 1 calendar day of initial receipt for fatal and life-threatening events and 
within 5 calendar days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca study representatives of any follow up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
The reference documents for definition of expectedness are the IBs for durvalumab and 
tremelimumab, as applicable to the tumor specific Module. 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study.  A medical emergency usually 
constitutes an SAE and is to be reported as such.
The Safety Handling Plan contains detailed timelines and region-specific instructions for 
safety reporting.
6.5
Adverse events of special interest
An AESI is one of scientific and medical interest specific to understanding of the 
Investigational Product and may require close monitoring and rapid communication by the 
Investigator to the Sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
AESIs for durvalumab ± tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 

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replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-mediated adverse event
(imAE) is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated MOA and where there is no clear alternate etiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE
diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes of the imAE. 
In Japan, in the event of imAE or suspected imAE, the AstraZeneca study team may request 
relevant clinical information (including images) for those patients who demonstrate the event, 
and may request the independent review by external experts based on the acquired clinical 
information.
If the Investigator has any questions in regards to an event being an imAE, the Investigator
should promptly contact the Study Physician.
AESIs/imAEs observed with durvalumab ± tremelimumab include pneumonitis, hepatitis, 
diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, 
rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis and rare/less frequent imAEs 
including neuromuscular toxicities such as myasthenia gravis and Guillain-Barré syndrome.
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis.  It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab IBs. More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (see Section 6.9.1). These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgement in treating these 
types of toxicities.  These guidelines apply to AEs considered causally related to the study 
drug/study regimen by the reporting Investigator.

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6.6
Overdose
6.6.1
Durvalumab or tremelimumab
Use of durvalumab or tremelimumab in doses in excess of that specified in the protocol is 
considered to be an overdose.  There is currently no specific treatment in the event of 
overdose of durvalumab or tremelimumab, and possible symptoms of overdose are not 
established. 

An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the CRF and in the Overdose 
CRF module.

An overdose without associated symptoms will only be reported in the 
Overdose CRF module.
If an overdose of an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately, or 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.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 6.6.  
For other overdoses, reporting must occur within 30 days.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. except for 
pregnancy discovered before the study patient has received any study drugs.
6.7.1
Maternal exposure
If a patient becomes pregnant during the course of the study durvalumab and tremelimumab 
should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that durvalumab ±
tremelimumab may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/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 
informs the appropriate AstraZeneca study representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca study representative (or designee) works with the Investigator to 
ensure that all relevant information is provided to the AstraZeneca Patient Safety data entry
site within 1 or 5 calendar days for SAEs (see Section 6.3.12) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
6.7.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period. 
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 180 days after the 
last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of
durvalumab monotherapy, whichever is the longer time period 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.
6.8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the patient received the drug

did not occur, but circumstances were recognized that could have led to 
an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

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
Dispensing error, eg, medication prepared incorrectly, even if it was not
actually given to the patient

Drug not administered as indicated, for example, wrong route or wrong 
site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should 
be taken as a solid tablet

Drug not stored as instructed, eg, kept in the fridge when it should be at 
room temperature 

Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which 
lead to one of the above listed events that would otherwise have been a 
medication error 

Patient accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard-of-care 
medication in open-label studies, even if an AZ product
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs 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 works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.3.12) and within 30 days for all other medication 
errors.

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Version 5.0
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6.9
Management Durvalumab ± Tremelimumab related toxicities
For AEs that are considered at least partly due to administration of durvalumab ±
tremelimumab the following general guidance should be followed for management of 
toxicities. 

Treat each of the toxicities with maximum supportive care (including 
holding the agent suspected of causing the toxicity where required).

If the symptoms promptly resolve with supportive care, consideration 
should be given to continuing the same dose of durvalumab or 
tremelimumab along with appropriate continuing supportive care.  If 
medically appropriate, dose modifications are permitted for durvalumab 
and tremelimumab (see Section 6.9.1).

