A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer
Phase: PHASE3
Conditions: Urothelial Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol
Drug Substance
Durvalumab (MEDI4736) + 
Tremelimumab
Study Code
D419BC00001
Version
9
Date
03 December  2019
A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global 
Study of First-Line MEDI4736 Monotherapy and MEDI4736 in 
Combination with Tremelimumab Versus Standard of Care Chemotherapy 
in Patients with Unresectable Stage IV Urothelial Cancer
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
(Japan) AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan
EudraCT Number: 2015-001633-24
VERSION HISTORY
Version 9, 03 December 2019
Section 1.3.2.1 (MEDI4736) was revised to reflect the most recent version of the IB and to 
provide the most current safety information to the Investigators.
Section 1.3.2.2 (Tremelimumab) was revised to reflect the most recent version of the IB 
and to provide the most current safety information to the Investigators.
Section 1.3.2.3 (MEDI4736 + tremelimumab combination therapy)  was revised to 
reflect the most recent version of the IB and to provide the most current safety information 
to the Investigators.

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Study Code D419BC00001
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Date 03 December  2019
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Section 6.7.1 (MEDI4736 monotherapy and MEDI4736 + tremelimumab combination 
therapy adverse events of special interest) 
This section has been updated with the following language, consistent with the IB: 
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab and durvalumab in 
combination with tremlimumab 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-Barre syndrome.
Section 6.7.1 (Specific toxicity management and dose modification information –
MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy)    
This section has been updated to clarify that the Toxicity Management Guidelines (TMGs) 
for durvalumab and tremelimumab will be provided to investigative sites as an Annex to the 
protocol document.
Appendix G-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), 1 November 2017 Version: Removed from the list of appendices and the 
document.
Version 8, 26 April 2019
Section 7.8 (Post-study access to study treatment): Revised this section to specify data 
collection and follow-up for patients who remain on treatment at the final data cutoff and 
database lock, and permit enrollment in a roll-over study at the final data cutoff and 
database lock. 
Synopsis, Section 8.2 (Sample size estimate), Section 8.5 (Methods for statistical analyses), 
Section 8.5.15 (Interim analyses), and Section 8.5.15.2 (Interim analysis of overall survival 
endpoints): Revised these sections as follows:
1. Removed the Interim 3 analysis (ie, second interim analysis for OS) and specified that 
only the final analysis will be conducted. The rationale for this change is based on the 
limited increase in maturity of the study between the Interim 2 and Interim 3 analyses 
(10%) and between the Interim 3 and final analyses (10%).

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2. Revised the timing of the final analysis to occur when the target number of events is 
reached in the durvalumab monotherapy versus standard of care arm only. The rationale 
for prioritizing durvalumab monotherapy is based on results from AstraZeneca-
sponsored studies in second-line urothelial carcinoma (Study CD-ON-MEDI4736-1108 
[NCT01693562] and Study D4190C00010 [NCT02261220]) and first-line non-small 
cell lung cancer (Study D419AC00001 [MYSTIC]).
Section 9.3 (Study timetable and end of study): Cross-referenced Section 7.8 for details 
regarding study treatment access, data collection, and patient follow-up at the end of study.
Version 7, 24 November 2017
Section 6.7 general guidance of management of IP-related toxicity was updated since the 
toxicity management guidance of immunotherapy was moved to section 6.7.1
Section 6.7.1 A new section number was given. Previous “MEDI4736 and MEDI4736 + 
tremelimumab” was now modified to “6.7.1 Specific toxicity management and dose 
modification information –MEDI4736  and MEDI4736  + tremelimumab”. The content was 
updated to match the latest version of Dosing Modification and Toxicity Management 
Guidelines (TMG, dated 01 Nov 2017). AESI was updated to match the updated 
durvalumab and tremelimumab Investigator’s Brochures and TMG.
Section number 6.7.2 was added as a result of addition of section number 6.7.1
Appendix G Dosing Modification and Toxicity Management Guidelines was updated to the 
latest version, 01 Nov 2017 Version
Version 6, 20 September 2017
Synopsis was modified to reflect the changes in Section 2 (Study objectives) and Section 8 
(Statistical analyses by Astrazeneca).
Protocol Synopsis and note for Table 3 was modified to reflect that Hepatitis B, C  and HIV 
assessments are not required to be collected a second time during retreatment. 

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Protocol Synopsis, Section 1.4 (Study design), note for Figure 1 (Overall study design) and 
Section 8.2 (Sample size estimate): Number of patients in China cohort was changed from 
approximately 96 to approximately 180, which was based on the change in co-primary 
endpoints.
Section 1.2.3 (Rationale for cisplatin-ineligible Interim Analysis): Rationale for Cisplatin-
ineligible Interim Analysis was added.
Section 1.4 (study design) -Table 1: Additional note was added to Table 1 definition of PD-
L1 high vs Low/negative to clarify the detail on scoring instructions for use in 
circumstances where tumor sample contains low immune cell content, which was used to 
stratify patients. 
Section 2 (study objectives) was revised to include the following major changes:
1. Changes to primary objectives: Removal of PFS from co-primary endpoint, and 
make it a secondary endpoint. This change is based on external data from 
competitor IO bladder cancer studies and data from AstraZeneca study 1108 
(NCT01693562) and study 10 (NCT02261220) in 2nd line bladder cancer patients 
treated with IO. 
2. Changes to secondary objectives: 
a.
Adding an interim analysis for the following purpose:

To evaluate the efficacy profile in MEDI4736 treated patients who 
are not eligible for cisplatin-based treatment.

For this interim analysis,  BICR review will be carried out only on 
patients who are not eligible for cisplatin-based treatment.

Adding safety objective to assess the safety and tolerability profile of  
MEDI4736 monotherapy and SoC in patients who are not cisplatin-
eligible.
b. Removing the efficacy comparison between monotherapy (or combination 
therapy) and SoC in cisplatin ineligible patients, as that is replaced by the above 
new interim analysis. 
c. Except cisplatin ineligible interim analysis, PFS, APF2, ORR, DoR and DCR 
will be based on investigator data according to RECIST 1.1 instead of BICR 
data.  

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d. Adding specific PRO endpoints to evaluate fatigue and pain as important 
symptoms of metastatic UC.  
e. Outcome measure of PK was updated to reflect the nature of the PK sampling 
scheme that is sparse and would not allow determination of meaningful PK 
parameters by non-compartmental PK analysis.
Section 4 (Study plan and timing of procedures): Table 3 footnote l, Table 4 footnote k, 
Table 5 footnote i, Table 6 footnote i, Table 7 footnote g was modified to add confirmation 
of response (PR/CR) in collecting of confirmatory scans.
Table 6 footnote g. ADA samples collection was cancelled from month 6 follow up visit 
based on safety input.
Table 6 footnote e. Table 7 footnote d was added to clairify that  PFS2 should be collected 
after the patient progression endpoint used for the first PFS.
Section 5.1 (Efficacy assessments) was revised to reflect the change in Appendix E to 
clearly define confirmation of progression.
Section 5.1.1 (Central reading of scans) was revised to reflect that BICR will be performed 
for cisplatin ineligible patients.
Section 5.2.1 (Laboratory safety assessments), Table 3, Table 4 and Table 5 have been 
amended to remove Urinalysis testing as it does not contribute to safety analysis. Original 
Table 10 for urinalysis is removed so that ‘Summary of outcome variables and analysis 
populations’ was changed from Table 11 to 10, ‘Preplanned statistical and sensitivity 
analyses to be conducted’ was changed from Table 12 to 11.  
Section 5.4.2 (Collection of samples to measure the presence of ADAs) was added to clarify
that ADA samples will be tested in AstraZeneca designated laboratory. The samples may 
need to be exported to USA for testing.
Section 6.3.1 (Time period for collection of adverse events) was added with clarity in the 
duration for SAE/AE collection and follow up.

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Section 7.2.1 (Treatment regimens), Table 4-footnote n, Table 5-footnote l: The section was 
updated to reflect that for patients receiving SoC treatment beyond 6 cycles, the exposure 
information will be reported in Exposure form and the schedule of assessment will be the 
same as the one for treatment within 6 cycles.
Section 8.1 (Statistical considerations) was updated to be consistent with Section 2 (study 
objectives). 
Section 8.2 (Sample size estimate)- Changes in this section includes the following: 
1. Change in sample size calculation. Based on external data from competitors 
(IMvigor 211 and Keynote 045) and data from AstraZeneca study 1108 
(NCT01693562) and study 10 (NCT02261220) in 2nd line bladder cancer trial,  PFS 
has been dropped from co-primary endpoints. The alpha previously assigned to PFS 
has been reassigned to OS (MEDI4736 monotherapy vs SoC in PD-L1-High).
2. Statisitical assumptions were revised: Based on the same data sources as mentioned 
above,  the previously assumed 2-month delay in separation of the OS curves should 
be revised to 6-month. Moreover, study D419BC00001 actually enrolled 40% 
cisplatin-ineligible patients,compared to 20% as originally planned. As a result, the 
sample size calculation of OS endpoints has been updated to accommodate these 
changes, and interim analysis timepoints has also been revised. 
3. Wording updated to be consistent with Section 2 (study objectives) and Section 8.5 
(MTP), i.e., removing wording regarding PFS (MEDI4736 monotherapy vs SoC) in 
PD-L1-High population, and adding content for OS (MEDI4736 monotherapy vs 
SoC) in all comers population.

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Section 8.3 (Definitions of analysis sets)- Changes include the following: 
1. Section 8.3- Table 10 (Summary of outcome variables and analysis populations) was 
updated to be consistent with Section 2 (study objectives). 
2. Section 8.3.5 (MEDI4736 cisplatin ineligible population) and Section 8.3.6 (Safety 
analysis set) was updated to add analysis sets definition to support interim analysis 
in patients who are not cisplatin-eligible.
3. Section 8.3.6 (Safety analysis set): Safety analysis set definition has been revised to 
be consistent with new Therapeutic Area standard.
4. Section 8.3.7 (PK analysis set): Definition of PK analysis set was updated to reflect 
the nature of the study design with a comparator arm.
Section 8.4 (Outcome measures for analyses)- Major changes include the following:
1. This section was updated to reflect the changes made in Section 2 (study objectives). 
2. Removal of the 3 month timepoint for DCR.
3. Further clarifications have been made around secondary endpoint, time from 
randomization to second progression.
4. Further clarification has been added around PK variables.
5. Section 8.4.3.1 FACT-BL: text has been added to characterize fatigue and pain as 
important symptoms of metastatic UC.
Section 8.4.4.1 (Population pharmacokinetics and exposure-response/safety analysis): text 
was revised to state that the population PK analysis and the relationship between PK and the 
effect on safety and efficacy endpoints “may” be evaluated instead of “will”; these 
modeling activities will be performed only if further evaluation of the data from this trial is 
required.
Section 8.4.4.2 (Pharmacokinetic analysis): text was revised to reflect that PK parameters 
will be derived from raw data and not from non-compartmental PK analysis due to the 
sparse PK sampling scheme that would not allow determination of meaningful PK 
parameters by non-compartmental PK analysis.

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Section 8.5 (Methods for statistical analyses)- Major changes include the following:
1. Table 11 was updated to reflect the changes in Section 2 (study objectives) and 
Section 8.4 (Outcome measures for analyses).
2. MTP was revised to reflect the change in co-primary and secondary endpoints.
a.
PFS (MEDI4736 monotherapy vs SoC) in PD-L1 High population was 
removed from MTP based on the same data souce as stated in Section 2 
(study objective). 
b. OS (Combination therapy vs SoC) in PD-L1 low/neg population was added 
into MTP as this population may benefit more from combination therapy.
3. Analysis methods was updated to match changes to primary and secondary study 
objectives.
4. Subsection 8.5.15 (Interim analyses) revised to include a new section. Section 
8.5.15.1 (Interim analysis focusing on ORR and DoR) was created to outline 
additional details regarding new interim analysis in patients who are not cisplatin-
eligible. Section 8.5.15.2 (Interim analysis of overall survival endpoints) was also 
updated to reflect the changes of OS interim analyses timing.
Appendix E (Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 
Criteria [Response Evaluation Criteria in Solid Tumors])- Changes in this section includes 
the following: 
1. Add clarification for Target lesion to clarify that a bilateral, segmented or multi-
lobular organ is considered as a single organ.
2. Table E1 (Summary of methods of assessment)- Add clarification in note for 
Clinical examination as one of the lesion assessment methods which refers to 
manually palpable tumor lesions.
3. Add Chest X-ray guidance as method of assessment to be used to assess NTL and to 
identify the presence of new lesions.

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Study Code D419BC00001
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4. Revised to clearly define confirmation of progression for SoC vs. Immunotherapy 
arm patients.
Version 5, 02 Feb 2017
Version history for Japan CSP is added as per local requirement.
An expansion cohort will continue in China once global enrollment has ended. The 
following sections have been amended to reflect this change: Protocol synopsis; Section 1.4 
Study design; Section 8.2 Sample size estimate. 
To further assess the efficacy of MEDI4736 +tremelimumab combination therapy compared 
to SoC and efficacy of MEDI4736 monotherapy compared to SoC in patients who are not 
cisplatin eligible is added in secondary objectives. The following sections have been 
amended to reflect this change: Protocol synopsis; Section 2 study objectives.  
The information “In Japan, this study will be started after the confirmation of tolerability of 
MEDI4736 (1.5 g q4W) + Tremelimumab (75 mg q4W) combination therapy in study 
D4880C00010 which is currently conducted in Japan.” is added in protocol synopsis as this 
is per PMDA requirement to ensure the safety of Japanese subjects.   
Emphasize that a further objective to evaluate consistency in efficacy and safety among 
Chinese subjects, as required by China FDA. The following sections have been amended to 
reflect this change: Protocol synopsis;  Section 2 study objectives.  
Protocol synopsis: “statistical methods” is updated to reflect the change in the split of alpha 
across the three proposed primary end-points and its impact.
Protocol synopsis: The paragraph “safety data” is about safety analyses, so remove the 
sentence not relevant with this, which is related with efficacy parameter PFS in subgroup 
analyses.
Statistical analysis is updated for China cohort. The following sections have been amended 
to reflect this change: Protocol synopsis; Section 8 Statistical considerations; Section 8.3.1 
Full analysis set; Section 8.3.5 Safety analysis set; 8.6 China cohort.     

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Clarify that written informed consent for retreatment and/or treatment through progression 
in the setting of PD will specify that treatment beyond evidence of initial PD is not the SoC 
and that alternative treatment options, including either locally licensed treatments or other 
clinical trials, are available for this patient population. The following sections have been 
amended to reflect this change: Protocol synopsis; Section 7.2.2 Duration of treatment, 
criteria for retreatment, and treatment through progression.
Table of contents: Section 8.3.4 Cisplatin ineligible analysis set and Section 8.6 China 
cohort are added in the table of contents.
The special term “PMDA” is added in the list of abbreviations and definition of terms.
Section 1.4 Study design: make clarification that the definition of PD-L1 high versus 
low/negative expression will be used for stratification. Different cutoff of PD-L1 expression 
may be utilized for analysis based on emerging data.
Section 1.4 Study design: clarify that approximately 96 Chinese patients will be randomized 
in the same criteria (stratification factors and 1:1:1 fashion) as globally.
Section 3.1 Inclusion criteria: clarify the New York Heart Association ≥Class III heart 
failure as one criteria for the Cisplatin ineligibility.
The optional genetic research is removed from informed consent. The following sections 
have been amended to reflect this change: Section 3.3 Patient enrollment and 
randomization; Footnote a in Section 4 Table 3, Table 4 and Table 5.
Section 3.10.2 withdrawal of the informed consent: give the clarification on the vital status 
follow up for all patients.        
Section 4 Table 3, Table 4 and Table 5: correct that the archival tumor sample should be ≤3 
years instend of < 3 years. 
Give clarification that after the initial assessment of PD, the confirmatory scan should be 
performed regardless if removed from drug. The following sections have been amended to 
reflect this change: Section 4 Table 3, Table 4, Table 5, Table 6 and Table 7; Section 5.1 
Efficacy assessments; Section 8.4.1.2 Co-primary endpoints.

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Give clarification that the scan in retreatment should occur relative to the date of first dose 
in retreatment. The following sections have been amended to reflect this change: Section 
5.1 Efficacy assessments; Section 7.2.2 Duration of treatment, criteria for retreatment, and 
treatment through progression.          
The appendix number is corrected in below sections: Section 5.2.1 Laboratory safety 
assessments; Section 5.5.4 Labeling and shipment of biological samples; Section 8.4.6 
Calculation or derivation of pharmacogenetics variables; Section 9.4 Data management by 
AstraZeneca; Section 10.2 Patient data protection.
Section 5.4 Pharmacokinetics: the blood volume collection of PK and ADA listed under the 
section has been removed and clarify that the samples will be collected, labelled, stored and 
shipped as detailed in the Laboratory Manual.  
Section 5.5.1.1 Exploratory biomarker data: the content is updated as the exploratory 
biomarker analyses is only applicable for the blood samples have already been obtained and 
tumor samples will be used for exploratory biomarker analyses in select countries only.   
Section 7.1 Identity of investigational products: the SoC drug supply strategy is added for 
Japan to clarify the procedure in Japan.
Section 7.2.2 Duration of treatment, criteria for retreatment, and treatment through 
progression: give clarification that Hepatitis B and C assessments, and HIV assessments 
don’t need to be collected again during retreatment.    
Section 7.7 Concomitant and other treatments: give clarification that the concurrent 
chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal therapy for cancer 
treatment, immunosuppressive medications, herbal and natural remedies are prohibited 
while the patient is on study treatment.   
Section 8.2 Sample size estimate: the statistical method in this part is updated to reflect the 
impact of the change in the split of alpha across the three proposed primary end-points.
Section 8.3 Definitions of analysis sets: the cisplatin ineligible analysis set is added in the 
section.

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Section 8.3.4 Cisplatin ineligible analysis set:clarify that “Cisplatin ineligible analysis set 
will include the subset of patients in the FAS whose are not eligible for Cisplatin 
treatment.”
Section 8.5 Methods for statistical analyses: the MEDI4736+tremelimumab combination 
therapy versus SoC and MEDI4736 monotherapy versus SoC in Cisplatin ineligible 
population are added under the stratified log-rank test for PFS and OS; The multiple testing 
strategy is updated to provide the investigators with the most current information; The 
figure 5 is updated for clarification; Give clarification that the effect of 
MEDI4736+tremelimumab combination therapy versus SoC treatment will be estimated by 
the HR together with its corresponding 99.5% CI and p-value for progression-free survival; 
The interim analyses is updated to provide the investigators with the most current 
information.
As the blood sample for pharmacogenetics research is only applicable for the samples 
already obtained, the following sections have been amended to reflect this change: Section 
8.4.6 Calculation or derivation of pharmacogenetic variables; Appendix C 
Pharmacogenetics Research.    
Version 4, 12 September 2016
Version 4 (Amendment 3) changes to Amendment 2 (Version 3, 19 August 2016) include 
all Amendment 2 (Version 3) changes and are summarized below.
Version number, amendment number, and date were updated throughout the document and 
cross-reference links to appendices were added.
The ordering of study objectives in Section 2 was corrected so that Primary objectives was 
changed from Section 2.3 to 2.1, Secondary objectives from Section 2.1 to 2.2, and Safety 
objectives from Section 2.2 to 2.3.  
In the final published version of the amendment, the portable document formats (PDFs) of 
the patient-reported outcomes (PROs) were inserted and the pagination and List of 
Appendices were updated.
Version 3, 19 August 2016 (not implemented)

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Version 3 (Amendment 2) changes to the original protocol (Version 1, 07 August 2015) are 
summarized below.
The AstraZeneca logo on the title page was updated, and the title page was revised to reflect 
the current AstraZeneca template, including deleting multiple title pages by country and 
rows for Administrative Amendment details.  The study title was revised to delete “bladder” 
from “urothelial bladder cancer,” and the abbreviation was changed from “UBC” to “UC.” 
“(Japan) AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan” was added to 
the title page per local requirement.
Header information was revised to reflect current information, and the footer was revised in 
accordance with the current AstraZeneca template.
Version history was added to reflect the current AstraZeneca template.  
The Synopsis was updated to reflect changes in the body of the amendment.  These changes 
and the rationale for them are detailed in the discussion of the specific sections.
The list of abbreviations was updated to include all abbreviations used in Amendment 2.  
Minor typographical errors, footnotes, and formatting were updated.  Editorial and 
formatting changes were also made for compliance with AstraZeneca’s new Clinical Study 
Protocol template.  Urothelial bladder cancer was revised to urothelial cancer, and the 
corresponding abbreviation was revised from UBC to UC throughout.  The designation of 
programmed cell death ligand 1 (PD-L1) status was changed from “positive” to “High” and 
from “negative” to “Low/Neg” throughout the document for clarity.
“Study Physician” was changed to “AstraZeneca” throughout to allow for responses from 
other Clinical and Operational Team Members as appropriate. 
“/Medimmune” was deleted from “Ventana/Medimmune” for clarity.
Revisions were made throughout the protocol to use IVRS/IWRS for Interactive Voice 
Response System and for Interactive Web Response System, respectively, consistently and 
delete the word “system” afterward because it is redundant.

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Subsection 1.2.1.1 (MEDI4736 + tremelimumab combination therapy dose rationale): 
“Clinical data” was updated to provide the Investigators with the most current information 
regarding the number of patients dosed and the doses they have received.  Revisions were 
made here and throughout the protocol to designate PD-L1 status as “High” or “Low/Neg” 
instead of positive or negative.
Subsection 1.3.2.1 (Potential risks: MEDI4736) was revised to reflect the most recent 
version of the Investigator’s Brochure (IB) and to provide the most current safety 
information to the Investigators.
Subsection 1.3.2.2 (Potential risks: Tremelimumab) was revised to reflect the most recent 
version of the IB and to provide the most current safety information to the Investigators.
Subsection 1.3.2.3 (Potential risks: MEDI4736 + tremelimumab combination therapy) was 
revised to reflect the most recent version of the IB and to provide the most current safety 
information to the Investigators.
Section 1.4 (Study design): The duration of treatment was removed to allow ongoing 
treatment.  This is based on emerging data that support the use of MEDI4736 beyond 
12 months.  A statement was added that crossover from Standard of Care (SoC) to either of 
the immunotherapy treatment arms will not be permitted.  The sample size was updated to 
1005 patients globally as a result of the addition of co-primary endpoints.
Table 1 was revised to include the footnote “Definition of PD-L1 of high versus 
low/negative expression will be used for stratification and primary analysis. Subset analyses 
on different definitions of PD-L1 expression may be performed based on emerging data.”  
This change was made to be consistent with the statistical analysis plan.
Visceral metastasis was more specifically defined as “presence or absence of lung and/or 
liver metastasis.”
Section 1.4 (Study design): Figure 1 (Overall study design) was revised to reflect the 
increased sample size (1005 patients, 335 per treatment arm) and to add definitions in the 
footnote.
Section 1.4 (Study design): Figure 2 (Study flow chart) was revised to reflect the change to 
the duration of treatment and add definitions to the footnote.

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Section 2 (Study objectives) was revised to include overall survival (OS) as a primary 
objective with progression-free survival (PFS) based on the emerging immunotherapy data.  
Section 2.1 (Primary objectives) was revised to include OS in the primary objectives and 
outcome measures.  An explanatory footnote and definitions of abbreviations were also 
added.
Section 2.2 (Secondary objectives) was revised to reflect the change in primary objectives, 
add new secondary objectives/outcome measures, and reorder them in order of priority.  
Redundant objectives were deleted.  The previous footnotes for ongoing data analysis and 
sensitivity analyses for objective response rate (ORR) and duration of response were 
removed because they are no longer applicable.  The Physical Well-Being (PWB) domain 
of the Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-BL) was 
replaced with FACT-BL Trial Outcome Index (FACT-BL TOI) as one of the outcome 
measures because it is a broader concept than PWB, incorporating the Functional 
Well-Being (FWB) and Bladder Cancer Subscale (BlCS) in addition to PWB.  
Abbreviations in the table footnote were updated. 
Section 2.3 (Safety objective): The definitions of abbreviations were added.
Section 2.4 (Exploratory objectives) was updated to clarify BICR assessments, to include 
PWB domain of the FACT-BL, BlCS, and Functional Assessment of Cancer Therapy -
General (FACT-G) Total score outcome measures and remove serum PD-L1 and circulating 
soluble factors as outcome measures.  The number of PRO-CTCAE (Patient-reported 
outcomes version of the Common Terminology Criteria for Adverse Events) symptoms was 
specified.  Additional definitions of abbreviations were added.
Section 3.1 (Inclusion criteria): 

Inclusion criterion 3 was revised to include a reference to the National 
Comprehensive Cancer Network Bladder Cancer Guidelines, revise and clarify 
the language regarding treatment for locally advanced disease, and clarify that 
progression is “to Stage IV disease.”  

Inclusion criterion 7 was revised to provide a more detailed description of the 
creatinine clearance level that would render a patient eligible or ineligible for 

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cisplatin-based therapy and to change the sub-bullet of CTCAE Grade >2 
peripheral neuropathy to ≥2.   These changes were made for safety and clarity.

Inclusion criterion 8 was revised to correct that available tumor samples could be 
taken ≤3 years instead of <3 years prior to screening.  A correction was made to 
the final sentence in this criterion: “eligibility” was corrected to “PD-L1 status.”

Inclusion criterion 9 was revised to provide a more detailed description of the 
creatinine clearance level that constitutes adequate organ function, and to clarify 
IVRS data entry requirements This change was made for safety and clarity.

Inclusion criterion 10 was revised for more detail regarding the definition of 
women as postmenopausal.  Having undergone surgical sterilization, bilateral 
oophorectomy, bilateral salpingectomy, and hysterectomy was added.
Section 3.2 (Exclusion criteria): The section was generally revised to include abbreviations 
and terminology per AstraZeneca formatting and standards.  

Exclusion criterion 4 was revised to add the following statement for clarity: 
“Prior local intervesical chemotherapy or immunotherapy is allowed if completed 
at least 28 days prior to the initiation of study treatment.”

Exclusion criterion 5 was revised to add the National Cancer Institute (NCI) 
CTCAE Version (4.03), and the first sub-bullet was corrected from Grade <2 
neuropathy to Grade ≥2 neuropathy.

Exclusion criterion 10 was revised for clarity; “but not limited to” was added, and 
the phrase “celiac disease, irritable bowel disease, or other serious GI chronic 
conditions associated with diarrhea” was deleted from the main criterion as well 
as the qualifier of “within the past 3 years prior to the start of treatment.” The 
following sub-bullets were deleted, edited, or added: “psoriasis requiring 
systemic treatment” was deleted and replaced with “Any chronic skin condition 
that does not require systemic therapy.”  “Patients without active disease in the 
last 3 years may be included but only after consultation with AstraZeneca” was 
added.  “Patients with celiac disease controlled by diet alone may be included but 
only after consultation with AstraZeneca” was added. These changes were made 

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to permit appropriate patients to enter the study while maintaining rigorous safety 
standards.

Exclusion criterion 11 was revised for clarity to add “uncontrolled diabetes” and 
“serious chronic GI conditions associated with diarrhea.”

Exclusion criterion 12 was revised to specify “Other malignancy within 5 years 
before first dose of IP, except for the following pending a discussion with 
AstraZeneca: 
-Patients with a history of prostate cancer (tumor/node/metastasis stage) of stage 
≤T2cN0M0 without biochemical recurrence or progression and that in the 
opinion of the Investigator are not deemed  to require active intervention”
-Patients who have been adequately treated for malignancy with a low potential 
risk for recurrence (eg, cervical carcinoma in situ, non-melanomatous carcinoma 
of the skin, or ductal carcinoma in situ of the breast that has been surgically 
cured).”

Exclusion criterion 14 was revised to provide more specificity regarding brain 
metastases or spinal cord compression that would exclude a patient and that 
magnetic resonance imaging (MRI) is the preferred test for patients with 
suspected brain metastases, preferably with intravenous (IV) contrast.  These 
changes were made for clarity, safety, and consistency.

Exclusion criterion 15 was revised to specify that a clinically significant 
electrocardiogram (ECG) abnormality at screening requires triplicate ECG results 
and a mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
≥470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes).  
This change was made as a safety measure.

Exclusion criterion 17, which had been active tuberculosis, was combined with 
the following criterion and now reads: “Active infection, including tuberculosis 
(clinical evaluation that includes clinical history, physical examination and 
radiographic findings, and TB testing in line with local practice), hepatitis B, 
hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 
antibodies).  Active hepatitis B virus (HBV) infection is defined by a positive  
HBV surface antigen (HBsAg) result.  Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core IgG antibody and the 

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absence of HBsAg, deoxyribonucleic acid [DNA] negative) are eligible.  Patients 
positive for hepatitis C virus (HCV ) antibody are eligible only if polymerase 
chain reaction is negative for HCV ribonucleic acid (RNA).”

Exclusion criterion 18 was revised from MEDI4736 or tremelimumab to “IP” 
since verifying eligibility occurs before randomization.
Section 3.3 (Patient enrollment and randomization) was revised in Item 1 under 
randomization to define the SoC “based on cisplatin eligibility.”  Item 2 was revised to read 
“Ensure PD-L1 status results are received by the IVRS/IWRS from the central laboratory 
prior to randomization.”  Item 3 was revised to define visceral metastases as “metastatic 
disease in lung and/or liver.”  PD-L1 status results was deleted from Item 4 since it is now 
part of Item 2.  The next to last paragraph now reads: “It is strongly recommended that 
patients commence study drug on the same day as randomization by IVRS/IWRS.  
If same-day treatment is not possible, then the study treatment must occur within 
3 working days of randomization.  Patients must not be randomized unless all eligibility 
criteria have been met.”. Clarifying language was added to ensure that creatinine clearance 
values obtained closest to Cycle 1 Day 1 be used for the purposes of IVRS data entry and 
randomization. 
Section 3.5 (Methods for assigning treatment arms) was revised to allow study treatment to 
begin within 3 working days of randomization if same-day treatment is not possible, as 
specified in Section 3.3.  This change was made for flexibility while maintaining temporal 
proximity to screening findings.
Section 3.8 (Restrictions) was revised and reordered for logic and clarity.  Bullet 1 now 
applies to all patients (in all treatment arms) and specifies restrictions on donating blood or 
blood components.  Bullet 2 is now designated for the immunotherapy treatment arms and 
specifies that 1 highly effective method of contraception is acceptable and to delete the 
requirement that female patients use a hormonal method in addition to a barrier method.  
Table 2 was updated to reflect highly effective methods of contraception.  A cross-reference 
to concomitant medication restrictions was added.
Section 3.9 (Discontinuation of investigational product) was revised: Criterion 7 was 
changed to state that “Confirmed PD and Investigator determination that the patient is no 
longer benefiting from treatment with IP.”  This change was made to clarify this criterion 
for discontinuation of IP.

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Section 3.9.1 (Procedures for discontinuation of a patient from investigational product) was 
revised to correct the reason(s) for discontinuation, not withdrawal, and to strongly 
recommend the Investigator to discuss a patient’s case with AstraZeneca prior to 
discontinuing the patient from the investigational product.  This change was made to ensure 
appropriate action was being taken regarding the patient’s care and treatment.  The 
statement “All study drugs should be returned by the patient” was deleted as all study drugs 
are administered at the investigational site.
Section 3.11 (Discontinuation of the study) was revised to add a cross-reference to Section 
6.7.2, the new section heading for the IDMC.
Section 4 (Study plan and timing of procedures), introductory paragraph: The following text 
was added for clarification: “Patients who continue beyond C13 continue with all C13 
assessments until termination of treatment (Table 3).”  In addition, in this section and 
throughout the protocol, clarification was made that PRO and RECIST assessments are 
based on the randomization date.  
Section 4 (Study plan and timing of procedures): Descriptions of assessment timing for all 
treatment arms and for immunotherapy and SoC treatment arms were added before all the 
tables of Schedules of Assessments to clarify dosing delays and subsequent assessments.  A 
statement was added to all Schedules of Assessments to clarify timing of assessments 
relative to dosing cycle and date of randomization.  The window of ±3 days and for tumor 
assessment ±7 days was deleted from within the tables since that is now specified above 
each table.  Bolded subheadings were added for clarification.  
For clarity, a footnote was added to Schedule of Assessment Tables 3 through 7 that states 
“PRO assessment dates remain as originally scheduled, as they are based on the date of 
randomization (not the date of therapy) and are not affected by dose delays.”

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Table 3 title was updated to reflect the possibility of extension of treatment beyond 
Cycle 13.  A statement was added above Table 3 to clarify IVRS data entry requirements.  
Table 3: a row was added for Patient follow-up contact on Day 14 of Cycles 1, 2, and 3.  
This was added for safety.  Vital sign checks at every cycle were added for clarity.  Timing 
of quality-of-life assessments was revised to provide the frequency of these assessments 
beyond Cycle 13.  The liver enzyme panel row was deleted because it is redundant with the 
complete chemistry panel row immediately above.  Other rows deleted for patients enrolled 
after implementation of this version of the protocol were as follows: serum PD-L1 
concentration, circulating soluble factors, PBMCs, and miRNA/mRNA, urine for 
exploratory biomarkers, SNP genotyping, MDSCs, and PGx sample (optional [DNA] 
element).  A window of ±7 days was added to the row for tumor assessment (computed 
tomography [CT] or MRI).  Specifications in the footnotes regarding “pre-dose” were 
revised from “within 60 minutes prior to start of infusion” to “may not exceed 6 hours prior 
to start of infusion” to allow flexibility yet maintain standards of safety and for consistency 
with changes to Section 5.2 (Safety assessments).  Sampling was also revised to specify 
within “1 hour” of the end of infusion for clarity.  Footnotes were re-designated in 
accordance with deletions of rows and items in the table.  Footnote “i” was revised to add 
“NOTE: All PROs MUST be administered before ALL procedures including medication 
infusion(s).  PROs must be completed using ONLY the electronic devices; paper 
questionnaires are not allowed.”  These changes were made to reinforce the use of validated 
PRO tools in the study and to ensure that they are administered before any medication 
infusion.  The “retreatment” note was revised to eliminate the limitation of 12 months and 
to specify that retreatment is only applicable to patients in the MEDI4736 + tremelimumab 
combination arm.  Additional definitions of abbreviations were also added.

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Section 4 (Study plan and timing of procedures), Table 4.  A statement was added above 
Table 3 to clarify IVRS data entry requirements.  Serum or plasma chemistry checks were 
revised with Day 2 assessments being deleted because it is no longer necessary.  The liver 
enzyme panel row was deleted because it is redundant with the complete chemistry panel 
row immediately above.  Other rows deleted for patients enrolled after implementation of 
this version of the protocol were as follows: serum PD-L1 concentration, circulating soluble 
factors, PBMCs, and miRNA/mRNA, urine for exploratory biomarkers, SNP genotyping, 
MDSCs, and PGx sample (optional [DNA] element).  The tumor assessment row was 
revised to add a window of ±7 days and to change from “until progression” to “until 
confirmed disease progression.”  Footnote “i” was revised to add “NOTE: All PROs MUST
be administered before ALL procedures including medication infusion(s).  PROs must be 
completed using ONLY the electronic devices; paper questionnaires are not allowed.”  
These changes were made to reinforce the use of validated PRO tools in the study and to 
ensure they are administered before any medication infusion.  Other footnotes were 
renumbered as appropriate.  Additional definitions of abbreviations were added.
Section 4 (Study plan and timing of procedures), Table 5.  A statement was added above 
Table 3 to clarify IVRS data entry requirements.  The liver enzyme panel row was deleted 
because it is redundant with the clinical chemistry panel row immediately above.  Other 
rows deleted for patients enrolled after implementation of this version of the protocol were 
as follows: serum PD-L1 concentration, circulating soluble factors, PBMCs, and 
miRNA/mRNA, urine for exploratory biomarkers, SNP genotyping, MDSCs, and PGx 
sample (optional [DNA] element).  The second tumor biopsy row was revised for 
consistency to add” is required.”  The row for tumor assessment (CT or MRI) was revised 
from “until progression” to “until confirmed disease progression.”  Table footnotes were 
updated for clarity and consistency. Footnote “h” was revised to add “NOTE: All PROs 
MUST be administered before ALL procedures including medication infusion(s).  PROs 
must be completed using ONLY the electronic devices; paper questionnaires are not 
allowed.” These changes were made to clarify to the site the use of validated PRO tools in 
the study to properly record this information. 

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Footnote “c” was revised to include “LFT results should be available and reviewed by the 
treating physician or Investigator prior to the start of each chemotherapy cycle, per local 
routine practice,” and to ensure that patients are adequately monitored.  Footnote “i” 
(previously j) was revised to add “Baseline assessments, ideally, should be performed as 
close as possible prior to the start of study treatment.  The confirmatory scans should 
preferably be performed at the next scheduled visit (relative to the date of randomization) 
and no less than 4 weeks after the initial assessment of PD (in the absence of clinically 
significant deterioration).  If an unscheduled assessment was performed and the patient has 
not progressed, every attempt should be made to perform the subsequent assessments at his 
or her scheduled visits (relative to the date of randomization).  All confirmatory scans 
should be recorded on the database.”  
Section 4 (Study plan and timing of procedures), Table 6: Serum PD-L1 concentration, 
circulating soluble factors, PBMCs, and miRNA/mRNA, urine for exploratory biomarkers, 
SNP genotyping, MDSCs, and PGx sample (optional [DNA] element).  Footnote “a” was 
revised to state “for women of childbearing potential” with the remainder of the text deleted 
because this is not applicable to this table.  Footnote “b” was revised to be 2-monthly calls 
instead of 3-monthly calls.  Footnote “d” was revised to state “Will be collected until the 
end of the clinical phase of the study (final study visit).”  Footnote “h” was revised to add 
“NOTE: All PROs MUST be administered before ALL procedures including medication 
infusion(s).  PROs must be completed using ONLY the electronic devices; paper 
questionnaires are not allowed.”  These changes were made to reinforce the use of validated 
PRO tools in the study.
Section 4 (Study plan and timing of procedures), Table 7: Footnote “a” was revised to state 
“for women of childbearing potential” with the remainder of the text deleted because this is 
not applicable to this table.  Footnote “b” was revised to be 2-monthly calls instead of 
3-monthly calls.  Footnote “e” was revised to add “NOTE: All PROs MUST be 
administered before ALL procedures including medication infusion(s).  PROs must be 
completed using ONLY the electronic devices; paper questionnaires are not allowed.”  
These changes were made to reinforce the use of validated PRO tools in the study and to 
ensure that they are administered before any medication infusion.

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Section 4.1 (Enrollment/screening period): The second sentence of paragraph 2 was revised 
to specify that all screening/baseline procedures must be performed within 28 days before 
randomization, with the exception of the patient’s tumoral PD-L1 status (must be performed 
within -56 days before randomization).”  This change was made because 28 days of 
randomization is more appropriate as the first dose may occur up to 3 days after 
randomization so this was added for clarity and to ensure consistency of the screening 
activities in relation to the randomization date.  Clarifying language was added to ensure 
that creatinine clearance values obtained closest to Cycle 1 Day 1 be used for the purposes 
of IVRS data entry and randomization.
Section 4.2 (Treatment period): The section was revised to extend treatment duration 
beyond Cycle 13 for patients randomized to the MEDI4736 ± tremelimumab or MEDI4736 
monotherapy treatment arms and also to add retreatment information “Note that patients 
randomized to the MEDI4736 ± tremelimumab or MEDI4736 monotherapy treatment arms 
may continue to be treated beyond Cycle 13.  Patients in the MEDI4736 + tremelimumab 
arm who complete 4 dosing cycles and subsequently have PD during treatment with 
MEDI4736 alone may restart combination treatment if they meet eligibility criteria for 
retreatment (see Section 7.2.2) and are deemed to have clinical benefit per Investigator 
judgment.”  This revision is based on emerging data that support the use of 
MEDI4736 ± tremelimumab past 12 months.  
Section 4.3 (Follow-up period): The following statement was added: “For patients who 
require IP treatment to be held for toxicity and subsequently discontinue therapy without 
restarting IP, all follow-up assessments will be based on the date of the last dose of IP.”  
This change was made for clarification of follow-up assessment timing.

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Section 5.1 (Efficacy assessments) was revised for clarity, to specify that PFS2 is defined 
by local standard clinical practice and to include that all on-study assessments should utilize 
the same mode of scanning (CT or MRI) as baseline scans for accurate comparisons.  The 
statement “Schedule of required RECIST assessments is based on the date of 
randomization, not on the date of C1D1” was added for clarity.  A window of ±7 days was 
added for objective tumor assessments every 8 weeks, and that every 8 weeks is relative to 
the date of randomization and regardless of dosing delays until confirmed disease 
progression.  Criteria for confirmed progression were added for clarity.  Retreatment 
information was also added.  Specific criteria for disease progression were added, and 
clarification was made regarding patients who discontinue treatment.  A paragraph was 
added to allow patients in the combination arm who subsequently have progressive disease 
during treatment with monotherapy to restart treatment if they meet the eligibility criteria 
for retreatment specified in Section 7.2.2.  Text in the paragraph on patients who achieve 
and maintain disease control being allowed to restart treatment was deleted, and the rest of 
the text was moved to the previous paragraph.  Minor edits for consistency and clarity were 
also made in this section.
Section 5.1.1 (Central reading of scans) was revised for clarity to include “and scans from 
subsequent non-protocol therapy (if required per protocol),” and regarding the collection of 
scans for analysis, the term “a random sample of patients” was deleted since central reading 
will apply to all scans.  In addition, the basis of the independent reviews was changed from 
“results of the RECIST assessment” to “local assessments.”  
Section 5.2.1 (Laboratory safety assessments): Table 8 was revised to allow optional testing 
of bicarbonate, gamma glutamyltransferase, and total protein in certain countries.  Footnote 
“b” was revised to change from “baseline” to “Screening, Cycle 1 Day 1” for clarity.
Table 9 was revised to remove the following hematology tests: Basophils, eosinophils, 
hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
mean corpuscular volume, and red blood cell count because these are unnecessary for safety 
and to reduce the amount of blood drawn from the patients.  Laboratory assessments that 
are not necessary to monitor safety based on the toxicity profile of the IP or SoC arms were 
removed to reduce patient burden. 
Clarifying language was added to ensure that creatinine clearance values obtained closest to 
Cycle 1 Day 1 be used for the purposes of IVRS data entry and randomization.

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Section 5.2.4 (Vital signs) was revised for clarity that vital signs, including body weight, 
will be recorded for all treatment arms at all visits and blood pressure will be performed 
with the patient supine or semi-supine.  These changes were made for safety purposes and 
clarity.  Additional clarification was made for patients in the immunotherapy treatment arms 
for the first infusions, and redundant text was deleted.  A paragraph specifying collection 
and measurement of blood pressure and pulse measurements was added for completeness 
and clarity, and a paragraph specifying monitoring of MEDI4736 combination and 
monotherapy patients at subsequent infusions was added for completeness and clarity.
A new paragraph providing the same level of detail for vital sign collection was added for 
patients in the SoC treatment arm for completeness and clarity.
Section 5.2.5 (Other safety assessments): A paragraph was added for additional safety 
monitoring: “If new or worsening pulmonary symptoms (eg, dyspnea) or radiological 
abnormality suggestive of pneumonitis/interstitial lung disease is observed, toxicity 
management as described in detail in the Dosing Modification and Toxicity Management 
Guidelines (see Appendix G) will be applied. The results of the full diagnostic workup 
(including high-resolution computed tomography (HRCT), blood and sputum culture, 
hematological parameters etc) will be captured in the eCRF. It is strongly recommended to 
perform a full diagnostic workup, to exclude alternative causes, such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines (Appendix G) should be followed.”  
Another paragraph was added (including emphasis) for patients to be contacted 2 weeks 
after receipt of the first 3 cycles of study drug: “It is strongly recommended that patients 
are contacted 2 weeks after receiving the first 3 cycles (Cycle 1 Day 14, Cycle 2 Day 14, 
and Cycle 3 Day 14) of study drug(s) to ensure early identification and management of 
toxicities.”  This was done to ensure early identification of toxicities.  
Section 5.3.1 (Patient-reported outcomes): All subsections were updated to reference 
“Appendix F” and for clarity a statement was added that PRO assessment dates are based on 
the randomization date.  
Section 5.3.1.3 (PGIC) was revised to add that PGIC was added “for assessing the overall 
impact of treatment.”

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Section 5.3.2 (Administration of the patient-reported outcome questionnaires): The first 
bullet was revised to add “including medication infusion(s)” for clarification. The fifth 
bullet had the following text added for clarification and consistency: “All questionnaires 
must be completed using the ePRO device; paper questionnaires are not allowed in this 
study.”  These changes were made to clarify that PROs must be administered electronically 
and before medication infusion.
Section 5.4.2 (Collection of samples to measure the presence of ADAs) was revised to 
specify blood draw volume.
Section 5.4.3 (Storage and destruction of pharmacokinetic/ADA samples): The first 
paragraph was revised to allow retention for 15 years from the last patient’s last visit date 
for research purposes.
Section 5.5 (Biomarker analysis) and Table 11: The following sentence was added “Based 
on availability of tissue, additional exploratory biomarkers may also be evaluated as 
described in Section 5.5.1.1.”  Paragraph 3 regarding additional exploratory biomarkers was 
deleted as these are no longer being collected.  The table of timepoints and blood and urine 
volumes was deleted for the same reason.  These exploratory biomarkers were removed to 
lessen patient burden.  The statement of how sPD-L1 concentration will be measured was 
deleted because that is no longer being performed.  Bullet 2 paragraphs 3 and 4 were 
revised to replace “eligibility” with “PD-L1 status.” These changes were made for clarity. 
Section 5.5.1 (Evaluation of candidate, predictive markers - tumor PD-L1), Bullet 3 of 
paragraph 1 was revised to add the phrase “and acceptable tissue sampling” at the end of the 
paragraph for completeness regarding the contents of the Laboratory Manual.  The wording 
of when the Investigator consults with AstraZeneca was revised from “must” to “should.” 
Following the bullets, the first paragraph was revised to add that PD-L1 status for 
stratification will be used “to evaluate potential predictive biomarkers.” Paragraph 5 was 
revised to delete the statement regarding RECIST 1.1 target lesions and added specification 
regarding use of core needle and the timing before imaging scans are acquired.  

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Subsection 5.5.1.1 (Exploratory biomarker data): This was revised to specify that only 
tumor and/or blood samples obtained prior to implementation of this version of the protocol 
will be used for exploratory biomarker analyses in selected countries only.  This was a 
result of the decision to delete sampling for PD-L1, PK, PGx, and soluble factors.  The 
pharmacodynamic changes in biomarker measures paragraph was revised to delete the note 
“Samples will be obtained from patients randomized to each treatment arm” since they are 
no longer being collected.  The sentence regarding data comparison was revised to include 
comparison across times of treatment.  The statement regarding “similar comparisons” of
baseline measures was deleted as those are no longer planned.
Subsection of 5.5.1.1, Tumor markers (in FFPET) was revised to delete the statement 
regarding CD8 and CD4/FoxP3 and add the statement that “Markers evaluated may change 
based on the best available information at the time  of the biomarker analysis.”  The second 
paragraph of the subsection was revised to add that tissues may be assessed for tumor 
burden and neo-antigen prediction,” to delete “CXCL10,” and to add “LAG3 and CD274.”  
The remainder of the sentence was deleted and replaced with “targeted RNAseq and/or 
other gene expression methodologies” as a refinement of what tumor markers will be 
analyzed and how.  The next paragraph heading was revised from “Whole blood for DNA” 
to “When available, genomic DNA” in recognition that this will apply only to patients 
enrolled prior to the implementation of this version of the protocol.  This statement was 
added to the next paragraph.
The paragraph regarding genotype correlation was deleted as was the heading “Whole 
blood gene expression (PaxGene RNA)” and the first sentence under that heading.  
The bolded section “Myeloid-derived suppressor cells” was revised to state that flow 
cytometry may be completed on available patient samples obtained prior to the 
implementation of this version of the protocol and delete analysis of MDSC count 
thresholds.  

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The bolded subsection “Peripheral blood mononuclear cells” was revised to add “Soluble 
factors (plasma)” to the heading and reduce the number of potential downstream analyses.  
The separate bolded subsection heading “Soluble factors (plasma)” was deleted as was the 
first paragraph, which was replaced with “Plasma will be obtained to explore expression of 
cytokines and chemokines, including but not limited to IFN-γ, interleukin (IL)-18, CXCL9, 
and CXCL10.”  The paragraph on use of plasma for detection/quantification of 
autoantibodies was deleted, as these tests are no longer being performed.
The bolded subsection “Urine-based markers” was revised to state that the samples will be 
used to explore gene expression analyses as well as cytokine/chemokine analyses and delete 
the remainder of the specifications.
Section 5.5.3 (Storage, re-use, and destruction of biological samples) was revised for clarity 
regarding the length of time the biological samples will be retained.
Section 5.6 (Pharmacogenetics) was deleted as these samples are no longer being collected.  
Section 6.1 (Definition of adverse events) was revised for clarity that a pre-existing medical 
condition does not include the progression of the malignancy under evaluation.
Section 6.3.1 (Time period for collection of adverse events) was revised to include the 
adverse event (AE) and serious adverse event (SAE) follow-up period for all treatment arms 
and that AEs and SAEs collected prior to randomization will be reported as 
pre-randomization AEs and SAEs for clarity.
Section 6.3.4 (Relationship to protocol procedures) was revised to add “and after an 
informed consent has been signed” into the parenthetical about SAEs that occur prior to the 
administration of IP to clarify that informed consent must be signed before administration 
of IP.
Section 6.3.7 (Hy’s Law) was revised for clarity and to reference “Appendix D.”
Section 6.3.8 (Disease progression) was revised for clarity to include “or SAE” regarding 
metastasis to the primary cancer under study being considered disease progression and not 
an AE or SAE.

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Section 6.3.10 (Deaths) “Safety Physician” was revised to “monitor” throughout this section 
for clarity of reporting, and the final phrase of Bullet 2 was revised to “and should assign a 
single main cause as well as any contributory causes of death.”
Section 6.4 (Reporting of serious adverse events) was revised to include “including 
supporting data” to be recorded in the eCRF and also include instructions to enter into the 
eCRF any follow-up information on a previously reported SAE.
Section 6.5 (Overdose) was revised to add information on overdose treatment for patients 
randomized to SoC and recording of an overdose for safety and clarity.
Section 6.7 (Management of IP-related toxicities) was revised to add “IP-related,” delete the 
specification regarding continuing “the same dose of the” IP, and add a bolded bullet 
specifying “It is important to note that these Guidelines are prepared by the Sponsor 
to assist the Investigator in the exercise of his or her clinical judgment in treating these 
types of toxicities.” A statement was made that all toxicities will be graded according to 
NCI CTCAE Version 4.03, and a paragraph was added referencing the IB for MEDI4736 
and tremelimumab and the Dosing Modification and Toxicity Management Guidelines.  An 
explanatory statement regarding the guidelines was added.  Outdated and redundant text 
was deleted.
The heading “MEDI4736 monotherapy and MEDI4736 + tremelimumab combination 
therapy adverse events of special interest” was added, and updated information for adverse 
events of special interests (AESIs) for MEDI4736 ± tremelimumab was added, including a 
bulleted list of AESIs observed with MEDI4736 ± tremelimumab.  These changes were 
made for clarity and safety, and outdated and redundant information was deleted. The last 
paragraph was expanded to provide for postponing dosing.
The heading 6.8 (Study governance and oversight) was deleted, and the heading 6.7.2 
“IDMC” was added for clarity.  Section 6.7.2 paragraph 2 the timing of the second IDMC 
meeting was changed to “approximately” 3 months after the first IDMC meeting or when 
90 patients are enrolled, whichever occurs first.
Section 7.1 (Identity of investigational products) and subsections were revised to update the 
investigational product information.

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Section 7.2.1 (Treatment regimens): Text and Figure 3 and Figure 4 were revised to reflect 
that dosing may continue beyond Cycle 13, and a paragraph was added to include more 
specific information on patients who are deemed by the Investigator as unable to tolerate a 
cisplatin regimen for clarity and as a safety measure.  A new paragraph was added 
regarding changing from cisplatin to carboplatin: “Patients randomized to the SoC arm with 
cisplatin and gemcitabine who receive at least 1 cycle of cisplatin and gemcitabine and by 
physician’s determination are unable to tolerate subsequent cisplatin cycles will be allowed 
to change from cisplatin to carboplatin 1 time.  The criteria justifying the change from 
cisplatin to carboplatin during study treatment must be documented in the eCRF.”
Section 7.2.2 (Duration of treatment, criteria for retreatment, and treatment through 
progression) was edited to revise the Section title and to add in italicized subheadings for 
clarity.  In addition, the limit of 12 cycles of treatment was deleted to allow continued study 
treatment at the Investigator’s discretion and to include retreatment information.  These 
changes were based on emerging data that support the use of MEDI4736 past 12 months.  
Revisions were made to clarify the criteria for retreatment (an italicized subheading, 
“Retreatment”).  Italicized subheading “Criteria for retreatment and treatment through 
progression” was added, new text was added, and the existing text under this subheading 
was revised for clarity and completeness.  The statement regarding continued safety 
monitoring and follow up for patients who discontinue treatment due to toxicity or 
symptomatic deterioration or who commenced subsequent anticancer therapy was revised 
for clarity.  Outdated and redundant text was deleted.  
Section 7.3 (Labeling) was revised to include Japan and other countries.
Section 7.6 (Accountability) was revised to remove the sentence that it is the responsibility 
of the Investigator to ensure that the patient has returned all unused study drug because this 
is not applicable since the study drugs are administered intravenously.
Section 7.7 (Concomitant and other treatments) was revised for clarity and to include 
collection of data for safety purposes regarding herbal and natural remedies and palliative
treatment for oncologic emergencies and the reason they were prescribed.  The table of 
prohibited medication/class of drug was revised for completeness.
Section 7.8 (Post-study access to study treatment) was revised to reflect the change in the 
duration of treatment.  

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Section 8.2 (Sample size estimate): Changes were made to sample size (approximately 
1340 patients enrolled to randomize 1:1:1 approximately 1005 patients over a period of 16 
months, with approximately 335 patients being randomized to each treatment arm.  
Explanation of the sample size was added, and corresponding changes throughout the 
section were made for consistency.  Also revised and/or added were the timing of the final 
analysis of PFS, the final analysis of OS, and a second interim analysis; specifications for 
all of these factors are provided.
Section 8.2 (Sample size estimate): Sections on MEDI4736 versus SoC (OS in PD-L1-High 
UC) and MEDI4736 versus SoC (PFS in PD-L1-High UC) were added.  Throughout the 
statistical section, changes were made to reflect the change in PD-L1 terminology from 
positive or negative to High or Low/Neg.
Section 8.3 (Definitions of analysis sets): Table 11 was revised to add OS as an outcome 
variable in addition to PFS.
Section 8.4.1 (Calculation or derivation of efficacy variables) and subsection 8.4.1.2 
(Co-primary endpoints: Progression-free survival) were revised for clarity and to change the 
analysis of PFS by the “Investigator” to by “BICR” as a more rigorous standard.  PFS 
analysis will be based on full Blinded Independent Central Review (BICR) data instead of 
site Investigator data (with a BICR random sample).
Subsection 8.4.1.1 (RECIST 1.1-based endpoints) was revised to move the new bolded 
subsection “Blinded Independent Central Review of RECIST 1.1-based assessments.”  The 
statement regarding prior radiotherapy reports was deleted, consistent with BICR strategy 
as outlined in the Imaging Charter. 
Subsection 8.4.1.2 (Co-primary endpoints) heading was revised from “primary” to 
“co-primary” endpoints and to clearly state the co-primary endpoints.  The section was also 
revised to change the analysis of PFS by the “Investigator” to by “BICR” as a more 
rigorous standard.  The rules for the determination of date of progression by the reviewer 
were revised for clarity. The section was also updated to move subsection “Overall 
survival” from the secondary endpoints to the co-primary endpoints section.  Additional text 
clarifying how the date of progression will be determined was added.
Section 8.4.1.3 (Secondary endpoints) was revised to delete “Overall survival” since it is 
now a co-primary endpoint and no longer a secondary endpoint.

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Subsection 8.4.1.3 (Secondary endpoints: Proportion of patients alive and progression free 
at 12 months, Objective response rate, and Duration of response) was revised to change the 
analysis of PFS by the “Investigator” to by “BICR” as a more rigorous standard.
Subsection 8.4.1.3 (Secondary endpoints: Objective response rate) was revised to remove 
the description of the algorithm for ORR.
Subsection 8.4.1.3 (Duration of response) was revised for assessment by BICR and delete 
the description of the algorithm regarding DoR.
Subsection 8.4.1.3 (Secondary endpoints: Disease control rate) was revised to change the 
duration of stable disease from“52 weeks” to “48 weeks,” and days were revised 
accordingly.  Analysis of PFS by the “Investigator” was changed to by “BICR” as a more 
rigorous standard to support the Phase 3 study.  Information for unconfirmed disease 
progressions was removed.
Subsection 8.4.1.3 (Secondary endpoints: Best objective response) was revised for clarity, 
and the analysis of PFS by the “Investigator” was changed to by “BICR” as a more rigorous 
standard.  The latter part of the paragraph on BoR being determined programmatically was 
deleted as redundant.
Section 8.4.3 (Calculation or derivation of patient-reported outcome variables) was edited 
for clarity and to delete the redundant use of “questionnaires.”
Subsection 8.4.3.1 (FACT-BL): The subsection was revised for clarity and to include the 
FACT-BL TOI as the sum of PWB, FWB, and BlCS and to detail the use of TOI as an 
efficient summary index for clinical trials.
Subsection 8.4.3.1 (FACT-BL: HRQoL visit responses) was updated to reference 
“Appendix F.”
Section 8.4.3.2 (PGIC) was revised to specify that “Very Much Improved and Much 
Improved” categories will be grouped and compared with the other response categories 
grouped.
Section 8.4.6 (Calculation or derivation of pharmacogenetic variables) was revised to 
include the statement “obtained prior to implementation of this version of the protocol” 
because no new samples will be taken after this version is implemented.  

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Section 8.5 (Methods for statistical analyses) was revised to include OS as a co-primary 
endpoint with PFS.  The number of PFS and the number of OS events were updated with 
the most recent data, and the terminology for PD-L1 status was updated.
Section 8.5 (Methods for statistical analyses): Table 12 was revised to change the analysis 
of PFS by the “Investigator” to by “BICR” as a more rigorous standard to support the Phase 
3 study.  A secondary analysis using stratified log-rank test was added for OS.  OS 
co-primary analysis using a stratified log-rank test for combination therapy and 
monotherapy versus SoC (intent-to-treat and PD-L1-High populations, respectively) was 
added, as was a secondary PFS analysis using BlCR tumor data: “MEDI4736 + 
tremelimumab combination therapy versus SoC (PD-L1-High population).”  The following 
analyses were added: “MEDI4736 monotherapy versus SoC (ITT population); MEDI4736 + 
tremelimumab combination therapy versus SoC (PD-L1-Low/Neg population); MEDI4736 
+ tremelimumab combination therapy versus MEDI4736 monotherapy (PD-L1-Low/Neg 
population) MEDI4736 + tremelimumab combination therapy versus MEDI4736 
monotherapy (ITT population).” The following other analyses were added: “MEDI4736 
monotherapy versus SoC (ITT population); MEDI4736 + tremelimumab combination 
therapy versus SoC (PD-L1-Low/Neg population); MEDI4736 + tremelimumab 
combination therapy versus MEDI4736 monotherapy (PD-L1-Low/Neg population); 
MEDI4736 + tremelimumab combination therapy versus MEDI4736 monotherapy (ITT 
population).” Changes were also made for DoR, BoR, and PROs in accordance with 
changes made elsewhere regarding statistical methodology.  Abbreviations were added to 
the table.  
Section 8.5 (Methods for statistical analyses): “Multiple testing strategy” was updated to 
include additional hypothesis testing and details of the analysis of OS and interim analyses 
for clarity.  
Section 8.5 (Methods for statistical analyses): Figure 5 was updated.

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Section 8.5.1 (Progression-free survival) was revised to change the heading from “Analysis 
of the primary variable” to “Progression-free survival.”  Analysis of PFS by the 
“Investigator” was changed to by “BICR” as a more rigorous standard.  The percent 
confidence interval was changed from “95%” to “99%,” and the secondary PFS analysis 
was removed.  An exploratory analysis of PFS using the immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) data obtained from the BICR was added.  
Secondary analysis of PFS based on the programmatically derived RECIST 1.1 using the 
Investigator tumor assessments was removed and replaced with a secondary analysis of PFS 
based on the programmatically derived RECIST 1.1 using the BICR data, and details on the 
analysis were added.  Obsolete and redundant text was deleted.  The description of the 
estimation of the HR and its CI was revised to state it will be estimated form the stratified 
Cox proportional hazards model and the Cox 1972 reference was added here and in the 
References section.
Section 8.5.2 (Overall survival) was revised for OS as a co-primary endpoint.  Assumption 
of proportionality, sensitivity analysis, and subgroup analyses were added.
Section 8.5.5 (Objective response rate) was revised to change the analysis of PFS by the 
“Investigator” to by “BICR” as a more rigorous standard.  ORR sensitivity analysis was 
removed since it is no longer needed.
Section 8.5.6 (Duration of response) was revised, deleting detailed analyses and stating that 
“Descriptive data will be provided for the DoR in responding patients.”  This programmatic 
change resulted in deletion of the Ellis et al 2008 reference.
Subsection 8.5.9.1 (FACT-BL) was revised to include the FACT-BL TOI and the FACT-G 
Total score, to delete the PWB for the secondary endpoints and put the PWB as an 
exploratory endpoint, and to delete the TOI from the exploratory endpoints.
Subsection 8.5.10 (Healthcare resource use [HOSPAD]) was revised to specify that “The 
module is for all non-study protocol-related hospital admissions; any routine hospital visits 
for study protocol-related requirements do not need to be captured.”
Subsection 8.5.15 (Interim analyses) was revised to include an additional interim analysis of 
OS, and details of the interim analyses were included. 

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Section 10.3 (Ethic and regulatory review) was revised to include Japan and other countries 
where applicable, and Institutional Review Board and informed consent form information 
was added.
Section 10.4 (Informed consent) was revised from “Japan sites only” to “Japan and other 
countries where this is applicable.”
Section 11 (List of references) was updated to include references for “Fleischer et al 2011, 
Cox 1972, and Investigator Brochures for Tremelimumab and Durvalumab” and delete 
reference to Ellis et al 2008.
Appendices A, B, C, D, E, F, G, and H were inserted into the document.
In Appendix C (Pharmacogenetics Research) the sentence referring to blood volume 
specifications in the protocol was deleted as no new samples will be taken upon 
implementation of this version of the protocol.
In Appendix D, “Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law,” a cross reference to Appendix G was added for clarity.

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Appendix E (Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 
Criteria [Response Evaluation Criteria in Solid Tumors]): In Section 2, the footnote was 
expanded for clarity; under Target lesions, clarification was provided regarding considering 
lymph nodes as a single organ.  Section 3.1 (CT and MRI) was revised to add “each 
preferably with IV contrast” for CT and MRI and equivalent changes throughout the 
appendix.  Additional detail was added regarding patients who are sensitive to IV CT 
contrast as well as recommendations to maintain the same imaging modality across all 
imaging timepoints; “is not feasible or it is medically contra indicated” was changed to 
“cannot be performed” for clarity.  In Section 3.7, clarifying text regarding cytological 
confirmation of the neoplastic origin of any effusion was added.  In Section 3.9, a paragraph 
was added regarding a recommendation not to use combined 18F-Fluoro-deoxyglucose 
positron emission tomography (FDG-PET)/CT.  In Section 4.2.1, clarifying language 
regarding lymph nodes considered as a single organ was added, and the last bullet was 
revised to include “and the intervention recorded in the RECIST eCRF.”  In Section 4.5, 
second paragraph, “regularly scheduled” was added before “tumor assessments” for clarity.  
In Section 5, italics were added to the bullets for emphasis, and “target lesion” was added 
before “diameters” for clarity.  In Section 5.1, “anatomical” was added before “sites” in 
paragraph 3 for clarity.  In Section 6, the following text was added: “All images will be 
collected, quality checked, and stored centrally by an Imaging CRO appointed by 
AstraZeneca.  Guidelines for image acquisition, anonymization, storage at the investigative 
site as source data, and transfer to the imaging CRO will be provided in a separate 
document.  The management of patients will be based solely upon the local assessments 
conducted by the Investigator.
Further details of the BICR will be documented in the Independent Review Charter (also 
referred to as ‘Imaging Charter’).”
Appendix F (Patient-reported outcomes questionnaires) cover page was revised to add the 
individual patient-reported outcome assessment questionnaires: FACT-BL, PRO-CTCAE, 
PGIC, and EQ-5D-5L.
Appendix H (Amendment 1 Summary of Changes) was added to include the summary of 
changes for Amendment 1 as an appendix instead of in the version history section.

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Clinical Study Protocol (Japan) version 3, 2 October 2015
Clinical Study Protocol Amendment J2
For changes to the protocol, refer to the above document.
Clinical Study Protocol (Japan) version 2, 14 September 2015
Clinical Study Protocol Amendment J1
For changes to the protocol, refer to the above document.
Clinical Study Protocol (Japan) version 1, 7 August 2015
Revised Clinical Study Protocol 1
(Translation only)
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study 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.
Version 2, 07 August 2015
Amendment 1.
The summary of changes for Amendment 1 is provided in Appendix H.
Version 1, 28 July 2015
Initial creation.

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PROTOCOL SYNOPSIS
A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global 
Study of First-Line MEDI4736 Monotherapy and MEDI4736 in 
Combination with Tremelimumab Versus Standard of Care 
Chemotherapy in Patients with Unresectable Stage IV Urothelial Cancer
International coordinating investigator
Professor Thomas Powles, Clinical Professor of Genitourinary Oncology, Barts Cancer 
Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of 
London, Charterhouse Square, London EC1M 6BQ
Study site(s) and number of patients planned
The study will plan to enroll approximately 1340 patients globally in order to randomize 
(1:1:1) approximately 1005 patients to MEDI4736 + tremelimumab combination therapy, 
MEDI4736 monotherapy, or Standard of Care (SoC) (cisplatin + gemcitabine or carboplatin + 
gemcitabine) over a period of 16 months.  Therefore, approximately 335 patients will be 
randomized to each of the treatment arms. Closing of global cohort enrollment will be defined 
as closing recruitment across all sites except for those located in China. The global ITT 
population will include all patients randomized into global cohort. Once global enrollment has 
ended, recruitment into an expansion cohort will continue in China until approximately 180 
Chinese patients have been randomized. Identification of China cohort patients will be clearly 
defined in SAP and by distinct Subject ID
Study period
Phase of development
Estimated date of first patient enrolled
Q3 2015 
III
Estimated date of last patient completed
Q3 2019
III
In Japan, this study will be started after the confirmation of tolerability of MEDI4736 (1.5 g 
q4W) + Tremelimumab (75 mg q4W) combination therapy in study D4880C00010 which is 
currently conducted in Japan.
Study design
This is a randomized, open-label, controlled, multi-center, global Phase III study to determine 
the efficacy and safety of MEDI4736 monotherapy (1.5 g intravenous [IV] every 4 weeks 
[q4w]) and MEDI4736 (1.5 g IV q4w) in combination with tremelimumab (75 mg IV q4w) 
for up to 4 doses/cycle each followed by MEDI4736 (1.5 g IV q4w) versus SoC 

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(cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in 
treatment-naïve patients with histologically or cytologically documented, unresectable, 
Stage IV (ie, T4b, any N; or any T, N2-N3; or M1) transitional cell carcinoma (transitional 
cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal 
pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators 
and patients to select the agents that reflect their normal clinical practice and national 
guidelines.
The patients enrolled in the study will be randomized (1:1:1) to treatment with MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC 
(cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility).  
Crossover from SoC to MEDI4736 monotherapy or MEDI4736 + tremelimumab combination 
therapy will not be permitted.  Patients will be stratified according to cisplatin eligibility 
(eligible or ineligible), programmed cell death ligand 1 (PD-L1) status (High or Low/Neg, 
based on Ventana assay), and visceral metastasis (presence or absence of lung and/or liver 
metastasis).  Tumor assessments will be performed every 8 weeks (q8w; ±7 days) relative to 
the date of randomization until confirmed disease progression (patients enrolled in the 
platinum-gemcitabine arm [SoC] will discontinue study drug at the first assessment of disease 
progression) according to the objective tumor response by Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST 1.1). 
Objectives
Primary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy versus 
SoC in terms of OS in patients with 
unresectable Stage IV UC
OS
To assess the efficacy of MEDI4736 
monotherapy versus SoC in terms of OS in 
patients with unresectable Stage IV 
PD-L1-High UC
OS
OS Overall survival; PD-L1 Programmed cell death ligand 1; SoC Standard of care; UC Urothelial 
cancer.
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
PFS in patients with PD-L1-High UC
PFS using Investigator assessments according to 
RECIST 1.1 a
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy versus 
SoC in terms of PFS in patients with UC
PFS using Investigator assessments according to 
RECIST 1.1 a

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Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
PFS and OS in patients with UC
PFS using Investigator assessments according to 
RECIST 1.1 a
OS
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to SoC in terms of PFS and OS in 
patients with PD-L1-Low/Neg UC
PFS using Investigator assessments according to 
RECIST 1.1 a
OS
To assess the efficacy profile of MEDI4736 
monotherapy in patients who are not 
cisplatin-eligible
ORR, DoR, DCR, TTR, and PFS, using BICR 
assessments according to RECIST 1.1b
OS 
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to MEDI4736 monotherapy in 
terms of PFS, OS, OS24, APF12, ORR, DoR, 
DCR, and PFS2 in patients with PD-
L1-Low/Neg UC and all patients with UC
OS
OS24
PFS, APF12, ORR, DoR, and DCR using 
Investigator assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in terms of OS24, APF12, 
ORR, DoR, DCR, and PFS2 in patients with 
UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
OS24, APF12, ORR, DoR, DCR, and PFS2 
in patients with PD-L1-High UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
OS24, APF12, ORR, DoR, DCR, and PFS2 
in patients with UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in terms of OS24, APF12, 
ORR, DoR, DCR, and PFS2 in patients with 
PD-L1-Low/Neg UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in patients with PD-L1-
High UC
PFS, APF12, ORR, DoR, and DCR using 
Investigator assessments according to RECIST 1.1 a
OS and OS24
PFS2 as defined by local standard clinical practice

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Secondary objectives:
Outcome measures:
To assess disease-related symptoms and 
HRQoL in UC patients treated with 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy 
compared with SoC and each other using the 
FACT-BL questionnaire
FACT-BL: Fatigue, Pain, Derived NFBlSI-18 
score, FACT-BL TOI, and FACT-BL Total score
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab 
combination therapy
Serum concentration of MEDI4736/tremelimumab  
PK parameters (such as peak concentration and 
trough, as data allow; sparse sampling)
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and 
tremelimumab (confirmatory results: positive or 
negative)
a
The analysis will be based on programmatically derived investigator assessments according to RECIST 1.1.  
See Section 8 for further details.
b
The analysis will be based on programmatically derived BICR assessments according to RECIST 1.1.  See 
Section 8 for further details.
ADA Antidrug antibody; APF12 Proportion of patients alive and progression free at 12 months from 
randomization; BICR Blinded Independent Central Review; DCR Disease control rate; DoR Duration of 
response; FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer; FACT-BL TOI Functional 
Assessment of Cancer Therapy - Bladder Cancer Trial Outcome Index; HRQoL Health-related quality of life; 
NFBlSI-18 National Comprehensive Cancer Network - FACT Bladder Symptoms Index-18; ORR Objective 
response rate; OS Overall survival; OS24 Proportion of patients alive at 24 months from randomization; 
PD-L1 Programmed cell death ligand 1; PFS Progression-free survival; PFS2 Time from randomization to 
second progression; PK Pharmacokinetics; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, 
version 1.1; SoC Standard of care; TTR Time to response; UC Urothelial cancer.
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy 
compared to SoC
AEs, laboratory findings, vital signs, and ECGs
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and SoC in patients 
who are not cisplatin-eligible
AEs, laboratory findings, vital signs, and ECGs
AE Adverse event; ECG Electrocardiogram; SoC Standard of care.
A further objective to meet China FDA requirement is to evaluate consistency in efficacy and 
safety among Chinese subjects for benefit-risk assessment of MEDI4736 monotherapy and 
MEDI4736 + tremelimumab combination therapy compared to SoC.
Target patient population
Adult patients (age ≥18 years) with histologically or cytologically documented, unresectable, 
Stage IV (ie, T4b, any N; or any T, N2-N3; or M1) transitional cell carcinoma (transitional 
cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal 

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pelvis, ureters, urinary bladder, and urethra), who have not been previously treated with 
first-line chemotherapy.  
Duration of treatment, criteria for retreatment, and treatment through progression
Duration of treatment
Patients randomized to the MEDI4736 + tremelimumab combination therapy and the 
MEDI4736 monotherapy arms will begin treatment on Day 1 until progressive disease (PD) is 
confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation 
criterion is met.  According to RECIST 1.1 modified for confirmation of progression, a 
confirmatory scan will be required following an overall timepoint assessment of progression, 
preferably at the next scheduled visit and no earlier than 4 weeks after the previous assessment 
of PD.
Patients randomized to treatment in the SoC arm (cisplatin + gemcitabine or 
carboplatin + gemcitabine) will begin treatment on Day 1 for up to 6 cycles until the first 
assessment of disease progression or until unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met.  A confirmatory scan will not be required if PD is 
identified on the SoC arm in order to discontinue treatment; however, a confirmatory scan is 
required following an overall timepoint assessment of initial progression, even if a subsequent 
treatment is started, and no earlier than 4 weeks after the previous assessment of PD.  
Retreatment
Patients randomized to the MEDI4736 + tremelimumab combination therapy arm who meet 
the retreatment criteria (described below) may receive retreatment 1 time at the Investigator’s 
discretion.  During retreatment, patients will follow the same schedule of assessments as the 
original treatment period (with the exception of the pharmacokinetics and anti-drug antibody 
assessments, Hepatitis B and C assessments, and HIV assessments which do not need to be 
collected a second time):

Patients who complete the 4 dosing cycles of the combination of durvalumab 
(MEDI4736) and tremelimumab portion of the regimen (with clinical benefit per 
Investigator judgment) but subsequently have evidence of PD during the 
durvalumab (MEDI4736) monotherapy portion of the combination regimen, with or 
without confirmation according to RECIST 1.1, may restart treatment with the 
combination.

Patients who restart treatment after PD must have a baseline tumor assessment 
within 28 days of restarting treatment with MEDI4736 + tremelimumab 
combination therapy; all further scans will occur q8w (±7 days) relative to the date 
of randomization until disease progression

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Criteria for retreatment and treatment through progression
Treatment through progression in either the MEDI4736 monotherapy arm, the 
MEDI4736 + tremelimumab combination therapy arm, or retreatment in the 
MEDI4736 + tremelimumab combination therapy arm are at the Investigator’s discretion.  The 
Investigator will ensure that patients do not have any significant, unacceptable, or irreversible 
toxicities that indicate that continuing treatment will not provide further benefit to patients.  
Moreover, these patients must meet the following specific criteria for treatment in the setting 
of PD: 

Written informed consent for retreatment and/or treatment through progression in 
the setting of PD will specify that treatment beyond evidence of initial PD is not the 
SoC and that alternative treatment options, including either locally licensed 
treatments or other clinical trials, are available for this patient population

Absence of clinical symptoms or signs (including worsening of laboratory values 
[eg, new or worsening hypercalcemia]) indicating clinically significant disease 
progression and no decline in Eastern Cooperative Oncology Group performance 
status that can be attributed to disease progression

Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (eg, central nervous system metastasis or respiratory failure due to tumor 
compression or spinal cord compression) that cannot be managed by 
protocol-allowed medical interventions

However, a patient in the MEDI4736 monotherapy arm with confirmed disease 
progression will not be permitted to continue therapy with MEDI4736 if disease 
progression occurred after confirmed response (complete response [CR] or partial 
response [PR], as defined by RECIST 1.1) in the target lesions.  Additionally, a 
patient in the MEDI4736 + tremelimumab combination treatment arm with 
confirmed disease progression during the combination portion of therapy that 
occurred after confirmed response (CR or PR, as defined by RECIST 1.1), will not 
be permitted to continue immunotherapy if disease progression occurred in the 
target lesions that previously responded to immunotherapy.  
Retreatment is not permitted for patients in the SoC arm.
Patients whom AstraZeneca and the Investigator determine may not continue treatment after 
PD will enter follow-up.  All 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.

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Study Code D419BC00001
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Investigational product, dosage, and mode of administration
MEDI4736 monotherapy

MEDI4736 1.5 g via IV infusion q4w, starting on Week 0 
MEDI4736 + tremelimumab combination therapy

MEDI4736 (1.5 g via IV infusion q4w) over a 1-hour period in combination with 
tremelimumab (75 mg IV q4w) over a 1-hour period for up to 4 doses/cycle each, 
followed by MEDI4736 (1.5 g IV q4w) until confirmed progression or until other 
discontinuation criteria are met.  The first MEDI4736 monotherapy dose (1.5 g IV 
q4w) will be administered 4 weeks after the final dose of MEDI4736 in 
combination with tremelimumab.  

Tremelimumab will be administered first; the MEDI4736 infusion will start 
approximately 1 hour after the end of the tremelimumab infusion.  If there are no 
clinically significant concerns after the first cycle, then, at the discretion of the 
Investigator, all other cycles of MEDI4736 can be given immediately after the 
tremelimumab infusion has finished.
SoC
Patients eligible for cisplatin will receive 1 of 2 gemcitabine + cisplatin options: 
1.
IV infusions of cisplatin 70 mg/m2 on Day 2 of each 28-day cycle + gemcitabine 
1000 mg/m2 on Days 1, 8, and 15 of each 28-day cycle, for up to 6 cycles or
2.
IV infusions of cisplatin 70 mg/m2 on Day 1 of each 21-day cycle + gemcitabine 
1000 to 1250 mg/m2 on Days 1 and 8 of each 21-day cycle, for up 6 cycles
Patients in the SoC arm who are ineligible for cisplatin will receive IV infusions of 
carboplatin with an area under the curve (AUC) of 4.5 to 5 (AUC 4 is permitted only if 
required by local standard clinical practice) on Day 1 of each 21-day cycle + gemcitabine 
1000 mg/m2 on Days 1 and 8 of each 21-day cycle, for up to 6 cycles. In a rare scenario, if at 
the Investigator’s discretion, patients in the SoC arm who have not progressed continue the 
SoC treatment beyond 6 cycles, the exposure information will be reported in exposure eCRF 
and the schedule of assessments beyond 6 cycles will be the same as the one for the treatments 
within 6 cycles.
Statistical methods
The primary objectives of this study are to assess the efficacy of MEDI4736 + tremelimumab 
combination therapy versus SoC in terms of overall survival (OS) in patients with 
unresectable Stage IV urothelial cancer (UC) and to assess the efficacy of MEDI4736 
monotherapy versus SoC in terms of OS in patients with unresectable Stage IV PD-L1-High 
UC.  

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Study Code D419BC00001
Version 9
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OS is defined as the time from the date of randomization until death due to any cause.  Thus, 
the co-primary endpoints of this study are OS in patients with UC and OS in patients with 
unresectable Stage IV PD-L1-High UC.  To control Type I error, the 5% alpha will be split 
into significance levels of 1.5%, and 3.5% and will be used for the analysis of OS in patients 
with UC and OS in patients with PD-L1-High UC, respectively.  The study will be considered 
positive (a success) if either of the OS analysis results (in patients with UC or in patients with 
PD-L1-High UC) is statistically significant.  
Secondary efficacy analyses include OS for MEDI4736 monotherapy versus SoC in patients 
with UC, OS for MEDI4736 + tremelimumab combination therapy versus SoC in patients 
with PD-L1-Low/Neg UC, the proportion of patients alive at 24 months from randomization 
(OS24), progression free survival (PFS), proportion of patients alive and progression-free at 
12 months from randomization (APF12), objective response rate (ORR), duration of response 
(DoR), disease control rate (DCR), and time from randomization to second progression
(PFS2) in the above populations, as well as ORR, DoR, DCR, time to response (TTR), PFS 
and OS in the MEDI4736 monotherapy treated UC patients who are not eligible for cisplatin-
based treatment at baseline (per eCRF). All tumor assessment-related endpoints will be 
assessed by Investigator except these defined for the subgroup of MEDI4736 monotherapy 
treated UC patients who are not eligible for cisplatin-based treatment. 
Unless otherwise specified, efficacy data will be summarized and analyzed on an intent-to-
treat (ITT) basis, and the treatment arms will be compared on the basis of randomized 
treatment, regardless of the treatment actually received.  Patients who were randomized but 
did not subsequently go on to receive study treatment are included in the ITT population.
Approximately 1005 patients will be randomized globally 1:1:1 to MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC.  The randomization 
will be stratified according to cisplatin eligibility (eligible or ineligible), PD-L1 status (High 
and/or Low/Neg), and visceral metastases (presence or absence of lung and/or liver 
metastasis).  PD-L1 status stratification will be based on natural prevalence rates.  
Randomization of cisplatin-eligible patients will be capped at a maximum 85% of the planned 
total number of patients.
The final analysis of OS will be performed when approximately 327 target OS events (81% 
maturity) have occurred in PD-L1-High UC patients treated across the 
MEDI4736 monotherapy and SoC treatment arms.
Two interim analyses will be performed. The first interim (Interim 1) will focus on ORR and 
DoR in patients who are not cisplatin-eligible and treated with MEDI4736 monotherapy, and 
the second interim (Interim 2) will focus on co-primary OS endpoints. Interim 1 will be 
conducted when all patients in the global cohort have at least 6 months follow-up. 
For the co-primary OS endpoints in the ITT population (MEDI4736 + tremelimumab 
combination therapy versus SoC), 1 interim analysis will be undertaken, and the interim 
analysis for OS endpoint in the PD-L1-High population (MEDI4736 monotherapy versus 
SoC) will be conducted at the same time: 

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Study Code D419BC00001
Version 9
Date 03 December  2019
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
The OS interim analysis (Interim 2) will be conducted when approximately 80% of 
target OS events have occurred in UC patients treated across the MEDI4736 + 
tremelimumab combination therapy and SoC treatment arms (440 events, 66% 
maturity); AND in PD-L1-High UC patients treated across the MEDI4736 
monotherapy and SoC treatment arms (262 events, 65% maturity). 
For the co-primary OS endpoint in the ITT population (MEDI4736 + tremelimumab 
combination therapy versus SoC), if exactly 80% of the target OS events are available at the 
time of the interim analysis (ie, 440/550 deaths have occurred), with an overall 2-sided alpha 
level of 1.5%, the 2-sided alpha to be applied at the OS interim analysis would be 0.56%. The 
2-sided alpha to be applied for the final OS analysis would be 1.33%.
For the co-primary OS endpoint in the PD-L1-High population (MEDI4736 monotherapy 
versus SoC), if exactly 80% of the target OS events are available at the time of the interim 
analysis (ie, 262/327 deaths have occurred), with an overall 2-sided alpha level of 3.5%, the 
2-sided alpha to be applied at the OS interim analysis would be 1.58%. The 2-sided alpha to 
be applied for the final OS analysis would be 3.03%.
MEDI4736 + tremelimumab versus SoC (OS in all-comers UC)
If OS at 12 months was 55% with MEDI4736 + tremelimumab combination therapy (with 
14.8-month median OS) and 48% with SoC (with 11.3-month median OS) and assuming the 
true average HR is 0.73, then the trial will have at least 87% power to demonstrate statistical 
significance at a 2-sided alpha level of 1.33% (with overall alpha for OS of 1.5%) for the 
comparison of MEDI4736 + tremelimumab combination therapy versus SoC, with the 
smallest treatment difference that could be statistically significant being an average HR of 
0.81. With a 16-month recruitment period and a minimum follow-up period of 30 months 
assumed, it is anticipated that this analysis will be performed approximately 46 months after 
the first patient has been randomized.
MEDI4736 versus SoC (OS in PD-L1-High UC)
If OS at 12 months was 56% with MEDI4736 monotherapy (with 15.3 month median OS) and 
48% with SoC (with 11.3 month median OS) and assuming the true average HR is 0.71, then 
the trial will have at least 84% power to demonstrate statistical significance at a 2-sided alpha 
level of 3.03% (with overall alpha for OS of 3.5%) for the comparison of MEDI4736 
monotherapy versus SoC, with the smallest treatment difference that could be statistically 
significant being an average HR of 0.79. With a 16-month recruitment period and a minimum 
follow-up period of 30 months assumed, it is anticipated that this analysis will be performed 
approximately 46 months after the first patient has been randomized.
MEDI4736 versus SoC (OS in all-comers UC)
If OS at 12 months was 55% with MEDI4736 monotherapy (with 14.4 month median OS) and 
48% with SoC (with 11.3 month median OS) and assuming the true average HR is 0.75, then 
the trial will have at least 91% power to demonstrate statistical significance at a 2-sided alpha 
level of 4.29% (with overall alpha for OS of 5%) for the comparison of MEDI4736 

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Study Code D419BC00001
Version 9
Date 03 December  2019
47 (275)
monotherapy versus SoC, with the smallest treatment difference that could be statistically 
significant being an average HR of 0.84.  With a 16-month recruitment period and a minimum 
follow-up period of 30 months assumed, it is anticipated that this analysis will be performed 
approximately 46 months after the first patient has been randomized.
OS will be analyzed using a stratified log-rank test (stratified for cisplatin eligibility 
[ie, eligible or ineligible], PD-L1 expression tumor status [High or Low/Neg, for analysis in 
the ITT population only], and visceral metastasis [presence or absence of lung and/or liver 
metastasis]).  The effect of treatment will be estimated by the HR together with corresponding 
([1-adjusted alpha] × 100%) confidence intervals and p-values.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.
Safety data
Data from all cycles of treatment will be combined in the presentation of safety data.  Adverse 
events (AEs; both in terms of Medical Dictionary for Regulatory Activities preferred terms 
and CTCAE grade) will be listed individually by patient.  The number of patients 
experiencing each AE will be summarized by treatment arm and CTCAE grade. Other safety 
data will be assessed in terms of physical examination, clinical chemistry, hematology, vital 
signs, and electrocardiograms.  At the end of the study, appropriate summaries of all safety 
data will be produced, as defined in the Statistical Analysis Plan.
China data 
After the end of global recruitment (i.e. LSI, globally), recruitment into an expansion cohort 
will continue in China until approximately 180 Chinese patients have been randomized. To 
evaluate consistency, the efficacy and safety data in China cohort will be analyzed separately 
as required by China FDA, applying the same statistical methods as for global cohort analysis 
unless specified (refer to Section 8.6 for further details). Due to patients in the expansion 
cohort being recruited late, data cutoffs for China cohort analyses may be different from 
global data cutoff to ensure an appropriate evaluation. The analysis will be performed when 
the OS data from the China patients is of similar maturity where significant clinical efficacy is 
established in the global cohort. Safety and tolerability will be summarized for the China-only 
Safety Analysis Set.