All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
All toxicities will be graded according to NCI CTCAE, Version 4.03.
6.9.1
Specific toxicity management and dose modification information-Durvalumab 
and durvalumab + tremelimumab
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
Investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) and tremelimumab
(CTLA-4 inhibitor).  Given the similar underlying mechanisms of toxicities observed with 
these 2 compounds, these guidelines are applicable to the management of patients receiving 
either drug as monotherapy or in combination.  Additionally, these guidelines are applicable
when either drug is used alone or in combination and is administered concurrently or 
sequentially with other anti-cancer drugs (ie, antineoplastic chemotherapy, targeted agents), as 
part of a protocol specific treatment regimen.  The TMGs provide information for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune 
mediated reactions that may be observed with checkpoint inhibitor monotherapy or 
combination checkpoint inhibitor regimens, with specific instructions for dose modifications 
(including discontinuations) and treatment interventions.  Investigators are advised however to 
use local practice guidelines and consult local references for the management of toxicities 
observed with other cancer treatment. The most current version of the TMGs entitled “Dosing 
Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, 
and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or Combination Therapy 
with Tremelimumab or Tremelimumab Monotherapy” is provided to the investigative site as 
an Annex document and is maintained within the Site Master File. In addition, a version of the 
current Dosing Modification and Toxicity Management Guidelines is available through the 
following link: https://tmg.azirae.com/. Please contact your clinical trial associate for 
information on how to gain access to this website.

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Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune-related.
In addition, there are certain circumstances in which durvalumab and tremelimumab should be
permanently discontinued (see Section 3.9 of this protocol and the Dosing Modification and 
Toxicity Management Guidelines).
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab 
can be modified based on toxicities observed as described in the Dosing Modification and 
Toxicity Management Guidelines.  These guidelines have been prepared by the Sponsor to 
assist the Investigator in the exercise of his/her clinical judgement in treating these types of 
toxicities.  These guidelines apply to AEs considered causally related to durvalumab 
monotherapy and the durvalumab + tremelimumab combination therapy regimen by the 
reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
6.10
Study governance and oversight
6.10.1
Data Monitoring Committee
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified in this study 
or in other studies but deemed relevant for this study will be addressed promptly, which could 
involve amendments to the study protocol and letters to Investigators, as appropriate.
In addition to the ongoing AstraZeneca overall safety monitoring, a Data Monitoring 
Committee (DMC) comprised of internal experts independent from the study team will be 
convened and will meet approximately every 6 months after the study has started to review 
safety assessments and make recommendations to continue, amend, or stop the study based on 
safety findings. Full details of the DMC remit, procedures, processes, meeting frequency, and 
interim analyses can be found in the DMC Charter.
6.10.2
Steering Committee
A Steering Committee (SC) will be assembled by AstraZeneca for the executive oversight and 
supervision of the study. The committee of oncology experts will serve this role through 
regular scheduled meetings or teleconferences and, if necessary, additional ad hoc meetings.  
Details of the SC remit, procedures, processes, and meeting frequency will be outlined in an
SC Charter. 

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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply durvalumab or durvalumab and tremelimumab as applicable for each 
Module.
Investigational product
Dosage form and strength
Manufacturer
Durvalumab (MEDI4736)
50 mg/mL solution for infusion 
after dilution
Astra Zeneca
Tremelimumab
20 mg/mL solution for infusion 
after dilution
7.1.1
Durvalumab
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0 and a density of 1.054 g/mL. The nominal fill volume 
is 10.0 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not 
be frozen.  Drug product should be kept in original packaging until use to prevent prolonged
light exposure.
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
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration. 
A dose of 1500 mg (only patients >30 kg in weight are eligible) will be administered using an
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22 μm filter. Add 30.0 mL of durvalumab (ie, 1500 mg of durvalumab 
[MEDI4736]) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using 
an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 