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Study Code D419BC00001
Version 9
Date 03 December  2019
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................1
PROTOCOL SYNOPSIS................................................................................... 38
TABLE OF CONTENTS................................................................................... 48
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 55
1.
INTRODUCTION ............................................................................................. 61
1.1
Background and rationale for conducting this study ........................................... 61
1.1.1
Immunotherapies ............................................................................................... 62
1.1.2
MEDI4736......................................................................................................... 63
1.1.3
Tremelimumab................................................................................................... 64
1.1.4
MEDI4736 in combination with tremelimumab.................................................. 65
1.1.5
Rationale for conducting this study .................................................................... 65
1.2
Rationale for study design, doses, and control arms............................................ 66
1.2.1
MEDI4736 and tremelimumab dose and treatment regimen justification............ 67
1.2.1.1
MEDI4736 + tremelimumab combination therapy dose rationale ....................... 67
1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy...................................................................................................... 68
1.2.1.3
MEDI4736 monotherapy dose rationale ............................................................. 69
1.2.1.4
Rationale for fixed dosing .................................................................................. 71
1.2.2
Rationale for Standard of Care as a comparator.................................................. 72
1.2.3
Rationale for cisplatin-ineligible Interim Analysis.............................................. 72
1.3
Benefit/risk and ethical assessment .................................................................... 73
1.3.1
Potential benefits................................................................................................ 73
1.3.1.1
MEDI4736......................................................................................................... 73
1.3.1.2
Tremelimumab................................................................................................... 73
1.3.1.3
MEDI4736 + tremelimumab combination therapy.............................................. 74
1.3.2
Potential risks .................................................................................................... 74
1.3.2.1
MEDI4736......................................................................................................... 74
1.3.2.2
Tremelimumab................................................................................................... 75
1.3.2.3
MEDI4736 + tremelimumab combination therapy.............................................. 75
1.3.3
Overall benefit and risk assessment.................................................................... 76
1.4
Study design ...................................................................................................... 77
2.
STUDY OBJECTIVES...................................................................................... 81
2.1
Primary objectives ............................................................................................. 81
2.2
Secondary objectives.......................................................................................... 81
2.3
Safety objective.................................................................................................. 83

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Study Code D419BC00001
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2.4
Exploratory objectives ....................................................................................... 83
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................... 85
3.1
Inclusion criteria ................................................................................................ 85
3.2
Exclusion criteria ............................................................................................... 87
3.3
Patient enrollment and randomization ................................................................ 90
3.4
Procedures for handling incorrectly enrolled or randomized patients.................. 92
3.5
Methods for assigning treatment arms................................................................ 92
3.6
Methods for ensuring blinding (not applicable) .................................................. 93
3.7
Methods for unblinding (not applicable)............................................................. 93
3.8
Restrictions........................................................................................................ 93
3.9
Discontinuation of investigational product ......................................................... 94
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 95
3.10
Criteria for withdrawal from the study................................................................ 95
3.10.1
Screen failures ................................................................................................... 95
3.10.2
Withdrawal of the informed consent................................................................... 96
3.11
Discontinuation of the study............................................................................... 97
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 97
4.1
Enrollment/screening period ............................................................................ 114
4.2
Treatment period.............................................................................................. 114
4.3
Follow-up period.............................................................................................. 114
5.
STUDY ASSESSMENTS................................................................................ 115
5.1
Efficacy assessments........................................................................................ 115
5.1.1
Central reading of scans ................................................................................... 117
5.1.2
Survival assessments........................................................................................ 117
5.2
Safety assessments........................................................................................... 118
5.2.1
Laboratory safety assessments.......................................................................... 118
5.2.2
Physical examination ....................................................................................... 120
5.2.3
ECG................................................................................................................. 120
5.2.4
Vital signs........................................................................................................ 120
5.2.5
Other safety assessments.................................................................................. 121
5.3
Other assessments............................................................................................ 122
5.3.1
Patient-reported outcomes................................................................................ 122
5.3.1.1
FACT-BL ........................................................................................................ 122
5.3.1.2
PRO-CTCAE................................................................................................... 123
5.3.1.3
PGIC................................................................................................................ 123
5.3.1.4
EQ-5D-5L........................................................................................................ 123

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5.3.2
Administration of the patient-reported outcome questionnaires ........................ 124
5.3.3
ECOG performance status................................................................................ 125
5.4
Pharmacokinetics ............................................................................................. 126
5.4.1
Collection of samples and determination of drug concentration........................ 126
5.4.2
Collection of samples to measure the presence of ADAs.................................. 126
5.4.3
Storage and destruction of pharmacokinetic/ADA samples............................... 126
5.5
Biomarker analysis........................................................................................... 127
5.5.1
Evaluation of candidate, predictive markers - tumor PD-L1 ............................. 127
5.5.1.1
Exploratory biomarker data.............................................................................. 129
5.5.2
Management of biomarker data........................................................................ 130
5.5.3
Storage, re-use, and destruction of biological samples...................................... 131
5.5.4
Labeling and shipment of biological samples ................................................... 131
5.5.5
Chain of custody of biological samples ............................................................ 131
5.5.6
Withdrawal of informed consent for donated biological samples...................... 132
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT........................... 132
6.1
Definition of adverse events............................................................................. 132
6.2
Definitions of serious adverse event ................................................................. 132
6.3
Recording of adverse events............................................................................. 133
6.3.1
Time period for collection of adverse events .................................................... 133
6.3.2
Variables.......................................................................................................... 133
6.3.3
Causality collection.......................................................................................... 134
6.3.4
Relationship to protocol procedures ................................................................. 135
6.3.5
Adverse events based on signs and symptoms.................................................. 135
6.3.6
Adverse events based on examinations and tests .............................................. 135
6.3.7
Hy’s Law ......................................................................................................... 136
6.3.8
Disease progression.......................................................................................... 136
6.3.9
New cancers..................................................................................................... 136
6.3.10
Deaths.............................................................................................................. 136
6.4
Reporting of serious adverse events ................................................................. 137
6.5
Overdose.......................................................................................................... 137
6.6
Pregnancy ........................................................................................................ 138
6.6.1
Maternal exposure............................................................................................ 138
6.6.2
Paternal exposure............................................................................................. 139
6.7
Management of IP-related toxicities................................................................. 139
6.7.1
Specific toxicity management and dose modification information –
MEDI4736 and MEDI4736 + tremelimumab ................................................... 139
6.7.2
Specific toxicity management and dose modification information -
Standard of Care .............................................................................................. 142
6.7.3
IDMC .............................................................................................................. 142
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 142

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7.1
Identity of investigational products .................................................................. 142
7.1.1
MEDI4736....................................................................................................... 143
7.1.2
Tremelimumab................................................................................................. 144
7.1.3
Standard of Care .............................................................................................. 145
7.2
Dose and treatment regimens ........................................................................... 145
7.2.1
Treatment regimens.......................................................................................... 145
7.2.2
Duration of treatment, criteria for retreatment, and treatment through 
progression ...................................................................................................... 148
7.3
Labeling........................................................................................................... 149
7.4
Storage............................................................................................................. 150
7.5
Compliance...................................................................................................... 150
7.6
Accountability.................................................................................................. 150
7.7
Concomitant and other treatments .................................................................... 150
7.7.1
Other concomitant treatment ............................................................................ 152
7.8
Post-study access to study treatment................................................................. 153
8.
STATISTICAL ANALYSES BY ASTRAZENECA........................................ 153
8.1
Statistical considerations .................................................................................. 153
8.2
Sample size estimate ........................................................................................ 154
8.3
Definitions of analysis sets............................................................................... 156
8.3.1
Full analysis set................................................................................................ 157
8.3.2
PD-L1-High analysis set .................................................................................. 158
8.3.3
PD-L1-Low/Neg analysis set............................................................................ 158
8.3.4
Cisplatin ineligible analysis set ........................................................................ 158
8.3.5
MEDI4736 cisplatin ineligible population........................................................ 158
8.3.6
Safety analysis set............................................................................................ 158
8.3.7
PK analysis set................................................................................................. 158
8.4
Outcome measures for analyses........................................................................ 158
8.4.1
Calculation or derivation of efficacy variables.................................................. 158
8.4.1.1
RECIST 1.1-based endpoints ........................................................................... 159
8.4.1.2
Co-primary endpoints....................................................................................... 159
8.4.1.3
Secondary endpoints ........................................................................................ 160
8.4.2
Calculation or derivation of safety variables..................................................... 162
8.4.2.1
Adverse events................................................................................................. 162
8.4.2.2
Other significant adverse events....................................................................... 163
8.4.2.3
Safety assessments........................................................................................... 163
8.4.3
Calculation or derivation of patient-reported outcome variables ....................... 163
8.4.3.1
FACT-BL ........................................................................................................ 164
8.4.3.2
PGIC................................................................................................................ 165
8.4.3.3
PRO-CTCAE................................................................................................... 165
8.4.3.4
Health state utility (EQ-5D-5L)........................................................................ 165

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8.4.4
Calculation or derivation of pharmacokinetic variables .................................... 165
8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis................ 165
8.4.4.2
Pharmacokinetic analysis ................................................................................. 166
8.4.4.3
Immunogenicity analysis.................................................................................. 166
8.4.5
Calculation or derivation of biomarker variables .............................................. 166
8.4.6
Calculation or derivation of pharmacogenetic variables.................................... 166
8.5
Methods for statistical analyses........................................................................ 166
8.5.1
Overall survival................................................................................................ 171
8.5.2
Progression-free survival.................................................................................. 172
8.5.3
Overall survival at 24 months........................................................................... 173
8.5.4
Proportion of patients alive and progression free at 12 months ......................... 173
8.5.5
Objective response rate .................................................................................... 173
8.5.6
Duration of response ........................................................................................ 174
8.5.7
Disease control rate.......................................................................................... 174
8.5.8
Time from randomization to second progression .............................................. 174
8.5.9
Patient reported outcomes ................................................................................ 174
8.5.9.1
FACT-BL ........................................................................................................ 174
8.5.9.2
PGIC................................................................................................................ 175
8.5.9.3
PRO-CTCAE................................................................................................... 175
8.5.9.4
EQ-5D-5L........................................................................................................ 175
8.5.10
Healthcare resource use (HOSPAD)................................................................. 175
8.5.11
Safety data ....................................................................................................... 175
8.5.12
Pharmacokinetic data ....................................................................................... 176
8.5.12.1
Immunogenicity analysis.................................................................................. 176
8.5.13
Pharmacokinetic/pharmacodynamic relationships ............................................ 176
8.5.14
Biomarker data................................................................................................. 176
8.5.15
Interim analyses............................................................................................... 176
8.5.15.1
Interim analysis focusing on ORR and DoR..................................................... 176
8.5.15.2
Interim analysis of overall survival endpoints................................................... 179
8.6
China cohort .................................................................................................... 180
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 181
9.1
Training of study site personnel ....................................................................... 181
9.2
Monitoring of the study.................................................................................... 181
9.2.1
Source data ...................................................................................................... 181
9.2.2
Direct access to source data in Japan only ........................................................ 182
9.2.3
Study agreements............................................................................................. 182
9.2.4
Archiving of study documents.......................................................................... 182
9.3
Study timetable and end of study...................................................................... 182
9.4
Data management by AstraZeneca ................................................................... 183
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 183
10.1
Ethical conduct of the study ............................................................................. 183

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10.2
Patient data protection...................................................................................... 184
10.3
Ethics and regulatory review ............................................................................ 184
10.4
Informed consent ............................................................................................. 185
10.5
Changes to the protocol and informed consent form......................................... 186
10.6
Audits and inspections ..................................................................................... 187
11.
LIST OF REFERENCES ................................................................................. 188
LIST OF TABLES
Table 1
PD-L1 status defined by scoring of an IHC assay developed by 
Ventana for stratification in D419BC00001*.........................................78
Table 2
Highly effective methods of contraception (<1% failure rate)................94
Table 3
Schedule of assessments for MEDI4736 monotherapy and 
MEDI4736 + tremelimumab combination therapy treatment and 
retreatment periods (Patients who continue beyond C13 continue 
with all C13 assessments until termination of treatment) .......................99
Table 4
Schedule of assessments for cisplatin + gemcitabine 28-day cycle 
treatment period .................................................................................. 103
Table 5
Schedule of assessments for cisplatin + gemcitabine 21-day cycle 
and carboplatin + gemcitabine treatment period .................................. 106
Table 6
Schedule of study procedures: follow-up for patients in the 
MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy arms ................................................................... 110
Table 7
Schedule of study procedures: follow-up for chemotherapy 
patients................................................................................................ 112
Table 8
Clinical chemistry (serum or plasma) .................................................. 119
Table 9
Hematology ........................................................................................ 119
Table 10
Summary of outcome variables and analysis populations..................... 157
Table 11
Preplanned statistical and sensitivity analyses to be conducted............ 168
Table E12
Summary of methods of assessment .................................................... 211
Table E13
Evaluation of target lesions ................................................................. 216
Table E14
Evaluation of non-target lesions .......................................................... 217
Table E15
Overall visit response.......................................................................... 218

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Study Code D419BC00001
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Date 03 December  2019
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LIST OF FIGURES
Figure 1
Overall study design..............................................................................79
Figure 2
Study flowchart.....................................................................................80
Figure 3
MEDI4736 monotherapy dosing schedule ........................................... 146
Figure 4
MEDI4736 + tremelimumab combination therapy dosing schedule ..... 147
Figure 5
Multiple testing procedures for controlling the type I error rate ........... 171
LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 198
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................ 201
Appendix C
Pharmacogenetics Research ................................................................ 202
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 205
Appendix E
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) .............................................................................................. 210
Appendix F
Patient-reported Outcomes Questionnaires .......................................... 221
Appendix H
Amendment 1 Summary of Changes ................................................... 232

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this clinical study protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APC
Antigen-presenting cells
APF12
Proportion of patients alive and progression free at 12 months from 
randomization
AST
Aspartate aminotransferase
AUC
Area under the curve
AUCss
Area under the plasma drug concentration-time curve at steady state
B7-H1
B7-homolog 1
β-hCG
beta-Human chorionic gonadotropin
BICR
Blinded Independent Central Review
BlCS
Bladder Cancer Subscale
BoR
Best objective response
BP
Blood pressure
BSC
Best supportive care
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CrC1
Creatinine clearance
CRF
Case report form
CRO
Contract Research Organization
CSA
Clinical Study Agreement
CSP
Clinical study protocol
CSR
Clinical study report

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Abbreviation or 
special term
Explanation
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T lymphocyte-associated antigen 4
Ctrough
Trough plasma concentration
Ctrough,ss
Trough plasma concentration at steady state
DCR
Disease control rate
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid 
DoR
Duration of response
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EQ-5D-5L
EuroQol 5-dimension, 5-level health state utility index
ESMO
European Society for Medical Oncology
EU
European Union
EWB
Emotional Well-Being
FACT-BL
Functional Assessment of Cancer Therapy - Bladder Cancer
FACT-G
Functional Assessment of Cancer Therapy – General
FAS
Full analysis set
FDA
Food and Drug Administration
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography
fT3
Free triiodothyronine
fT4
Free thyroxine
FWB
Functional Well-Being
GCP
Good Clinical Practice
Japan only: Unless otherwise noted, ‘GCP’ shall mean ‘the International 
Conference on Harmonisation Tripartite Guideline for Good Clinical 
Practise’ (ICH GCP) and the Japanese ‘Good Clinical Practice for Trials on 
Drugs (Ministry of Health, Labour and Welfare [MHLW] Ordinance 
No. 28, 27 March 1997, partially revised by MHLW Ordinance and their 
related notifications’ [GCP Ordinance]).

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Abbreviation or 
special term
Explanation
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
HBsAg
HBV surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
HRCT
High-resolution computed tomography
HRQoL
Health-related quality of life
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN-γ
Interferon-gamma
IHC
Immunohistochemistry
IL
Interleukin
ILD
Interstitial lung disease
IP
Investigational Product 
irAE
Immune-related adverse event
IRB
Institutional review board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LFT
Liver function test
LIMS
Laboratory Information Management System
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cells

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Abbreviation or 
special term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labor, and Welfare
MIBC
Muscle-invasive bladder cancer 
miRNA
Micro-ribonucleic acid
MMRM
Mixed Model Repeated Measurements
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MTP
Multiple testing procedure
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
Not evaluable
NFBlSI-18
National Comprehensive Cancer Network - FACT Bladder Symptoms 
Index-18
NMIBC
Non-muscle-invasive bladder cancer
NSCLC
Non-small-cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
OS24
Proportion of patients alive at 24 months from randomization
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PD-1
Programmed cell death 1 
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PFS2
Time from randomization to second progression
PGIC
Patient Global Impression of Change
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PMDA
Pharmaceuticals and Meidcal Devices Agency
PR
Partial response

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Abbreviation or 
special term
Explanation
PRO
Patient-reported outcomes
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PS
Performance status
PWB
Physical Well-Being
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q8w
Every 8 weeks
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumors 
RNA
Ribonucleic acid
RT-qPCR
Reverse transcription quantitative polymerase chain reaction 
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SNP
Single nucleotide polymorphism
SoC
Standard of care
sPD-L1
Soluble programmed cell death ligand 1
SWB
Social Well-Being
TBL
Total bilirubin
TFST
Time to first subsequent therapy
TKI
Tyrosine kinase inhibitor
TL
Target lesions
TOI
Trial Outcome Index
TSH
Thyroid-stimulating hormone
TSST
Time to second subsequent therapy or death
TTR
Time to response
UC
Urothelial cancer
ULN
Upper limit of normal
WBDC
Web Based Data Capture

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Abbreviation or 
special term
Explanation
WT
Weight
W/V
Weight/volume

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Bladder cancer is the most common tumor of the entire urinary tract and is the ninth most 
common cancer diagnosis worldwide, with more than 330000 new cases each year and more 
than 130000 deaths per year, with an estimated male:female ratio of 3.8:1.0.  At any point in 
time, 2.7 million people have a history of urinary bladder cancer (Ploeg et al 2009, 
Babjuk et al 2014).  Almost 90% of carcinomas of the urinary bladder are transitional cell 
carcinomas, the most common primary malignancy of the urinary tract, and may be found 
along its entire length.
At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle-invasive 
bladder cancer (NMIBC) and approximately 30% as muscle-invasive bladder cancer (MIBC) 
(Babjuk et al 2014).  Nevertheless, approximately 40% of the patients with NMIBC will 
progress to muscle-invasive disease in 5 years depending on tumor pathological features 
(Sylvester 2006).  
Muscle-invasive tumors are usually treated by radical cystectomy and chemotherapy.  
Cisplatin-containing combination chemotherapy with gemcitabine/cisplatin or methotrexate, 
vinblastine, adriamycin, and cisplatin is standard in advanced surgically unresectable and 
metastatic patients who are fit enough to tolerate cisplatin.  
In first-line cisplatin/gemcitabine-based chemotherapy, the reported objective response rate 
(ORR) is approximately 49% with a limited median duration of response (DoR) of 
9.6 months.  ORR is represented by partial response (PR) of approximately 37% and complete 
response (CR) of approximately 12%.  Approximately 33% of patients achieved stable disease 
(SD).  The median time to progressive disease (PD) was 7.4 months (95% confidence interval 
[CI], 6.6 to 8.1 months) with a median survival of 13.8 months (95% CI, 12.3 to 15.8 months) 
(Von der Maase et al 2000).  
Despite the high rate of disease control (above 80%) in the first-line setting (Von der Maase 
et al 2000), disease progression invariably occurs after discontinuing chemotherapy, even in 
patients who initially respond to chemotherapy.  
Besides response to chemotherapy, other prognostic factors are the Karnofsky performance 
status (PS) of <80% and presence of visceral metastases, ie, lung or liver.  These so-called 
Bajorin prognostic factors have also been validated for newer combination chemotherapy 
regimens and carboplatin combinations.  
Approximately 40% of patients are unfit for cisplatin-containing chemotherapy due to a poor 
PS, impaired renal function, or comorbidity (de Wit 2003).  Patients unfit for cisplatin-based 
chemotherapy may be offered with a carboplatin-based regimen or single-agent taxane or 
gemcitabine (Bellmunt et al 2014).  

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Carboplatin containing chemotherapy is less effective than cisplatin-based chemotherapy in 
terms of CR and survival and should not be considered interchangeable or standard.  Several 
randomized Phase II trials of carboplatin versus cisplatin combination chemotherapy have 
produced lower CR rates and shorter overall survival (OS) for the carboplatin arms.  In 
patients who are not eligible for cisplatin-based chemotherapy, ORR values are approximately 
30% to 40%, median progression-free survival (PFS) was 5.8 months, with median OS rarely 
exceeding 10 months (De Santis et al 2012).
To date, no standard therapy has been established for patients who recur or are refractory to 
first-line therapy, or in the maintenance setting (National Comprehensive Cancer Network 
(NCCN Bladder Cancer Guidelines).  Second-line vinflunine, by way of superiority over best 
supportive care (BSC), has shown modest activity and is approved in Europe.  Treatment at 
the time of relapse has been largely unsuccessful, with low response rates and a median time 
to relapse of approximately 2 to 3 months.  
The limited number of treatment options reflects the poor outcome.  There is still a significant 
unmet medical need in urothelial cancer (UC).
1.1.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs et al 2009).  This amplification may be accomplished by blocking co-inhibitory 
molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed 
cell death 1 (PD-1), from binding with their ligands, B7 or B7-homolog 1 (B7-H1) 
(programmed cell death ligand 1 [PD-L1]).
Several lines of evidence documenting the immune dysfunction associated with bladder 
cancer support the hypothesis that immunotherapy can alter the process of carcinogenesis 
(Carneiro et al 2014).  
PD-L1 is a protein expressed in a broad range of cancers, including bladder cancer, at a high 
frequency.  In some cancers (eg, lung and renal cell carcinoma), taking into consideration the 
limitation of published literature, the expression of PD-L1 seems to be associated with 
reduced survival and an unfavorable prognosis (Mu et al 2011, Topalian et al 2012).  
Regarding bladder cancer, PD-L1 is expressed by 12% of bladder tumor cells, 27% of 
tumor-infiltrating immune cells, and up to 50% of malignant urothelial cells in carcinoma in 
situ (Carneiro et al 2014).  However, such estimates are preliminary, based on small sample 
sizes, and without standardized methods for measuring PD-L1.  In addition, 95% of 
lymphocytes that invade bladder tumors express the PD-1 receptor.  Urothelial expression of 
PD-L1 was also predictive of mortality following cystectomy in patients with organ-limited 
disease.  PD-L1 expression is significantly associated with higher grade and stage in bladder 
cancer patients (Inman et al 2007).  Results of non-clinical and clinical studies of monoclonal 
antibodies (mAbs) targeting the PD-L1/PD-1 pathway have shown evidence of clinical 

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activity and a manageable safety profile, supporting the hypothesis that an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune response in patients with 
bladder cancer (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 PD-L1-High tumors (Powles et al 2014).
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory 
signal, which limits T-cell activation. Therefore, it is expected that treatment with an 
anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation of the human 
immune system, increasing antitumor activity in patients with solid tumors.  In a recent work 
published by Carthon et al (Carthon et al 2010), all 12 patients with localized urothelial 
carcinoma of the bladder treated with ipilimumab, administered in a preoperative setting, had 
measurable immunologic pharmacodynamic effects, consisting of an increased frequency of 
CD4+ICOShi T cells, a marker shown to correlate with improved OS, in tumor tissues and the 
systemic circulation.  
Combining immunotherapy agents has been shown to result in improved response rates 
relative to monotherapy, for example in the concurrent administration of nivolumab and 
ipilimumab to patients with advanced melanoma (Wolchok et al 2013).  The rationale for 
combining MEDI4736 and tremelimumab is that the mechanisms of CTLA-4 and PD-1 are 
non-redundant, suggesting that targeting both pathways may have additive or synergistic 
activity in both PD-L1-High and -Low/Neg populations (Pardoll 2012).  In addition, CTLA-4 
antagonists have been shown to upregulate PD-1, and PD-1 has been shown to upregulate 
CTLA-4, further strengthening the rationale for combining tremelimumab and MEDI4736 
(Curran et al 2010).  Initial data from ongoing studies have demonstrated higher ORRs and 
disease control rates (DCRs) in non-small-cell lung cancer (NSCLC) patients with PD-L1-
Low/Neg tumors receiving MEDI4736 + tremelimumab combination therapy (30% and 70% 
[7 out of 10 patients], respectively) compared to MEDI4736 monotherapy (10% and 42%, 
respectively; Antonia et al 2014a, Antonia et al 2014b).  In melanoma, the combination of 
CTLA-4 and PD-1 blockades has been shown to result in higher ORRs and 1-year and 2-year 
survival compared with either agent alone, regardless of PD-L1 expression status 
(Sznol et al 2014).
1.1.2
MEDI4736
MEDI4736 is a human mAb of the immunoglobulin G 1 kappa subclass that inhibits the 
binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the 
treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document).  The 
proposed mechanism of action for MEDI4736 is interference of the interaction of PD-L1, 
expressed on cancer cells and a subset of leukocytes, with the PD-1 (cluster of differentiation 
[CD] 279) and B7-1 (CD80) molecules on antigen-presenting cells (APCs) and T cells.  By 
binding to PD-L1 on tumor cells, the mechanism of action of MEDI4736 includes stimulation 
of the patient’s antitumor immune response.

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MEDI4736 has been given to humans as part of ongoing studies as monotherapy or in 
combination with other drugs.  As of 14 July 2014, 509 patients have been enrolled and 
treated in 10 ongoing clinical studies of MEDI4736 (5 employing MEDI4736 as monotherapy
and 5 as combination therapy).  No studies have yet been completed.  Currently, AstraZeneca 
is investigating the efficacy and safety of MEDI4736 both as monotherapy and in combination 
with other anticancer agents in a range of different tumor types, including 2 ongoing Phase I/II 
studies with UC patient cohorts where the effect of MEDI4736 monotherapy and MEDI4736 
in combination with tremelimumab, respectively, are being investigated.  Details on the safety 
profile of MEDI4736 are summarized in Section 1.3.2.1.  Refer to the MEDI4736 
Investigator’s Brochure (IB) for a complete summary of non-clinical and clinical information; 
see Section 6.7 for guidance on management of MEDI4736-related toxicities (MEDI4736 IB).
The majority of the safety data currently available for MEDI4736 is based on the 
first-in-human monotherapy study (Study CD-ON-MEDI4736-1108; referred to hereafter as 
Study 1108) in patients with advanced solid tumors and is summarized in Section 1.3.2.1.  
Expansions in different tumor types are ongoing, including a bladder cancer expansion cohort 
that has a target enrollment of 60 patients.  Patient recruitment and data collection in this 
cohort are ongoing.
MEDI4736 monotherapy exhibits non-linear (dose-dependent) pharmacokinetics (PK) 
approaching linearity with the ≥3-mg/kg dose, likely due to saturable target-mediated 
clearance, and has a half-life of approximately 21 days.  Of the 220 patients who received 
MEDI4736 monotherapy from Study 1108 for whom PK/anti-drug antibody (ADA) data were 
available as of 14 July 2014, 5 patients (1 patient each in the 0.1- and 3-mg/kg cohorts and 
3 patients in 10-mg/kg cohort) were ADA positive, with an impact on PK/pharmacodynamics
in 1 patient in the 3-mg/kg cohort.  
1.1.3
Tremelimumab
Tremelimumab, a CTLA-4 mAb of the immunoglobulin G 2 kappa isotype, is an 
immunomodulatory therapy  that is being developed by AstraZeneca for use in the treatment 
of cancer.  CTLA-4 is a critical regulatory signal for T-cell expansion and activation following 
an immune response, and it serves as a natural braking mechanism that maintains T-cell 
homeostasis.  During T-cell activation, T-cells upregulate CTLA-4, which binds to B7 ligands 
on APCs, sending an inhibitory signal that limits T-cell activation.  Tremelimumab blocks the 
inhibitory signal resulting from CTLA-4 binding to B7, leading to indirect prolongation and 
enhancement of T-cell activation and expansion.  Thus, the mechanism of action of 
tremelimumab is indirect and is applied through enhancing T-cell-mediated immune response.
An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules.  As of the data 
cutoff date of 12 November 2014 (for all studies except Study D4190C00006, which has a 
cutoff date of 4 December 2014), 1010 patients have received tremelimumab monotherapy 
(excluding 497 patients who have been treated in the blinded Phase IIb study, D4880C00003) 
and 197 patients have received tremelimumab in combination with other agents.  More than 

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800 of these patients had melanoma and were treated at a dose of 15 mg/kg every 90 days.  
Details on the safety profile of tremelimumab monotherapy are summarized in 
Section 1.3.2.2.  Refer to the Tremelimumab IB for a complete summary of non-clinical and 
clinical information; see Section 6.7 for guidance on management of tremelimumab-related 
toxicities.  
Tremelimumab exhibited a biphasic PK profile with a long-terminal phase half-life of 
22 days.  Overall, a low incidence of ADAs (<6%) was observed in treatment with 
tremelimumab.  
1.1.4
MEDI4736 in combination with tremelimumab
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics, and preliminary antitumor activity of MEDI4736 + tremelimumab 
combination therapy in patients with advanced NSCLC.  The dosing schedule utilized was 
MEDI4736 every 2 weeks (q2w) or every 4 weeks (q4w) up to Week 50 and 48 (12 months), 
combined with tremelimumab q4w up to Week 24 for 7 doses, then tremelimumab every 
12 weeks for 2 additional doses for up to 12 months.  The study is ongoing and continues to 
accrue.  
As of 27 January 2015, a total of 74 patients have been treated in the study, including 
58 patients on the q4w dosing schedule and 16 patients on the q2w dosing schedule.  Patients 
have received between 1 and 13 doses of MEDI4736 and between 1 and 9 doses of 
tremelimumab.  Details on the safety profile of MEDI4736 + tremelimumab combination 
therapy are summarized in Section 1.3.2.3.  Refer to the MEDI4736 IB and Tremelimumab IB
for a complete summary of non-clinical and clinical information; see Section 6.7 for guidance 
on management of MEDI4736 + tremelimumab-related toxicities.
As of 27 January 2015 in Study D4190C00006, an approximately dose-proportional increase 
in PK exposure (maximum plasma concentration [Cmax], trough plasma concentration [Ctrough], 
and area under the plasma drug concentration-time curve from time zero to Day 28 post-dose ) 
of both MEDI4736 and tremelimumab was observed over the dose range of 3 to 20 mg/kg 
MEDI4736 q4w or q2w and 1 to 10 mg/kg tremelimumab q4w.  Four of 60 patients with 
ADA data available were ADA positive for either anti-MEDI4736 or anti-tremelimumab 
antibodies post-treatment; MEDI4736 PK was impacted in only 2 of these 4 patients.  
Complete soluble programmed cell death ligand 1 (sPD-L1) suppression was observed in all 
patients over the dose range of 3 to 20 mg/kg of MEDI4736 q4w or q2w.   
1.1.5
Rationale for conducting this study
Current therapies for advanced MIBC have poor outcomes (1-year survival rate of 
approximately 25%, low 5-year survival of 15% for the United States), an ORR of 30% to 
40%, and a median OS of approximately 14 months (Steinberg et al 2014).  Cisplatin-based 
chemotherapy continues to be the standard first-line treatment in advanced surgically 
unresectable and metastatic cancers in patients fit enough to tolerate cisplatin.  In first-line 
cisplatin/gemcitabine-based chemotherapy, the reported ORR is approximately 49%, 
represented by PR of approximately 37% and CR of approximately 12%.  Approximately 

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33% of patients achieved SD, with a median time to PD of 7.4 months (95% CI, 6.6 to 
8.1 months) and a median survival of 13.8 months (95% CI, 12.3 to 15.8 months) (
Von der Maase et al 2000).  Patients unfit for cisplatin-based chemotherapy may be palliated 
with a carboplatin-based regimen or single-agent taxane or gemcitabine (Bellmunt et al 2014, 
NCCN Bladder Cancer Guidelines).  It remains difficult to say with certainty which regimen 
should be the reference in unfit patients.  At best, ORR values are approximately 30% to 40%, 
with median OS rarely exceeding 10 months (Fizazi 2013).  
Thus, there is still a significant unmet medical need for additional treatment options for use in 
this patient population.
Despite the high rate of disease control (above 80%) in the first-line setting, disease 
progression invariably occurs after discontinuing chemotherapy, even in patients who initially 
respond to chemotherapy (
Von der Maase et al 2000).  
Combining immunotherapy agents has been shown to result in improved response rates 
relative to monotherapy; for example, the concurrent administration of nivolumab and 
ipilimumab to patients with advanced melanoma induced higher ORRs than those obtained 
with single agent therapy.  Importantly, responses appeared to be deep and durable 
(Wolchok et al 2013).  The rationale for evaluating the combination of MEDI4736 with 
tremelimumab is that the mechanisms of CTLA-4 and PD-1 are non-redundant, suggesting 
that targeting both may have additive or synergistic activity (Pardoll 2012).  Similar results 
have been observed in an ongoing study of MEDI4736 + tremelimumab combination therapy 
in NSCLC (Antonia et al 2014a).
Based on the preliminary clinical data that include the safety and tolerability profile of 
MEDI4736 monotherapy observed in particular in the UC cohort of Study 1108 and the 
combination treatment observed in Study D4190C00006 with MEDI4736 + tremelimumab in 
NSCLC (see Section 1.1.4), data across multiple indications, and evidence of clinical activity 
observed by other mAbs currently in development that target the PD-L1/PD-1 pathway, 
AstraZeneca plans to determine the activity of MEDI4736 monotherapy and MEDI4736 in 
combination with tremelimumab in patients with UC and other indications.  This Phase III 
study will determine the activity of MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy compared to Standard of Care (SoC; cisplatin + gemcitabine or 
carboplatin + gemcitabine) in the first-line treatment of patients with PD-L1 unselected 
tumors that contain histologically or cytologically documented, unresectable, Stage IV 
(ie, T4b, any N; or any T, N2-N3; or M1) transitional cell carcinoma (transitional cell and 
mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, 
ureters, urinary bladder, and urethra).

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1.2
Rationale for study design, doses, and control arms
This study will utilize an open-label design due to the different treatment administration 
schedules and treatment durations.
1.2.1
MEDI4736 and tremelimumab dose and treatment regimen justification
1.2.1.1
MEDI4736 + tremelimumab combination therapy dose rationale
The MEDI4736 + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of MEDI4736 and 
tremelimumab that would yield sPD-L1, demonstrate promising efficacy, and have an 
acceptable safety profile.  
Pharmacokinetics/Pharmacodynamics data
In order to reduce the dosing frequency of MEDI4736 to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/pharmacodynamics, safety, and efficacy 
profile, cohorts in Study D4190C00006 were narrowed to 15 and 20 mg/kg MEDI4736 q4w.  
PK simulations from the MEDI4736 monotherapy data indicated that a similar area under the 
plasma drug concentration-time curve at steady state (AUCss; 4 weeks) was expected 
following both 10 mg/kg q2w and 20 mg/kg q4w MEDI4736.  The observed MEDI4736 PK 
data from the D4190C00006 study were well in line with the predicted monotherapy PK data 
developed preclinically.  This demonstrates similar exposure of MEDI4736 20 mg/kg q4w and 
10 mg/kg q2w, with no alterations in PK when MEDI4736 and tremelimumab (doses ranging 
from 1 to 3 mg/kg) are dosed together.  While the median maximum plasma concentration at 
steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w (approximately 1.5 fold) and 
median trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg 
q2w (approximately 1.25 fold), this is not expected to impact the overall safety and efficacy 
profile, based on existing preclinical and clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with MEDI4736 
monotherapy.  There was evidence of augmented pharmacodynamic activity relative to 
MEDI4736 monotherapy with combination doses containing 1 mg/kg tremelimumab, 
inclusive of both the 15 and 20 mg/kg MEDI4736 plus 1 mg/kg tremelimumab combinations.  
Clinical data
As of 15 April 2015, a total of 102 patients with advanced NSCLC have been treated with 
MEDI4736 and tremelimumab across 10 dose cohorts in Study D4190C00006.  The 
102 patients have received between 1 and 13 doses of MEDI4736.  Various dose combinations 
were explored, with doses of tremelimumab ranging from 1 to 10 mg/kg and doses of 
MEDI4736 ranging from 3 to 20 mg/kg.  Seventy-four of these patients were in the 
MEDI4736 q4w dosing schedule and 28 patients were in the MEDI4736 q2w dosing schedule, 
with the goal of identifying the dose combination that best optimizes the risk-benefit profile in 
an acceptable range of PK and pharmacodynamic values.

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Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious adverse events (SAEs), and 
severe AEs.  Between the 10 mg/kg MEDI4736 + 1 mg/kg tremelimumab and 10 mg/kg 
MEDI4736 + 3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of 
patients reporting any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 
10 mg/kg MEDI4736 + 3 mg/kg tremelimumab cohort than the 10 mg/kg MEDI4736 + 
1 mg/kg tremelimumab cohort.  A similar pattern was noted in the q4w regimens, suggesting 
that, as the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related 
events may be anticipated.  Further, the SAEs frequently attributed to immunotherapy, 
pneumonitis and colitis, were more commonly seen in cohorts using either 3 mg/kg or 
10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts.  Together, these data 
suggest that a combination using a tremelimumab dose of 1 mg/kg appeared to minimize the 
rate of toxicity when combined with MEDI4736.  As a result, all combination doses utilizing 
either the 3 or 10-mg/kg doses of tremelimumab were eliminated in the final dose selection.
In contrast, cohorts assessing higher doses of MEDI4736 with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of MEDI4736 may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of MEDI4736.
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg MEDI4736 + 1 mg/kg tremelimumab arm had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 
activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or treatment 
related SAEs.  No dose-limiting toxicities (DLTs) were reported.  
Preliminary clinical activity of the MEDI4736 and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg MEDI4736 q4w 
cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.  A total of 5 of 
11 patients in the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with PR, 
1 patient (20%) with SD, and 1 patient (20%) with PD.  (The fifth patient had only a single 
scan, which was conducted outside the window for these evaluations.)
Additionally, of all cohorts, the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 
showed some evidence of clinical activity.  All together, the data suggested that a 20 mg/kg
MEDI4736 + 1 mg/kg tremelimumab dose combination should be selected for further 
development.  

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1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%.  Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up (Schadendorf et al 2013).  
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 

Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I 
dose-escalation and expansion study, and showed responses were maintained for a 
median of 22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months 
for NSCLC (doses 1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma 
patients (doses 1 and 10 mg/kg) at the time of data analysis (Brahmer et al 2014, 
Drake et al 2013, Hodi et al 2014).  Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped 
nivolumab treatment (either due to protocol specified end of treatment, CR, or 
toxicity) for up to 56 weeks at the time of data analysis (Topalian et al 2014).  

MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in 
which patients were dosed for a finite time period and responses maintained beyond 
treatment discontinuation have been reported (Herbst et al 2013, 
Wolchok et al 2013).
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as MEDI4736, or the combination of the 2.  
The MEDI4736 + tremelimumab combination regimen will be administered for 4 doses 
followed by monotherapy MEDI4736 1.5 g q4w.
1.2.1.3
MEDI4736 monotherapy dose rationale
A dose of MEDI4736 dose of 20 mg/kg q4w is supported by in-vitro data, non-clinical 
activity, clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in 
patients with advanced solid tumors (ongoing first-time-in-humans study) and from a Phase I 
trial performed in Japanese patients with solid tumors (NCT01938612).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg q2w or 15 mg/kg q3w, MEDI4736 exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the MEDI4736 dosing frequency can be adapted to a 
particular regimen given the linearity seen at higher doses than 3 mg/kg.   The expected 

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half-life with doses ≥3 mg/kg q2w is approximately 21 days.  A dose-dependent suppression 
in peripheral sPD-L1 was observed over the dose range studied, consistent with engagement 
of MEDI4736 with PD-L1.  Dose-related changes in a variety of peripheral biomarkers have 
been observed over the dose range of 0.1 to 15 mg/kg.  A low level of immunogenicity has 
been observed.  No patients have experienced immune-complex disease following exposure to 
MEDI4736.  Of the 220 patients who received MEDI4736 monotherapy and for whom 
PK/ADA data were available as of14 July 2014, 5 were ADA positive, with an impact on 
PK/pharmacodynamics reported in 1 patient at 3 mg/kg.  
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
MEDI4736 and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for MEDI4736 over the dose range of 3 to 20 mg/kg MEDI4736 q4w or q2w.  (For 
further information on PK observations in Study D4190C00006, please refer to 
Section 1.2.1.1).  
The observed MEDI4736 PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a q4w regimen.  (For 
further information on PK observations in Study D4190C00006, please refer to 
Section 1.2.1.1).
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with 
20 mg/kg q4w (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg q2w 
(~1.25 fold).  Clinical activity with the 20 mg/kg q4w dosing regimen is anticipated to be 
consistent with 10 mg/kg q2w with the proposed similar dose of 20 mg/kg q4w expected to 
(a) achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; 
(c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both 
regimens maintain complete sPD-L1 suppression at trough, and the available clinical data, the 
20 mg/kg q4w and 10 mg/kg q2w regimens are expected to have similar efficacy and safety 
profiles, supporting further development with a dose of 20 mg/kg q4w.  
Clinical data
As of 8 April 2015, there is initial safety data for 16 patients receiving the 20 mg/kg q4w 
dosing regimen (12 patients from Study 1108 and 4 patients from the Japan Phase I trial).  The 
toxicities observed with 20 mg/kg q4w are consistent with the 10 mg q2w regimen, and there 
were no DLTs observed.  Of the 12 patients in Study 1108, 42% of patients have experienced 
any grade AE, with 2 being Grade 3 and above (17%).  None of the Grade 3 and higher events 
was considered treatment-related.  No patients on the Japan Phase I trial have experienced a 

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Grade 3 or above AE.  At present, the data do not suggest that the safety profile of MEDI4736 
will be different in the 20 mg/kg q4w dosing regimen when compared to 10 mg/kg q2w 
regimen.  In fact, as of 14 July 2014, 393 patients enrolled in Study 1108 have received 
MEDI4736, predominantly at 10 mg/kg q2w (either in the dose-escalation or dose-expansion 
phase of the study).  Data presented at the European Society for Medical Oncology (ESMO) 
meeting 2014 with a later cutoff of 21 August 2014 showed that MEDI4736 was well 
tolerated at all doses in the NSCLC subset of patients enrolled into Study 1108, with 
drug-related Grade ≥3 AEs reported in 3% of patients and drug-related AEs leading to 
discontinuation reported in 1% of patients.  No drug-related colitis or hyperglycemia of any 
grade, no Grade ≥3 pneumonitis  and no drug-related AEs leading to death were reported 
(Antonia et al 2014b).  No DLTs were observed up to a dose of 10 mg/kg q2w or 15 mg/kg 
q3w.
Efficacy data on the NSCLC patients in Study 1108, presented at ESMO 2014 (cutoff date of 
21 August 2014), showed a DCR at 12 weeks of 41% and ORR of 16% among 162 evaluable 
patients, with activity observed in both squamous and non-squamous histologies.  The ORR 
was higher (25%; 12 CR/PR; n=48) in patients with PD-L1-High tumors, defined as those 
with ≥25% of tumor cells with membrane staining for PD-L1, compared to patients with 
PD-L1-Low/Neg UC (10%; 7 CR/PR; n=74) (Antonia et al 2014b).  
1.2.1.4
Rationale for fixed dosing
A population PK model was developed for MEDI4736 using monotherapy data from 
Study 1108 (Phase I study; N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid 
tumors).  Population PK analysis indicated only a minor impact of body weight (WT) on the 
PK of MEDI4736 (coefficient of ≤0.5).  The impact of body WT-based (10 mg/kg q2w) and 
fixed dosing (750 mg q2w) of MEDI4736 was evaluated by comparing predicted steady state 
PK concentrations (5th, median, and 95th percentiles) using the population PK model.  A 
fixed dose of 750 mg was selected to approximate 10 mg/kg (based on a median body WT of 
approximately 75 kg).  A total of 1000 patients were simulated using a body WT distribution 
of 40 to 120 kg.  Simulation results demonstrated that body WT-based and fixed dosing 
regimens yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with the fixed dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase I 
through Phase III studies (N=654; doses=0.01 to 15 mg/kg q4w or every 90 days; metastatic 
melanoma; Wang et al 2014).  A population PK model indicated minor impact of body WT on 
the PK of tremelimumab (coefficient of ≤0.5).  The WT-based (1 mg/kg q4w) and fixed 
dosing (75 mg/kg q4w; based on a median body WT of approximately 75 kg) regimens were 
compared using predicted PK concentrations (5th, median, and 95th percentiles) using a 
population PK model in a simulated population of 1000 patients with a body WT distribution 
of 40 to 120 kg.  Similar to MEDI4736, simulations indicated that both body WT-based and 
fixed dosing regimens of tremelimumab yield similar median steady state PK concentrations 
with slightly less overall between-patient variability with the fixed dosing regimen. 

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Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, 
Wang et al 2009, Zhang et al 2012).  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 PK/pharmacodynamics parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given the expectation of similar PK exposure and variability, 
AstraZeneca considered it feasible to switch to fixed dosing regimens.  Based on an average 
body WT of 75 kg, a fixed dose of 1.5 g q4w MEDI4736 (equivalent to 20 mg/kg q4w) and 
75 mg q4w tremelimumab (equivalent to 1 mg/kg q4w) is included in the current study.
1.2.2
Rationale for Standard of Care as a comparator
The choice of SoC options provided in this study includes cisplatin + gemcitabine or 
carboplatin + gemcitabine.  Patients in the SoC arm will receive treatment based on their 
cisplatin eligibility, until progression per standard practice.  The SoC options provided in this 
study include agents that are commonly used in unresectable, Stage IV (ie, T4b, any N; or any 
T, N2-N3; or M1) transitional cell carcinoma (transitional cell and mixed transitional/ 
non-transitional cell histologies) of the urothelium and allow sufficient flexibility for 
Investigators and patients to select the agents that reflect their normal clinical practice and 
national guidelines (Bellmunt et al 2014).  
1.2.3
Rationale for cisplatin-ineligible Interim Analysis
Cisplatin-based combination chemotherapy is widely considered standard therapy for first line 
advanced metastatic UC (Von der Maase et al 2000). However, roughly 40-50% of patients 
are ineligible for standard cisplatin based chemotherapy due to impaired renal function, 
advanced age, poor performance status or medical comorbidities (Galsky 2011).  In addition, a 
review of US SEER database demonstrated that only 45% of patients with metastatic bladder 
cancer were able to receive treatment with any type of chemotherapy (Galsky 
2015). Carboplatin-based regimens are widely used as treatment alternatives to cisplatin 
combination chemotherapy for patients unable to tolerate cisplatin, but are generally 
associated with poor response rates and shorter OS. Although no formal comparison can be 
made, first line UC patients who received carboplatin-based chemotherapy demonstrate lower 
ORR (30-40%) as compared to cisplatin- based chemotherapy, with OS rarely exceeding 10 
months (De Santis et al 2012). It’s expected that those patients who are unfit for cisplatin-
containing chemotherapy or any chemotherapy would have much worse prognosis, i.e. lower 
response to chemotherapy or none, and much shorter survival. Taken together, the need for 
more efficacious and tolerable treatment alternatives for UC patients who are unable to 
tolerate cisplatin-based regimens highlights a significant unmet medical need.
Emerging clinical data suggests that PD-1/PD-L1 pathway inhibitors may be a reasonable 
treatment options for patient with UC cancer, including those unable to tolerate cisplatin-
based therapy. Considering the short response duration and poor survival for patients which 
are treated with carboplatin based first-line chemotherapy and the encouraging activity with 

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PD-1/PD-L1 pathway inhibitors in UC, AstraZeneca plans to determine the activity of 
MEDI4736 monotherapy in UC patients that are cisplatin-ineligible.
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab 
combination therapy, respectively, prior to the overall benefit/risk assessment.
1.3.1
Potential benefits
1.3.1.1
MEDI4736
Of the 414 patients treated with MEDI4736 (all dose levels) in all tumor types in Study 1108 
as of 14 July 2014, a total of 169 patients were evaluable for response analysis, which 
included patients who had at least 24 weeks of follow-up as of 14 July 2014 and had either at 
least 1 post-baseline tumor assessment or experienced clinical PD or death.  Nineteen patients 
(11.2%) had a best overall response of confirmed and unconfirmed CR/PR.  The DCR (CR + 
PR + SD ≥12 weeks) was 32% (54 of 169 patients).  PD-L1 status (based on Ventana assay) 
was known for 143 of 169 evaluable patients, of whom 30 had PD-L1-High tumors (defined 
by tumor staining >25%).  A best overall response of CR/PR (confirmed and unconfirmed) 
was observed in 7 of 30 (23.3%) patients with PD-L1-High tumors and in 6 of 113 (5.3%) 
patients with PD-L1-Low/Neg tumors.  
The most recent data from the UC cohort in Study 1108 as of 20 March 2015 included 
20 previously treated (median of 2 prior systemic therapies) patients who had UC regardless 
of their PD-L1 expression status and who were treated with MEDI4736.  Among the 
16 patients with at least 1 post-baseline disease assessment (or death or disease progression 
prior to their first assessment), 4 patients have achieved a PR, 4 patients have maintained SD 
as of their last available disease assessment, and 8 patients have experienced PD.  One of the 
patients with PD had an initial 46% increase in tumor burden at the first disease assessment, 
followed by a subsequent 21% tumor reduction relative to baseline (54% decrease from 
maximal tumor burden), which may be considered pseudoprogression.  This patient remained 
on study at data cutoff.  A retrospective analysis of the relationship between tumoral and 
immune cell PD-L1 expression and clinical activity is ongoing.  Other mAbs targeting the 
PD-L1/PD-1 pathway have shown clinical activity in this indication, as summarized in 
Section 1.1.4.
1.3.1.2
Tremelimumab
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, a response rate of 7% and a median OS of 
10 months in the second-line setting (compared to approximately 6 months with BSC reported 
from a retrospective analysis; Korn et al 2008) were observed (Kirkwood et al 2010).  In a 
randomized, open-label, first-line Phase III study of tremelimumab (administered at 15 mg/kg 
every 90 days) versus chemotherapy (dacarbazine or temozolomide) in advanced melanoma 
(Study A3671009), results of the final analysis showed a response rate of 11% and median OS 
of 12.58 months in the first-line setting compared to 10.71 months with standard 

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chemotherapy (Ribas et al 2013).  Additionally, in a Phase II maintenance study, patients with 
NSCLC (Study A3671015), PFS at 3 months was 22.7% in the tremelimumab arm compared 
with 11.9% in the BSC arm.  At this time there are no sources of tremelimumab monotherapy 
data in patients with UC.  Currently AstraZeneca is planning a multi-indication Phase I/II 
study of tremelimumab monotherapy, including a UC patient cohort.
1.3.1.3
MEDI4736 + tremelimumab combination therapy
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also 
supports the synergy of this combination.  Available data, such as those presented by Wolchok 
et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may have 
profound and durable benefits in patients with melanoma (Wolchok et al 2013).  Further, 
preliminary efficacy data from Study D4190C00006 have demonstrated that this combination 
is clinically active and well tolerated.  As of 27 January 2015, 53 patients were evaluable for 
response across various MEDI4736 + tremelimumab combination therapy dose regiments.  Of 
these, 12 patients (23%) had a best response of PR and 14 patients (26%) had a best response 
of SD.  In the MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg q4w cohort, a total of 5 of 
11 patients were evaluable for efficacy with at least 8 weeks of follow-up.  Of these, there 
were 2 patients (40%) with PR, 1 patient (20%) with SD, and 1 patient (20%) with PD.  (The 
fifth patient had only a single scan, which was conducted outside the window for these 
evaluations.)  
1.3.2
Potential risks
1.3.2.1
MEDI4736
Identified risks with MEDI4736 are diarrhea, increases in transaminases, pneumonitis, and 
colitis. 
Potential risks include endocrinopathies (hypothyroidism and hyperthyroidism, 
hypophysitis/hypopituitarism, and adrenal insufficiency, type I diabetes mellitus and diabetes 
insipidus ), hepatitis/hepatotoxicity, neurotoxicities, nephritis/increases in creatinine, 
pancreatitis, and dermatitis/rash, myocarditis, myositis/polymyositis.  Additional important 
potential risks include infusion-related reactions, hypersensitivity reactions, serious infections, 
and other rare or less frequent inflammatory events including neuromuscular toxicities (e.g. 
Guillain Barre syndrome, myasthenia gravis). Further information on these risks can be found 
in the current version of the MEDI4736 IB.
In MEDI4736 monotherapy clinical studies, AEs at an incidence of > 20% are fatigue, 
nausea, decreased appetite, dyspnea, cough Approximately 10% of patients experienced an 
AE that resulted in permanent discontinuation of MEDI4736, and approximately 3.5% of 
patients experienced an SAE that was considered to be related to MEDI4736 by the study 
Investigator.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and, in the case of events suspected to have an immune basis, the use of established 

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treatment guidelines for immune-mediated toxicity (see Dosing Modification and Toxicity 
Management Guidelines).
A detailed summary of MEDI4736 monotherapy AE data can be found in the most recent 
MEDI4736 IB.
1.3.2.2
Tremelimumab
Identified risks with tremelimumab monotherapy are gastrointestinal (GI) effects (colitis, 
diarrhea, enterocolitis, and intestinal perforation), endocrine disorders (hypothyroidism and 
hyperthyroidism, hypophysitis, and adrenal insufficiency), skin effects (rash and pruritus), and 
elevations in lipase and amylase.
Potential risks based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated reactions including other GI events, for 
example, ulcerative colitis, dehydration, nausea, and vomiting; hepatic events including 
hepatitis and liver enzyme elevations; pneumonitis and interstitial lung disease; clinical 
manifestations of pancreatitis; nervous system events including encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré syndrome, and proximal muscle weakness; 
cytopenias including thrombocytopenia, anemia, and neutropenia; infusion-related reactions
and  hypersensitivity, 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, 
Sjögren’s syndrome, and giant cell temporal arteritis and ulcerative colitis; hyperglycemia and 
diabetes mellitus; and.  Further information on these risks can be found in the current version 
of the Tremelimumab IB.
With the use of pooled data from monotherapy clinical studies, AEs reported at an incidence
of > 20% 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.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the Tremelimumab IB.
1.3.2.3
MEDI4736 + tremelimumab combination therapy
The safety of MEDI4736 + tremelimumab combination therapy is being evaluated in the 
ongoing dose escalation and dose expansion Study D4190C00006, in patients with NSCLC, 
and has so far shown a manageable safety and tolerability profile.
The potential risks with the combination of MEDI4736 + tremelimumab are similar to those 
for MEDI4736 and tremelimumab monotherapy.  Emerging data from Study D4190C00006 
and from combinations of other agents in the same class indicate an increased frequency 
and/or severity of some of these potential immune-mediated toxicities.

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As of 15 April 2015, a total of 102 patients with advanced NSCLC have been treated with 
MEDI4736 and tremelimumab across 10 dose cohorts in Study D4190C00006.  The 
102 patients have received between 1 and 13 doses of MEDI4736.  Various dose combinations 
were explored, with doses of tremelimumab ranging from 1 to 10 mg/kg and doses of 
MEDI4736 ranging from 3 to 20 mg/kg.  Seventy-four of these patients were in the 
MEDI4736 q4w dosing schedule, and 28 patients were in the MEDI4736 q2w dosing 
schedule, with the goal of identifying the dose combination that best optimizes the risk-benefit 
profile in an acceptable range of PK and pharmacodynamic values.
In Study D4190C00006, AEs (all grades) reported very commonly (≥10% of patients) were 
diarrhea, fatigue, nausea, dyspnea, pruritus, rash, increased amylase, decreased appetite, 
pyrexia, increased alanine aminotransferase (ALT), cough, colitis, and increased lipase.  In 
this dose-finding study, all patients in the tremelimumab 3 and 10 mg/kg dose cohorts 
experienced AEs; patients in the MEDI4736 20 mg/kg and tremelimumab 1 mg/kg q4w cohort 
experienced the lowest AE rate (14 of 18 patients, 77.8%).
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 15% of patients experienced an SAE that was considered to 
be related to MEDI4736 and tremelimumab by the study investigator.
A detailed summary of MEDI4736 + tremelimumab combination AE data can be found in the 
current version of the MEDI4736 IB.
1.3.3
Overall benefit and risk assessment
There remains a significant unmet medical need for additional treatment options for treatment-
naïve patients with histologically or cytologically documented, unresectable, Stage IV 
(ie, T4b, any N; or any T, N2-N3; or M1) transitional cell carcinoma (transitional cell and 
mixed transitional/non-transitional cell histologies) of the urothelium.   
Treatment with agents targeting PD-1/PD-L1 (such as MEDI4736) 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 MEDI4736 
monotherapy in the bladder cancer cohort have shown some clinical activity.  Additionally, 
MEDI4736 + tremelimumab combination therapy has shown clinical activity in patients with 
recurrent or metastatic squamous cell cancer of the head and neck.  Preliminary data generated 
from patients with NSCLC treated with MEDI4736 + tremelimumab combination therapy 
have shown early signs of clinical activity, and data from competitors indicate that the 

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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 IPs (including MEDI4736, tremelimumab, and SoC).
The toxicity profile of the combination of MEDI4736 and tremelimumab included fatigue, 
colitis, diarrhea, aspartate aminotransferase (AST) or 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.
In particular, based on the specific mechanism of action of MEDI4736 and tremelimumab 
leading to T-cell activation and proliferation, there is the possibility of observing immune-
related adverse events (irAEs) during the conduct of this study.  Potential irAEs 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 irAEs.  In the absence of an alternate etiology (eg, infection or PD), an 
immune-related etiology should be considered for signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy.  It is recommended that management of irAEs 
follow the guidelines outlined in Section 6.7.
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 MEDI4736 in this tumor type, and the strength 
of the scientific hypotheses under evaluation, the MEDI4736 monotherapy and MEDI4736 + 
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 (QoL) and potentially extending 
survival.  Furthermore, preclinical 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 MEDI4736 monotherapy and MEDI4736 + 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 a randomized, open-label, controlled, multi-center, global Phase III study to determine 
the efficacy and safety of MEDI4736 monotherapy (1.5 g intravenous [IV] q4w) and 
MEDI4736 (1.5 g IV q4w) in combination with tremelimumab (75 mg IV q4w) for up to 
4 doses/cycle each followed by MEDI4736 1.5 g IV q4w) versus SoC (cisplatin + gemcitabine 
or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with 
histologically or cytologically documented, unresectable, Stage IV (ie, T4b, any N; or any T, 
N2-N3; or M1) transitional cell carcinoma (transitional cell and mixed 

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transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, 
urinary bladder, and urethra).  Crossover from SoC to MEDI4736 monotherapy or MEDI4736 
+ tremelimumab combination therapy will not be permitted.  A schematic diagram and flow 
chart of the overall study design are shown in Figure 1 and Figure 2, respectively.
This study will randomize approximately 1005 patients globally. After the end of global 
enrollment (i.e. LSI, globally), recruitment into an expansion cohort will continue in China 
until approximately 180 Chinese patients have been randomized.
Patients will provide a tumor tissue sample at screening to determine PD-L1 status (defined by 
an immunohistochemistry [IHC] assay developed by Ventana, see Table 1) for stratification*.
Table 1
PD-L1 status defined by scoring of an IHC assay developed by Ventana 
for stratification in D419BC00001*
Interpretation
Staining description
PD-L1-High
≥25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control
OR
≥25% tumor associated immune cell positivity for PD-L1 at any intensity 
above background staining as noted on the corresponding negative control
PD-L1-Low/Neg
<25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control
AND
<25% tumor associated immune cell positivity for PD-L1 at any intensity 
above background staining as noted on the corresponding negative control
IHC Immunohistochemistry; PD-L1 Programmed cell death ligand 1.
*Definition of PD-L1 high versus low/negative expression will be used for stratification. Different cutoff of PD-
L1 expression  may be utilized for analysis based on emerging data. 
Note: PD-L1 High ( >=25% tumor cell membrane positivity for PD-L1 or 1) IF IC area >1%: >=25% tumor 
associated immune cell positivity for PD-L1; 2) If IC area=1%: 100% tumor associated immune cell positivity 
for PD-L1). PD-L1 Low if criteria not met for PD-L1 High 
Patients enrolled in the study will be randomized (1:1:1) to treatment with MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC 
(cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility).  Patients 
will be stratified according to cisplatin eligibility (eligible or ineligible; see Inclusion 
Criterion 7 in Section 3.1), PD-L1 status (High or Low/Neg, based on Ventana assay), and 
visceral metastasis (presence or absence of lung and/or liver metastasis).  Doses and treatment 
regimens are described in Section 7.2.  Assessments will be conducted as indicated in Table 3, 
Table 4, Table 5, Table 6, and Table 7.  

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Figure 1
Overall study design
OS Overall survival; PD-L1 Programmed cell death ligand 1.
Note: approximately 180 Chinese patients will be randomized in the same criteria (stratification factors and 1:1:1 fashion) as globally.

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Figure 2
Study flowchart
a
Informed consent may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy 
sample acquisition and analysis prior to randomization.
b
In addition to PR and CR, a confirmatory scan is required following the initial demonstration of PD (patients enrolled in 
the SoC arm will discontinue study drug at the first assessment of disease progression).  (See Section 5.1 for more 
information.)
CR Complete response; PD Progressive disease; PR Partial response; RECIST 1.1 Response Evaluation Criteria in Solid 
Tumors, version 1.1; SoC Standard of care.

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2.
STUDY OBJECTIVES
The assessments of OS will be considered primary objectives.
2.1
Primary objectives
Primary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy versus 
SoC in terms of OS in patients with 
unresectable Stage IV UC
OS
To assess the efficacy of MEDI4736 
monotherapy versus SoC in terms of OS in 
patients with unresectable Stage IV 
PD-L1-High UC
OS
OS Overall survival; SoC Standard of care; UC Urothelial cancer.
2.2
Secondary objectives
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
PFS in patients with PD-L1-High UC
PFS using Investigator assessments according to 
RECIST 1.1 a
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy versus 
SoC in terms of PFS in patients with UC
PFS using Investigator assessments according to 
RECIST 1.1 a
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
PFS and OS in patients with UC
PFS using Investigator assessments according to 
RECIST 1.1 a
OS
To assess the efficacy of 
MEDI4736 + tremelimumab combination 
therapy compared to SoC in terms of PFS 
and OS in patients with PD-L1-Low/Neg UC 
PFS using Investigator assessments according to 
RECIST 1.1 a
OS
To assess the efficacy profile of MEDI4736 
monotherapy in patients who are not 
cisplatin-eligible
ORR, DoR, DCR, TTR, and PFS, using BICR 
assessments according to RECIST 1.1 b
OS 

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Secondary objectives:
Outcome measures:
To further assess the efficacy of 
MEDI4736 + tremelimumab combination 
therapy compared to MEDI4736 
monotherapy in terms of PFS, OS, OS24, 
APF12, ORR, DoR, DCR, and PFS2 in 
patients with PD-L1-Low/Neg UC and all 
patients with UC
OS
OS24
PFS, APF12, ORR, DoR, and DCR using 
Investigator assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in terms of OS24, APF12, 
ORR, DoR, DCR, and PFS2 in patients with 
UC
OS24
APF12, ORR, DoR, and DCR using Investigator  
assessments according to RECIST 1.1a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
OS24, APF12, ORR, DoR, DCR, and PFS2 
in patients with PD-L1-High UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
OS24, APF12, ORR, DoR, DCR, and PFS2 
in patients with UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in terms of OS24, APF12, 
ORR, DoR, DCR, and PFS2 in patients with 
PD-L1-Low/Neg UC
OS24
APF12, ORR, DoR, and DCR using Investigator 
assessments according to RECIST 1.1 a
PFS2 as defined by local standard clinical practice
To further assess the efficacy of MEDI4736 
+ tremelimumab combination therapy 
compared to SoC in patients with PD-L1-
High UC
PFS, APF12, ORR, DoR, and DCR using 
Investigator assessments according to RECIST 1.1 a
OS and OS24
PFS2 as defined by local standard clinical practice
To assess disease-related symptoms and 
HRQoL in UC patients treated with 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy 
compared with SoC and each other using the 
FACT-BL questionnaire 
FACT-BL: Fatigue, Pain, Derived NFBlSI-18 
score, FACT-BL TOI, and FACT-BL Total score
To assess the PK of MEDI4736 monotherapy 
and MEDI4736 + tremelimumab 
combination therapy
Serum concentration of MEDI4736/tremelimumab 
PK parameters (such as peak concentration and 
trough, as data allow; sparse sampling)
To investigate the immunogenicity of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy
Presence of ADAs for MEDI4736 and 
tremelimumab (confirmatory results: positive or 
negative)

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a
The analysis will be based on programmatically derived investigator assessments according to RECIST 1.1.  
See Section 8 for further details.
b
The analysis will be based on programmatically derived BICR assessments according to RECIST 1.1.  See 
Section 8 for further details.
ADA Anti-drug antibody; APF12 Proportion of patients alive and progression free at 12 months from 
randomization; BICR Blinded Independent Central Review; DCR Disease control rate; DoR Duration of 
response; FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer; FACT-BL TOI Functional 
Assessment of Cancer Therapy - Bladder Cancer Trial Outcome Index; HRQoL Health-related quality of life; 
NFBlSI-18 National Comprehensive Cancer Network - FACT Bladder Symptoms Index-18; ORR Objective 
response rate; OS Overall survival; OS24 Proportion of patients alive at 24 months from randomization; 
PD-L1 Programmed cell death ligand 1; PFS Progression-free survival; PFS2 Time from randomization to 
second progression; PK Pharmacokinetics; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, 
version 1.1; SoC Standard of care; TTR Time to response; UC Urothelial cancer.
2.3
Safety objective
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy 
compared to SoC
AEs, laboratory findings, vital signs, and ECGs 
To assess the safety and tolerability profile of 
MEDI4736 monotherapy and SoC in patients 
who are not cisplatin-eligible
AEs, laboratory findings, vital signs, and ECGs
AE Adverse event; ECG Electrocardiogram; SoC Standard of care.
2.4
Exploratory objectives
Exploratory objectives:
Outcome measures:
To explore irRECIST as an assessment 
methodology for clinical benefit of 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy versus 
SoC with assessment by BICR
PFS, APF12, ORR, DoR, and DCR using BICR 
assessment according to irRECIST
To assess AEs directly by patient self-
reporting of specific PRO-CTCAE symptoms
Sixteen PRO-CTCAE symptoms considered 
relevant to study treatments
To assess disease-related symptoms and 
HRQoL in UC patients treated with 
MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy versus 
SoC and each other using the FACT-BL 
questionnaire  
FACT-BL: PWB, SWB, EWB, FWB, BlCS, and 
FACT-G Total score

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Exploratory objectives:
Outcome measures:
To investigate the relationship between PK 
exposure and clinical outcomes, efficacy, 
AEs, and/or safety parameters, if deemed 
appropriate
A graphical and/or a data modeling approach will 
be used to analyze PK exposure and the relationship 
with clinical outcomes, efficacy, AEs, and/or safety 
parameters, as deemed appropriate
To describe and evaluate resource use 
associated with assigned treatments and 
underlying disease during assigned treatment
Health resource utilization measures including 
hospitalization, outpatient visits, or emergency 
department visits, measured via the HOSPAD 
module
To explore the impact of treatment and 
disease state on health state utility using the 
EQ-5D-5L during assigned treatment
EQ-5D-5L health state utility index will be used to 
derive health state utility based on patient-reported 
data
To collect blood and tissue samples for 
defining biological responses to MEDI4736 
and tremelimumab and for identifying 
candidate markers that may correlate with 
likelihood of clinical benefit
Protein expression detected by IHC (eg, PD-L1)
miRNA/mRNA
T-cell and MDSC phenotyping
SNP genotyping
Urine-derived factors, where applicable
To assess patients’ overall impression of the 
change in their health status since the start of 
study treatment
Single-item PGIC measure 
Note: Exploratory objective analyses may be reported separately from the main clinical study report.
AE Adverse event; APF12 Proportion of patients alive and progression free at 12 months from randomization; 
BICR Blinded Independent Central Review; BlCS Bladder Cancer Subscale; DCR Disease control rate; 
DoR Duration of response; EQ-5D-5L EuroQol 5-dimension, 5-level health state utility index; EWB Emotional 
well-being; FWB Functional well-being; FACT-BL Functional Assessment of Cancer Therapy - Bladder 
Cancer; FACT-G Functional Assessment of Cancer Therapy - General; FACT-BL TOI Functional Assessment 
of Cancer Therapy - Bladder Cancer Trial Outcome Index; HRQoL Health-related quality of life; 
IHC Immunohistochemistry; irRECIST Immune-related Response Evaluation
Criteria in Solid Tumors; MDSC Myeloid-derived suppressor cells; miRNA Micro-ribonucleic acid; 
mRNA Messenger ribonucleic acid; ORR Objective response rate; PD-L1 Programmed cell death ligand 1; 
PFS Progression-free survival; PGIC Patient Global Impression of Change; PK Pharmacokinetics; 
PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; 
PWB Physical Well-Being; SNP Single nucleotide polymorphism; SoC Standard of care; SWB Social/family 
well-being; TFST Time to first subsequent therapy; TSST Time to second subsequent therapy or death; 
UC Urothelial cancer.
A further objective to meet China FDA requirement is to evaluate consistency in efficacy and 
safety among Chinese subjects for benefit-risk assessment of MEDI4736 monotherapy and 
MEDI4736 + tremelimumab combination therapy compared to SoC.

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3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria (Section 3.1) and none of the exclusion 
criteria (Section 3.2) for this study.  Under no circumstances can there be exceptions to this 
rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfill the following criteria:
1.
Age ≥18 years at the time of screening.
2.
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.)
3.
Patients with histologically or cytologically documented, unresectable, Stage IV 
(ie, T4b, any N; or any T, N2-N3 (Note: The Investigators will use their discretion 
to confirm the cause of N2 disease [reactive or inflammatory]); or M1) transitional 
cell carcinoma (transitional cell and mixed transitional/non-transitional cell 
histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and 
urethra) (see NCCN Bladder Cancer Guidelines), who have not been previously 
treated with first-line chemotherapy.  (Patients who have received prior definitive 
chemoradiation, adjuvant or neoadjuvant treatment for locally advanced disease, 
are eligible, provided that progression to Stage IV disease has occurred >6 months 
from last therapy [for chemoradiation and adjuvant treatment] or >6 months from 
last surgery [for neoadjuvant treatment].)
4.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have 
a short axis ≥15 mm) with a computed tomography (CT) or magnetic resonance 
imaging (MRI) and that is suitable for accurate repeated measurements as per 
Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) 
guidelines.
5.
Eastern Cooperative Oncology Group (ECOG) PS 0 or 1
6.
Life expectancy ≥12 weeks (in the opinion of the Investigator)
7.
Patients eligible or ineligible for cisplatin-based chemotherapy.  Cisplatin 
ineligibility is defined as meeting one of the following criteria: 

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
Creatinine clearance (CrCl) <60 mL/min calculated by Cockcroft-Gault 
equation (using actual body weight; see Appendix A) or by measured 24-hour 
urine collection.  (In cases where both are performed, measured 24-hour urine 
collection will be used to determine eligibility, providing an adequate 
collection was performed.)*

Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 
audiometric hearing loss

CTCAE Grade ≥2 peripheral neuropathy

New York Heart Association ≥Class III heart failure
8.
Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be 
known prior to randomization.  As such, all patients must be able to provide a 
newly acquired tumor biopsy during screening (preferred) or provide an available 
tumor sample taken ≤3 years prior to screening.  Tumor lesions used for newly 
acquired biopsies should not be target lesions, unless there are no other lesions 
suitable for biopsy.  Samples with limited tumor content and fine needle aspirate 
specimens are not acceptable.  Specimens from metastatic bone lesions are 
typically unacceptable unless there is a significant soft tissue component.  The 
tumor specimen submitted to establish PD-L1 status should be of sufficient 
quantity to allow for PD-L1 IHC and other exploratory biomarker analyses and is 
preferred in formalin-fixed paraffin embedded blocks.
9.
Adequate organ and marrow function as defined below:

Hemoglobin ≥9 g/dL

Absolute neutrophil count ≥1500/mm3

Platelet count ≥100000/mm3

Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of 
evidence of hemolysis or hepatic pathology), who will be allowed in 
consultation with their physician and AstraZeneca.

ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT, and 
AST ≤5 × ULN

CrCl ≥30 mL/min calculated by Cockcroft-Gault equation (using actual body 
weight; see Appendix A) or by measured 24-hour urine collection for 
determination.  (In cases where both are performed, measured 24-hour 

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measured urine collection will be used to determine eligibility, providing an 
adequate collection was performed.)*
10.
Evidence of postmenopausal status or negative urinary or serum pregnancy test for 
female premenopausal patients.  Women will be considered postmenopausal 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 postmenopausal 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 postmenopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy).

Women ≥50 years of age would be considered postmenopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments , had radiation-induced oophorectomy with last menses 
>1 year ago, had chemotherapy-induced menopause with >1 year interval since 
last menses, or underwent surgical sterilization (bilateral oophorectomy, 
bilateral salpingectomy, or hysterectomy).
*Method used to determine CrCl for study eligibility will be the same method used to 
determine cisplatin eligibility at study entry. See Section 3.3 for detailed requirements 
regarding IVRS data entry for purposes of randomization.
Additional details pertaining to retreatment are presented in Section 7.2.  Additional details 
pertaining to restrictions are presented in Section 3.8.
3.2
Exclusion criteria
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/MedImmune staff and/or staff at the study site)
2.
Previous investigational product (IP) assignment in the present study
3.
Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an 
interventional study
4.
Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette 
Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, 
or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.  Prior local 
intervesical chemotherapy or immunotherapy is allowed if completed at least 
28 days prior to the initiation of study treatment.

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5.
Any unresolved toxicity National Cancer Institute (NCI) CTCAE Version 4.03 
Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, 
and the laboratory values defined in the inclusion criteria 

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with AstraZeneca.

Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with MEDI4736 or tremelimumab may be included after consultation 
with AstraZeneca.  
6.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment.  Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable.  Note: Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is acceptable 
(eg, local surgery or radiotherapy).
7.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 28 days of the first dose of study drug
8.
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.  
9.
History of allogenic organ transplantation that requires use of immunosuppressive 
agents.
10.
Active or prior documented autoimmune or inflammatory disorders (including but 
not limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], 
diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, 
Sarcoidosis syndrome, 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 3 years may be included but only after 
consultation with AstraZeneca.

Patients with celiac disease controlled by diet alone may be included but only 
after consultation with AstraZeneca.

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11.
Uncontrolled intercurrent illnesses, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, 
uncontrolled diabetes, unstable angina pectoris, cardiac arrhythmia, interstitial lung 
disease, 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.
Other malignancy within 5 years before first dose of IP, except for the following 
pending a discussion with AstraZeneca:

Patients with a history of prostate cancer (tumor/node/metastasis stage) of 
stage ≤T2cN0M0 without biochemical recurrence or progression and who in 
the opinion of the Investigator are not deemed to require active intervention 

Patients who have been adequately treated for a malignancy with a low 
potential risk for recurrence (eg, cervical carcinoma in situ, non-melanomatous 
carcinoma of the skin, or ductal carcinoma in situ of the breast that has been 
surgically cured).
13.
History of leptomeningeal carcinomatosis
14.
Brain metastases or spinal cord compression unless the patient’s condition is stable 
(asymptomatic, no evidence of new or emerging brain metastases) and off steroids 
for at least 14 days prior to the start of study treatment.  Patients with suspected or 
known brain metastases at screening should have an MRI (preferred)/CT, 
preferably with IV contrast to access baseline disease status.
15.
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms 
calculated.  Any clinically significant abnormalities detected require triplicate ECG 
results and a mean QTcF ≥470 ms calculated from 3 ECGs obtained over a brief 
period (eg, 30 minutes). 
16.
History of active primary immunodeficiency 
17.
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, hepatitis C, or human immunodeficiency 
virus (HIV, positive HIV 1 or 2 antibodies).  Active hepatitis B virus (HBV) 
infection is defined by a positive HBV surface antigen (HBsAg) result.  Patients 
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA] negative) 
are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

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18.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of IP.  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

Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication)
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 during the study and up 
to 30 days after the last dose of IP.
20.
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 90 days after the last dose of MEDI4736 monotherapy or 180 days 
after the last dose of MEDI4736 + tremelimumab combination therapy
21.
Known allergy or hypersensitivity to IP or any IP excipient, or to other humanized 
mAbs
22.
Any medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy
23.
Patient <30 kg in weight
For procedures for withdrawal of incorrectly enrolled patients, see Section 3.4.
3.3
Patient enrollment and randomization
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening.
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will:
1.
Obtain signed informed consent  before any study specific procedures are 
performed.  (Informed consent may be obtained prior to the 28-day screening 
window in order to permit tumor biopsy sample acquisition which must be analyzed 
prior to randomization.)
2.
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) in the 
following format (ECCNNXXX: CC being the country code, NN being the center 
number, and XXX being the patient enrollment code at the center).  This number is 

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the patient’s unique identifier and is used to identify the patient on the electronic 
case report forms (eCRFs).
3.
Obtain tumor sample and send for PD-L1 expression analysis.  (Obtaining the 
tumor biopsy sample should be given the highest priority and, as such, the 
sample may be obtained and sent for PD-L1 status evaluation prior to the 
28-day screening window in order to permit analysis prior to randomization.)  
PD-L1 status must be available in the IVRS/IWRS in order for the patient to be 
randomized, as it is a stratification factor.
4.
Determine patient eligibility (see Sections 3.1 and 3.2)
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
Define the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) treatment (based on 
cisplatin eligibility) that the patient would receive in the absence of randomized therapy.  This 
must be completed for all patients.  The information will be recorded in the IVRS/IWRS.  
NOTE:  If more than 1 evaluation of creatinine clearance has been obtained during the 
screening period, the creatinine clearance value closest to Cycle 1 Day 1 should be 
entered into the IVRS system for randomization purposes (see Section 3.1 for details). 
Method used to determine CrCl for study eligibility should be the same method used to 
determine IVRS randomization at study entry
5.
Ensure PD-L1 status results are received by the IVRS/IWRS from the central 
laboratory prior to randomization.
6.
Record the presence or absence of visceral metastases (as defined as metastatic 
disease in lung and/or liver) as a stratification factor in the IVRS/IWRS.
7.
Obtain a unique randomization number via the IVRS/IWRS.  Numbers will be 
assigned strictly sequentially by IVRS/IWRS as patients are eligible for entry into 
the study.  The system will randomize the eligible patient to 1 of the 3 treatment 
arms.  
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system.  
It is strongly recommended that patients commence study drug on the same day as 
randomization by IVRS/IWRS.  If same-day treatment is not possible, then the study 
treatment must occur within 3 working days of randomization. Patients must not be 
randomized unless all eligibility criteria have been met.

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If a patient withdraws from participation in the study, then his or her enrollment/ 
randomization code or patient identification number cannot be reused.  Withdrawn patients 
will not be replaced.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients who 
are enrolled but found not to meet all the eligibility criteria must not be randomized or 
initiated on treatment and must be withdrawn from the study as a screen failure.
Where a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on treatment, the Investigator should inform AstraZeneca immediately, and 
a discussion should occur between AstraZeneca and the Investigator regarding whether to 
continue or discontinue the patient from treatment.  AstraZeneca must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment arms
Patients must not be randomized unless all eligibility criteria have been met.
At baseline, patients who satisfy all the entry criteria will be centrally assigned to study drug 
by the IVRS/IWRS, according to the randomization scheme generated by the Biostatistics 
Group, AstraZeneca, or delegate.  
Patients enrolled in the study will be randomized (1:1:1) to treatment with MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC 
(cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility).  Patients 
will be stratified according to cisplatin eligibility (ie, eligible or ineligible; see Inclusion 
Criterion 7 in Section 3.1), PD-L1 status (High or Low/Neg, based on Ventana assay), and 
visceral metastasis (presence or absence of lung and/or liver metastasis).  PD-L1 status 
stratification will be based on natural prevalence rates.  Randomization of cisplatin-eligible
patients will be capped at a maximum 85% of the planned total number of patients.
The actual treatment given to patients will be determined by the randomization scheme in the 
IVRS/IWRS.  The randomization scheme will be produced by a computer software program 
that incorporates a standard procedure for generating randomization numbers.  
One randomization list will be produced for each of the randomization strata.  A blocked 
randomization will be generated, and all centers will use the same list in order to minimize 
any imbalance in the number of patients assigned to each treatment arm.  
Patients will be identified to the Centralized Randomization Center per country regulations.  
Randomization codes will be assigned strictly sequentially, within each stratum, as patients 
become eligible for randomization.  

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Every effort should be made to minimize the time between randomization and starting 
study drug.  It is strongly recommended that patients commence study drug on the same 
day as randomization by IVRS/IWRS. If same-day treatment is not possible, then the 
study treatment must occur within 3 working days of randomization.
If a patient discontinues participation in the study, then their enrollment/randomization code 
cannot be reused.  
3.6
Methods for ensuring blinding (not applicable)
Not applicable.  This is an open-label study.
3.7
Methods for unblinding (not applicable)
Not applicable.  This is an open-label study.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:

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 
MEDI4736 + tremelimumab combination therapy or 90 days after receipt of the 
final dose of MEDI4736 or until alternate anti-cancer therapy is started.  For 
patients on SoC, follow local prescribing information related to blood donations.

Patients in the MEDI4736 monotherapy or MEDI4736 + tremelimumab 
combination arms: Female patients of childbearing potential who are sexually 
active with a non-sterilized male partner must use at least 1 highly effective method 
of contraception (Table 2) from screening and must agree to continue using such 
precautions for 90 days after the last dose of MEDI4736 monotherapy or 180 days 
after the last dose of MEDI4736 + tremelimumab combination therapy; cessation of 
birth control after this point should be discussed with a responsible physician.  Not 
engaging in sexual activity is an acceptable practice; however, periodic abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of birth 
control.  Female patients should refrain from breastfeeding and egg cell donation 
throughout this period.

It is strongly recommended for the male partner of a female patient to also use a 
male condom plus spermicide throughout this period.  

Females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) or postmenopausal (defined as 12 months with no menstruation 
without an alternative medical cause).

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
The acceptable methods of contraception are described in Table 2.  A highly 
effective method of contraception is defined as 1 that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly.  Not all 
methods of acceptable contraception are highly effective.  

Non-sterilized male patients who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from Day 1 and for 
90 days after the last dose of MEDI4736 monotherapy or 180 days after the last 
dose of MEDI4736 + tremelimumab combination therapy.  Not engaging in sexual 
activity is an acceptable practice; however, occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception.  
Male patients should refrain from sperm donation throughout this same period.

It is strongly recommended for the female partner of a male patient also use an 
effective method of contraception throughout this period 

Patients in the SoC arm: Follow the local prescribing information related to 
contraception, the time limits for such precautions, and any additional restrictions 
for agents in the SoC arm.
Table 2
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)a

Etonogestrel implants: 
eg, Implanon or Norplan

Intravaginal device: 
eg, ethinylestradiol and 
etonogestrel

Medroxyprogesterone injection: 
eg, Depo-Provera 

Normal and low-dose combined 
oral contraceptive pill

Norelgestromin/ethinylestradiol 
transdermal system

Cerazette (desogestrel)
a
This is also considered a hormonal method.
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 (MEDI4736 monotherapy, MEDI4736 + 
tremelimumab combination therapy, or SoC [cisplatin + gemcitabine or carboplatin + 
gemcitabine]) if any of the following occur in the patient in question:

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1.
Withdrawal of consent from further treatment with IP 
2.
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates 
further dosing
3.
Any AE that meets the criteria for discontinuation as defined in Section 6
4.
Pregnancy or intent to become pregnant
5.
Non-compliance that, in the opinion of the Investigator or Sponsor, warrants 
withdrawal from study medication (eg, refusal to adhere to scheduled visits)
6.
Initiation of alternative anticancer therapy including another investigational agent
7.
Confirmed PD and Investigator determination that the patient is no longer 
benefiting from treatment with IP.  Patients enrolled in the SoC arm will 
discontinue study drug at the first assessment of disease progression.
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue the IP without prejudice to further treatment.  A 
patient who decides to discontinue the IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs.  If possible, they will be seen and assessed by an 
Investigator.  AEs will be followed up (see Section 6).  AstraZeneca should be notified of any 
ongoing AE that may delay treatment or necessitate permanent discontinuation of treatment.  
Prior to discontinuing a patient from study therapy, it is strongly recommended that the 
patient’s case be discussed with AstraZeneca in consultation with the treating physician.  
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 6 and Table 7).  All patients will be 
followed up for survival until the end of the study.  Details of any treatment for bladder cancer 
(including surgery) after the last dose of study treatment must be recorded in the eCRF, 
including the identity of subsequent anticancer therapies.  Patients who decline to return to the 
site for evaluations should be contacted by telephone every 2 months as an alternative.  
Patients who are permanently discontinued from receipt of IP should also be discontinued in 
the IVRS/IWRS.
3.10
Criteria for withdrawal from the study
3.10.1
Screen failures 
Screening failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not be enrolled and randomized.  These patients should have the reason for 
study withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the 
required inclusion/exclusion criteria).  This reason for study withdrawal is only valid for 

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screen failures (ie, not randomized patients).  Patients can be rescreened a single time, but 
they cannot be re-randomized.
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.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn his or her 
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.  
The patient will return electronic patient-reported outcomes (PRO) devices, if applicable.  
If a patient withdraws from participation in the study, then his or her randomization or patient 
identification number cannot be reused.  Withdrawn patients will not be replaced.
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 3.11), 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 
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 any evaluations 
should resume according to the protocol.
At the time of PFS and OS analyses, the survival status of all patients in the full analysis and 
the safety analysis sets should be re-checked, this includes those patients who withdrew 
consent or are classified as “lost to follow up.”    

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 in the 7 days following data cutoff.  (The applicable CRF 
modules will be updated.)

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 in the 7 days 
following data cutoff.  (The applicable CRF modules will be updated.)   

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3.11
Discontinuation of the study
The study may be stopped if, in the judgment 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 drug

Are not considered to be consistent with continuation of the study
In addition, the study may be stopped based on the findings of the interim safety analysis 
conducted by the Independent Data Monitoring Committee (IDMC) (see Section 6.7.3).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation or follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.  If this study is discontinued, all other studies involving 
MEDI4736 or tremelimumab will remain open to enrollment and screening, if deemed 
appropriate by AstraZeneca.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and treatment periods in this study are presented in Table 3, 
Table 4, and Table 5, and the procedures for the follow-up period are presented in Table 6 and 
Table 7.  Patients who continue beyond C13 continue with all C13 assessments until 
termination of treatment (Table 3). 
For all treatment arms

PRO and tumor efficacy (RECIST) assessment dates are not affected by dose delays 
and remain as originally scheduled, as they are based on the date of randomization 
(not the date of therapy).