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concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter. See the study specific drug handling plan for an example of a 
weightbased dose calculation.  
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered.
In the event that either preparation time or infusion time exceeds the time limits a new dose 
must be prepared from new vials. Durvalumab does not contain preservatives, and any 
unused portion must be discarded. 
Preparations are to be in accordance with the study specific drug handling instructions.
7.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400 mg vial solution for infusion after 
dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine-
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate and 0.02% 
(w/v) polysorbate 80; it has a pH of 5.5 and a density 1.034 g/mL. The nominal fill volume is 
20 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen. Drug product should be kept in original container until use to prevent prolonged light 
exposure.
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab 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 
tremelimumab vial to start of administration should not exceed

24 hours at 2°C to 8°C (36°F to 46°F) or

4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 75 mg (for patients >30 kg in weight; patients ≤30 kg are not eligible for entry to 
the study) will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 3.8 mL (ie,
75 mg of tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV bag. 

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The IV bag size should be selected such that the final concentration is within 0.10 to
10 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
If patient weight falls to ≤30 kg, weight-based dosing at 1 mg/kg will be administered using 
an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab 
concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm filter. See the study specific drug handling plan for an example of a 
weight-based dose calculation.
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials.  Tremelimumab does not contain preservatives, and any unused 
portion must be discarded.
Preparations are to be in accordance with the study specific drug handling instructions. 
7.2
Dose and treatment regimens
Durvalumab monotherapy
Patients in the durvalumab monotherapy treatment group will receive 1500 mg durvalumab 
via IV infusion Q4W until confirmed disease progression unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. (Note: If a patient’s weight 
falls to 30 kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg 
of durvalumab Q4W after consultation between Investigator and study physician, until the 
weight improves to >30 kg, at which point the patient should start receiving the fixed dosing 
of durvalumab 1500 mg Q4W).
Figure 2
Durvalumab dosing regimen
Durvalumab + tremelimumab combination therapy
Patients in the durvalumab + tremelimumab combination therapy Modules will receive 
durvalumab (1500 mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 
4 doses/cycles each, followed by durvalumab 1500 mg Q4W until disease progression, unless
there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is 

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met.  The first durvalumab monotherapy dose at 1500 mg Q4W will be 4 weeks after the final 
dose of durvalumab in combination with tremelimumab. (Note: If a patient’s weight falls to 
30 kg or below [≤30 kg], then the patient should receive weight-based dosing equivalent to 
20 mg/kg of durvalumab Q4W and 1 mg/kg tremelimumab Q4W after consultation between 
Investigator and study physician, until the weight improves to above 30 kg [>30 kg], at which 
point the patient should start receiving the fixed dosing of durvalumab 1500 mg plus 
tremelimumab 75 mg Q4W).
Tremelimumab will be administered first; the durvalumab infusion will start approximately 
1 hour (maximum 2 hours) after the end of the tremelimumab infusion.  Standard infusion 
time for each is 1 hour; however, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature per infusion. If there are no clinically 
significant concerns after the first cycle, then, at the discretion of the Investigator, all other 
cycles of durvalumab can be given immediately after the tremelimumab infusion has finished.
Figure 3
Durvalumab + tremelimumab dosing regimen
7.2.1
Duration of treatment and criteria for treatment through progression and for 
retreatment
All treatment will be administered beginning on Day 1 for durvalumab monotherapy or 
durvalumab + tremelimumab combination therapy until RECIST 1.1-defined radiological 
progression unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.
During the treatment period, patients may continue receiving therapy in the setting of 
unconfirmed radiologic progressive disease (PD) according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1), at the Investigator’s discretion, until progression is 
confirmed*. A confirmatory scan is required following a RECIST 1.1 overall time point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 
4 weeks after the previous assessment of PD.
                                               
*Where treatment is discontinued due to progressive disease, it is recommended that a confirmatory scan be 
performed prior to discontinuation to verify progression. According to RECIST 1.1 modified for confirmation of 
progression, a confirmatory scan is required following an overall time point assessment of progression (PD), no 
earlier than 4 weeks after the previous assessment of PD.

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Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (eg, CNS metastasis, respiratory failure due to tumor compression, spinal 
cord compression) will not be eligible for continuing durvalumab±tremelimumab. 
For all patients who are treated through progression, the Investigator should ensure patients do 
not have any significant, unacceptable or irreversible toxicities that indicate continuing would 
not further benefit the patient. 
Patients meeting the retreatment criteria below will follow the same treatment guidelines 
followed during the original treatment period, including the same dose and frequency of 
treatments and the same schedule of assessments.
Patients who meet the criteria for retreatment may only receive retreatment once.  
Patients receiving durvalumab + tremelimumab combination therapy may undergo retreatment 
as described below:

Patients who complete the 4 dosing cycles of the combination of 
durvalumab and tremelimumab portion of the regimen (with clinical 
benefit per Investigator judgement), but subsequently have evidence of 
RECIST 1.1 (or other tumor assessment method)-defined PD during the 
durvalumab monotherapy portion of the combination regimen, with or 
without confirmation according to RECIST 1.1, may restart treatment 
with the combination.
For all patients who are treated through progression and for patients who are restarting 
durvalumab + tremelimumab, the Investigator should ensure that:

The patient does not have any significant, unacceptable, or irreversible 
toxicities that indicate continuing treatment will not further benefit the 
patient

There is absence of clinical symptoms or signs indicating clinically 
significant disease progression accompanied by a decline in WHO/ECOG 
performance status to >1

There is absence of rapid disease progression or threat to vital organs or 
critical anatomical sites (eg, CNS metastasis, respiratory failure due to 
tumor compression, or spinal cord compression) requiring urgent 
alternative medical intervention

The patient still fulfills the eligibility criteria for this study (see 
Sections 3.1 and 3.2) with the exception of inclusion criteria 6 and
exclusion criteria 2 and 3. Patients must also agree to re-consenting to 
restart durvalumab + tremelimumab combination therapy 

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Patients will not be permitted to continue immunotherapy if progression occurs after 
confirmed response (CR or PR as defined by RECIST 1.1) to immunotherapy treatment in 
target lesions (regardless of the appearance of new lesions), ie, the response and progression 
events both occurred in the target lesions while receiving immunotherapy during the same 
treatment period. 
During the retreatment period, patients in the durvalumab + tremelimumab combination 
therapy group will resume durvalumab dosing at 1500 mg Q4W with 75 mg of tremelimumab 
Q4W for 4 doses (or cycles) each.  Patients will then continue with durvalumab monotherapy 
at 1500 mg Q4W, beginning at Week 16, 4 weeks after the last dose of combination therapy, 
until disease progression.  
Patients who AstraZeneca and the Investigator determine may not continue treatment after 
RECIST 1.1-defined PD will be followed up for survival.  Patients who have discontinued 
treatment due to toxicity or symptomatic deterioration, or who have commenced subsequent 
anticancer therapy, will be followed up until confirmed RECIST 1.1-defined PD and for 
survival.
Post final data cut off (DCO)
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure may continue to receive their assigned treatment for as long as they and their 
physician considers they are gaining clinical benefit. For patients continuing to receive 
durvalumab treatment following the final DCO and database closure, it is recommended that 
the patients continue the scheduled site visits and Investigators monitor the patients’ safety 
laboratory results prior to and periodically during treatment with durvalumab in order to 
manage AEs in accordance with the durvalumab Dosing Modification and Toxicity 
Management Guidelines (see Section 6.9.1). 
In the event that a roll-over or safety extension study is available at the time of, or subsequent
to, the final DCO and database closure, patients receiving treatment with durvalumab may be 
transitioned to such a study, and the study would reach its end. The roll-over or safety 
extension study would ensure treatment continuation with visit assessments per its protocol. 
Any patient who would be proposed to move to such a study would be given a new Informed
Consent.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labeling. Label 
text will be translated into local language in accordance with local requirements.
In Japan, labels will be prepared in accordance with Good Clinical Practice (GCP) Ordinance. 
Details are specified in the document explaining the reconstitution procedures and other 
handling procedures for the IPs.