All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures, etc required for dosing should be 
performed within 3 days prior to dosing.
For MEDI4736 monotherapy or MEDI4736 + tremelimumab combination arms

Patients may delay dosing under certain circumstances.   
o
Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-related AE.  

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o
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible
o
Dosing intervals of subsequent cycles may be shortened as clinically feasible in 
order to gradually align treatment cycles with the schedule of tumor efficacy 
(RECIST) and PRO assessments.  Subsequent time between 2 consecutive 
doses cannot be less than 22 days, based on the half-lives of MEDI4736 and 
tremelimumab (see Sections 1.1.3 and 1.1.4, respectively).  
Standard of Care Arm:

Patients may delay and subsequently resume dosing per local standard clinical 
practice.
o
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will occur as soon as feasible.

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Table 3
Schedule of assessments for MEDI4736 monotherapy and MEDI4736 + tremelimumab combination 
therapy treatment and retreatment periods (Patients who continue beyond C13 continue with all C13 
assessments until termination of treatment)
*All scheduled assessments (safety, etc) must be performed within 3 days prior to the start of that dosing cycle, with the exception 
of tumor efficacy (RECIST) assessments (±7-day window, based on date of randomization regardless of dosing delays).  If more 
than 1 evalaution of creatinine clearance has been obtained during the screening period, the creatinine clearance value 
closest to Cycle 1 Day 1 should be entered into the IVRS system for randomization purposes (see Section 3.3 for details).
Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For 
details 
see 
CSP 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28
32
36
40
44
48
Day
-28 to -1
1
1
1
1
1
1
1
1
1
1
1
1
1
Informed consent
Written informed consent
Xa
3.3
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical exam (based on symptoms)
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.2
ECGb
X
As clinically indicated
5.2.3
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including medical and surgical 
history and history of tobacco use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete clinical 
chemistry panel) and hematologyd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Hepatitis B and C and HIV
X
5.2.1

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Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For 
details 
see 
CSP 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28
32
36
40
44
48
Day
-28 to -1
1
1
1
1
1
1
1
1
1
1
1
1
1
Urine hCG or serum β-hCGe and coagulation 
parametersc
X
As clinically indicated
5.2.1
Pharmacokinetics
MEDI4736 PK sample (serum)
Xf
Xg
Xf
Xf
5.4.1
Tremelimumab PK sample (serum; combination 
therapy arm only)
Xf
Xg
Xf
5.4.1
Monitoring
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment
Xh
All visits
6.3
Patient follow-up contact
Day 14 of Cycles 1, 2, and 3 
5.2.5
IP administrationi
Monotherapy arm
MEDI4736 (monotherapy)
X
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Combination arm
Tremelimumabi
X
X
X
X
7.2.1
MEDI4736 (combination therapy)i
X
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Quality-of-life assessments
FACT-BLj
X
X
X
X
q8w
5.3.1
PRO-CTCAEj
q2w through 
Week 8
X
X
X
X
X
q4w
5.3.1
PGICj
X
X
q16w
5.3.1
EQ-5D-5Lj
X
X
X
X
q8w
5.3.1

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Screenin
g
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
For 
details 
see 
CSP 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28
32
36
40
44
48
Day
-28 to -1
1
1
1
1
1
1
1
1
1
1
1
1
1
Immunogenicity assessment (ADA sampling 
[including ADA neutralizing antibodies] to identify 
ADA responses in patient circulation) 
X
X
X
Xk
5.4.2
Tumor biopsy (newly acquired  or archival 
≤3 years old)
Xa
5.5
Tumor biopsy (archival, if available, is required  for 
all patients who submit a  newly acquired biopsy at 
screening for PD-L1 status)
X
5.5
Tumor assessment (CT or MRI)l
X
q8w (±7 days) relative to the date of randomization until confirmed disease progression
5.1
Health economics assessments
Health resource use (HOSPAD module)m
To be completed at each hospitalization 
8.5.10
a
Informed consent includes consent for study procedures and biopsy for PD-L1 status.  Informed consent may be obtained prior to the 28-day screening window, if 
necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization.  For patients undergoing retreatment, if clinically feasible, a new 
biopsy should be obtained.
b
Any clinically significant abnormalities detected require triplicate ECG results.  
c
For patients in the immunotherapy treatment arms vital signs will be evaluated prior to the start of the infusion and subsequent BP and pulse will be measured during and 
after infusion per institutional standard.  Body weight will also be collected for all patients at each visit along with vital signs.
d
If screening laboratory assessments are performed within 3 days prior to Day 1, then tests do not need to be repeated at Day 1.  Serum or plasma chemistry, hematology, 
and/or LFT monitoring may be performed more frequently if clinically indicated.  Results for serum or plasma chemistry and LFT monitoring must be available and 
reviewed by the treating physician or Investigator prior to dosing.  fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related 
to the endocrine system.  Coagulation tests include activated partial thromboplastin time and international normalized ratio.  Gamma glutamyltransferase tested at 
screening, Cycle 1 Day 1, and as clinically indicated.
e
Women of childbearing potential are required to have a pregnancy test within  3 days prior to the first dose of study drug.  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.
f
Predose (may not exceed 6 hours prior to start of infusion) and within 1 hour of the end of infusion.
g
Predose only (may not exceed 6 hours prior to the start of infusion).
h
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
i
Patients will be randomly assigned to treatment with MEDI4736 monotherapy, MEDI4736 + tremelimumab combination therapy, or SoC (cisplatin + gemcitabine or 
carboplatin + gemcitabine).  Tremelimumab will be administered first; MEDI4736 infusion will start approximately 1 hour after the end of the tremelimumab infusion.  If 
there are no clinically significant concerns after the first cycle, and at the discretion of the Investigator, then for all other cycles MEDI4736 can be given immediately 
after the tremelimumab infusion has finished. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
102 (275)
j
PRO assessment dates remain as originally scheduled, as they are based on the date of randomization (not the date of therapy) and are not affected by dose delays.  PRO-
CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the PGIC, the 
EQ-5D-5L, and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides with a 
scheduled site visit; otherwise, patients will complete PROs at home.  NOTE: All PROs MUST be administered before ALL procedures including medication infusion(s).  
PROs must be completed within 3 days (-3 days) prior to dosing.  PROs must be completed using ONLY the electronic devices; paper questionnaires are not allowed.
k
ADAs for MEDI4736 only.  
l
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  Baseline assessments, ideally, should be performed as close as possible prior to the start of study treatment.  The confirmatory 
scans should preferably be performed at the next scheduled visit relative to the date of randomization and no less than 4 weeks after the initial assessment of CR/PR/PD.  
If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at his or her 
scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the database.  
m
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit.
Note: For “retreatment” patients (only applicable to the MEDI4736 + tremelimumab combination arm), the schedule of assessments should be continued with the exception of 
PK and ADA assessments,  Hepatitis B and C assessments, and HIV assessments which do not need to be collected a second time. 
Note: Assessments to be performed at the times stipulated in the table (with ± windows as provided) and as clinically required in the management of the patient.
Note: All assessments on treatment days are to be performed pre-infusion unless otherwise indicated.
AE adverse event; ADA anti-drug antibody; β-hCG beta-Human chorionic gonadotropin; C Cycle; CSP Clinical study protocol; CT computed tomography; 
ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional Assessment of 
Cancer Therapy-Bladder Cancer; fT3 Free triiodothyronine; fT4 Free thyroxine; hCG Human chorionic gonadotropin; HIV human immunodeficiency virus; LFT Liver 
function test; MRI magnetic resonance imaging; PD-L1 Programmed cell death ligand 1; PGIC Patient Global Impression of Change; PK pharmacokinetic; 
PRO Patient-reported outcome; PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; PS performance status; 
q8w Every 8 weeks; SAE serious adverse event; TSH Thyroid-stimulating hormone.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
103 (275)
Table 4
Schedule of assessments for cisplatin + gemcitabine 28-day cycle treatment period
*All scheduled assessments (safety, etc) must be performed within 3 days prior to the start of that dosing cycle, with the exception 
of tumor efficacy (RECIST) assessments (±7-day window, based on date of randomization regardless of dosing delays If more 
than 1 evaluation of creatinine clearance has been obtained during the screening period, the creatinine clearance value 
closest to Cycle 1 Day 1 should be entered into the IVRS system for randomization purposes (see Section 3.3 for details). 
Screening
C1
C2, C3, C4, and C5
C6n
For details see 
CSP Section
Week
-4 to -1
0
0
1
2
4
4
5
6
20
20
21
22
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Informed consent
Written informed consent
Xa
3.3
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical exam (based on symptoms)
X
X
X
5.2.2
ECGb
X
As clinically indicated
5.2.3
Vital signs
X
X
Xc
Xd
5.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including medical and surgical history 
and history of tobacco use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete clinical 
chemistry panel) and hematologye
X
X
X
X
X
X
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)f
X
Xc
5.2.1
Hepatitis B and C, and HIV
X
5.2.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
104 (275)
Screening
C1
C2, C3, C4, and C5
C6n
For details see 
CSP Section
Week
-4 to -1
0
0
1
2
4
4
5
6
20
20
21
22
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Urine hCG or serum β-hCGg and coagulation 
parameterse
Xg
As clinically indicated
5.2.1
Monitoring
ECOG PS
X
X
X
X
5.3.3
AE/SAE assessment
Xh
All visits
6.3
IP administration
Cisplatin
X
X
X
7.2.1
Gemcitabine
X
X
X
X
X
X
X
X
X
7.2.1
Quality of life assessments
FACT-BLi
X
q8w
5.3.1
PRO-CTCAEi
X
X
X
Xj
X
5.3.1
PGICi
Weeks 8 and 16 
5.3.1
EQ-5D-5Li
X
q8w
5.3.1
Other laboratory assessments and assays
Tumor biopsy (newly acquired  or archival ≤3  years 
old)
Xa
5.5
Tumor biopsy (archival, if available, is required for all 
patients who submit a  newly acquired biopsy at 
screening for PD-L1 status)
X
5.5
Tumor assessment (CT or MRI)k
X
q8w (±7 days) relative to the date of randomization until confirmed disease 
progressionl
5.1
Health economics assessments
Health resource use (HOSPAD module)m
To be completed at each hospitalization
8.5.10
a
Informed consent includes consent for study procedures and biopsy for PD-L1 status.  Informed consent may be obtained prior to the 28-day screening window, if 
necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
105 (275)
b
Any clinically significant abnormalities detected require triplicate ECG results.
c
Day 1 of Cycle 4 only.
d
Day 1 of Cycle 6 only.
e
If screening laboratory assessments are performed within 3 days prior to Day 1, then tests do not need to be repeated at Day 1, if applicable as per local routine practice.  
Hematology and chemistry results should be available and reviewed prior to chemotherapy administration on each dosing day and as per local routine practice.  LFT 
results should be available and reviewed by the treating physician or Investigator prior to the start of each chemotherapy cycle and as per local routine practice.  
Chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.  Coagulation tests include activated partial thromboplastin time 
and international normalized ratio.
f
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g
Women of childbearing potential are required to have a pregnancy test within 3 days prior to the first dose of study drug.  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.
h
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
i
PRO assessment dates remain as originally scheduled, as they are based on the date of randomization (not the date of therapy) and are not affected by dose delays.  PRO-
CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the PGIC, the 
EQ-5D-5L, and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides with a 
scheduled site visit; otherwise, patients will complete PROs at home.  NOTE: All PROs MUST be administered before ALL procedures including medication infusion(s).  
PROs must be completed within 3 days (-3 days) prior to dosing.  PROs must be completed using ONLY the electronic devices; paper questionnaires are not allowed.
j
Cycle 2 only.
k
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  Ideally, baseline assessments should be performed as close as possible prior to the start of study treatment.  The confirmatory 
scans should preferably be performed at the next scheduled visit (±7 days relative to the date of randomization) and no less than 4 weeks after the initial assessment of 
CR/PR/PD.  If an unscheduled assessment was performed and the patient’s disease has not progressed, every attempt should be made to perform the subsequent 
assessments at his or her scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the database.
l
Patients enrolled in the SoC arm will discontinue study drug at the first assessment of disease progression. 
m
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit. 
n             In a rare scenario, if at the Investigator’s discretion, patients in the SoC arm who have not progressed continue the SoC treatment beyond 6 cycles, the exposure 
information will be reported in exposure form and the schedule of assessments beyond 6 cycles will be the same as the one for the treatments within 6 cycles.  
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments on treatment days are to be performed pre-infusion unless otherwise indicated.
AE adverse event; β-hCG Beta-human chorionic gonadotropin; C Cycle; CSP Clinical study protocol; CT Computed tomography; ECG electrocardiogram; ECOG Eastern 
Cooperative Oncology Group; EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional Assessment of Cancer Therapy-Bladder Cancer; fT3 Free 
triiodothyronine; fT4 Free thyroxine; hCG Human chorionic gonadotropin; HIV human immunodeficiency virus; IP investigational product; LFT Liver function test;; 
MRI Magnetic resonance imaging; PD Progressive disease; PGIC Patient Global Impression of Change; PRO Patient-reported outcome; PRO-CTCAE Patient-reported 
outcomes version of the Common Terminology Criteria for Adverse Events; PS performance status; q8w Every 8 weeks; SAE serious adverse event; SoC Standard of 
care; TSH Thyroid-stimulating hormone.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
106 (275)
Table 5
Schedule of assessments for cisplatin + gemcitabine 21-day cycle and carboplatin + gemcitabine treatment 
period
*All scheduled assessments (safety, etc) must be performed within 3 days prior to the start of that dosing cycle, with the exception 
of tumor efficacy (RECIST) assessments (±7-day window, based on date of randomization regardless of dosing delays If more 
than 1 evaluation of creatinine clearance has been obtained during the screening period, the creatinine clearance value 
closest to Cycle 1 Day 1 should be entered into the IVRS system for randomization purposes (see Section 3.3 for details). 
Screening
C1
C2
C3
C4
C5
C6l
Week
-4 to -1
0
1
3
4
6
7
9
10
12
13
15
16
For details see 
CSP Section
Day
-28 to -1
1
8
1
8
1
8
1
8
1
8
1
8
Informed consent
Written informed consenta
Xa
3.3
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
X
5.2.2
ECGb
X
As clinically indicated
5.2.3
Vital signs
X
X
X
X
5.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including medical and 
surgical history and history of tobacco 
use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete 
clinical chemistry panel) and 
hematologyc
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
107 (275)
Screening
C1
C2
C3
C4
C5
C6l
Week
-4 to -1
0
1
3
4
6
7
9
10
12
13
15
16
For details see 
CSP Section
Day
-28 to -1
1
8
1
8
1
8
1
8
1
8
1
8
Thyroid function tests (TSH, fT3, and 
fT4)d
X
X
5.2.1
Hepatitis B and C and HIV
X
5.2.1
Urine hCG or serum β-hCGe and 
coagulation parametersc
X
As clinically indicated
5.2.1
Monitoring 
ECOG PS
X
X
X
X
X
X
X
5.3.3
AE/SAE assessmentf
Xf
All visits
6.3
IP administrationg
Cisplatin + gemcitabine arm
Cisplatin
X
X
X
X
X
X
7.2.1
Gemcitabine (+ cisplatin arm)
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Carboplatin + gemcitabine arm
Carboplatin
X
X
X
X
X
X
7.2.1
Gemcitabine (+ carboplatin arm)
X
X
X
X
X
X
X
X
X
X
X
X
7.2.1
Quality of life assessments
FACT-BLh
X
q8w
5.3.1
PRO-CTCAEh
X
q2w through Week 8
q4w from Week 8
5.3.1
PGICh
Weeks 8 and 16
5.3.1
EQ-5D-5Lh
X
q8w
5.3.1
Other laboratory assessments and assays
Tumor biopsy (newly acquired  or 
archival ≤3  years old)
Xa
5.5

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
108 (275)
Screening
C1
C2
C3
C4
C5
C6l
Week
-4 to -1
0
1
3
4
6
7
9
10
12
13
15
16
For details see 
CSP Section
Day
-28 to -1
1
8
1
8
1
8
1
8
1
8
1
8
Tumor biopsy (archival, if available, is 
required for patients who submit a  
newly acquired biopsy at screening for 
PD-L1 status)
X
5.5
Tumor assessment (CT or MRI)i
X
q8w relative to the date of randomization until confirmed disease progressionj
5.1
Health economics assessments
Health resource use (HOSPAD 
module)k
To be completed at each hospitalization
8.5.10
a
Informed consent includes consent for study procedures andbiopsy for PD-L1 status.  Informed consent may be obtained prior to the 28-day screening window, if 
necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization.    
b
Any clinically significant abnormalities detected require triplicate ECG results.
c
If screening laboratory assessments are performed within 3 days prior to Day 1, then tests do not need to be repeated at Day 1, if applicable as per local routine practice.  
Hematology and chemistry results should be available and reviewed by the treating physician or Investigator prior to chemotherapy administration on each dosing day 
and as per local routine practice.  LFT results should be available and reviewed by the treating physician or Investigator prior to the start of each chemotherapy cycle and 
as per local routine practice.  Chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.  Coagulation tests include 
activated partial thromboplastin time and international normalized ratio.
d
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
e
Women of childbearing potential are required to have a pregnancy test within 3 days prior to the first dose of study drug.  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.  
f
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
g
Patients randomized to the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) arm will receive either cisplatin + gemcitabine or carboplatin + gemcitabine based 
on their cisplatin eligibility.
h
PRO assessment dates remain as originally scheduled, as they are based on the date of randomization (not the date of therapy) and are not affected by dose delays.  PRO-
CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the PGIC, the 
EQ-5D-5L, and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides with a 
scheduled site visit; otherwise, patients will complete PROs at home.  NOTE: All PROs MUST be administered before ALL procedures including medication infusion(s).  
PROs must be completed within 3 days (-3 days) prior to dosing.  PROs must be completed using ONLY the electronic devices; paper questionnaires are not allowed.
i
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  Baseline assessments, ideally, should be performed as close as possible prior to the start of study treatment.  The confirmatory 
scans should preferably be performed at the next scheduled visit (relative to the date of randomization) and no less than 4 weeks after the initial assessment of CR/PR/PD.  
If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at his or her 
scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the database.   
j
Patients enrolled in the SoC arm will discontinue study drug at the first assessment of disease progression.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
109 (275)
k
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit. 
l             In a rare scenario, if at the Investigator’s discretion, patients in the SoC arm who have not progressed continue the SoC treatment beyond 6 cycles, the exposure 
information will be reported in exposure form and the schedule of assessments beyond 6 cycles will be the same as the one for the treatments within 6 cycles.  
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments on treatment days are to be performed pre-infusion unless otherwise indicated.
AE adverse event; β-hCG Beta-human chorionic gonadotropin; C Cycle; CSP Clinical study protocol; CT computer tomography; FACT-BL Functional Assessment of 
Cancer Therapy-Bladder Cancer; fT3 Free triiodothyronine; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; EQ-5D-5L EuroQol five-dimensional 
descriptive system; fT4 Free thyroxine; hCG Human chorionic gonadotropin; HIV human immunodeficiency virus; LFT Liver function test;  MRI magnetic resonance 
imaging; PD-L1 programmed cell death 1; PGIC Patient Global Impression of Change; PRO Patient-reported outcome; PRO-CTCAE Patient-reported outcomes version of 
the Common Terminology Criteria for Adverse Events; PS performance status; q8w Every 8 weeks; SAE serious adverse event; TSH Thyroid-stimulating hormone.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
110 (275)
Table 6
Schedule of study procedures: follow-up for patients in the MEDI4736 monotherapy and MEDI4736 + 
tremelimumab combination therapy arms
Evaluation
Time since last dose of IP 
For 
details 
see CSP 
Section
Day (±3)
Months (±1 week)
12 months 
and every 
6 months 
(±2 weeks)
30
2
3
4
6
8
10
Physical examination (full)
X
5.2.2
Vital signs
X
5.2.4
Urine hCG or serum β-hCGa
X
5.2.1
AE/SAE assessment
X
X
X
6.3
Concomitant medications
X
X
X
7.7
ECOG PSb
X
X
X
X
X
X
X (every 2 
months)
5.3.3
Survival status: for all patients, including phone contact 
with patients who refuse to return for evaluations and 
agree to be contactedc
X
X
X
X
X
X (every 
2 months)
5.1
Subsequent anticancer therapyd and second progression 
assessmente
X
X
X
X
X
X
X
X
NA
Serum or plasma chemistry and hematology
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)f
X
5.2.1
PK assessment
X
5.4.1
Immunogenicity assessment (ADA sampling [including 
ADA neutralizing antibodies] to identify ADA responses 
in patient circulation)
X
5.4.2
FACT-BLg
q8w up to Month 6 after disease progression
5.3.1
PRO-CTCAEg
q4w up to Month 6 after disease progression
5.3.1
EQ-5D-5Lg
q8w up to Month 6 after disease progression
5.3.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December 2019
111 (275)
Evaluation
Time since last dose of IP 
For 
details 
see CSP 
Section
Day (±3)
Months (±1 week)
12 months 
and every 
6 months 
(±2 weeks)
30
2
3
4
6
8
10
Health resource use (HOSPAD module)h
X
8.5.10
Tumor assessment (CT or MRI)i
q8w  (±7 days) relative to the date of randomization until confirmed disease progression 
5.1
a
For women of childbearing potential 
b
ECOG PS should be collected if available at the 2-monthly calls to obtain subsequent anticancer therapy and survival status.
c
Patients may be contacted in the week following data cutoffs to confirm survival status.  Details of any treatment for bladder cancer (including surgery) after the last dose 
of study treatment must be recorded in the eCRF.
d
Will be collected until the end of the clinical phase of the study (final study visit).
e
Second disease progression (PFS2) assessment will be performed by the Investigator and defined according to local standard clinical practice and may involve any of the 
following: objective radiological imaging, symptomatic progression, or death. PFS2 should be collected after the progression used for the PFS endpoint.
f
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g
PRO assessment dates remain as originally scheduled, as they are based on the date of randomization (not the date of therapy) and are not affected by dose delays.  PRO-
CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the EQ-5D-5L 
and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides with a scheduled site visit; 
otherwise, patients will complete PROs at home.  NOTE: All PROs MUST be administered before ALL procedures including medication infusion(s).  PROs must be 
completed within 3 days (-3 days) prior to dosing.  PROs must be completed using ONLY the electronic devices; paper questionnaires are not allowed.
h
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit.
i
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  The confirmatory scans should preferably be performed at the next scheduled visit (relative to the date of randomization) and 
no less than 4 weeks after the initial assessment of CR/PR/PD.  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be 
made to perform the subsequent assessments at his or her scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the 
database.   
AE adverse event; ADA anti-drug antibody; β- hCG beta-Human chorionic gonadotropin; CSP Clinical study protocol; CT computed tomography; eCRF electronic case 
report form; ECOG Eastern Cooperative Oncology Group; EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional Assessment of Cancer 
Therapy-Bladder Cancer; fT3 Free triiodothyronine; fT4 Free thyroxine; hCG Human chorionic gonadotropin; IP investigational product; MRI magnetic resonance imaging; 
NA Not applicable; PK pharmacokinetic; PD progressive disease; PRO Patient-reported outcome; PRO-CTCAE Patient-reported outcomes version of the Common 
Terminology Criteria for Adverse Events; PS performance status;  q8w Every 8 weeks; SAE serious adverse event; TSH Thyroid-stimulating hormone.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
112 (275)
Table 7
Schedule of study procedures: follow-up for chemotherapy patients 
Evaluation
Time since last dose of IP 
For details see 
CSP Section
Day 
(±3)
Months (±1 week)
12 months 
and every 
6 months 
(±2 weeks)
30
2
3
4
6
8
10
Physical examination (full)
X
5.2.2
Vital signs
X
5.2.4
Urine hCG or serum β-hCGa
X
5.2.1
AE/SAE assessment
X
X
X
6.3
Concomitant medications
X
X
X
7.7
ECOG PSb
X
X
X
X
X
X
X (every 
2 months)
5.3.3
Survival status: for all patients, including phone 
contact with patients who refuse to return for 
evaluations and agree to be contactedc
X
X
X
X
X
X (every 
2 months)
5.1
Subsequent anticancer therapy and second 
progression assessmentd
X
X
X
X
X
X
X
X
NA
Serum or plasma chemistry and hematology
X
X
X
5.2.1
FACT-BLe
q8w up to Month 6 after disease progression
5.3.1
PRO-CTCAEe
q4w up to Month 6 after disease progression
5.3.1
EQ-5D-5Le
q8w up to Month 6 after disease progression
5.3.1
Health resource use (HOSPAD module)f
X
8.5.10
Tumor assessment (CT or MRI)g
q8w (±7 days) relative to the date of randomization until confirmed disease progression 
5.1
a
For women of childbearing potential. 
b
ECOG PS to be collected if available at the 2 monthly calls to obtain subsequent anticancer therapy and survival status.
c
Patients may be contacted in the week following data cutoffs to confirm survival status.  Details of any treatment for bladder cancer (including surgery) after the last dose
of study treatment must be recorded in the eCRF.
d
Second disease progression (PFS2) assessment will be performed by the Investigator and defined according to local standard clinical practice and may involve any of the 
following: objective radiological imaging, symptomatic progression, or death. PFS2 should be collected after the progression used for the PFS endpoint.
e
PRO assessment dates remain as originally scheduled, as they are based on the date of randomization (not the date of therapy) and are not affected by dose delays.  PRO-
CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the EQ-5D-5L 

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and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides with a scheduled site visit; 
otherwise, patients will complete PROs at home.  NOTE: All PROs MUST be administered before ALL procedures including medication infusion(s).  PROs must be 
completed within 3 days (-3 days) prior to dosing.  PROs must be completed using ONLY the electronic devices; paper questionnaires are not allowed.
f
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit.
g
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  The confirmatory scans should preferably be performed at the next scheduled visit (relative to the date of randomization) and 
no less than 4 weeks after the initial assessment of CR/PR/PD.  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be 
made to perform the subsequent assessments at his or her scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the 
database.   
AE adverse event; β- hCG beta-Human chorionic gonadotropin; CSP Clinical study protocol; CT computed tomography; ECOG Eastern Cooperative Oncology Group; 
EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional Assessment of Cancer Therapy-Bladder Cancer; fT3 Free triiodothyronine; fT4 Free thyroxine; 
hCG Human chorionic gonadotropin; IP investigational product; MRI magnetic resonance imaging; NA Not applicable; PRO Patient-reported outcome; PRO-CTCAE 
Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; PS performance status; q8w Every 8 weeks; SAE serious adverse event; 
TSH Thyroid-stimulating hormone.

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4.1
Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Table 3, Table 4, and Table 5.  
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening/baseline 
evaluations.  All patients will be required to provide consent to supply a sample of their tumor 
(archival or recently obtained biopsy for PD-L1 testing for study entry. Additionally, archival 
tissue (if available) is required for all patients who submit a newly acquired biopsy at 
screening for PD-L1 status. This consent is included in the main patient informed consent 
form (ICF).  
All screening/baseline procedures, must be performed within 28 days before randomization 
(Days -28 to -1), with the exception of the patient’s tumoral PD-L1 status (must be performed 
within -56 days before randomization).  Informed consent may be obtained prior to the 28-day 
screening window in order to permit tumor biopsy sample acquisition, which must be 
analyzed prior to randomization.
The timing of ECGs and vital sign assessments should be such that it allows the blood draw 
(eg, PK blood sample) to occur at the exact nominal time.
If more than 1 evaluation of creatinine clearance has been obtained during the screening 
period, the creatinine clearance value closest to Cycle 1 Day 1 should be entered into the 
IVRS system for randomization purposes (see Section 3.3 for details).
4.2
Treatment period
All procedures to be conducted during the respective treatment periods for MEDI4736 
monotherapy, MEDI4736 + tremelimumab combination therapy, or SoC will be performed 
according to the assessment schedules (see Table 3, Table 4, and Table 5).  Note that patients 
randomized to the MEDI4736 ± tremelimumab combination or MEDI4736 monotherapy 
treatment arms may continue to be treated beyond Cycle 13.  Patients in the 
MEDI4736 + tremelimumab combination arm who complete 4 dosing cycles and 
subsequently have PD during treatment with MEDI4736 alone may restart combination  
treatment if they meet eligibility criteria for retreatment (see Section 7.2.2) and are deemed to 
have clinical benefit per Investigator judgment.  
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.  The 
timing of the first 2 assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the exact nominal time.  
4.3
Follow-up period
All procedures will be performed according to the assessment schedules (see Table 6 and 
Table 7).  For patients who require IP treatment to be held for toxicity or other reasons and 

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subsequently discontinue therapy without restarting IP, all follow-up assessments will be 
based on the date of the last dose of IP.
Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws.  The 
timing of the first 2 assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the exact nominal time.  
5.
STUDY ASSESSMENTS
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRF 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 (CSA).  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
The Investigator will record data on the observations, tests, and assessments specified in the 
protocol on the eCRFs provided by AstraZeneca.  The eCRF will be accompanied with 
“Instructions for the Investigator,” which should be followed.  These instructions provide 
guidance for the recording of study data in the eCRF including how to change data incorrectly 
recorded.
5.1
Efficacy assessments
RECIST 1.1 criteria will be used to assess patient response to treatment by determining PFS, 
proportion of patients alive and progression free at 12 months from randomization (APF12), 
ORR, DoR, and DCR.  The RECIST 1.1 guidelines for measurable, non-measurable, target, 
and non-target lesions and the objective tumor response criteria (CR, PR, SD, or PD) are 
presented in Appendix E.  Time from randomization to second progression (PFS2) defined by 
local standard clinical practice, OS, and proportion of patients alive at 24 months from 
randomization (OS24) will also be evaluated.
The methods of assessment of tumor burden used at baseline are CT and MRI scans of the 
chest, abdomen, and pelvis. Any other areas of disease involvement should be additionally 
imaged based on the signs and symptoms of individual patients.  All on-study assessments 
should utilize the same mode of scanning (CT or MRI) as baseline scans for accurate 
comparisons.
Schedule of required RECIST assessments is based on the date of randomization, not on 
the date of C1D1. The baseline assessment should be performed no more than 28 days before 
randomization and ideally as close as possible to the start of the assigned IP. Efficacy for all 
patients will be assessed by objective tumor assessments every 8 weeks (q8w, ±7 days) 

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relative to the date of randomization and regardless of dosing delays until confirmed disease 
progression.  If an unscheduled assessment is performed, and the patient has not progressed, 
every attempt should be made to perform the subsequent assessments at his or her originally 
scheduled visits (relative to the date of randomization).  
For patients who discontinue treatment due to toxicity or other reasons in the absence of 
confirmed objective progression, objective tumor assessments per the scheduled assessments 
should be continued q8w (±7 days) relative to the date of randomization until confirmed 
disease progression.  
In addition to the required confirmatory scan for PR and CR, a confirmatory scan is also 
required following the initial demonstration of PD.  The confirmatory scan should occur 
preferably at the next regularly scheduled imaging visit (based on randomization date) and no 
earlier than 4 weeks after the prior assessment of radiological PD, by RECIST 1.1. In the 
absence of clinically significant deterioration after the initial assessment of disease 
progression, treatment with MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy will continue between the initial assessment of progression and confirmation of 
disease progression.  
Immediate prior radiologic progression would be considered confirmed if the following 
criteria are met:

≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir 
at 2 consecutive visits, with an absolute increase of at least 5 mm in the sum of 
diameters compared with nadir

and/or significant progression (worsening) of non-target lesions (NTLs) and/or of 
pre-existing new lesions at the confirmatory scan timepoint compared with the 
immediate prior timepoint (Note: Pre-existing new lesions are evaluated as NTLs at 
the confirmatory scan timepoint.)

and/or additional new unequivocal lesions at the confirmatory scan timepoint
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to or 
after the initial assessment of progression, then the patient should continue to submit imaging 
assessments (q8w ±7 days) relative to the date of randomization until objective disease 
progression is confirmed.
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD.  Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumor response (CR or PR) and 
SD will be calculated in comparison to the baseline tumor measurements obtained before 
starting treatment.

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Objective tumor response (CR or PR) should be confirmed preferably at the next scheduled 
visit and not less than 4 weeks after the visit when the response was first observed.
Following confirmed disease progression, all patients should continue to be followed up for 
survival every 2 months (8 weeks) as outlined in the study plan (Table 6 and Table 7).  
Patients enrolled in the SoC arm will discontinue study drug at the first assessment of disease 
progression.  An exception is patients with PD who continue to receive MEDI4736 
monotherapy or MEDI4736+tremelimumab combination arms at the discretion of the 
Investigator (after consultation with AstraZeneca); these patients will have scans for RECIST 
1.1 assessments q8w (per Table 3, Table 4, and Table 5, based on randomization date) until 
confirmed disease progression.  In addition, all patients will be contacted in the week 
following data cutoffs to confirm survival status.
Patients in the MEDI4736 + tremelimumab combination arm who complete 4 doses/dosing 
cycle (with clinical benefit per Investigator judgment) and subsequently have PD during 
treatment with MEDI4736 alone may restart combination  treatment if they meet eligibility 
criteria for retreatment (see Section 7.2.2).  Patients who restart treatment after PD must 
have a baseline tumor assessment within 28 days of restarting treatment with MEDI4736 
+ tremelimumab combination therapy; all further scans should occur q8w (±7 days) 
relative to the date of first dose of retreatment until confirmed disease progression.
It is important to follow the assessment schedule as closely as possible.  Refer to the study 
plans (Table 3 [screening and the treatment period for MEDI4736 monotherapy and 
MEDI4736 + tremelimumab combination therapy], Table 4 [screening and 28-day cycle 
treatment period for cisplatin + gemcitabine], Table 5 [screening and 21-day cycle treatment 
period for cisplatin + gemcitabine and carboplatin + gemcitabine], Table 6 [for follow-up of 
patients in the MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy 
arms] and Table 7 [for follow up of patients in the chemotherapy arm]), and Appendix E.
5.1.1
Central reading of scans
All imaging assessments, including unscheduled visit scans and scans from subsequent 
non-protocol therapy (if required per protocol), will be collected on an ongoing basis and sent 
to an AstraZeneca-appointed Contract Research Organization. Central analysis of images will 
be used for analysis of efficacy profile of MEDI4736 monotherapy in patients who are not 
cisplatin-eligible.  Results of these independent reviews will not be communicated to 
Investigators, and the management of patients will be based solely upon the results of the local 
assessments conducted by the Investigator.
5.1.2
Survival assessments
Assessments for survival must be made every 2 months following treatment discontinuation.  
Survival information may be obtained via telephone contact with the patient or the patient’s 
family, or by contact with the patient’s current physician.  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  

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In addition, patients on treatment or in survival follow-up will be contacted following the data 
cutoff for the primary analysis and all subsequent survival analyses to provide complete 
survival data.  These contacts should generally occur within 7 days of the data cutoff.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology will be taken at 
the times indicated in the assessment schedules and as clinically indicated (see Table 3
through Table 7).  
If more than 1 evaluation of creatinine clearance has been obtained during the screening 
period, the creatinine clearance value closest to Cycle 1 Day 1 should be entered into the 
IVRS system for randomization purposes (see Section 3.3 for details). 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.  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, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 8 (clinical chemistry), Table 9
(hematology).

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Table 8
Clinical chemistry (serum or plasma)
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate (optional for Japan and other 
countries where available)
Sodium
Calcium
Total bilirubina
Chloride
Total protein (optional for Japan and other countries 
where available)
Creatinine
Urea or blood urea nitrogen, depending on local 
practice
Gamma glutamyltransferaseb (optional for 
Japan and other countries where available)
Uric acid
a
If total bilirubin is ≥2 × ULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin.
b
At Screening, Cycle 1 Day 1, and as clinically indicated.
ULN upper limit of normal
Table 9
Hematology
Hemoglobin
Neutrophils
Lymphocytes
Platelet count
Monocytes
Total white cell count
Note: Coagulation parameters: activated partial thromboplastin time and international normalized ratio to be 
assessed at screening and as clinically indicated
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix D for further instructions.  These cases should be reported as SAEs if, after 
evaluation, they meet the criteria for a Hy’s Law case or if any of the individual liver test 
parameters fulfill any of the SAE criteria.  All patients with an elevated AST, ALT, or 
bilirubin value (the latter at ≥1.5 × ULN) at the time of the last dose of study treatment should 
have a further liver chemistry profile (AST, ALT, bilirubin, and alkaline phosphatase) 
performed 30 days (±3 days) after permanent discontinuation of study treatment.
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  Situations in which laboratory safety results should be 
reported as AEs are described in Section 6.3.6.

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All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must have further tests performed until the laboratory values have 
returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see Table 3
through Table 7).  Full physical examinations will include assessments of the head, eyes, ears, 
nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, psychiatric, dermatological, hematologic/lymphatic, and endocrine systems.  
Height will be measured only at screening.  Targeted physical examinations are to be utilized 
by the Investigator on the basis of clinical observations and symptomatology.  All physical 
examinations will include body weight measurement.  Situations in which physical 
examination results should be reported as AEs are described in Section 6.3.6.
5.2.3
ECG
Resting 12-lead ECGs will be recorded according to the assessment schedule (see 
Table 3, Table 4, and Table 5).  ECGs should be obtained after the patient has been in a supine 
position for 5 minutes and should be recorded while the patient remains in that position.
At screening, ECGs will be obtained in which QTcF must be <470 ms.  
Following screening, any clinically indicated ECGs must be performed within an hour prior to 
the start of the infusion and at least 1 timepoint 0 to 3 hours after the infusion.  
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
prolongation.  
Situations in which ECG results should be reported as AEs are described in Section 6.3.6.
5.2.4
Vital signs
For all treatment arms, vital signs (blood pressure [BP], pulse, temperature, and respiration 
rate) will be evaluated according to the assessment schedules (see Table 3 through Table 7). 
Body weight is also recorded at each visit along with vital signs.
Supine or semi-supine BP will be measured using a BP recording device with an appropriate 
cuff size, after the patient has rested for at least 5 minutes.
For patients in the MEDI4736 + tremelimumab combination and MEDI4736 
monotherapy treatment arms:
For the first infusion (based on a 60-minute infusion):

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
All vital signs (BP, pulse, respiratory rate, and temperature ) will be collected prior 
to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])

BP and pulse will be collected approximately 30 minutes during the infusion 
(halfway through infusion) (±5 minutes)

BP and pulse will be collected at the end of the infusion (approximately 60 minutes 
±5 minutes)

A 1-hour observation period is required after the first infusion of tremelimumab or 
MEDI4736.  If no clinically significant infusion reactions are observed during or 
after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion.
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated.  The date 
and time of collection and measurement will be recorded on the appropriate eCRF.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.
On subsequent infusion days, patients in the MEDI4736 + tremelimumab combination and 
MEDI4736 monotherapy treatment arms will have all vital signs (BP, pulse, respiratory rate, 
and temperature) evaluated prior to  the start of the infusion, and subsequent BP and pulse will 
be measured during and after infusion per institutional standard and as clinically indicated.  
Any clinically significant changes in vital signs should be entered onto an unscheduled vital 
signs eCRF page.  
For patients in the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) arm, all 
vital signs (BP, pulse, respiratory rate, and approximately 30 minutes before up to 0 minute).  
BP and pulse may additionally be evaluated  as clinically indicated.  
Situations in which vital signs results should be reported as AEs are described in 
Section 6.3.6.
5.2.5
Other safety assessments
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines  will be 
applied. The results of the full diagnostic workup (including high-resolution computed 
tomography (HRCT), blood and sputum culture, hematological parameters etc) will be 
captured in the eCRF. It is strongly recommended to perform a full diagnostic workup, to 
exclude alternative causes, such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage.  In the presence of confirmatory HRCT scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of pneumonitis 

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(ILD) should be considered and the Dosing Modification and Toxicity Management 
Guidelines should be followed.  
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
beta-human chorionic gonadotropin [β-hCG]) samples will be performed for premenopausal 
women of childbearing potential at the times specified in the assessment schedule (see Table 3
through Table 7).  Tests will be performed by the hospital’s local laboratory.  If results are 
positive, the patient is ineligible and must be discontinued from treatment.  In the event of a 
suspected pregnancy during the study, the test should be repeated.
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, HIV antibodies, thyroid stimulating hormone, free 
triiodothyronine (fT3), and free thyroxine (fT4).
It is strongly recommended that patients are contacted 2 weeks after receiving the first 
3 cycles of MEDI4736 + tremelimumab combination or MEDI4736 monotherapy 
(Cycle 1 Day 14, Cycle 2 Day 14, and Cycle 3 Day 14) of study drug(s) to ensure early 
identification and management of toxicities.  
5.3
Other assessments
5.3.1
Patient-reported outcomes
PRO assessment dates remain as originally scheduled, as they are based on the date of 
randomization (not the date of therapy) and are not affected by dose delays.  “PRO” is an 
umbrella term referring to all outcomes and symptoms that are directly reported by the patient.  
PROs have become a significant endpoint when evaluating effectiveness of treatments in 
clinical studies.  The following PROs will be administered in this study: Functional 
Assessment of Cancer Therapy-Bladder Cancer (FACT-BL); patient-reported outcomes 
version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE); the Patient 
Global Impression of Change (PGIC); and the EuroQol 5-dimension, 5-level health state 
utility index (EQ-5D-5L; see Appendix F).
5.3.1.1
FACT-BL
The FACT-BL (Appendix F) is a disease-specific 39-item questionnaire included for the 
purpose of assessing health-related quality of life (HRQoL) and bladder cancer-specific 
symptoms.  It is a well-established measure of HRQoL/health status commonly used in 
bladder cancer clinical studies.  The FACT-BL was developed specifically for patients with 
advanced bladder cancer and has been found to be reliable and valid in this population 
(Cella et al 1993).  The FACT-BL consists of 5 subscales: Physical Well-Being (PWB; 
7 items), Functional Well-Being (FWB; 7 items), Emotional Well-Being (EWB; 6 items), 
Social Well-Being (SWB; 7 items), and Additional Concerns or Bladder Cancer Subscale 
(BlCS) specific to bladder cancer (12 items).  The BlCS assesses 5 domains: urinary function 
(3 items), bowel function (2 items), sexual function (2 items; 1 item is not applicable to 
women), body image (1 item), weight loss/appetite (2 items), and the care of ostomy appliance 
or urinary diversion (2 items) (Cella et al 1993).  Patients without any urinary diversion 

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procedure do not have to answer the ostomy appliance questions.  Thus, specifically for the 
patients in the current study, the BlCS items are 10 and 9 for males and females, respectively.  
All FACT-BL questions are scored on a 5-point Likert scale from 0 to 4 (0 being not at all and 
4 being very much).  Negatively stated items are reversed by subtracting the response from 4.  
After reversing proper items, all subscale items are summed to a total, which is the subscale 
score.  For all subscales, symptoms index, and individual item scores, the higher the score, the 
better the HRQoL/symptom.  Thus, a score of 0 is a severely symptomatic patient, and the 
highest possible score is an asymptomatic patient.
5.3.1.2
PRO-CTCAE
The PRO-CTCAE (Appendix F) is included to address tolerability from the patients’ 
perspective.  It was developed by the NCI.  The PRO-CTCAE will only be administered in 
those countries where a linguistically validated version exists.  It was developed in recognition 
that collecting symptom data directly from patients using PRO tools can improve the accuracy 
and efficiency of symptomatic AE data collection.  This was based on findings from multiple 
studies demonstrating that physicians and nurses underestimate symptom onset, frequency, 
and severity in comparison with patient ratings (Basch et al 2009, Litwin et al 1998, Sprangers 
and Aaronson 1992).  These symptoms have been converted to patient terms (eg, CTCAE 
term “myalgia” converted to “aching muscles”).  For several symptoms, like fatigue and pain, 
additional questions are asked about symptom frequency, severity, and interference with usual 
activities.  The items included in the PRO-CTCAE have undergone extensive qualitative 
review among experts and patients.  These items have been extensively evaluated by patients 
with cancer to be clear, comprehensible, and measuring the symptom of interest.  In this study, 
only items that are considered relevant for the trial, site of cancer, and cancer treatment are 
selected (see Appendix F).
5.3.1.3
PGIC
The PGIC item (Appendix F) is included to assess how a patient perceives his or her overall 
change in health status since the start of study treatment.  Patients will choose from response 
options from “Very Much Improved” to “Very Much Worse.”  This item is included to assist 
with the interpretation of other PRO measures and for assessing the overall impact of 
treatment (see Appendix F).
5.3.1.4
EQ-5D-5L
The EQ-5D-5L (Appendix F) is a standardized measure of health status developed by the 
EuroQol Group to provide a simple, generic measure of health for clinical and economic 
appraisal (EuroQol Group 1990).  Applicable to a wide range of health conditions and 
treatments, it provides a simple, descriptive profile and a single index value for health status 
that can be used in the clinical and economic evaluation of health care as well as in population 
health surveys.  The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension has 5 response options (no 
problems, slight problems, moderate problems, severe problems, and extreme problems) that 
reflect increasing levels of difficulty (EuroQol Group 2013).