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IP will be provided with either single panel labels or multi-language booklet labels.
Label text prepared for durvalumab will show the product name as “MEDI4736” or 
“durvalumab (MEDI4736)” depending upon the agreed product name used in the approved 
study master label document.  All naming conventions are correct during this transitional 
period.
7.4
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements.  A temperature log will be used to record the temperature 
of the storage area.  Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection.  A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage 
facility.  Storage conditions stated in the IB may be superseded by the label storage.
7.5
Compliance
The administration of all study treatments (including IPs) should be recorded in the 
appropriate sections of the CRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
7.6
Accountability
The study treatment provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Drug accountability should be performed until the patient stops durvalumab and 
tremelimumab completely. Study site personnel will account for all vials of durvalumab and 
tremelimumab received at the site, for all unused vials, and for appropriate destruction of 
durvalumab and tremelimumab. Certificates of delivery, destruction, and return should be 
signed.
In Japan, study drug will not be distributed to the study site until the contract is concluded 
between the study site and AstraZeneca. The Investigational Product Storage Manager is 
responsible for managing the study drug from receipt by the study site until the return of all 
unused study drug to AstraZeneca.  AstraZeneca will provide the study documents 
‘Procedures for drug accountability’ and ‘Procedures for drug storage’, which describe the 
specific requirements.  The Investigator(s) is responsible for ensuring that the patient has 
returned all unused study drug.

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7.7
Concomitant medications and other treatments 
Screening and baseline medications, use of corticosteroid or other immunosuppressive drugs, 
and any other drugs to manage AESIs or imAEs (including dose, route, duration) should be 
recorded in the appropriate sections of the CRF.
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 90 day 
follow up period following the last dose of study drug.  Any concomitant medication(s), 
including herbal preparations, taken during this time will be recorded in the CRF.  
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.  Refer also to the Dosing Modification and Toxicity Management Guidelines as
indicated in Section 6.9.1.  

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Table 4
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
For the durvalumab ± tremelimumab treatment arms only
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:

Use of immunosuppressive medications for 
the management of IP-related AEs

Use in patients with contrast allergies

In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted
A temporary period of steroids will be allowed if
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (eg, chronic 
obstructive pulmonary disease, radiation, nausea, 
etc.).
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 90 days after 
the last dose of tremelimumab during the study
Sunitinib
Should not be given concomitantly or through 90 
days after the last dose of tremelimumab (acute renal 
failure has been reported with combination therapy of 
tremelimumab and sunitinib)
Epidermal growth factor receptor tyrosine 
kinase inhibitors (EGFR TKIs) 
Should not be given concomitantly. 
Should be used with caution in the 90 days post last 
dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
Herbal and natural remedies which may have
immune-modulating effects
Should not be given concurrently unless agreed by 
the Sponsor

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Table 5
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary 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, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc.])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the
influenza vaccine
Permitted
7.7.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
7.8
Post-study access to study treatment
The study will close to new enrollment when accrual targets for each module in each country 
have been met (or for other reasons as outlined in Section 3.11). 
In the opinion of the Investigator, if patients are still benefiting from treatment at the time of 
study closure, the patients will continue to be provided with study drug.  This may include, but 
not be limited to, transition to a long-term extension trial or an early access program as 
permitted by applicable regulations.  
8.
STATISTICAL ANALYSES BY ASTRAZENECA
See tumor specific Modules (APPENDIX F) for statistical details.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
The sections below outline general principles.  Any additional specific details applicable to 
tumor specific modules or countries will be described in the Modules. 

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9.1
Training of study site staff
Before the first patient is entered into the study, an AstraZeneca study representative will 
review and discuss the requirements of the Clinical Study Protocol and related documents 
with the investigational staff and also train them in any study specific procedures and eCRF
system(s) utilized. Additional recommendations and training requirements regarding the 
recognition, monitoring, and management of AESIs/imAEs will be provided to study 
personnel.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca study representative will have regular contacts with the 
study site, including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the CRFs, that biological 
samples are handled in accordance with the Laboratory Manual, and that 
study treatment accountability checks are being performed

Perform source data verification (a comparison of the data in the CRFs 
with the patient's medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients. This will require direct access to all original 
records for each patient (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient
Details will be outlined in a Monitoring Plan. 
The AstraZeneca study representative will be available between visits if the Investigator(s) or 
other staff at the center need information and advice about the study conduct.