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Since 2009, the EuroQol group has been developing a more sensitive version of the EQ-5D 
(the EQ-5D-5L) that expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the EQ-5D-5L 
version improves upon the properties of the 3L measure in terms of reduced ceiling effect, 
increased reliability, and an improved ability to differentiate between different levels of health 
(Janssen et al 2008a, Janssen et al 2008b, Pickard et al 2007).
The patient will be asked to indicate his or her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual analog 
scale, where the patient will be asked to rate current health status on a scale of 0 to 100, with 
0 being the worst imaginable health state (see Appendix F).
5.3.2
Administration of the patient-reported outcome questionnaires
The PRO instruments will be self-administered by the patients as ePROs using handheld 
devices.  All assessments should be completed without assistance from site staff or 
relatives/friends according to the assessment schedules (see Table 3 through Table 7), before 
any other study procedures are conducted at a given visit.  Each center must allocate the 
responsibility for the administration of the PRO instruments to a specific individual (eg, a 
research nurse or study coordinator) and, if possible, assign a back-up person to cover if that 
individual is absent.  PROs must be completed within 3 days (-3 days) prior to dosing.  Study 
coordinators should ensure that patients have completed the PRO assessment for that visit 
before the patient is seen by a study nurse or physician.  It takes approximately 15 to 
30 minutes for patients to complete the questionnaires; therefore, the burden to the patient is 
moderate.  Patients will complete PROs at study sites if the assessment timepoint coincides 
with a scheduled site visit; otherwise, patients will complete PROs at home.  Similarly, during 
the post-progression period, patients should complete PROs at home or at the study site if a 
scheduled visit coincides with the timepoint.  If patients have had scans or other tests at an 
outside facility or missed a scheduled data collection site visit, PRO questionnaires should still 
be completed by the patient at home on that scheduled visit date.  Reminders should be sent to 
patients at home as needed to ensure compliance with the assessment schedules.  
The following best practice guidelines should be followed when collecting PRO data via an 
electronic device:

PRO questionnaires must be completed prior to any other study procedures 
(following informed consent), including medication infusion(s), and before 
discussion of disease progression to avoid bias in patient’s responses to the 
questions

When each instrument is due to be completed, the following order should be 
observed; FACT-BL should be administered first followed by PGIC, EQ-5D-5L, 
and then PRO-CTCAE 

PRO questionnaires must be completed by the patient in private.

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
The research nurse or appointed site staff must explain to patients the value and 
relevance of study participation and inform them that these questions are being 
asked to find out, directly from them, how they feel.  The research nurse or 
appointed site staff should also stress that the information is confidential.  
Therefore, if the patients have any medical problems, they should discuss them with 
the doctor or research nurse separately from the ePRO assessment.

The research nurse or appointed site staff must train the patient on how to use the 
ePRO device, using the materials and training provided by the ePRO vendor, and 
provide guidance on whom to call if there are problems with the device if the
patient is completing the ePRO at home.  All questionnaires must be completed 
using the ePRO device; paper questionnaires are not allowed in this study.

The research nurse or appointed site staff must remind patients that there are no 
right or wrong answers and avoid introducing bias by not clarifying items.

The patient should not receive help from relatives, friends, or clinic staff to answer 
the PRO questionnaires.  If a patient uses visual aids (eg, spectacles or contact 
lenses) for reading and does not have them when he or she attends the clinic, the 
patient will be exempted from completing the PROs.  

Site staff must not read or complete the PRO questionnaires on behalf of the patient.  
If the patient is unable to read the questionnaire (eg, is blind or illiterate), that 
patient should be exempted from completing PRO questionnaires but may still 
participate in the study.  Patients exempted in this regard should be flagged 
appropriately by the site staff.

The patient should be given sufficient time to complete the PRO questionnaires at 
his or her own speed.

The research nurse or appointed site staff must monitor compliance; minimizing 
missing data is a key aspect of study success.  Compliance must be checked at each 
study visit and should be checked more frequently to identify problems early.  If 
compliance drops below 85%, a check-in call from the site to ask the patient if he or 
she has any difficulties is highly recommended.
5.3.3
ECOG performance status
ECOG PS will be assessed at the times specified in the assessment schedules (see Table 3
through Table 7) based on the following:

0=Fully active; able to carry out all pre-disease activities without restrictions

1=Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work

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
2=Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.

3=Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours

4=Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair

5=Dead
Any significant changes from baseline or screening must be reported as an AE.
5.4
Pharmacokinetics
5.4.1
Collection of samples and determination of drug concentration
Blood samples for determination of MEDI4736 and tremelimumab concentration in serum 
will be obtained according to the assessment schedules (see Table 3 and Table 6).  
Samples for determination of MEDI4736 and tremelimumab concentration in serum will be 
analyzed by a designated third party on behalf of AstraZeneca.  Samples will be collected, 
labeled, stored, and shipped as detailed in the Laboratory Manual.  Full details of the 
analytical method used will be described in a separate Bioanalytical Validation Report.
5.4.2
Collection of samples to measure the presence of ADAs
The presence of ADAs (including ADA neutralizing antibodies) will be assessed in serum 
samples taken according to the assessment schedules (see Table 3 and Table 6).   Samples will 
be collected, labelled, stored and shipped as detailed in the Laboratory Manual. Samples will 
be tested in AstraZeneca designated laboratory. The samples may need to be exported to USA 
for testing.
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
both IPs (MEDI4736 and tremelimumab) using validated assays.  Tiered analysis will be 
performed to include screening, confirmatory, and titer assay components, and 
positive-negative cut points previously statistically determined from drug-naïve validation 
samples will be used.  
5.4.3
Storage and destruction of pharmacokinetic/ADA samples
PK and ADA samples, if not exhausted by analyses outlined herein, may be retained for 
15 years from the patient’s last visit date for research purposes.
PK and ADA samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Results from such analyses may be reported 
separately from the clinical study report (CSR).

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Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but will 
be reported separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca-assigned Biobank; see 
details in the Laboratory Manual).
5.5
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory.  
Pre-randomization tumor PD-L1 expression will be evaluated in all patients, and PD-L1 status 
is included as a stratification factor.  Putative associations with clinical endpoints will be 
assessed.  Baseline tumor requirements are briefly described in Section 5.5.1.  Based on 
availability of tissue, additional exploratory biomarkers may also be evaluated as described in 
Section 5.5.1.1.
Comparisons of PD-L1 expression in tumor will be made between arms to determine if PD-L1 
status is prognostic or predictive of outcomes associated with MEDI4736 monotherapy and/or 
MEDI4736 + tremelimumab combination therapy.  These results may be pooled with 
biomarker data from other MEDI4736 and tremelimumab studies to evaluate biological 
responses across indications and to compare results in other monotherapy versus combination 
settings.  
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 research relevant to 
evaluating biological and/or clinical response to immunotherapy.
5.5.1
Evaluation of candidate, predictive markers - tumor PD-L1
Provision of tissue for PD-L1 IHC is as follows:

MANDATORY – Provision of a newly acquired tumor sample (preferred) OR 
formalin fixed and paraffin embedded archival tissue obtained within 3 years prior 
to screening.  ONLY 1 sample (either newly acquired or archival tissue) will be 
used to determine PD-L1 status.  Where multiple samples have been submitted for 
the same patient, the initial result will determine a patient’s PD-L1 status. 

Samples should be collected via an image-guided core needle (18 gauge or larger) 
or be collected as an excisional or incisional tumor biopsy sample.
Where institutional practice, in this setting, uses a smaller gauge needle,  samples 
should be submitted in sufficient number to ensure that a valid result can be 
achieved.

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When tissue is acquired for this study, effort should be made to maximize material 
for downstream analyses.  Two cores using an 18 gauge or larger needle are 
required for establishing PD-L1 status.  These should be placed in formalin and 
processed to a single paraffin embedded block, as described in the Pathology 
Manual.  When a smaller gauge needle is used, the number of cores rises to 3 or 4.  
As a guidance, it is anticipated that 4 passes of a core needle will provide sufficient 
tissue for establishing PD-L1 status and for delivering protocol-defined exploratory 
objectives.  Whenever feasible, additional cores (beyond those required to establish 
PD-L1 status) should be obtained and immediately frozen as described in the 
laboratory manual. 
The tumor specimen submitted to establish PD-L1 status should be of sufficient 
quantity to allow for PD-L1 IHC analyses (see the pathology Manual).  Samples 
with limited tumor content and fine needle aspirates are inadequate for defining 
tumor PD-L1 status.
Tumor lesions used for biopsies acquired during screening should not be the same 
lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable 
for biopsy, and in this instance, only core needle (not excisional/incisional) biopsy 
is allowed.  For patients with a single target lesion, if screening biopsy is collected 
prior to screening imaging for baseline tumor assessment, allow approximately 
2 weeks before imaging scans are acquired.  

If a newly acquired tumor sample is submitted to determine PD-L1 status during 
screening, archived tumor tissue block (formalin-fixed paraffin-embedded) is 
required, when available and accessible, and where such samples exist in a quantity 
sufficient to allow for analysis.  Tumor tissue block is preferred.  If a tissue block is 
unavailable, unstained sections from the tissue block may be submitted.  An 
archived tumor tissue block or sections may be delivered at any time during the 
study (when newly acquired tissue was used to establish PD-L1 status).  Please 
consult the Laboratory Manual for specific instructions and guidelines regarding 
sections and acceptable tissue sampling. 

The collection of tumor biopsies at the time of progression and prior to retreatment 
is strongly encouraged.  The biopsy procedure at retreatment should be omitted only 
if there is unacceptable clinical risk or the procedure is otherwise considered not 
feasible.  The Investigator should consult with AstraZeneca prior to making the 
decision not to biopsy at retreatment. 

The collection of additional biopsies upon progression of patients in the MEDI4736 
+ tremelimumab combination therapy and MEDI4736 monotherapy arms is 
strongly encouraged.  
Tumor biopsies collected after determination of PD-L1 status for stratification will be used to 
evaluate potential predictive biomarkers and only for exploratory analyses.  

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Please review the Laboratory Manual for further details of requirements including sample 
quality control and shipping.
A brief description of exploratory tumor markers likely to be explored by IHC is provided in 
Section 5.5.1.1.
To meet the requirement of Food and Drug Administration (FDA) approval of a companion 
diagnostic, sections of the tumor will be retained at Ventana or a Ventana-approved laboratory 
for potential additional studies, as requested by the FDA, to support potential test approval.
5.5.1.1
Exploratory biomarker data
Blood samples already obtained will be used for exploratory biomarker analyses and tumor 
samples will be used for exploratory biomarker analyses in selected countries only.  Details 
for tumor samples collection, volumes, storage, and shipment of biologic samples are 
presented in a separate Laboratory Manual.  
Pharmacodynamic changes in biomarker measures will be monitored, when applicable.  
Baseline measures (and early, on-treatment changes) will be correlated with outcomes.  Data 
will be compared across treatment arms and times of treatment to determine if 
pharmacodynamic changes are specific to 1 treatment arm versus the other.  
Additional sample collections and analyses may be completed at select study sites by 
site-specific amendments.  All samples collected for such exploratory analyses will be stored 
at the site, a reference laboratory, or at Sponsor’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The exploratory biomarker plan is described by sample type below.
Tumor markers (in FFPET)
Tissue obtained as part of screening procedures (or at progression) for establishing PD-L1 
status may be analyzed for additional markers by IHC.  Markers evaluated may change based 
on the best available information at the time  of the biomarker analysis.  Markers of special 
interest include, but are not limited to, Ox40, GITR, PD-L2, Tim-3, CD137, and Lag-3.  
Tissues obtained may also be assessed for somatic mutations, tumor burden, neo-antigen 
prediction, and/or for an interferon-gamma (IFN-γ) gene expression signature (eg, IFN-γ, 
CXCL9, LAG3, and CD274) by targeted RNAseq and/or other gene expression methodologies.  
For geomic DNA which has been extracted, genotyping of immunomodulatory genes such as 
PD-1, PD-L1, CTLA-4, and human leukocyte antigen loci may be completed to determine 
whether natural variation within such genes is associated with likelihood of clinical benefit 
and/or with likelihood of drug-related AEs.  Genes associated with solid tumor development, 
disease progression, or likelihood of tumor response to chemotherapy may, likewise, be 
investigated.  Genotyping will occur retrospectively, data will not be shared with patients, and 
results will not impact treatment decisions.

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For the whole blood samples which have been collected, total RNA may be prepared for 
quantification of RNA and/or micro-ribonucleic acid (miRNA) expression using reverse 
transcription quantitative polymerase chain reaction (RT-qPCR), microarray, sequencing, or 
similar methodology.  Focus is likely to be given to the expression of immunomodulatory 
genes previously found to be up-regulated in response to MEDI4736 and/or tremelimumab 
(data not shown).  Pretreatment expression of such genes may indicate active immune 
responses that may be augmented by checkpoint inhibitor immunotherapies; correlations with 
outcome data will be completed on select candidate predictive markers with the aim of 
characterizing useful expression thresholds for identifying patients likely to receive benefit.  
Similar procedures may be completed using select peripheral blood mononuclear cell (PBMC) 
samples described below.
Myeloid-derived suppressor cells
Recent collective findings suggest that a baseline measure of circulating myeloid-derived 
suppressor cells (MDSCs) may be used as a prognostic tool in different disease settings and 
may specifically predict the likelihood of response to ipilimumab (anti-CTLA-4 therapy) 
(Kitano et al 2014, Meyer et al 2014).  Flow cytometry may be completed on available patient 
samples obtained to quantify pretreatment circulating MDSC subtypes and analyzed for their 
ability to predict clinical benefit from tremelimumab.
Peripheral blood mononuclear cells and soluble factors (plasma)
Whole blood samples may be collected for preparation of PBMCs and storage for potential 
downstream analyses, including: immune cell composition/activation status, epigenetic 
analyses, T-cell functional assays, and/or the assessment of the diversity and clonality of 
T-cell receptor gene rearrangements using DNA.  
Plasma will be obtained to explore expression of cytokines and chemokines, including but not 
limited to IFN-γ, interleukin (IL)-18, CXCL9, and CXCL10.  
Similarly, the concentrations of a battery of immune cell ligands or receptors may be assessed.  
Proteins of special interest include CTLA-4, PD-1, B7-1, B7-2, and IL6R.
Urine-based markers
Urine may be obtained before and after treatment from patients who have not undergone a full 
cystectomy and who have tumor lesion(s) present in the urothelium.  These samples will be 
used to explore gene expression analyses by RT-qPCR or similar methodologies as well as 
cytokine/chemokine analyses.
5.5.2
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, any 
employer, clinical study Investigator, general physician, or any other third party, unless 

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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.
5.5.3
Storage, re-use, and destruction of biological samples
Biological samples for future research will be retained at AstraZeneca or its designee for a 
maximum of 15 years following last patient, last visit, after which they will be destroyed.  The 
results of this biomarker research may be reported in the CSR itself, as an addendum, or 
separately in a scientific report or publication.  The results of this biomarker research may be 
pooled with biomarker data from other studies involving MEDI4736 or tremelimumab to 
generate hypotheses to be tested in future research.
5.5.4
Labeling and shipment of biological samples
The Principal Investigator (PI) 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 materials in Category A 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.
5.5.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The PI 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 by  the AstraZeneca Biobank team during 
the entire life cycle.

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5.5.6
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 will be documented.  If samples have already been 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
The PI will:

Ensure that AstraZeneca is immediately notified of the patient’s 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 that the action is documented

Ensure that the laboratory(ies) 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

Ensure that the patient and AstraZeneca are informed about the sample disposal
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition (other than progression of the malignancy under evaluation) 
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 or 
chest pain), signs (eg, tachycardia or enlarged liver), or the abnormal results of an 
investigation (eg, laboratory findings or electrocardiogram).  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
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, or 
follow-up) that fulfills 1 or more of the following criteria:

Results in death

Is immediately life-threatening

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
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 1 of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs and SAEs for all treatment arms will be collected from the time the informed consent is 
signed through 90 days after the last dose of the last study treatment. 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient.  Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation or study completion.
Any AEs that are unresolved 90 days after the last dose of study treatment are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the eCRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) prior to the end of the 
study, if judged to be necessary.
6.3.2
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

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

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
Whether the AE caused the patient’s withdrawal from the study (yes or no)

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 fulfilled

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)

Description of the AE
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 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.  An AE of severe 
intensity does not necessarily need to be considered serious.  For example, nausea that persists 
for several hours may be considered severe nausea, but it is not an SAE unless it meets the 
criteria shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree 
of disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Section 6.2.
6.3.3
Causality collection
The Investigator will assess causal relationship between the IPs 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 the investigational product?”

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For SAEs causal relationship will also be assessed for other medication and study procedures.  
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. 
6.3.4
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 after an informed consent has been 
signed) 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.
6.3.5
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 eCRF.  
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.
6.3.6
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration, as compared with 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 
if they are considered the reason for discontinuation of treatment with the IPs.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator 
uses 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 AE(s).

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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.
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation.  
Occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to 
be reported as SAEs.  Further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s Law are shown in Appendix D.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP 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 or SAE.  Events that are unequivocally due to disease 
progression should not be reported as an AE during the study.
6.3.9
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 the study treatment and have 
been identified after the patient’s inclusion in this study.
6.3.10
Deaths
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study treatment, must be reported as follows:

Death clearly resulting from disease progression should be reported to the monitor 
at the next monitoring visit and should be documented in the eCRF.  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 monitor as an SAE within 
24 hours.  The report should contain a comment regarding the co-involvement of 
PD, if appropriate, and should assign a single main cause as well as any 
contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE.  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 
Drug Safety or its representative within the usual timeframes.

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6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IPs or to the 
study procedure(s).  All SAEs, including supporting data, will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel should 
inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative 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 should inform 
AstraZeneca representatives (and enter into the eCRF) of any follow-up information on a 
previously reported SAE within 1 calendar day, ie, immediately but no later than 24 hours of 
when he or she becomes aware of it.
Once the Investigators or other site personnel indicate that an AE is serious in the WBDC 
system, an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigators or other study site personnel 
reports an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigators/study site personnel how to 
proceed.  
The reference documents for definition of expectedness/listedness are the IBs for MEDI4736 
and tremelimumab.
The PI 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.
6.5
Overdose
Use of IP 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 IP, and possible symptoms 
of overdose are not established.  

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.

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If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigators or other site personnel should inform appropriate AstraZeneca representatives 
immediately or 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 provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply (see 
Section 6.4).  For other overdoses, reporting must occur within 30 days.
For patients randomized to the SoC arm, please refer to the local prescribing information for 
the treatment of cases of overdose.  An overdose in the SoC arm with associated SAEs is 
recorded as the AE diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose eCRF module.  An overdose in the SoC arm without associated SAE symptoms 
should not be reported on the Overdose eCRF module.  
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/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 Investigators or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, 
ie, immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy, and the PREGOUT is 
used to report the outcome of the pregnancy.

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Study Code D419BC00001
Version 9
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6.6.2
Paternal exposure 
Male patients must refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 90 days 
after the last dose of MEDI4736 monotherapy.  For patients receiving standard of care agents 
for chemotherapy, please follow the local prescribing information relating to contraception 
and the time limit for such precautions. 
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, 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.  
6.7
Management of IP-related toxicities
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 if required).

If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care.  If medically appropriate, dose modifications are 
permitted.

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.
6.7.1
Specific toxicity management and dose modification information – MEDI4736 
and MEDI4736 + tremelimumab
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for MEDI4736 monotherapy and MEDI4736 + 
tremelimumab are provided in Dosing Modification and Toxicity Management Guidelines.
The most current version of the TMGs is also available through the following link: 
https://tmg.azirae.com. In addition a version of the 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.    
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 

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Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
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diagnosis.. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitors, durvalumab [MED4736] (PD-L1 inhibitor) and tremelimumab 
(CTLA-4 inhibitor). Given the similar underlying mechanism of toxicities observed with these 
two compounds, these TMGs are applicable to the management of patients receiving either 
drug as monotherapy or both drugs in combination. Additionally, these guidelines are 
applicable when either drug is used alone or both drugs are used in combination and, also 
other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) are administered 
concurrently or sequentially 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 
checkpoint inhibitor-specific dose modifications (including discontinuation) and treatment 
interventions. Investigators are advised however to use local practice guidelines and consult 
local references for the management of toxicities observed with other anti-cancer treatment.
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document 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),” and is maintained within the Site Master File. In addition, a current version of 
TMGs is available through the following link: https://tmg.azirae.com. Please contact the 
clinical study associate for information on how to gain access to this website.
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 MEDI4736 and tremelimumab should be 
permanently discontinued (see Section 3.9 of this protocol and Dosing Modification and 
Toxicity Management Guidelines).
Following the first dose of IP, subsequent administration of MEDI4736 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 judgment in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to MEDI4736 
monotherapy and the MEDI4736 + tremelimumab regimen by the reporting investigator.

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Dose reductions are not permitted for the MEDI4736 monotherapy or MEDI4736 + 
tremelimumab combination therapy.  In case of doubt, the Investigator should consult with 
the Study Physician.
MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy adverse 
events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP 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 IP. 
If any AESI occurs in the course of the study, then the Investigators or other site personnel 
should report to AstraZeneca by recording in the eCRF within 48 hours of when he or she 
becomes aware of it.  AESIs for MEDI4736 ± tremelimumab combination therapy include, 
but are not limited to, events with a potential inflammatory or immune-mediated mechanism 
and that may require more frequent monitoring and/or interventions such as steroids, 
immunosuppressants, and/or hormone replacement therapy.  These AESIs are being closely 
monitored in clinical studies with MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy.  In the event of irAE or suspected irAE, 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.
An irAE is defined as an AE that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology.  
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to
support an irAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions with regards to an AE being an irAE, the Investigator 
should immediately contact AstraZeneca.
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab and durvalumab in 
combination with 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-Barre 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.

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In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 IB and the Tremelimumab IB.  More specific guidelines for the 
evaluation and treatment of these AESIs are described in, the Dosing Modification and 
Toxicity Management Guidelines (please see Section 6.7.1). These guidelines have been 
prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical judgment 
in treating these types of toxicities.  These guidelines apply to AEs considered causally related 
to the study drug/study regimen by the reporting investigator.
6.7.2
Specific toxicity management and dose modification information - Standard of 
Care
Investigators should follow local standard clinical practice regarding dose modifications for 
agents used in the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) arm.  For 
specific information regarding the individual agent used in this study, please refer to the local 
prescribing information for the relevant agent.
6.7.3
IDMC
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC will be established to perform an interim assessment of the safety of MEDI4736 
monotherapy and MEDI4736 + tremelimumab combination therapy in this population.  The 
IDMC will be comprised of independent experts.  The committee will meet approximately 
6 months after the study has started or after the randomization of 30 patients, whichever 
happens first.  The second IDMC meeting will occur approximately 3 months after the first 
IDMC meeting or when 90 patients are enrolled, whichever occurs first.  A subsequent IDMC 
meeting will occur 3 months after 90 patients are enrolled.  Further IDMC meetings will occur 
every 6 months, unless otherwise requested by the IDMC.  IDMC members will be consulted 
to ensure appropriate frequency.  Following each meeting, the IDMC will report to 
AstraZeneca and may recommend changes in the conduct of the study.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational products
AstraZeneca will supply MEDI4736 and tremelimumab.  Gemcitabine, cisplatin, and 
carboplatin will be supplied locally.

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Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
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Investigational product
Dosage form and strength
MEDI4736
50 mg/mL solution IV
Tremelimumab
20 mg/mL solution IV
Standard of Care
Gemcitabinea
IV (as sourced locally)
Cisplatin
IV (as sourced locally)
Carboplatina
IV (as sourced locally)
a
Under certain circumstances when local sourcing is not feasible, an SoC treatment may be supplied 
centrally through AstraZeneca. 
IV intravenous; SoC standard of care
In Japan, a SoC treatment will be supplied from Astrazeneca K.K.
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial for solution for infusion after 
dilution.  The solution contains 50 mg/mL MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume 
[w/v]) polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 mL.  Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.  
Preparation of MEDI4736 doses for administration with an IV bag
The dose of MEDI4736 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 
MEDI4736 vial to the start of administration should not exceed the following:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature 
A dose of 1500 mg will be administered in IV bags containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2-μm or 0.22-μm in-line 
filter.  
The calculated volume of MEDI4736 (30.0 mL for 1500-mg dose) is added to an 
appropriately sized IV bag such that final concentration is within 1 to 20 mg/mL.  Mix the bag 
by gently inverting to ensure homogeneity of the dose in the bag. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  In the event that either 
preparation time or infusion time exceeds the time limit, a new dose must be prepared using 
new vials.  MEDI4736 does not contain preservatives, and any unused portion must be 
discarded.
Preparations are to be in accordance with the study-specific drug handling instructions.

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Study Code D419BC00001
Version 9
Date 03 December  2019
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No incompatibilities between MEDI4736 and polyvinylchloride or polyolefin IV bags have 
been observed.
Dose calculation
For 1500-mg fixed dose:
The volume of MEDI4736 (in mL) for a fixed dose of 1500 mg is 30.0 mL: 
Dose (30.0 mL) = MEDI4736 dose level (1500 mg)
MEDI4736 concentration (50 mg/mL)
The corresponding volume should be rounded to the nearest tenth of an mL (0.1 mL).  
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.  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.
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 the following:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature 
A dose of 75 mg will be administered using an IV bag containing 0.9% (w/v) saline and 
delivered through an IV administration set with a 0.2-μm or 0.22-μm in-line filter.
The calculated volume of tremelimumab (3.8 mL for 75 mg dose) is added to an appropriately 
sized IV bag such that final concentration is within 0.15 to 10 mg/mL.  Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag.
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  In the event that either 
preparation time or infusion time exceeds the time limit, a new dose must be prepared using 
new vials.  Tremelimumab does not contain preservatives, and any unused portion must be 
discarded.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
145 (275)
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed.  However, administration sets containing cellulose-based filters should not be 
used with tremelimumab. 
Dose calculation
For 75-mg fixed dose:
The volume of tremelimumab (in mL) for a fixed dose of 75 mg is 3.8 mL:
Dose (mL) = Tremelimumab dose level (75 mg)
Tremelimumab concentration (20 mg/mL)
The corresponding volume should be rounded to the nearest tenth of an mL (0.1 mL).  
7.1.3
Standard of Care
Each SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) agent will be sourced as 
commercially available material/locally sourced, prescribed according to local regulations, 
and will be administered according to prescribing information or treatment guidance in 
general use by the Investigating site.  Under certain circumstances when local sourcing is not 
feasible, a SoC will be supplied centrally by AstraZeneca.  This will be labeled with local 
language translated text in accordance with regulatory guidelines.
7.2
Dose and treatment regimens
7.2.1
Treatment regimens
MEDI4736 monotherapy 
Patients in the MEDI4736 monotherapy treatment arm will receive 1.5 g MEDI4736 via IV 
infusion q4w at Week 0.  See Figure 3.  

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Study Code D419BC00001
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Figure 3
MEDI4736 monotherapy dosing schedule
Q4W every 4 weeks
MEDI4736 + tremelimumab combination therapy
Patients in the MEDI4736 + tremelimumab combination therapy treatment arm will receive 
MEDI4736 (1.5 g IV q4w) over a 1-hour period in combination with tremelimumab (75 mg 
IV q4w) over a 1-hour period for up to 4 doses/cycle each, followed by MEDI4736 (1.5 g IV 
q4w) until confirmed disease progression or until other discontinuation criteria are met.  The 
first MEDI4736 monotherapy dose at 1.5 g IV q4w will be 4 weeks after the final dose of 
MEDI4736 in combination with tremelimumab (see Figure 4).
Tremelimumab will be administered first; the MEDI4736 infusion will start approximately 
1 hour after the end of the tremelimumab infusion.  If there are no clinically significant 
concerns after the first cycle, then, at the discretion of the Investigator, all other cycles of 
MEDI4736 can be given immediately after the tremelimumab infusion has finished.

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Study Code D419BC00001
Version 9
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Figure 4
MEDI4736 + tremelimumab combination therapy dosing schedule
Q4W every 4 weeks
Standard of Care
Patients in the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) arm who are 
eligible for cisplatin will receive 1 of 2 gemcitabine + cisplatin options: 
1.
IV infusions of cisplatin (70 mg/m2) on Day 2 of each 28-day cycle + gemcitabine 
(1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle, for up to 6 cycles or 
2.
IV infusions of cisplatin (70 mg/m2) on Day 1 of each 21-day cycle + gemcitabine 
(1000 to 1250 mg/m2) on Days 1 and 8 of each 21-day cycle, for up to 6 cycles.  
Patients in the SoC arm who are ineligible for cisplatin will receive IV infusions of 
carboplatin at an AUC of 4.5 to 5 (AUC 4 is permitted only if required by local standard 
clinical practice) on Day 1 of each 21-day cycle + gemcitabine 1000 mg/m2 on Days 1 and 8 
of each 21-day cycle, for up to 6 cycles.  
Patients randomized to the SoC arm with cisplatin and gemcitabine who receive at least 
1 cycle of cisplatin and gemcitabine and by physician’s determination are unable to tolerate 
subsequent cisplatin cycles will be allowed to change from cisplatin to carboplatin 1 time.  

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The criteria justifying the change from cisplatin to carboplatin during study treatment must be 
documented in the eCRF.
In a rare scenario, if at the Investigator’s discretion, patients in the SoC arm who have not 
progressed continue the SoC treatment beyond 6 cycles, the exposure information will be 
reported in exposure eCRF.
7.2.2
Duration of treatment, criteria for retreatment, and treatment through 
progression
Duration of treatment
Patients randomized to the MEDI4736 + tremelimumab combination therapy and the 
MEDI4736 monotherapy arms will begin treatment on Day 1 until PD is confirmed, 
unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is 
met.  According to RECIST 1.1 modified for confirmation of progression, a confirmatory scan 
will be required following an overall timepoint assessment of progression, preferably at the 
next scheduled visit and no earlier than 4 weeks after the previous assessment of PD.
Patients randomized to treatment in the SoC arm (cisplatin + gemcitabine or 
carboplatin + gemcitabine) will begin treatment on Day 1 for up to 6 cycles until the first 
assessment of disease progression or until unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met. A confirmatory scan will not be required if PD is 
identified on the SoC arm in order to discontinue treatment; however, a subsequent scan is 
required following an overall timepoint assessment of initial progression, even if a subsequent 
treatment is started and no earlier than 4 weeks after the previous assessment of PD.  
Retreatment is not permitted for patients in the SoC arm. 
Retreatment
Patients randomized to the MEDI4736 + tremelimumab combination therapy arm who meet 
the retreatment criteria described below may receive retreatment 1 time at the Investigator’s 
discretion.  During retreatment, patients will follow the same schedule of assessments as the 
original treatment period (with the exception of the PK and ADA assessments, Hepatitis B and 
C assessments, and HIV assessments which do not need to be collected a second time):

Patients who complete the 4 dosing cycles of the combination of durvalumab 
(MEDI4736) and tremelimumab portion of the regimen (with clinical benefit per 
Investigator judgment), but subsequently have evidence of PD during the 
durvalumab (MEDI4736) monotherapy portion of the combination regimen, with or 
without confirmation according to RECIST 1.1, may restart treatment with the 
combination.

Patients who restart treatment after PD must have a baseline tumor assessment 
within 28 days of restarting treatment with MEDI4736 + tremelimumab 
combination therapy; all further scans should occur q8w (±7 days) relative to the 
date of  first dose of retreatment until disease progression.

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Study Code D419BC00001
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Criteria for retreatment and treatment through progression 
Treatment through progression in either the MEDI4736 monotherapy arm, 
MEDI4736 + tremelimumab combination therapy arm or retreatment in the 
MEDI4736 + tremelimumab combination therapy arm are at the Investigator’s discretion.  The 
Investigator will ensure that patients do not have any significant, unacceptable, or irreversible 
toxicities that indicate that continuing treatment will not provide further benefit to patients.  
Moreover, these patients must meet the following specific criteria for treatment in the setting 
of PD: 

Written informed consent for retreatment and/or treatment through progression in 
the setting of PD will specify that treatment beyond evidence of initial PD is not the 
SoC and that alternative treatment options, including either locally licensed 
treatments or other clinical trials, are available for this patient population

Absence of clinical symptoms or signs (including worsening of laboratory values 
[eg, new or worsening hypercalcemia]) indicating clinically significant disease 
progression and no decline in ECOG performance status that can be attributed to 
disease progression

Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (eg, central nervous system metastasis or respiratory failure due to tumor 
compression or spinal cord compression) that cannot be managed by 
protocol-allowed medical interventions

However, a patient in the MEDI4736 monotherapy arm with confirmed disease 
progression will not be permitted to continue therapy with MEDI4736 if disease 
progression occurred after confirmed response (CR or PR, as defined by RECIST 
1.1) in the target lesions.  Additionally, a patient randomized to the MEDI4736 + 
tremelimumab combination treatment arm with confirmed disease progression 
during the combination portion of therapy that occurred after confirmed response 
(CR or PR, as defined by RECIST 1.1), will not be permitted to continue 
immunotherapy if disease progression occurred in the target lesions that 
previously responded to immunotherapy
Patients whom AstraZeneca and the Investigator determined may not continue treatment after 
PD will enter follow-up.  All patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed until confirmed disease progression and for survival.  
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labeling.  Label 
text will be translated into local language.

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Japan and other countries where this is applicable: 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 investigational products.
Labels will be provided as either a single panel label or as multi-language booklet labels.
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 drugs (including IP) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by site reconciliation of medication dispensed and 
returned.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.  The 
study personnel will account for all study drugs 
Drug accountability should be performed until the patient stops study treatment completely.  
Study site personnel will account for all study drugs received at the site, for all unused study 
drugs, and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and 
return should be signed.
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca.  The IP 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.  
7.7
Concomitant and other treatments 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until 90 days after the last dose of IP (final study visit).  Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF, in addition to the reason they were prescribed.   

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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 to Section 6.7 for guidance on management of IP-related toxicities.  For agents 
in the SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) arm, also refer to the local 
prescribing information with regards to warnings, precautions, and contraindications.
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly while the patient 
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study
Should not be given concomitantly while the patient 
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment
Should not be given while the patient is on study 
treatment.  (Concurrent use of hormones for non-
cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable.  
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by 
local surgery or radiotherapy])
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be givenwhile the patient is on study 
treatment. Short-term use of immunosuppressive 
medications, including corticosteroids for the acute 
management of non-IP emergencies (eg, COPD, 
asthma) or IP-related emergent AEs, is permitted. In 
addition, immunosuppressive medication for 
palliative treatment for oncologic emergencies or 
prior to imaging procedures in patients with contrast 
allergies is acceptable.  Use of inhaled, topical, and 
intranasal corticosteroids is permitted for all 
treatment arms.  Immunosuppressive premedication 
is permitted only for patients randomized to the SoC 
arm.
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC)
Sunitinib
Should not be given to patients within 3 months of a 
dose of tremelimumab, as acute renal failure has 
been reported with combination therapy of 
tremelimumab and sunitinib

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Prohibited medication/class of drug:
Usage:
EGFR TKIs
Should be used with caution in the 90 days after the 
last dose of durvalumab.  Increased incidence of 
pneumonitis (with third-generation EGFR TKIs) 
and increased incidence of transaminase increases 
(with first-generation EGFR TKIs) has been 
reported when durvalumab has been given 
concomitantly.
Drugs with laxative properties 
Should be used with caution through 90 days after 
the last dose of tremelimumab during the study.  In 
case of strong medical need, should be used with 
caution.
Herbal and natural remedies
Should be avoided while the patient is on study 
treatment(with the exception of homeopathic 
remedies, which may be used following discussion 
with AstraZeneca).
AE adverse event; CTLA-4 cytotoxic T lymphocyte-associated antigen 4; IP investigational product; PD-
1 programmed cell death 1; PD-L1 programmed cell death ligand 1 SoC standard of care
Rescue/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
BSC (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
BSC best supportive care
7.7.1
Other concomitant treatment
Medication other than that described in Section 7.7 that is considered necessary for the 
patient’s safety and well-being may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.

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7.8
Post-study access to study treatment
Patients who continue to receive benefit from their assigned treatment at the scheduled data 
cutoff for final analysis of the global cohort and final database lock may continue to receive 
their assigned treatment for as long as they and their physician feel they are gaining clinical 
benefit or until meeting any other discontinuation criteria as defined in Section 3.9. For 
patients continuing to receive duravalumab or durvalumab + tremelimumab treatment 
following the scheduled data cutoff for final analysis of the global cohort, it is recommended 
that the patients continue the scheduled site visits. For those patients from China who are in 
the global cohort, final data cutoff and database lock will occur when the China cohort 
conducts its final data cutoff and final database lock.
Investigators should continue to monitor and document data for all study patients in the 
database after scheduled data cutoff for final analysis of the global cohort and final database 
lock. Dependent on the analysis results of the global cohort, a decision may be made to 
continue further data collection for a longer period with intent to analyze long-term OS and 
safety data to fulfill any other potential Health Authority requirements. Any additional long-
term analysis may be further clarified through an addendum to the main statistical analysis 
plan, which will be developed before data cutoff for the long-term analysis. Data will be 
collected until any of following conditions are met:

Until remaining patients in the study (including patients after discontinuation of study 
treatment) have discontinued the study; OR 

Remaining patients have been transferred into a roll-over study; OR

If the Sponsor decides to stop data collection, patients remaining on study treatment at 
that time and deriving clinical benefit from their assigned treatment will be allowed to 
continue treatment and only SAEs will be collected
Patients moving to the the roll-over study will require a new Informed Consent. The OS data 
collected in the roll-over study may be combined with the OS data from the current Study 
D419BC00001 and evaluated as a combined dataset.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) within 3 months of the first randomized 
patient and any subsequent amendments will be documented, with final amendments 
completed prior to reporting of the data.
Section 8.1 to 8.5 describes the statistical analyses that applies to global cohort data. For 
China cohort, same definitions of outcome measures (Section 8.4) and methods for statistical 

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analyses (Section 8.5) will be applied unless specified in Section 8.6 or SAP. The same OS 
treatment effect under the alternative hypothesis is assumed in the plan of China cohort 
analyses.
8.2
Sample size estimate
The study will plan to enroll approximately 1340 patients globally in order to randomize 
(1:1:1) approximately 1005 patients to MEDI4736 + tremelimumab combination therapy, 
MEDI4736 monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) over 
a period of 16 months.  Therefore, approximately 335 patients will be randomized to each of 
the treatment arms. Once global enrollment completes, recruitment to the expansion cohort 
will continue in China until approximately 180 Chinese patients have been randomized.
The global study is sized to characterize OS benefit of MEDI4736 in combination with 
tremelimumab versus SoC in patients with unresectable Stage IV UC and OS benefit of 
MEDI4736 versus SoC in patients with unresectable Stage IV PD-L1-High UC.  The sizing 
assumes a 6-month delay in separation of the OS curves between each arm, hence the use of 
average hazard ratios (HRs).  
Non-uniform accrual of patients (with k=2) is assumed when estimating the analysis times.  
The total proportion of patients randomized at time t [t≤16 months] following the start of the 
study is assumed to be (t/16)2.
The final analysis of OS will be performed when approximately 327 target OS events (81% 
maturity) have occurred in PD-L1-High UC patients treated across the 
MEDI4736 monotherapy and SoC treatment arms.
For the co-primary OS endpoints in the intent-to-treat (ITT) population (MEDI4736 + 
tremelimumab combination therapy versus SoC), 1 interim analysis will also be undertaken; 
and the interim analysis for OS endpoint in the PD-L1-High population (MEDI4736 
monotherapy versus SoC) will be conducted at the same time: 

The interim analysis will be conducted at the time when approximately 80% of the 
target OS events have occurred across the MEDI4736 + tremelimumab combination 
therapy and SoC treatment arms (440 events, 66% maturity); AND in the PD-L1-High 
population across the MEDI4736 monotherapy and SoC treatment arms (262 events, 
65% maturity). 

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MEDI4736 + tremelimumab versus SoC (OS in all-comers UC)
The assumed OS treatment effect under the alternative hypothesis is an average HR of 0.73 
for MEDI4736 + tremelimumab combination therapy versus SoC.  The OS on the control arm 
is assumed to be characterized by an exponential distribution with a median OS of 11.3 
months.  The OS on the MEDI4736 + tremelimumab combination therapy treatment arm is 
therefore assumed to be characterized by a piece-wise exponential distribution with a median 
OS of 14.8 months.  Assuming that the survival curves of the two treatment arms do not 
separate for 6 months then the HR after that point would need to be 0.61 to produce an 
average HR of 0.73 over the follow-up period.
The SoC control arm OS assumptions are based on a weighted average between median OS 
from gemcitabine/carboplatin (40% weighting) published in De Santis et al 2012 and 
gemcitabine/cisplatin published in Bellmunt et al 2012 (60% weighting). An exponential 
distribution was assumed with median OS of 0.4×9.3 months+0.6×12.7 months=11.3 months.  
Final analysis of OS based on 550 events for the comparison of MEDI4736 + tremelimumab 
combination therapy versus SoC (82% maturity, 550/670), from all randomized patients, is 
expected to occur approximately 46 months after the first patient is randomized and will 
provide at least 87% power to demonstrate a statistically significant difference in OS at a 
2-sided alpha level of 1.33% (with overall alpha for OS of 1.5%).  With a minimum follow-up 
time of 30 months from the end of patient recruitment, this yields an anticipated overall 
average HR of 0.73, with a critical value for statistical significance of 0.81.
MEDI4736 versus SoC (OS in PD-L1-High UC)
It will be assumed that approximately 60% of patients will have PD-L1-High tumors. 
The assumed OS treatment effect under the alternative hypothesis is an average HR of 0.71 
for MEDI4736 monotherapy versus SoC, and the OS on the control arm is assumed to be the 
same regardless of PD-L1 status.  The OS on the MEDI4736 monotherapy treatment arm is 
therefore assumed to be characterized by a piece-wise exponential distribution with a median 
OS of 15.3 months. Assuming that the survival curves of the two treatment arms do not 
separate for 6 months then the HR after that point would need to be 0.57 to produce an 
average HR of 0.71 over the follow-up period. 
By the time of the final analysis of OS in the PD-L1-High population, it is expected that there 
will be around 327 OS events in PD-L1-High UC patients treated in the MEDI4736 
monotherapy and SoC arms, from approximately 402 PD-L1-High patients in total (81% 
maturity, 327/402), which will provide at least 84% power to demonstrate a statistically 
significant difference in OS at a 2-sided alpha level of 3.03% (with overall alpha for OS of 
3.5%). With a minimum follow-up time of 30 months from the last patient randomized, this 
yields an anticipated overall average HR of 0.71, with a critical value for statistical 
significance of 0.79.

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MEDI4736 versus SoC (OS in all-comers UC)
The analysis of OS for MEDI4736 monotherapy versus SoC in all UC patients is a key 
secondary endpoint.  For illustrative purposes, it will be assumed that the significance level 
applied to the test will be a 2-sided 5% significance level, that is, assuming the analysis of 
both coprimary endpoints are significant at the 1.5% and 3.5% alpha level, respectively. 
The assumed OS treatment effect under the alternative hypothesis is an average HR of 0.75 
for MEDI4736 monotherapy versus SoC, and the OS on the control arm is assumed to be the 
same regardless of PD-L1 status.  The OS on the MEDI4736 monotherapy treatment arm is 
therefore assumed to be characterized by a piece-wise exponential distribution with a median 
OS of 14.4 months.  Assuming that the survival curves of the two treatment arms do not 
separate for 6 months then the HR after that point would need to be 0.63 to produce an 
average HR of 0.75 over the follow-up period.
By the time of the analysis of the co-primary endpoints, it is expected that there will be around 
553 OS events in UC patients treated in the MEDI4736 monotherapy and SoC arms, from 
670 patients in total (83% maturity, 553/670), which will provide approximately 91% power 
to demonstrate a statistically significant difference in OS at a 2-sided 4.29% significance level 
(with overall alpha for OS of 5%). With a minimum follow-up time of 30 months from the 
end of patient recruitment, this yields an anticipated overall average HR of 0.75, with a critical 
value for statistical significance of 0.84.
This power calculation is illustrative only and relies on the assumptions specified above.  Any 
results presented from these tests will consider the impact of the percent prevalence of 
PD-L1-High tumors and the significance level applied on the power of the test when 
interpreting the results.
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 10.

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Table 10
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
OS
Full analysis set (ITT population)
PD-L1-High analysis set
PD-L1-Low/Neg analysis set
MEDI4736 cisplatin ineligible population
PFS, OS24, APF12, ORR, DoR, DCR, PFS2, 
PROs, and symptom endpoints
Full analysis set (ITT population)
PD-L1-High analysis set
PD-L1-Low/Neg analysis set
-
ORR will be based on the subset of patients 
in each analysis set with measurable disease 
at baseline.  
-
DoR will be based on the subset of patients 
in each analysis set which achieves objective 
tumor response.
MEDI4736  cisplatin ineligible population
-
ORR, DoR, and DCR
Demography
Full analysis set (ITT population)
PK data
PK analysis set
Safety Data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
ECOG performance status
Safety analysis set
Vital signs
Safety analysis set
AE adverse event; APF12 proportion of patients alive and progression free at 12 months from randomization; 
DCR disease control rate; DoR duration of response; ECOG Eastern Cooperative Oncology Group; ITT Intent-
to-treat; ORR objective response rate; OS overall survival; OS24 proportion of patients alive at 24 months from 
randomization; PD-L1 programmed cell death ligand 1; PFS progression-free survival; PFS2 time from 
randomization to second progression; PK pharmacokinetic; PRO patient-reported outcomes.
8.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients prior to the end of global 
recuriment. Any patients recruited in China, after global recruitment has ended, will not be 
included in the FAS (see Section 8.6).  Unless otherwise specified, the FAS will be used for 
all efficacy analyses (including PROs).  Treatment arms will be compared on the basis of 
randomized study treatment, regardless of the treatment actually received.  Patients who were 

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randomized but did not subsequently go on to receive study treatment are included in the 
analysis in the treatment arm to which they were randomized.
8.3.2
PD-L1-High analysis set
The PD-L1-High analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1-High as defined by an IHC assay developed by Ventana (see Table 1).  
8.3.3
PD-L1-Low/Neg analysis set
The PD-L1-Low/Neg analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1-Low/Neg as defined by an IHC assay developed by Ventana (see Table 1). 
8.3.4
Cisplatin ineligible analysis set 
The Cisplatin ineligible analysis set will include the subset of patients in the FAS who are not 
eligible for cisplatin treatment at baseline (per eCRF). 
8.3.5
MEDI4736 cisplatin ineligible population
All patients who have received MEDI4736 monotherapy and are not eligible for cisplatin 
treatment at baseline (per eCRF) will be included in this analysis set. 
8.3.6
Safety analysis set
All patients recuited prior to the end of global recruitment who received at least 1 dose of IP 
will be included in the safety analysis set. Any patients recruited in China, after global 
recruitment has ended, will not be included in the safety anlysis set (see Section 8.6). The 
patients will be classified on the basis of the treatment actually received. When assessing 
safety and tolerability, summaries will be produced based on the safety analysis set. 
The cisplatin ineligible safety analysis set will include the subset of patients in the safety 
anlysis set who are not eligible for cisplatin treatment at baseline (per eCRF) and have 
received either MEDI4736 monotherpay or SoC (carboplatin + gemcitabine). 
8.3.7
PK analysis set
All patients who received at least 1 dose of MEDI4736 or tremelimumab per protocol and had 
at least one post-dose evaluable PK data of MEDI4736 or tremelimumab will be included in 
the PK analysis set.  The population will be defined by AstraZeneca/MedImmune, the 
Pharmacokineticist, and the Statistician prior to any analyses being performed.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
The analysis of the secondary endpoints of PFS, APF12, ORR, DoR, and DCR on all analysis 
sets (excluding MEDI4736 cisplatin ineligible population) will be based on Investigator 
assessments according to RECIST 1.1. For analysis regarding MEDI4736 cisplatin ineligible 
population, see Section 8.5.15. 

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8.4.1.1
RECIST 1.1-based endpoints
Investigator RECIST 1.1-based assessments
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.  
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments.  Baseline will be assessed within the 28 days prior to randomization.  If a patient 
has had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression, in which case the response will be 
assigned as PD).  Endpoints (of PFS, APF12, ORR, DoR, and DCR) will be derived from the 
overall visit response data and the scan dates.
Please refer to Appendix E for the definitions of CR, PR, SD, and PD.
Blinded Independent Central Review of RECIST 1.1-based assessments
The BICR of all radiological imaging data will be carried out using RECIST 1.1.  All 
radiological scans for cisplatin ineligible patients (including those at unscheduled visits or 
outside visit windows) will be provided to the BICR.  The imaging scans will be reviewed by 
2 independent radiologists using RECIST 1.1 and will be adjudicated, if required.  For each 
patient, the BICR will define the overall visit response data (CR, PR, SD, PD, or not evaluable 
[NE]) and the relevant scan dates for each timepoint (ie, for visits where response or 
progression is/is not identified).  If a patient has had a tumor assessment that cannot be 
evaluated, then the patient will be assigned a visit response of NE (unless there is evidence of 
progression in which case the response will be assigned as PD).  Endpoints (such as PFS, 
ORR, and DoR) in the cisplatin ineligible patients will be derived from the overall visit 
response date and the scan dates.  Further details of the BICR will be documented in the 
Imaging Charter.
8.4.1.2
Co-primary endpoints
OS in patients with UC, and OS in patients with PD-L1-High UC are the co-primary 
endpoints.
OS is defined as the time from the date of randomization until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  In order to minimize confounding 
of OS, patients randomized to SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) will 
not be allowed to crossover to MEDI4736 monotherapy or MEDI4736 + tremelimumab 
combination therapy.
Note: Survival calls will be made in the week following the date of data cutoff for the 
analysis, and if patients are confirmed to be alive or if the death date is after the data cutoff 

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date, these patients will be censored at the date of data cutoff.  Death dates may be found by 
checking publicly available death registries.
8.4.1.3
Secondary endpoints
Proportion of patients alive at 24 months
The OS24 will be defined as the Kaplan-Meier estimate of OS at 24 months.
Progression-free survival
PFS (per RECIST 1.1 as assessed by Investigator or BICR) will be defined as the time from 
the date of randomization until the date of first objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the patient withdraws from 
randomized therapy or receives another anticancer therapy prior to progression.  Patients who 
have not progressed or died at the time of analysis will be censored at the time of the latest 
date of assessment from their last evaluable RECIST 1.1 assessment.  However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of the 
latest evaluable RECIST 1.1 assessment.  If the patient has no evaluable visits or does not 
have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline.  
The PFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied:

The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression for the adjudicated reviewer selecting 
PD or of either reviewer where both select PD as a timepoint response and there is 
no adjudication for BICR data.

For investigational assessments, the date of progression will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates 
progression.

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.  
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
Proportion of patients alive and progression free at 12 months
The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed 
by the Investigator) at 12 months.

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Objective response rate
ORR (per RECIST 1.1 as assessed by Investigator) is defined as the number (%) of patients 
with at least 1 visit response of CR or PR and will be based on a subset of all randomized 
patients.  The denominator is a subset of the ITT population who has measurable disease at 
Baseline.  Therefore, data obtained up until progression, or the last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR.  Patients who go off 
treatment without progression receive a subsequent therapy, and then respond will not be 
included as responders in the ORR.  
For the definion of ORR (per RECIST 1.1 as assessed by BICR) used for the first interim 
analysis, see Section 8.5.15.1.  
Duration of response
DoR (per RECIST 1.1 as assessed by Investigator) will be defined as the time from the date of 
first documented response until the first date of documented progression or death in the 
absence of disease progression.  The end of response should coincide with the date of 
progression or death from any cause used for the RECIST 1.1 PFS endpoint.  
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit response of CR or PR.  If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time.  DoR will not be defined for those 
patients who do not have documented response.
For the definion of DoR (per RECIST 1.1 as assessed by BICR) used for the first interim 
analysis, see Section 8.5.15.1.  
Disease control rate
DCR at 6 or 12 months is defined as the percentage of patients who have a best objective 
response (BoR) of CR or PR in the first 6 or 12 months, respectively, or who have 
demonstrated SD for a minimum interval of 24 or 48 weeks, respectively (-7 days, ie, 161 or 
329 days, respectively), following the start of study treatment.  
DCR will be determined programmatically based on RECIST 1.1 using Investigator data and 
all data up until the first progression event.  This will use all data up until the progression 
event that is used for the analysis.
For the definion of DCR (per RECIST 1.1 as assessed by BICR) used for the first interim 
analysis, see Section 8.5.15.1.  
Time from randomization to second progression
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression events subsequent to that used for the PFS endpoint or death.  The date of 
second progression will be recorded by the Investigator in the eCRF and defined according to 

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local standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death. Patients alive and for whom a second disease 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression.
Best objective response
BoR is calculated based on the overall visit responses from each RECIST assessment, 
described in Appendix E.  It is the best response a patient has had during their time in the 
study up until RECIST progression (or confirmed disease progression where applicable) or the 
last evaluable assessment in the absence of RECIST progression.
Categorization of BoR will be based on RECIST (Appendix E) using the following response 
categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST using all Investigator or BICR 
data up until the first progression event.  
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤17 weeks 
(ie, 16 weeks ±7 days) after randomization, then BoR will be assigned to the PD category.  
For patients who die with no evaluable RECIST assessments, if the death occurs >17 weeks 
(ie, 16 weeks ±7 days) after randomization, then BoR will be assigned to the NE category.
Progression events that have been censored due to them being >17 weeks after the last 
evaluable assessment will not contribute to the BoR derivation.
8.4.2
Calculation or derivation of safety variables
8.4.2.1
Adverse events
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient.  
Any AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs.  Any AE occurring within 90 days of discontinuation 
of IP (ie, the last dose of MEDI4736 monotherapy, MEDI4736 + tremelimumab combination 
therapy, or SoC [cisplatin + gemcitabine or carboplatin + gemcitabine]) may be included in 
the AE summaries, but the majority of those summaries will omit the AEs observed after a 
patient has received further therapy for cancer.  Further details will be provided in the SAP.  
Any events in this period that occur after a patient has received further therapy for cancer 
(following discontinuation of IP) will be flagged in the data listings.

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A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced.  These events will not be included in AE summaries.  
8.4.2.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation.  Based on 
the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the CSR.  A similar review of laboratory/vital 
signs/ECG data will be performed for identification of OAEs.  Examples of these are marked 
hematological and other laboratory abnormalities, and certain events that lead to intervention 
(other than those already classified as serious) or significant additional treatment.
8.4.2.3
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment.  
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT).
QTcF=QT/RR^ (1/3) where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L)=Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will only include evaluable patients, in other 
words, those who had sufficient data to have the possibility of an abnormality.  
For example:

If a CTCAE criterion involves a change from Baseline, evaluable patients would 
have both 1 pre-dose and at least 1 post-dose value recorded

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.3
Calculation or derivation of patient-reported outcome variables
PROs will be assessed using the FACT-BL, PGIC, PRO-CTCAE, and EQ-5D-5L 
questionnaires.  All items/questionnaires will be scored according to published scoring 

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guidelines or the developer’s guidelines, if published guidelines are not available.  All PRO 
analyses will be based on the FAS (ITT population), unless stated otherwise.
8.4.3.1
FACT-BL
Two total, 5 subscales, and a symptoms index score are computed using the FACT-BL 
questionnaire.  Four of the 5 subscales are derived from the Functional Assessment of Cancer 
Therapy-General (FACT-G) component of the FACT-BL: PWB, FWB, EWB, and SWB.  The 
fifth subscale, derived from Additional Concerns items of the FACT-BL form the Additional 
Concerns or BlCS subscale.  The sum of the FACT-G subscales (PWB, FWB, EWB, and 
SWB) gives the FACT-G Total score.  All the 5 subscales (PWB, FWB, EWB, SWB, and 
BlCS) are summed as the FACT-BL Total score, while the sum of PWB, FWB, and BlCS 
constitutes the FACT-BL TOI.  The FACT-BL TOI is an efficient summary index of 
physical/functional outcomes used as a PRO endpoint in clinical trials because it is responsive 
to change in physical/functional outcomes.  The National Comprehensive Cancer Network -
FACT Bladder Symptoms Index-18 (NFBlSI-18) is based on the scores of 16 items available 
in the FACT-BL TOI (Jensen et al 2013).  
In this study, the change from baseline in the following total/index scores will be evaluated as 
secondary endpoints: NFBlSI-18, FACT-BL TOI, and FACT-BL Total score. The change 
from baseline in the individual subscales (PWB, FWB, EWB, SWB, and BlCS), and the 
FACT-G Total score will also be examined as exploratory analyses.  Fatigue and pain are 
prioritized as important symptoms of metastatic UC and will be evaluated as single items of 
the FACT-BL questionnaire. Time to improvement in fatigue (based the item GP1 “I have 
lack of energy”) will be a relevant secondary endpoint as fatigue is expected to be present at 
baseline, improve with response to therapy, and then decline with progressive disease. 
Similarly, time to deterioration in pain (based on item GP4 “I have pain”) is important as pain 
may arise from new bony metastasis upon progression. Details about each subscale/item will 
be provided in the SAP.
HRQoL visit responses
Scores for the FACT-BL will be derived using the developer instructions/manual (see 
Appendix F).  If there are missing items, subscale scores can be prorated.  This is done by 
multiplying the sum of the subscale by the number of items in the subscale, then dividing by 
the number of items actually answered.  This can be done on the scoring guide or by using the 
formula below:
Prorated subscale score=[Sum of item scores] × [N of items in subscale] [N of items 
answered]
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the items were answered (a minimum of 4 of 7 items, 4 of 6 items, etc).  The total 
score is then calculated as the sum of the unweighted subscale scores.  The FACT scale is 
considered to be an acceptable indicator of patient QoL as long as overall item response rate is 
greater than 80% (eg, at least 22 of 27 FACT-G items completed).  For individual subscale 

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item response rate, a subscale score is prorated for missing items if greater than 50% of items 
are answered.  In addition, a total score should only be calculated if all of the component 
subscales have valid scores.  If at least 50% of the items are missing, then that subscale will be 
treated as missing.  Missing single items are treated as missing.  The reason for any missing 
questionnaire will be identified and recorded.  If there is evidence that the missing data are 
systematic, missing values will be handled to ensure that any possible bias is minimized.  For 
the “Additional Concerns” subscale (BlCS) and the symptoms index, the procedures for 
scoring are the same as described above for the FACT-G.  Again, over 50% of the items 
(eg, 7 of 12 items) must be completed in order to consider each subscale score valid.
The NFBlSI-18 is scored the same way as the FACT-BL (Jensen et al 2013).
8.4.3.2
PGIC
The response options of the PGIC are scored as follows: Very Much Improved (+3), Much 
Improved (+2), Minimally Improved (+1), No Change (0), Minimally Worse (-1), Much 
Worse (-2) and Very Much Worse (-3).  Very Much Improved and Much Improved categories 
will be grouped together and compared with the other response categories grouped together.
8.4.3.3
PRO-CTCAE
The PRO-CTCAE items are not currently scored.  The data will be descriptively summarized.  
Further details will be provided in the SAP.
8.4.3.4
Health state utility (EQ-5D-5L)
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems, and extreme 
problems).  A unique EQ-5D health state is referred to by a 5-digit code allowing for a total of 
3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the United Kingdom valuation set, with other country value sets applied in scenario analyses).  
Where EQ-5D-5L values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be 
applied (Oemar and Oppe 2013).  
In addition to the descriptive system, respondents also assess their health on the day of 
assessment on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health).  This score is reported separately.  The evaluable population will comprise 
the FAS (ITT population).
8.4.4
Calculation or derivation of pharmacokinetic variables
8.4.4.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model may be developed using a non-linear mixed-effects modelling 
approach.  The impact of physiologically-relevant patient characteristics (covariates) and 

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disease on PK may be evaluated.  The relationship between the PK exposure and the effect on 
safety and efficacy endpoints may be evaluated.  The results of such an analysis, if conducted, 
will be reported in a separate report.  The PK, pharmacodynamics, demographic, safety, and 
efficacy data collected in this study may also be combined with similar data from other studies 
and explored using population PK and/or PK-pharmacodynamic methods.
8.4.4.2
Pharmacokinetic analysis
PK concentration data and summary statistics will be tabulated.  PK parameters will be 
determined from raw data. The following PK parameters will be determined after the first and 
steady-state doses: peak and trough concentration (as data allow).  
8.4.4.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736 and tremelimumab.  
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs.  The effect of immunogenicity on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
8.4.5
Calculation or derivation of biomarker variables
Biomarker status, as defined in the secondary objectives, will be assessed for evaluable 
patients in each cohort according to prespecified criteria that will be detailed in the SAP.
8.4.6
Calculation or derivation of pharmacogenetic variables
For the genetic data already obtained, only the date that the patient gave consent to 
participation in the genetic research and the date the blood sample was taken from the patient 
will be recorded in the eCRF and database.  The genetic data generated from the study will be 
stored in the AstraZeneca Laboratory Information Management System (LIMS) database or 
other appropriate system.  This database is a secure database, which is separate from the 
database used for the main study.  Some or all of the dataset from the main study may be 
duplicated within the AstraZeneca LIMS database for exploratory genetic analysis.  Data will 
be reported outside the CSR (please see Appendix C).
8.5
Methods for statistical analyses
In patients with UC, the following formal statistical analysis of OS (as co-primary endpoints) 
will be performed: 

H0: No difference between MEDI4736 + tremelimumab combination therapy and 
SoC

H1: Difference between MEDI4736 + tremelimumab combination therapy and SoC
In patients with PD-L1-High UC, the following formal statistical analysis of OS (as 
co-primary endpoints) will be performed: 

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
H0: No difference between MEDI4736 monotherapy and SoC

H1: Difference between MEDI4736 monotherapy and SoC
The study has been sized to characterize the OS benefit of MEDI4736 + tremelimumab 
combination therapy versus SoC in patients with UC, and the OS benefit of MEDI4736 
monotherapy versus SoC in patients with PD-L1-High UC. 
The final analysis of OS will be performed when approximately 327 target OS events (81% 
maturity) have occurred in PD-L1-High UC patients treated across the 
MEDI4736 monotherapy and SoC treatment arms.
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm.
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to randomization.
All data collected will be listed.  Efficacy and PRO data will be summarized and analyzed 
based on the FAS.  PK data will be summarized and analyzed based on the PK analysis set.  
Safety data will be summarized on the safety analysis set.
All outputs will be summarized by treatment arm for all randomized patients (ITT) and where 
required, for all randomized patients within the PD-L1-Low/Neg subgroup.  
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
Table 11 details which endpoints are to be analyzed, together with preplanned sensitivity 
analyses indicating which analysis is regarded as primary for that endpoint.  
Unless otherwise stated, data and endpoints derived from RECIST 1.1 tumor assessments will 
refer to Investigator assessed data.

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Table 11
Preplanned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Overall survival
Co-primary analysis using a stratified log-rank test
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(ITT population)
-
MEDI4736 monotherapy versus SoC (PD-L1-High population)
Sensitivity analysis using a Kaplan-Meier plot of time to censoring where 
the censoring indicator of the primary analysis is reversed – attrition bias
Secondary analysis using stratified log-rank test:
-
MEDI4736 monotherapy versus SoC (ITT population) 
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(PD-L1-Low/Neg population)
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (PD-L1-Low/Neg population)
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (ITT population) 
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(PD-L1-High population)
Secondary analysis of OS: 
-
Median OS and 95% CI (MEDI4736 cisplatin ineligible 
population)
Progression free survival
Stratified log-rank tests for:
Secondary analysis using site Investigator tumor data (RECIST 1.1):
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(ITT population)
-
MEDI4736 monotherapy versus SoC (PD-L1-High population) 
-
MEDI4736 monotherapy versus SoC (ITT population)
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(PD-L1-Low/Neg population)
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (PD-L1-Low/Neg population) 
-
MEDI4736 + tremelimumab combination therapy versus 
MEDI4736 monotherapy (ITT population) 
-
MEDI4736 + tremelimumab combination therapy versus SoC 
(PD-L1-High population)
Secondary analysis using BICR tumor data (RECIST 1.1) 
-
Median PFS and 95% CI (MEDI4736 cisplatin ineligible 
population)
Proportion of patients alive at 
24 months
HR using the Kaplan-Meier estimates of survival at 24 months (following 
the method described by Section 8.5.38.5.4)
Proportion of patients alive and 
progression-free at 12 months 
HR using the Kaplan-Meier estimates of patients alive and progression-free 
at 12 months (following the method described by Section 8.5.3) 
Objective response rate
Logistic regression using Investigator data (RECIST 1.1)
ORR and 95% CI using BICR data (MEDI4736 cisplatin ineligible 
population)

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Endpoints analyzed
Notes
Duration of response
Analysis following the method described by Section 8.5.6 using 
Investigator data (RECIST 1.1)
Analysis following the method described by Section 8.5.15.1 using BICR 
data
Disease control rate
Summarized by treatment arm n (%)
Time from randomization to 
second progression
Stratified log-rank test
Best objective response
N (%) using Investigator or BICR data (RECIST 1.1) 
Change from baseline FACT-
BL TOI, FACT-BL Total 
score, FACT-BL subscales, 
FACT-G Total score, and 
NFBlSI-18 score 
Average change from baseline using a Mixed Model Repeated 
Measurements (MMRM) analysis
Time to improvement in 
fatigue, and Time to 
deterioration in pain
Stratified log-rank test
EQ-5D-5L (health state utility 
values and Visual Analog 
Scale)
Average change from baseline using a (MMRM) analysis.  
Summary statistics for health state utilities and visual analogue scale, 
including change from baseline.
BICR Blinded Independent Central Review; EQ-5D-5L EuroQol 5-dimension, 5-level health state utility index; 
FACT-BL Functional Assessment of Cancer Therapy - Bladder Cancer; FACT-G Functional Assessment of 
Cancer Therapy - General; FACT-BL TOI Functional Assessment of Cancer Therapy - Bladder Cancer Trial 
Outcome Index; HR Hazard ratio; ITT Intent-to-Treat; MMRM Mixed Model Repeated Measurements; 
NFBlSI-18 National Comprehensive Cancer Network - FACT Bladder Symptoms Index-18; 
PD-L1 Programmed cell death 1; RECIST Response Evaluation Criteria In Solid Tumors; SoC Standard of 
care; 
Multiple testing strategy
In order to strongly control the Type I error at 5% 2-sided, a multiple testing procedure (MTP) 
with gatekeeping strategy will be used across the co-primary endpoints (OS), analysis 
populations (ITT, PD-L1-High, and PD-L1-Low/Neg populations), and treatment regimens 
(MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, and SoC). If the 
higher level hypothesis in the MTP is rejected for superiority, the following hypotheses will 
then be tested as shown in Figure 5.
Hypotheses will be tested using a multiple testing procedure with an alpha-exhaustive 
recycling strategy (Burman et al 2009). With this approach, hypotheses will be tested in a 
pre-defined order by first splitting the 5% alpha into 1.5%, and 3.5% for OS for MEDI4736 + 
tremelimumab combination therapy versus SoC (ITT population), and OS for MEDI4736 
monotherapy versus SoC (PD-L1-High population), as outlined in Figure 5.  
According to alpha (test mass) splitting and alpha recycling, the test mass that becomes 
available after each rejected hypothesis is recycled to secondary hypotheses not yet rejected. 

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Since OS is tested at multiple timepoints (ie, 1 interim analysis and final analysis), the OS 
tests for the same comparison/population (ie, shown in 1 box in the MTP) will be considered 
as 1 test family. As long as 1 test in the family can be rejected, the family is rejected; thus, the 
assigned total alpha to the family can be recycled to the next MTP level.  This testing 
procedure stops when the entire test mass is allocated to non-rejected hypotheses.  
Implementation of this pre-defined ordered testing procedure, including recycling, will 
strongly control type I error at 5% (2-sided), among all key hypotheses.  Figure 5 shows the 
multiple testing framework for the co-primary endpoints and several key secondary endpoints.  
Once the hypothesis of OS for MEDI4736 monotherapy versus SoC (ITT) is rejected, the 
remaining alpha will be assigned to test MEDI4736 + tremelimumab combination therapy 
versus SoC (PD-L1-Low/Neg population).  The details of the complete MTP and the alpha-
exhaustive recycling procedure will be provided in the Statistical Analysis Plan.
Both OS co-primary endpoints will be tested at 1 interim timepoint and a final timepoint.  The 
alpha level allocated to OS will be controlled at the interim and primary timepoints by using 
the Lan DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach, where the alpha level applied at the interim depends on the proportion of 
information available. 
For the co-primary OS endpoint in the ITT population (MEDI4736 + tremelimumab 
combination therapy versus SoC), the interim analysis will be conducted at the time when 
approximately 80% of the target OS events have occurred across the MEDI4736 + 
tremelimumab combination therapy and SoC treatment arms (440 events, 66% maturity). If 
exactly 80% of the target OS events are available at the time of the interim analysis (ie, 
440/550 deaths have occurred), with an overall 2-sided alpha level of 1.5%, the 2-sided alpha 
to be applied at the OS interim analysis would be 0.56%. The 2-sided alpha to be applied for 
the final OS analysis would be 1.33%.
For the co-primary OS endpoint in the PD-L1-High population (MEDI4736 monotherapy 
versus SoC), the interim analysis will be conducted at the time when approximately 80% of 
the target OS events have occurred across the MEDI4736 monotherapy and SoC treatment 
arms in the PD-L1-High population (262 events, 65% maturity). If exactly 80% of the target 
OS events are available at the time of the interim analysis (ie, 262/327deaths have occurred), 
with an overall 2-sided alpha level of 3.5%, the 2-sided alpha to be applied at the OS interim 
analysis would be 1.58%. The 2-sided alpha to be applied for the final OS analysis would be 
3.03%.

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Figure 5
Multiple testing procedures for controlling the type I error rate
Combo MEDI4736 + tremelimumab combination therapy; Mono MEDI4736 monotherapy; OS, overall 
survival; PD-L1, Programmed cell death ligand 1; SoC Standard of care.
8.5.1
Overall survival
OS in the ITT population and PD-L1 subgroups will be analyzed using a stratified log-rank 
tests adjusting for cisplatin eligibility (ie, eligible or ineligible), PD-L1 status (High and 
Low/Neg), and visceral metastasis (presence or absence of lung and/or liver metastasis). The
effect of treatment versus SoC treatement will be estimated by the HR together with its 
corresponding ([1-adjusted alpha] × 100%) CI and p-value. The HR and its CI will be 
estimated from the stratified Cox proportional hazards model (Cox 1972).
All of the secondary analyses will be performed using the same methodology as for the 
primary analyses described above.
Kaplan-Meier plots of OS will be presented by treatment arm.  Summaries of the number and 
percentage of patients who have died, those still in survival follow-up, those lost to follow up, 
and those who have withdrawn consent will be provided along with the median OS for each 
treatment. 
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias, 
achieved by a Kaplan-Meier plot of time to censoring where the censoring indicator of OS is 
reversed.
Subgroup analyses will be conducted comparing OS between MEDI4736 + tremelimumab
combination therapy (or MEDI4736 monotherapy) versus SoC in the following subgroups of 
the FAS (but not limited to):

Sex (male versus female)

Age at randomization (<65 versus ≥65 years of age)

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
PD-L1 status (High versus Low/Neg)

Visceral metastases (present versus absent, ie, lung or liver)

Eligibility for cisplatin containing chemotherapy at randomization (eligible or 
ineligible)

Race (Asian versus non-Asian)
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of OS.
For each subgroup factor, the HR (MEDI4736 + tremelimumab:SoC) and HR (MEDI4736 
monotherapy:SoC) and 95% CI will be calculated from a single model that contains treatment 
within each subgroup.  These will be presented on a forest plot including the HR and 95% CI 
from the overall population.  
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analyzed.  In 
this case, only descriptive summaries will be provided.
For the analysis method of OS used in the interim analysis, see Section 8.5.15.2.
8.5.2
Progression-free survival
The PFS analysis will be based on the programmatically derived RECIST 1.1 using 
Investigator data.  The analysis will be performed in the corresponding population using a 
stratified log-rank test based on the same methodology as described for the OS endpoint. The 
effect of treatment versus SoC treatment will be estimated by the HR together with its 
corresponding 95% CI and p-value.
Kaplan-Meier plots of PFS will be presented by treatment arm.  Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each treatment.
In addition, as a sensitivity analysis, patients who take subsequent therapy prior to progression 
or death will be censored at their last evaluable assessment prior to taking the subsequent 
therapy. 
For the analysis method of PFS used in the interim analysis, see Section 8.5.15.1.

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8.5.3
Overall survival at 24 months
The OS24 will be summarized (using the Kaplan-Meier curve) and presented by treatment 
arm.  OS24 will be compared between treatments by using the Kaplan-Meier estimator of OS 
at 24 months for each treatment to obtain the HR.  The HR and CI will be presented using the 
following approach (Klein et al 2007):

The HR(group1:group2) is estimated as 

The variance for ln(HR) is estimated as 
where 




t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2

is the variance for ln(S(t)) derived from Greenwood’s formula 
for the variance of S(t) and can be estimated from standard software packages, where di and ni 
refer to the number of deaths and patients at risk for each risk set.  
The ln(HR) and its variance in each strata will be estimated and combined by weighting 
inversely proportionately according to each within stratum variance (Whitehead and 
Whitehead 1991).
8.5.4
Proportion of patients alive and progression free at 12 months
APF12 will be summarized using the same methodology as OS24 (see Section 8.5.3).
8.5.5
Objective response rate
The ORR will be based on the programmatically derived RECIST using the Investigator data.  
The ORR will be compared between MEDI473 + tremelimumab combination therapy versus 
SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) and MEDI4736 monotherapy 
versus SoC using logistic regression models adjusting for the same factors as the primary 
endpoint.  The results of the analysis will be presented in terms of an odds ratio together with 
its associated profile likelihood 95% CI and p-value (based on twice the change in log-
likelihood resulting from the addition of a treatment factor to the model).  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  Overall visit response data will be listed and summarized over time for all 
patients (ie, the FAS).  For each treatment arm, BoR will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE).  No formal statistical analyses are planned for BoR.
For the analysis method of ORR used in the first interim analysis, see Section 8.5.15.1.
)
(
ˆ
ln
)
(
ˆ
ln
2
1
t
S
t
S
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
174 (275)
8.5.6
Duration of response
Descriptive data will be provided for the DoR in responding patients, including the associated 
Kaplan-Meier curves (without any formal comparison of treatment arms or p-value attached).
For the analysis method of DoR used in the first interim analysis, see Section 8.5.15.1.
8.5.7
Disease control rate
The DCR will be summarized (ie, number of patients).
8.5.8
Time from randomization to second progression
Second progression (PFS2) will be analyzed using identical methods as outlined for the 
analysis of PFS and stratifying for the same set of covariates.  Medians and Kaplan–Meier 
plots will be presented to support the analysis.  The sensitivity analysis outlined in 
Section 8.5.2 will not be repeated for PFS2 with the exception of a Kaplan-Meier plot of the 
time to censoring where the censoring indicator of PFS2 is reversed.
For supportive purposes, the time to the start of subsequent therapy will be analyzed using the 
same methodology and model.  The HR for the treatment effect together with its 95% CI will 
be presented.  In addition, a Kaplan-Meier plot of the time to the start of subsequent therapy 
will be presented by treatment arm and the time between progression and starting subsequent 
therapy will be assessed.  No multiplicity adjustment will be applied as these are viewed as 
supportive endpoints.
A summary table of first subsequent therapies by treatment arm will be provided, as well as 
response to first subsequent therapy by treatment arm.
This analysis will be performed in the ITT population and PD-L1 status subsets.
8.5.9
Patient reported outcomes
8.5.9.1
FACT-BL
A separate family of endpoints is defined in order of importance (highest to lowest) for the 
secondary endpoints of NFBlSI-18 (a bladder symptoms index), FACT-BL TOI, and 
FACT BL Total score.  The mean change in score from baseline will be analyzed for each 
measure using a mixed model for repeated measures.  Full details of this and appropriate 
sensitivity analyses will be described in full in the SAP.
Additionally, the endpoints of PWB, FWB, EWB, SWB, and BlCS subscales as well as the 
FACT-G Total score may also be analyzed in a similar way as exploratory analyses.  Data will 
be summarized at each visit and graphical presentations may also be produced as appropriate.  
Time to improvement in fatigue and time to deterioration/worsening in pain as time to event 
analyses using the same analysis methods described for OS will be done. Depending on the 
baseline scores, consideration will also be given to analyzing the data (NFBlSI-18, FACT-BL 
TOI and FACT-BL Total score) using time to worsening or time to improvement as time to 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
175 (275)
event analysis using the same analysis methods described for OS.  This will be an exploratory 
analysis, and further details will be provided in the SAP.
8.5.9.2
PGIC
PGIC data will be presented using summaries and descriptive statistics based on the FAS.  
Further details will be provided in the SAP.
8.5.9.3
PRO-CTCAE
PRO-CTCAE data will be presented using summaries and descriptive statistics based on the 
FAS.  Further details will be provided in the SAP.
8.5.9.4
EQ-5D-5L
Descriptive statistics, graphs and listings will be reported for health state utility index values 
(United Kingdom base case) and visual analogue scale by visits as well as change in these 
scores from baseline.  To support future economic evaluations of the study treatment, 
additional appropriate analyses may be undertaken, for example, mean health state utility pre-
and post-treatment, and pre- and post-progression.
8.5.10
Healthcare resource use (HOSPAD)
Using the HOSPAD module, an exploratory health economic analysis of hospital episodes 
including type of contact (hospitalization, outpatient, or day case), reason, length of stay by 
ward type (including intensive care unit), procedures, and tests may be undertaken to examine 
the impact of disease and treatment on resource use to primarily support the economic 
evaluation of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy 
in comparison to SoC (cisplatin + gemcitabine or carboplatin + gemcitabine).  The module is 
for all non-study protocol-related hospital admissions; any routine hospital visits for study 
protocol-related requirements do not need to be captured.  This would include providing 
descriptive statistics as appropriate, including means, median, and ranges.
8.5.11
Safety data
Safety and tolerability data will be presented by treatment arm using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient.  The number of patients experiencing each AE will be summarized by treatment arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  Any safety summaries examining retreatment with MEDI4736 
monotherapy and MEDI4736 + tremelimumab combination therapy will be produced 
separately.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs.  Exposure to MEDI4736 monotherapy, MEDI4736 + 
tremelimumab combination therapy, and SoC (cisplatin + gemcitabine or carboplatin + 
gemcitabine) will be summarized.  Time on study, MEDI4736 monotherapy, MEDI4736 + 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
176 (275)
tremelimumab combination therapy, and SoC dose delays/interruptions and dose reductions in 
the SoC arm will also be summarized.  At the end of the study, appropriate summaries of all 
safety data will be produced, as defined in the SAP.  
8.5.12
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients.
8.5.12.1
Immunogenicity analysis
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736 and 
anti-tremelimumab antibodies.  The immunogenicity titer and neutralizing ADA data will be 
listed for samples confirmed positive for the presence of anti-MEDI4736 and 
anti-tremelimumab antibodies.  
The effect of immunogenicity on PK, pharmacodynamics, efficacy, and safety will be 
evaluated if data allow.
8.5.13
Pharmacokinetic/pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modelling approach.
8.5.14
Biomarker data
The relationship of PD-L1 status determined by the Ventana IHC assay and if applicable, of 
exploratory biomarkers to OS, OS24, APF12, ORR, DoR, and PFS2 will be presented for a 
subset of patients in the ITT population who are evaluable for each biomarker.  
This will be assessed using similar summary and graphical representations to those that are 
outlined for the efficacy outputs in Section 8.5.2 to Section 8.5.3.  
PD-L1 status determined by the Ventana IHC assay will be reported in the CSR.  Summaries 
and analyses for exploratory biomarkers will be documented in a separate analysis plan and 
will be reported outside the CSR in a separate report.
8.5.15
Interim analyses
Two interim analyses will be performed. The first interim (Interim 1) will focus on ORR and 
DoR in patients who are not cisplatin-eligible and treated with MEDI4736 monotherapy 
(Section 8.5.15.1), and the second interim (Interim 2) will focus on co-primary OS endpoints 
(Section 8.5.15.2). Interim 1 will be conducted when all patients in the global cohort have at 
least 6 months follow-up. 
8.5.15.1
Interim analysis focusing on ORR and DoR
This interim analysis will take place when all patients in the global cohort have at least 6 
months follow-up. Results of this interim analysis will be used for potential interaction with 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
177 (275)
regulatory agencies regarding future development of MEDI4736 monotherapy in patients who 
are ineligible for cisplatin treatment. OS will remain as the co-primary endpoints in this study. 
The evaluation in MEDI4736 cisplatin ineligible population will be considered as a secondary 
analysis outside of the MTP.  Hence, there are no plans to stop the study early based on any 
results from this interim analysis and no formal statistical adjustments are planned, and no 
alpha adjustment on the primary analyses and secondary analyses in the MTP due to the 
evaluation of MEDI4736 cisplatin ineligible population is planned.
In order to maintain the integrity of this ongoing study, the interim results will be reviewed by 
the IDMC.  If IDMC recommends the interim analysis indicate favorable benefit:risk profile 
of MEDI4736 monotherapy in cisplatin-ineligible patients, the interim results will be shared 
with a separate unblinded internal (AstraZeneca) committee, consisting of personnel who are 
not involved in the day-to-day study conduct. The details of IDMC and internal committee 
process and decision criteria will be detailed in the IDMC Charter. Finally, results will not be 
communicated externally, except with regulators for a potential discussion on registration in 
the cisplatin-ineligible population.
Details of this interim analysis, such as analysis set definition, endpoint definition (if different 
from which used in Section 8.3) and analysis methods will be specified in the following 
sections.
8.5.15.1.1 Analysis set
For the analysis sets used for this interim analysis, see Section 8.3.5 and Section 8.3.6.
8.5.15.1.2 Sample size
In the case of 130 patients in the MEDI4736 cisplatin ineligible population, the maximum 
width between the observed ORR and its lower limit of the exact 95% CI will be no more than 
9%. 
8.5.15.1.3 Analysis endpoints
ORR (per RECIST 1.1 as assessed by the BICR) is defined as the number (%) of patients with 
a confirmed overall response of CR or PR and will be based on MEDI4736 cisplatin ineligible 
population. A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 
visit and confirmed by repeat imaging not less than 4 weeks after the visit when the response 
was first observed with no evidence of progression between the initial and CR/PR 
confirmation visit. Therefore, data obtained up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR. Any 
patient who discontinues treatment without progression, receives a subsequent therapy and 
then responds will not be included as responders in the ORR.
Duration of response (per RECIST 1.1 as assessed by the BICR) will be defined as the time 
from the date of first documented response (which is subsequently confirmed) until the first 
date of documented progression or death in the absence of disease progression. 

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Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
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Time to response (per RECIST 1.1 as assessed by the BICR) is defined as the time from the 
date of randomisation until the date of first documented response. The date of first 
documented response should coincide with that used for the DoR endpoint. TTR will not be 
defined for those patients who do not have documented response.
DCR and PFS (per RECIST 1.1 as assessed by the BICR), and OS will also be evaluated as 
secondary endpoints.
ORR, DoR, TTR, DCR and PFS will be obtained using the algorithm described above for the 
RECIST1.1 site investigator tumor data.
PK and ADA will be assessed in patients who are in the MEDI4736 cisplatin ineligible 
population with the corresponding samples taken.
Safety will be evaluated in the Cisplatin ineligible safety analysis set.
8.5.15.1.4 Analysis methods
ORR will be estimated with a 95% exact CI by Clopper-Pearson method. The primary 
analysis will be based on the programmatically derived ORR based on BICR assessments, and 
using all scans regardless of whether they were scheduled or not. The primary analysis 
population for ORR will be the MEDI4736 cisplatin ineligible population. 
A sensitivity analysis excluding patients who do not have measurable disease at baseline per 
BICR will be presented. 
An analysis of ORR using the results of the programmatically derived RECIST site 
investigator tumor data from all scans will be conducted as a sensitivity analysis to confirm 
the results of the primary analysis. 
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). The number (%) of patients with a confirmed response and the number (%) 
of patients with a single visit response (ie, an unconfirmed response) will also be presented.
Kaplan Meier plots of DoR based on the BICR assessment of RECIST will be presented. 
Median DoR will also be summarized. Only patients who have a response will be included in 
this summary table. DoR will also be analyzed based upon the site investigator tumor data.
Descriptive summary statistics (ie, minimum, maximum, and median) will also be presented 
for TTR based on BICR assessments. TTR will also be summarised based upon the site 
investigator tumor data.
The DCR based upon the BICR assessment of RECIST will be summarized (ie, number of 
patients [%]). DCR will also be summarized based upon the site investigator tumor data.
Kaplan-Meier plots of PFS (per BICR assessment) will be presented. Summaries of the 
number and percentage of patients experiencing a PFS event, and the type of event (RECIST 
1.1 or death) will be provided along with median PFS. The proportion of patients alive and 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
179 (275)
progression free at 3, 6, 9 and 12 months will be summarized (using the Kaplan-Meier curve) 
and presented. This analysis will be repeated for site investigator data.
Kaplan-Meier plots of OS will be presented. Summaries of the number and percentage of 
patients who have died, are still in survival follow-up, are lost to follow-up and have 
withdrawn consent will be provided along with median OS. The proportion of patients alive at 
6, 9, and 12 months will be summarized (using the Kaplan-Meier curve).
Analyses of safety, PK and ADA data will be conducted as outlined in Section 4. 
Demographic and baseline characteristic will be presented. 
Subgroup analyses will be conducted using the factors specified in Section 8.5.2 as 
appropriated. 
8.5.15.2
Interim analysis of overall survival endpoints
One interim analysis of OS will be carried out for superiority:

The interim analysis will be conducted at the time when approximately 80% of the
target OS events have occurred across the MEDI4736 + tremelimumab combination 
therapy and SoC treatment arms (440 events, 66% maturity); AND across the 
MEDI4736 monotherapy and SoC treatment arms in PD-L1-High population 
(262 events, 65% maturity), projected approximately 16 months after the last patient 
being randomized. 
This analysis will be assessed by an IDMC. Details of the plan and communication process 
will be provided in the statistical analysis plan and the IDMC charter.
The criterion for superiority in the OS co-primary endpoint is a statistically significant 
improvement in OS.  The alpha level that is to be spent at the interim and final analyses for 
the OS analyses in the ITT population and PD-L1-High population will be calculated using 
the Lan DeMets spending function separately. 
For the co-primary OS endpoint in the ITT population (MEDI4736 + tremelimumab 
combination therapy versus SoC), if exactly 80% of the target OS events are available at the 
time of the interim analysis (ie, 440/550 deaths have occurred), with an overall 2-sided alpha 
level of 1.5%, the 2-sided alpha to be applied at the OS interim analysis would be 0.56%. The 
2-sided alpha to be applied for the final OS analysis would be 1.33%.
For the co-primary OS endpoint in the PD-L1-High population (MEDI4736 monotherapy 
versus SoC), if exactly 80% of the target OS events are available at the time of the interim 
analysis (ie, 262/327 deaths have occurred), with an overall 2-sided alpha level of 3.5%, the 
2-sided alpha to be applied at the OS interim analysis would be 1.58%. The 2-sided alpha to 
be applied for the final OS analysis would be 3.03%.