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9.2.1
Source data
Study sites will maintain source data in accordance with GCP or local regulations.
9.2.2
Study agreements
The Principal Investigator at each/the center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
9.3
Study timetable and end of study
The end of the study is defined as the last visit of the last patient undergoing the study.
The overall study is expected to start in Q1 2017 and end by Q2 2021.
See individual modules for the definition of final DCO.
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with durvalumab or tremelimumab.
In the event that a roll-over or safety extension study is available at the time of or subsequent
to the final DCO and database closure, patients receiving treatment with durvalumab may be 
transitioned to such a study, and the study would reach its end. The roll-over or safety 
extension study would ensure treatment continuation with visit assessments per its protocol. 
Any patient who would be proposed to move to such a study would be given a new Informed 
Consent.
9.4
Data management by AstraZeneca or delegate
Data Management details will be provided separately for each module and country dependent 
on delivery model and so are not specified in the protocol. 
Any data collected through third party sources will be obtained and reconciled against study 
data.

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Data queries will be raised for inconsistent, impossible or missing data. All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in data management plans. Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. Data management plans will also clarify the roles and responsibilities of 
the various functions and personnel involved in the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced according to the SAE reconciliation plan and 
reconciled with the Patient Safety database and/or the investigational site.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Patient data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
If mandatory genetic testing is required on any of the STRONG modules, the following 
applies.  AstraZeneca will not provide individual genotype results to patients, any insurance
company, any employer, their family members, general physician, unless required to do so by 
law.
Precautions will be taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of 
a medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred. 

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The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.3
Ethics and regulatory review
An EC (ie, IRB and Independent Ethics Committee [IEC]) should approve the final study 
protocol, including the final version of the ICF and any other written information and/or 
materials to be provided to the patients. The Investigator will ensure the distribution of these 
documents to the applicable EC, and to the study site staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca before enrollment of any patient into the study.
The EC should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, ECs and Principal Investigators with safety 
updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the ECs with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with tremelimumab. 
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
In Japan:
An IRB should approve the final study protocol, including the final version of the ICF and any 
other written information and/or materials to be provided to the patients. The head of the 
study site will ensure the distribution of these documents to the applicable IRB, and the 
Principal Investigator to the Investigator and study site staff.

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The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the Principal Investigator before enrollment of any patient into the study.
The IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to 
the IRB via the head of the study site at the time of the protocol re-approval.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities.
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca.
10.4
Informed consent
The Principal Investigator(s) at each center will:

Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study.

Ensure each patient is notified that he/she is free to discontinue from the
study at any time.

Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided.

Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study.

Ensure the original, signed ICF(s) is/are stored in the Investigator's Study 
File.

Ensure a copy of the signed ICF is given to the patient.

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
Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the ICF that is approved by an EC.
10.5
Changes to the clinical study protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
coordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority approval, before implementation. Local requirements are to be followed 
for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to EC see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s EC 
are to approve the revised ICF before the revised form is used.
If local regulations require, any administrative change will be communicated to or approved 
by each EC.
In Japan:
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the study protocol to be amended, the 
amendment should be submitted to the head of the study site and be approved by its IRB.  If 
applicable, AstraZeneca should submit a notification to the regulatory authority before it is 
implemented.  If a protocol amendment requires a change to a particular center's ICF, then 
AstraZeneca and the center's IRB should be notified by the Principal Investigator. Approval 
of the revised ICF by AstraZeneca and by the IRB is required before the revised form is used.  
If an administrative change is required, such a change should be notified to or approved by 
each IRB according to local requirements.
10.6
Audits and inspections
Authorized study representatives of AstraZeneca, a regulatory authority, or an EC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the center.

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11.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and Tremelimumab
Study Code D4191C00068
Version 5.0
Date 13 December 2019
127(143)
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Document Name: d4191c00068-csp-v5
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D4191C00068 Clinical Study Protocol version 5
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