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Study Code D419BC00001
Version 9
Date 03 December  2019
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If the interim analysis indicates superiority, then subsequent analyses of the further secondary 
endpoints will be performed in accordance with the hierarchical multiple testing strategy. If 
the interim results do not meet the criterion of stopping for superiority, then follow-up will 
continue until final OS analysis. 
8.6
China cohort
China cohort consists of all patients from China sites and Taiwan sites accredited by China 
regulation recruited prior to the end of global recruitment and after the completion of global 
recruitment. The global cohort includes Chinese patients recruited prior to the end of global 
recruitment. Once global enrollment has completed, recruitment into an expansion cohort 
continues. Hence a patient randomized in China cohort prior to the end of global recruitment 
will be included in both the (globally recruited) FAS and the China FAS. A patient 
randomized in China after the end of global recruitment will be included only in the China 
FAS.
Per China FDA guidance, in addition to the evaluation of global cohort data for primary, 
secondary and safety objectives, evaluation of consistency in efficacy and safety in China and 
Asia population is required to facilitate the benefit-risk assessment for Chinese patients.  
Hence, the safety and efficacy data in China cohort will be analyzed separately where the 
same endpoint definitions (as detailed in Section 8.4) and the same analysis methods (as 
detailed in Section 8.5) are applied.  
The China full analysis set (China FAS) will include all patients randomized in China 
cohort and will be used for all China only efficacy analyses. 
The China safety analysis set will consist of all patients recruited in China cohort who 
received at least 1 dose of study treatment and for whom post-dose data are available.
Efficacy analyses for China cohort will be performed when the OS data from the China 
patients is of similar maturity where significant clinical efficacy is established in the global 
cohort, e.g. if OS efficacy is established at the second OS interim analysis, a similar maturity 
to this will be used for consistency evaluation. 
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or patients are available (e.g. ≥20 OS events) unless specified, otherwise 
descriptive statistics only will be presented. No adjustment for multiplicity will be made and 
so the procedure for hierarchical testing detailed in Section 8.5 will not be followed. OS 
efficacy evaluation for China cohort will be performed only once. 
Details of China cohort and Asia population analysis, including vendor to perform the 
analysis, will be specified in China supplementary SAP, which is to be finalized before global 
cohort data lock for analysis.  

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Drug Substance Durvalumab (MEDI4736) + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
181 (275)
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca 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 IVRS/IWRS, 
WBDC, and any electronic PRO systems to be utilized.
The PI 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 PI 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 representative will have regular contact 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 eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed

Perform source data verification (a comparison of the data in the eCRFs 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 or 
destroyed accordingly, and the action is documented and reported to the patient
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centers need information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for the location of source data.

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Study Code D419BC00001
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Source data are any data generated as a result of the patient’s inclusion in the study (including 
run-in and/or follow-up related to the study) and includes all related medical examinations and 
other records.  
9.2.2
Direct access to source data in Japan only
The Head of the study site and the PI/Investigator will cooperate with monitoring and auditing 
by AstraZeneca and accept inspection by the Institutional Review Board (IRB) or regulatory 
authorities.  All study documents, such as raw data, will be open for direct access to source 
data at the request of the monitor and the auditor of AstraZeneca, the IRB, or regulatory 
authorities.
The monitor(s) will verify data from the eCRFs against source data before the PI signs the 
eCRFs to ensure accuracy and completeness of documentation, and assure that the PI has 
submitted the eCRFs to AstraZeneca.  If the Investigator wishes to amend the collected 
eCRFs, the monitor will ensure that the PI has recorded the amendment with signature and 
date and provided this to AstraZeneca.
9.2.3
Study agreements
The PI at each center should comply with all the terms, conditions, and obligations of the CSA 
for this study.  In the event of any inconsistency between this clinical study protocol and the 
CSA, the terms of clinical study protocol shall prevail with respect to the conduct of the study 
and the treatment of patients.  In all other respects not relating to study conduct or treatment of 
patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place or before any patients are enrolled.
9.2.4
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
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 study is expected to start in Q3 2015 and to end by Q3 2019.  
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 MEDI4736 or tremelimumab.
Refer to Section 7.8 for details regarding study treatment access, data collection, and patient 
follow-up at the end of study.

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Study Code D419BC00001
Version 9
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9.4
Data management by AstraZeneca
Data management will be performed by a chosen vendor according to the Data Management 
Plan.  AEs and medical/surgical history will be classified according to the terminology of the 
latest version of MedDRA.  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the chosen vendor.
The data collected through third party sources will be obtained and reconciled against study 
data.
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 the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan 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, a clean file will be declared.  
Any treatment-revealing data may thereafter be added and the final database will be locked.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.  
Data management of genotype data
Data management of genotype data is described in Appendix C.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratories internal or 
external to AstraZeneca.
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.

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The applicable regulatory requirements in Japan are “Good Clinical Practice for Trials on 
Drugs” (Ministry of Health, Labor, and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications.
10.2
Patient data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation.  In some cases, such wording will be in a separate accompanying document.
Patient data protection for genetic data is described in Appendix C.
10.3
Ethics and regulatory review
An ethics committee (EC)/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 Investigator will ensure the distribution of these documents to the applicable 
EC/IRB and to the study site staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study.  
The EC/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.
If required by local regulations, the protocol should be re-approved by the EC/IRB 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/IRBs, and PIs with safety 
updates/reports according to local requirements.
Each PI is responsible for providing the EC/IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  AstraZeneca will provide 
this information to the PI so that he/she can meet these reporting requirements.
Japan and other countries where this is applicable:
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 enrolment of any patient should into the study.
The IRB/EC should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF, which 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 1 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 enrolment 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 provide regulatory authorities, IRB, the head of the study site, and the PIs 
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 relative safety information reported by AstraZeneca.
10.4
Informed consent
The PI(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 her or 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

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/IRB.

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For Japan and other countries where this is applicable:
If any new information on the study medication becomes available that may influence the 
decision of the patient to continue the study, the Investigator(s) should inform the patient of 
such information immediately, record this in a written form, and confirm with the patient if he 
or she wishes to continue their participation in the study.  In addition, if the Investigator(s) 
deem it necessary to revise the ICF, they should revise it immediately (refer to Section 10.5).  
The Investigator(s) should re-explain to the patients using an updated ICF even if the patients 
have already been informed of the new information verbally.  Written informed consent to 
continue participation in the study should be provided separately.
10.5
Changes to the protocol and informed consent form
For sites outside Japan:
Study procedures will not be changed without the mutual agreement of the PI 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 (clinical study protocol).
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority, 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 PI(s).  For distribution to EC/IRB see Section 10.3.
If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
EC/IRB 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/IRB.
For Japan sites only:
Study procedures will not be changed without the mutual agreement of the PI 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.  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.

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10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB 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, ICH guidelines, and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the center.
For Japan sites only: All study data may undergo a reliability review and onsite-GCP 
inspection by the regulatory authorities.  

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11.
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Appendix A
Additional Safety Information
Further guidance on the definition of a serious adverse event (SAE)
Life threatening
“Life-threatening” means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred, or it is suspected that use or continued use of the product would 
result in the patient’s death.  “Life-threatening” does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation, but requires intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
A guide to interpreting the causality question

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When making an assessment of causality, consider the following factors when deciding if 
there is a “reasonable possibility” that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, or other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped?  AstraZeneca would not normally 
recommend or support a re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of “related” is made if, following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case.  The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.  
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as “not related.”
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as “no reasonable possibility.”
Creatinine calculation
Cockcroft-Gault equation

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Males:
Creatinine CL =
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL =
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
MEDI4736 and tremelimumab
There is no information to date on drug-drug interactions with MEDI4736 or tremelimumab, 
either pre-clinically or in patients.  As MEDI4736 and tremelimumab are monoclonal 
antibodies and therefore proteins, they will be degraded to small peptides and amino acids and 
will be eliminated by renal and reticuloendothelial clearance.  It is therefore not expected that 
MEDI4736 or tremelimumab will induce or inhibit the major drug metabolizing cytochrome 
P450 pathways.  As a result, there are no expected pharmacokinetic drug-drug interactions.  
No formal drug-drug interaction studies have been conducted with tremelimumab.  However, 
in renal cell carcinoma studies, acute renal failure has been reported with the combination of 
tremelimumab and sunitinib.
The mechanism of action of MEDI4736 involves binding to programmed cell death ligand 1 
(PD-L1), and the mechanism of action of tremelimumab involves binding to cytotoxic T 
lymphocyte-associated antigen 4 (CTLA-4); therefore, significant pharmacodynamic drug 
interactions with the commonly administered concomitant medications are not expected.  
Despite this, appropriate clinical monitoring in all of the planned clinical studies will be 
conducted to evaluate any potential drug-drug interactions.

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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labeling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations  in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between Risk Groups and Categories A and B.
Category A Infectious substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, Hepatitis A, B, C, D, and E viruses 
and Human immunodeficiency virus types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological substance, Category B

Are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations.

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging. 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content.

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable.

Samples routinely transported by road or rail are subject to local regulations, which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

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Appendix C
Pharmacogenetics Research
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or 
special term
Explanation
DNA
Deoxyribonucleic acid
LIMS
Laboratory information management system
Below information is only applicable for the blood samples for the genetic research have been 
obtained.
Background and rationale
AstraZeneca intends to perform genetic research in the MEDI4736 and MEDI4736+ 
tremelimumab clinical development program to explore how genetic variations may affect the 
clinical parameters associated with MEDI4736, MEDI4736+ tremelimumab, and/or agents 
used as comparators.  Collection of deoxyribonucleic acid (DNA) samples from populations 
with well described clinical characteristics may lead to improvements in the design and 
interpretation of clinical trials and, possibly, to genetically guided treatment strategies.
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to MEDI4736, MEDI4736+ tremelimumab, and/or agents used as comparators, 
but also susceptibility to the disease for which MEDI4736 and/or MEDI4736+ tremelimumab 
may be evaluated.  Thus, this genetic research may involve study of additional un-named 
genes or gene categories, but only as related to disease susceptibility and drug action.
Genetic research objectives
The objective of this research is to collect and store DNA for future exploratory research into 
genes/genetic variation that may influence response (ie, distribution, safety, tolerability and 
efficacy) and/or susceptibility to disease to MEDI4736, MEDI4736+ tremelimumab, and/or 
agents used as comparators.
Discontinuation of patients from this genetic research
Specific reasons for discontinuing a patient from this genetic research are:
Withdrawal of consent for genetic research: Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study.  Voluntary discontinuation will not prejudice further treatment.  Procedures for 
discontinuation are outlined in Section 3.9 of the main Clinical Study Protocol.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 

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15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
For all samples, irrespective of the type of coding used, the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube.  Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrollment/randomization code and the DNA number will be maintained and 
stored in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and trace samples for destruction in the case of 
withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, patient family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are 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.
Data management
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyze the samples.
The results from this genetic research may be reported in the clinical study report for the main 
study, or in a separate report as appropriate.

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Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate.
References
None

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Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on managing liver abnormalities can be 
found in Sections 5.2.1 and of the protocol and in the Toxicity Management Guidelines. 
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree on whether Hy’s Law (HL) 
criteria are met.  HL criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug induced liver injury (DILI) caused by the Investigational 
Product (IP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≥3 × Upper limit of 
normal (ULN) together with Total bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN

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
AST ≥3 × ULN

TBL ≥2 × ULN
If a central laboratory is used
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Request a repeat of the test (new blood draw) by the central laboratory.

Complete the appropriate unscheduled laboratory case report form (CRF) module(s) 
with the original local laboratory test result.
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see earlier section of this 
appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results).
If a local laboratory is used
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the patient meets PHL criteria (see earlier section of this 
appendix for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory CRF.
Follow-up
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team. 

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AstraZeneca contacts the Investigator, to provide guidance, discuss and agree on an approach 
for the study patient’s 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 AstraZeneca.  If a central laboratory is used, this includes deciding 
which of the tests available in the Hy’s law lab kit should be used.

Complete the three Liver CRF Modules as information becomes available. 

If at any time (in consultation with AstraZeneca) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
Review and assessment of Potential Hy’s Law cases
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, AstraZeneca 
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 IP.  The 
AstraZeneca Medical Science Director and Global Safety Physician will also be involved in 
this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
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 an 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 AstraZeneca 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. 

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
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.
Actions required when Potential Hy’s Law criteria are met before and after starting 
study treatment
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:

Determine if there has been a significant change in the patient’s condition#
compared with the last visit where PHL criteria were met#

If there is no significant change, no action is required.

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
the Section “Potential Hy’s Law criteria met” of this appendix.
# 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 AstraZeneca if there is any uncertainty.
Actions required for repeat episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  

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The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, eg, chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in the 
section “Actions required when Potential Hy’s Law criteria are met before and after 
starting study treatment?”  
If No: follow the process described in the section “Potential Hy’s Law criteria met “of this 
appendix.
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change, follow the process described in the section 
“Potential Hy’s Law criteria met “of this appendix.
# 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 AstraZeneca if there is any uncertainty.
References
FDA Guidance for Industry. Drug-induced liver injury: Premarketing clinical evaluation, July 
2009. Available 
from:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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Appendix E
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the D419BC00001 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study.
Definition of measurable, non-measurable, target and non-target lesions
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined (by RECIST 1.1) as the presence of at least 1 measurable  
lesion which has not been previously irradiated.  A tumor lesion in a previously irradiated 
field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression.
Measurable:
A lesion, not previously irradiated per the protocol prior to enrollment, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must 
have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging 
(MRI) and that is suitable for accurate repeated measurements.  A tumor lesion in a previously 
irradiated field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline1).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI.

Previously irradiated lesions that have not demonstrated progression2

Brain metastasis
                                               
1 The short axis is defined as the longest axis perpendicular to the long axis of the tumor.  Nodes with <10 mm 
short axis are considered non-pathological and should not be recorded or followed as non-target lesions (NTLs).
2 Localized post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated and have not demonstrated progression will not be considered measurable and must be 
selected as NTL at baseline and followed up as part of the NTL assessment.

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Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these should be selected as target lesions (TLs).
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved and suitable for accurate repeated measurement, should be identified as 
TLs at baseline.  Lymph nodes, in any location, are collectively considered as a single organ, 
with a maximum of 2 lymph nodes as TLs.  A bilateral, segmented, or multi-lobular organ is 
considered as a single organ.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TLs should be identified as non-target 
lesions (NTLs) at baseline.
Methods of assessment
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST 1.1 assessment is provided in Table E12, 
and those excluded from tumor assessments for this study are highlighted with the rationale 
provided.
Table E12
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18F-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging; Clinical examination refers to manually palpable tumor lesions.

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CT and MRI 
CT and MRI, each preferably with intravenous (IV) contrast, are generally considered to be 
the best currently available and reproducible methods to measure TLs selected for response 
assessment and to assess NTLs and identify  any new lesions. 
In this study, it is recommended that IV contrast-enhanced CT examinations of the chest, 
abdomen, and pelvis be used to assess tumor burden at baseline and follow-up visits.  Any 
other areas of disease involvement should be additionally imaged based on the signs and 
symptoms of individual patients. In patients who are sensitive to IV CT contrast, a 
non-contrast CT examination of the chest and an MRI with IV contrast of the abdomen and 
pelvis are appropriate.  In patients with severely compromised renal function, a non-contrast 
CT examination of the chest, abdomen, and pelvis is appropriate.  For brain lesion assessment, 
MRI with IV contrast is the preferred method over contrast-enhanced CT.  It is strongly 
recommended to maintain use of the same imaging modality (CT or MRI), acquisition 
protocol, facility, and scanner across all imaging timepoints per patient.
Clinical examination 
In this study, clinical examination will not be used for assessment of TL.  Clinically detected 
lesions can be selected as TLs if they are assessed by CT or MRI scans.  Clinical examination 
can be used to assess NTL and to identify the presence of new lesions.
Chest X-ray
In this study, chest X-ray assessment will not be used for assessment of TL as they will be 
assessed by CT or MRI examination.  Chest X-ray can, however, be used to assess NTL and 
to identify the presence of new lesions.
Plain X-ray 
In this study plain X-ray may be used as a method of assessment for bone NTLs and to 
identify the presence of new bone lesions. 
Ultrasound
In this study, ultrasound examination will not be used for assessment of TLs and NTLs as it is 
not a reproducible method, does not provide an accurate assessment of tumor size and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed, 
new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
In this study, endoscopy and laparoscopy will not be used for tumor assessments as they are 
not validated in the context of tumor assessment.

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Tumor markers
In this study, tumor markers will not be used for tumor response assessments as per 
RECIST 1.1.
Cytology and histology
In this study, histology on biopsy samples will not be used as part of the tumor response 
assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met criteria for response or stable 
disease.  In such circumstances, the cytology is necessary for the Investigator to differentiate 
between response/stable disease (an effusion may be a side effect of the treatment) and 
progressive disease (if the neoplastic origin of the fluid is confirmed).  Where cytology 
findings are not available, any effusion that significantly worsens (from trace to large) or gives 
the appearance of clinically significant effusion (requiring change in drug therapy) during the 
study treatment will be considered to be NTL progression or disease progression due to new 
lesions.
Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.
In this study, isotopic bone scans may be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits.  New lesions will be recorded where a 
positive hot-spot that was not present on the baseline bone scan assessment is identified on a 
bone scan performed at any time during the study.  The Investigator should consider the 
positive hot-spot to be a significant new site of malignant disease and represent true disease 
progression in order to record the new lesion.  Confirmation by CT, MRI and X-ray is 
recommended where bone scan findings are equivocal.
FDG-PET scan
In this study, 18F-Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans may 
be used as a method for identifying new lesions in accordance with the following algorithm: 
New lesions will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake3 not 
present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI 
at the same follow-up visit.  If there is no baseline FDG-PET scan available, and no evidence 
of new lesions on CT/MRI scans, then follow-up CT/MRI assessments should be continued as 
scheduled per protocol or clinically indicated in order to confirm new lesions.
                                               
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the 
surrounding tissue is observed.

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At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT are of 
limited use in anatomically based efficacy assessments, and it is therefore suggested that they 
should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed as part of a PET/CT examination is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 measurements. However, this is not recommended because the PET portion 
of the CT introduces additional (PET) data that may bias an Investigator if it is not routinely 
or serially performed.
Tumor response evaluation 
Schedule of evaluation
RECIST 1.1 assessments will be performed using contrast-enhanced CT/MRI assessments of 
chest, abdomen, and pelvis.  Additional anatomy should be imaged based on signs and 
symptoms of individual patients at baseline and follow-up.  Baseline assessments should be 
performed no more than 28 days before start of study treatment, and ideally should be 
performed as close as possible to the start of study treatment (see Schedules of Assessments 
tables in Section 4 of the Clinical Study Protocol).  Follow-up assessments will be performed 
every 8 weeks (relative to the date of randomization) until confirmed objective disease 
progression as defined by RECIST 1.1 (irrespective of the reason for stopping treatment or 
subsequent therapy).  
Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on assigned treatment, retreatment, or until subsequent cancer therapy 
according to the clinical study protocol.
Any other anatomical sites at which new disease is suspected should also be adequately 
imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at his or her scheduled visits.  This 
schedule is to be followed in order to minimize any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline.  Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis for nodal lesions), but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion, which can be measured reproducibly, should be 
selected.

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The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

If a TL splits into two or more parts, then record the sum of the diameters of those 
parts. 

If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion. 

When a TL has had any intervention eg, radiotherapy, embolization, surgery, during 
the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST 1.1 electronic case report form.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TLs (see Table E13).

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Table E13
Evaluation of target lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological 
lymph nodes selected as TLs must have a reduction in short axis 
to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not 
evaluable or had a lesion intervention at this visit.  Note: if the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response.
TL  Target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Table E14).

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Table E14
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases, the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
NTL  Non-target lesion; TL  Target lesion.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.

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Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo regularly 
scheduled tumor assessments where possible until objective disease progression is observed.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table E15.
Table E15
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, 
NA  Not applicable (only relevant if there were no non-target lesions at baseline).
Confirmation of progression
Confirmation of progression guidelines are set for the following reasons: 

For patient management and treatment decisions

In the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 
disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression (in MEDI4736 monotherapy and MEDI4736 + Tremelimumab 
immunotherapy treatment arms)

When scans are evaluated by Investigator and by BICR, to reduce informative 
censoring by Investigator assessments (when Investigator assesses PD and collects 
no additional scans, and BICR does not assess PD by RECIST 1.1).
Objective disease progression refers to one of the following scenarios: 

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
For All Treatment Arms: Clinical progression/deterioration followed by a 
radiologic scan, if clinically feasible.

For MEDI4736 monotherapy and MEDI4736 + Tremelimumab Treatment 
Arms (confirmed objective disease progression): In the absence of significant 
clinical deterioration, radiologic PD by RECIST 1.1 is considered confirmed if an 
immediate subsequent scan has PD assessed according to the specific confirmation 
of progression criteria listed below. The confirmatory scan should occur preferably 
at the next scheduled imaging visit and no earlier than 4 weeks following the date of 
the immediate prior assessment of RECIST 1.1 PD.  
Note: In the absence of clinical progression/deterioration, in order to have 
confirmed objective disease progression, there should be 2 consecutive radiologic 
PDs, the first radiologic PD by RECIST 1.1 and the second radiologic PD using the 
confirmation of progression criteria below. If the first radiologic PD by RECIST 1.1 
is not confirmed (unconfirmed), continue with assessments until the next radiologic 
PD by RECIST 1.1, which in turn will need its own immediate subsequent 
confirmation scan.

For Standard of Care Arm: In the absence of significant clinical deterioration, at 
least 1 scan documenting unequivocal radiographic progression.
Criteria for confirmation of progression:
Immediate prior radiologic progression would be considered confirmed if the following 
criteria are met:

≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir 
at 2 consecutive visits, with an absolute increase of at least 5 mm in the sum of 
diameters compared with nadir

and/or significant progression (worsening) of non-target lesions (NTLs) and/or of 
pre-existing new lesions at the confirmatory scan timepoint compared with the 
immediate prior timepoint (Note: Pre-existing new lesions are evaluated as NTLs at 
the confirmatory scan timepoint.)

and/or additional new unequivocal lesions at the confirmatory scan timepoint
For patients in the MEDI4736 monotherapy and MEDI4736 + Tremelimumab Treatment 
Arms: 

In the absence of significant clinical deterioration, treatment with study drug may 
continue between the initial assessment of progression and the scan to confirm 
progression.

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
If the confirmation scan confirms progression, then the date of the prior scan with 
PD should be declared as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan.  If the first PD is not confirmed by the 
immediate next scan, then the Investigator should not change the PD assessment of the 
first scan. If a patient discontinues treatment (and/or receives a subsequent cancer therapy) 
prior to progression, then the patient should still continue to be followed until confirmed 
objective disease progression.
Central review
The Contract Research Organization (CRO) appointed by AstraZeneca to perform the 
independent central review for this study will provide specification for radiological imaging 
protocols in standard acquisition guidelines documentation. 
All images will be collected, quality checked, and stored centrally by an Imaging CRO 
appointed by AstraZeneca.  Guidelines for image acquisition, anonymization, storage at the 
investigative site as source data, and transfer to the imaging CRO will be provided in a separate 
document.  The management of patients will be based solely on the local assessments conducted 
by the Investigator.
Further details of the Blinded Independent Central Review will be documented in the 
Independent Review Charter (also referred to as “Imaging Charter”).
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix F
Patient-reported Outcomes Questionnaires
FACT-Bl (Version 4)
NCI- PRO-CTCAE ITEMS
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)
EQ-5D-5L, Health Questionnaire, English version for the UK

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Appendix H
Amendment 1 Summary of Changes

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Clinical Study Protocol Amendment
Amendment Number 01
Drug Substance
MEDI4736 + Tremelimumab
Study Code
D419BC00001
Date
7 August 2015
Protocol Dated
9 June 2015
A Phase III, Randomized, Open-label, 
Controlled, Multi-Center, Global 
Study of First-Line MEDI4736 
Monotherapy and MEDI4736 in 
Combination with Tremelimumab 
Versus Standard of Care 
Chemotherapy in Patients with 
Unresectable Stage IV Urothelial 
Bladder Cancer
This submission /document contains trade secrets and 
confidential commercial information, disclosure of which 
is prohibited without providing advance notice to 
AstraZeneca and opportunity to object.
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Centers affected by the Amendment: All centers
The protocol for the study is to be amended as follows: 
Change 1
Deletion of the “peer review” text “This clinical study 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 

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published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.”
The following section of the protocol has been amended to reflect this change:
1.
The bottom of the cover page
Change 2
The deletion of “bone” to the list of example of visceral metastasis to read 
“(presence or absence, ie, lung or liver).”
The following sections of the protocol have been amended to reflect this change:
1.
PROTOCOL SYNOPSIS, Study design
2.
PROTOCOL SYNOPSIS, Statistical methods 
3.
PROTOCOL SYNOPSIS, MEDI4736 + tremelimumab combination therapy versus 
SoC (primary endpoint)
4.
INTRODUCTION, Section 1.4 Study design, Figure 1
5.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.3 
Patient enrollment and randomization
6.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.5 
Methods of assigning treatment groups
7.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.5 Methods for 
statistical analysis, Table 12
8.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.5.1 Analysis of the 
primary variable (2 occurrences)
Change 3
Addition of the statement “(patients enrolled in the platinum gemcitabine arm 
will discontinue study drug at the first assessment of disease progression)” or the 
statement “Patients randomized to treatment in the SoC arm will discontinue study 
drug at the first assessment of disease progression.” or similar
The following sections of the protocol have been amended to reflect this change:
1.
PROTOCOL SYNOPSIS, Study design
2.
PROTOCOL SYNOPSIS, Duration of treatment
3.
INTRODUCTION, Figure 2 footnotes

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4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.9 
Discontinuation of investigational product
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnotes 
6.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnotes 
7.
STUDY ASSESSMENTS, Section 5.1 Efficacy assessments
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS, Section 7.2.2 
Duration of treatment and criteria for retreatment
Change 4
Addition of the word “first” to define PFS as “...the time from the date of 
randomization until the first date of objective disease progression or death...”
The following sections of the protocol have been amended to reflect this change:
1.
PROTOCOL SYNOPSIS, Statistical methods
2.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.4.1.2 Primary 
endpoint
Change 5
Addition of the statement “Randomization of cisplatin-eligible patients will be
capped at a maximum of 85% of the planned total number of patients.”
The following sections of the protocol have been amended to reflect this change:
1.
PROTOCOL SYNOPSIS, Statistical methods
2.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.5 
Methods of assigning treatment groups
Change 6
Addition of the text “Among the overall fatal cases (67.7%) reported in the 
patients treated with tremelimumab monotherapy, the most frequent cause of death 
was ascribed to the patient’s underlying malignant disease (61.8%), whereas the 
remaining causes included other or unknown/missing (7.1%), and due to 
investigational product (IP; 0.5%).”
The following section of the protocol has been amended to reflect this change:
1.
INTRODUCTION, Section 1.3.2.2 Tremelimumab
Change 7
Deletion of the text “(newly acquired or archived sample <3 months old [if not 
available, a sample <6 months old may be provided with Sponsor approval])” or 
“When a tumor sample taken <3 months prior to screening is not available for any 

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reason, a sample <6 months old may be provided, only after Sponsor approval.” or 
similar (including change from “<3 years” to “<3 months”).  Note: Change 8 and 
Change 10 are related to this change.
The following sections of the protocol have been amended to reflect this change:
1.
INTRODUCTION, Section 1.4 Study design
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 2 footnotes 
3.
STUDY ASSESSMENTS, Section 5.5.1 Evaluation of candidate, predictive 
markers - tumor PD-L1
Change 8
Addition of Table 1, PD-L1 status defined by scoring of an IHC assay 
developed by Ventana for stratification in D419BC00001
The following section of the protocol has been amended to reflect this change:
1.
INTRODUCTION, Section 1.4 Study design
Change 9
Addition of the note “(Note: The Investigators will use their discretion to 
confirm the cause of N2 disease [reactive or inflammatory])”
The following section of the protocol has been amended to reflect this change:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.1 
Inclusion criteria
Change 10
Change from “As such, all patients must be able to undergo a fresh tumor 
biopsy during screening or to provide an available tumor sample taken <3 months 
prior to screening.  When a tumor sample taken <3 months prior to screening is not 
available for any reason, a sample <6 months old may be provided, only after 
Sponsor approval.”
to 
“As such, all patients must be able to provide a newly acquired biopsy during 
screening (preferred) or provide an available tumor sample taken <3 years prior to 
screening.”
The following sections of the protocol have been amended to reflect this change:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.1 
Inclusion criteria

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2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnote 
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnotes
4.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnote a
6.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 footnote a
Change 11
Addition of the text “(with exclusion of Bacillus Calmette Guerin, BCG)” from 
exclusion criterion 4; addition of the text “, or to other humanized mAbs” in 
exclusion criterion 22; change from “No” to “Any” to read “Any medical 
contraindication to platinum...” for exclusion criterion 23; and addition of “Patient 
<30 kg in weight” for exclusion criterion 24 
The following section of the protocol has been amended to reflect this change:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.2 
Exclusion criteria
Change 12
Deletion of the text “or without” to read “Male or female condom with 
spermicide” and addition of the text “Progesterone T”
The following section of the protocol has been amended to reflect this change:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.8 
Restrictions, Table 1
Change 13
Addition of “Women of childbearing potential are required to have a pregnancy 
test within 7 days prior to the first dose of study drug.  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.”
The following sections of the protocol have been amended to reflect this change:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnotes 
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnotes 
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 footnotes
4.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 footnotes
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 footnotes

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Change 14
Changes to cycle timing; changes to timing of vital signs assessment, thyroid 
function tests, QoL assessments, serum PD-L1 concentration, circulating soluble factors,
PBMCs, and miRNA/mRNA, and urine for exploratory biomarkers; correction from 
“<3 months” to “<3 years” for tumor biopsy; and correction from “Tumor biopsy (archival 
≥months old, if available)” to “Tumor biopsy (archival if available, for patients who submit a 
fresh biopsy at screening for PD-L1 status).”
The following section of the protocol has been amended to reflect this change: 
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 and Table 4 footnotes
Change 15
Clarification of “serum chemistry” to “chemistry” or addition of “or plasma”
The following sections of the protocol have been amended to reflect this change:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnote c
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 
4.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnote e
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 
6.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 footnote c
7.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 
8.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 
9.
STUDY ASSESSMENTS, Section 5.2 Safety assessments
Change 16
Replacement of “X” with “q8w up to Month 6 after disease progression” to 
EQ-5D-5L on Day 30 (±3)” and addition of the text “(±7 days)” to read “q8w 
(±7 days) relative to the date of randomization until confirmed progression”
The following sections of the protocol have been amended to reflect this change:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 
Change 17
Replacement of “IP” with “MEDI4736 monotherapy or 
MEDI4736 + tremelimumab combination arms” 
The following section of the protocol has been amended to reflect this change:

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1.
STUDY ASSESSMENTS, Section 5.1 Efficacy assessments
Change 18
Changes to provisions of tissue for PD-L1 IHC and clarifications to related text
The following section of the protocol has been amended to reflect this change:
1.
STUDY ASSESSMENTS, Section 5.5.1 Evaluation of candidate, predictive 
markers - tumor PD-L1
Change 19
Addition of the text “after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 monotherapy.  For 
patients receiving standard of care agents for chemotherapy, please follow the local 
prescribing information relating to contraception and the time limit for such 
precautions.”
to read 
“Male patients must refrain from fathering a child or donating sperm during the 
study and for 180 days after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 monotherapy.  For 
patients receiving standard of care agents for chemotherapy, please follow the local 
prescribing information relating to contraception and the time limit for such 
precautions.”
The following section of the protocol has been amended to reflect this change:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.6.Paternal 
exposure
Change 20
Addition of “[MEDI4736 and MEDI4736 + tremelimumab, only; for SOC refer 
to Section 6.7.2]).”
The following section of the protocol has been amended to reflect this change:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, 
Section 6.7.Management of IP-related toxicities
Change 21
Addition of “Adverse events of special interest (AESIs) are events of scientific 
and medical interest specific to the further understanding of the MEDI4736 and 
tremelimumab safety profile and require close monitoring and rapid communication 
by the Investigator to AstraZeneca.  MEDI4736 and tremelimumab AESIs may be 
serious or non-serious.  The rapid reporting of these AESIs allows ongoing analysis 
of these events in order to characterize and understand them in association with the 
use of these IPs.” and deletion of “adverse events of special interest and deletion of 
“adverse events of special interest” in the following paragraph to read as 
“Information on MEDI4736 and MEDI4736 + tremelimumab AESIs and 
guidelines...””

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The following section of the protocol has been amended to reflect this change:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.7.1 
MEDI4736 and MEDI4736 + tremelimumab
Change 22
Clarifications in the text regarding the IDMC
The following section of the protocol has been amended to reflect this change:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.8 Study 
governance and oversight
Change 23
Addition of the following prohibited medications/classes of drugs: Sunitinib, 
usage - Should not be given to patients within 3 months of a dose of tremelimumab, 
as acute renal failure has been reported with combination therapy of tremelimumab 
and sunitinib; Drugs with laxative properties and herbal or natural remedies for 
constipation, usage - Should be avoided through 90 days after the last dose of 
tremelimumab during the study, if possible.  In case of strong medical need, should 
be used with caution.
The following section of the protocol has been amended to reflect this change:
1.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS, Section 7.7 
Concomitant and other treatments
Change 24
Deletion of “Treatment through PD in the SoC group is at the Investigator’s 
discretion; however, a” to read “A confirmatory scan is required for all patients in 
the SoC group, even if a subsequent treatment is started.”
The following section of the protocol has been amended to reflect this change:
1.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.4.1.2 Primary 
endpoint
Change 25
Typographical errors have been corrected, and minor text clarifications have 
been made throughout the document.  These minor changes do not affect patient 
safety or study assessments and, therefore, are not further described in this 
Amendment.
The specific modifications to the protocol implemented by Changes 1 through 24 are 
presented on the following pages.

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Change 1
Section of protocol affected:
1.
The bottom of the cover page
Deleted text:
This clinical study 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.
[...]
Reason for Amendment: 
This edit was made due to template language modifications.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 2
Sections of protocol affected:
1.
PROTOCOL SYNOPSIS, Study design
2.
PROTOCOL SYNOPSIS, Statistical methods 
3.
PROTOCOL SYNOPSIS, MEDI4736 + tremelimumab combination therapy versus 
SoC (primary endpoint)
4.
INTRODUCTION, Section 1.4 Study design, Figure 1
5.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.3 
Patient enrollment and randomization
6.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.5 
Methods of assigning treatment groups
7.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.5 Methods for 
statistical analysis, Table 12

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8.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.5.1 Analysis of the 
primary variable (2 occurrences)
Previous text:
ie, bone, lung, or liver
[...]
Revised text:
ie, lung or liver
[...]
Reason for Amendment: 
This correction was made based on comments from the Food and Drug Administration (FDA) 
in its review of the protocol.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 3
Sections of protocol affected:
1.
PROTOCOL SYNOPSIS, Study design
2.
PROTOCOL SYNOPSIS, Duration of treatment
3.
INTRODUCTION, Figure 2 footnotes
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.9 
Discontinuation of investigational product
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnotes 
6.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnotes 
7.
STUDY ASSESSMENTS, Section 5.1 Efficacy assessments
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS, Section 7.2.2 
Duration of treatment and criteria for retreatment

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Previous text:
Not applicable
[...]
Revised text:
Tumor assessments will be performed every 8 weeks until confirmed progression (patients 
enrolled in the platinum gemcitabine arm will discontinue study drug at the first 
assessment of disease progression) according to objective tumor response by Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).  
or
Unless specific treatment discontinuation criteria are met, treatment will continue for a 
12-month period for the MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy groups and for up to 6 cycles for the SoC (cisplatin + gemcitabine or carboplatin 
+ gemcitabine) group.  
Patients randomized to treatment in the SoC arm will discontinue study drug at the first 
assessment of disease progression.
Patients randomized to treatment with MEDI4736 monotherapy may undergo retreatment if 
they
or similar
[...]
Reason for Amendment: 
Text was amended for clarification.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 4
Sections of protocol affected:
1.
PROTOCOL SYNOPSIS, Statistical methods
2.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.4.1.2 Primary 
endpoint

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Previous text:
Statistical methods
PFS (per RECIST 1.1, using site Investigator tumor assessments) will be defined as the time 
from the date of randomization until the date of objective disease progression or death (by any 
cause in the absence of progression) regardless of whether the patient withdraws from 
randomized therapy or receives another anticancer therapy prior to progression.
[...]
Revised text:
Statistical methods
PFS (per RECIST 1.1, using site Investigator tumor assessments) will be defined as the time 
from the date of randomization until the date of first objective disease progression or death 
(by any cause in the absence of progression) regardless of whether the patient withdraws from 
randomized therapy or receives another anticancer therapy prior to progression.  
[...]
Reason for Amendment: 
This text was revised to clarify a definition.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 5
Sections of protocol affected:
1.
PROTOCOL SYNOPSIS, Statistical methods
2.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.5 
Methods of assigning treatment groups
Previous text:
Approximately 525 patients will be randomized 1:1:1 to MEDI4736 + tremelimumab, 
MEDI4736 monotherapy, or SoC.  The randomization will be stratified according to cisplatin 

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eligibility (eligible or ineligible), PD-L1 status (positive and negative), and visceral metastases 
(presence or absence, ie, bone, lung, or liver).
[...]
Revised text:
Approximately 525 patients will be randomized 1:1:1 to MEDI4736 + tremelimumab, 
MEDI4736 monotherapy, or SoC.  The randomization will be stratified according to cisplatin 
eligibility (eligible or ineligible), PD-L1 status (positive and negative), and visceral metastases 
(presence or absence, ie, lung or liver).  Randomization of cisplatin-eligible patients will be 
capped at a maximum 85% of the planned total number of patients..
[...]
Reason for Amendment: 
This correction was made based on comments from the FDA in its review of the protocol.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 6
Section of protocol affected:
1.
INTRODUCTION, Section 1.3.2.2 Tremelimumab
Previous text: 
Tremelimumab
The profile of AEs and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target.  To 
date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to patients with melanoma).  Overall, 944 of the 973 patients (97.0%) 
treated with tremelimumab monotherapy as of the IB data cutoff date of 12 November 2014 
(for all studies except D4190C00006 that has a cutoff date of 04 December 2014, and not 
including 497 patients who have been treated in the ongoing blinded Phase IIb 
Study D4880C00003) experienced at least 1 AE.  The events resulted in discontinuation of 
tremelimumab in 10.0% of patients, were serious in 36.5%, were Grade ≥3 in severity in 
49.8%, were fatal in 67.7%, and were considered to be treatment related in 79.1% of patients.  
The frequency of any AEs and Grade ≥3 AEs was generally similar across the tremelimumab 
dose groups.  However, a higher percentage of patients in the 10 mg/kg every 28 days and 

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15 mg/kg every 90 days groups compared with the All Doses <10 mg/kg group experienced 
treatment-related AEs, SAEs, AEs resulting in discontinuation of investigational product (IP), 
and deaths.
[...]
Revised text:
Tremelimumab
The profile of AEs and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target.  To 
date, no tumor type or stage appears to be associated with unique AEs (except for vitiligo that 
appears to be confined to patients with melanoma).  Overall, 944 of the 973 patients (97.0%) 
treated with tremelimumab monotherapy as of the IB data cutoff date of 12 November 2014 
(for all studies except D4190C00006 that has a cutoff date of 04 December 2014, and not 
including 497 patients who have been treated in the ongoing blinded Phase IIb 
Study D4880C00003) experienced at least 1 AE.  The events resulted in discontinuation of 
tremelimumab in 10.0% of patients, were serious in 36.5%, were Grade ≥3 in severity in 
49.8%, were fatal in 67.7%, and were considered to be treatment related in 79.1% of patients.  
Among the overall fatal cases (67.7%) reported in the patients treated with 
tremelimumab monotherapy, the most frequent cause of death was ascribed to the 
patient’s underlying malignant disease (61.8%), whereas the remaining causes included 
other or unknown/missing (7.1%), and due to investigational product (IP; 0.5%).  The 
frequency of any AEs and Grade ≥3 AEs was generally similar across the tremelimumab dose 
groups.  However, a higher percentage of patients in the 10 mg/kg every 28 days and 
15 mg/kg every 90 days groups compared with the All Doses <10 mg/kg group experienced 
treatment-related AEs, SAEs, AEs resulting in discontinuation of IP, and deaths.
[...]
Reason for Amendment: 
Text was added to clarify the most frequent cause of death in this population.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 7
Sections of protocol affected:
1.
INTRODUCTION, Section 1.4 Study design

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2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 2 footnotes 
3.
STUDY ASSESSMENTS, Section 5.5.1 Evaluation of candidate, predictive 
markers - tumor PD-L1
Previous text:
Study design
Patients will provide a tumor tissue sample at screening (newly acquired or archived sample 
<3 months old [if not available, a sample <6 months old may be provided with Sponsor 
approval]) to determine PD-L1 status (defined by an immunohistochemistry [IHC] assay 
developed by Ventana) for stratification.
[...]
Revised text:
Study design
Patients will provide a tumor tissue sample at screening to determine PD-L1 status (defined by 
an immunohistochemistry [IHC] assay developed by Ventana, see Table 1) for stratification.
[...]
Reason for Amendment: 
The text was amended to clarify tumor biopsy sampling.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 8
Section of protocol affected:
1.
INTRODUCTION, Section 1.4 Study design
Previous text:
Table not present
[...]

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Revised text:
Table 1
PD-L1 status defined by scoring of an IHC assay developed by Ventana 
for stratification in D419BC00001
Interpretation
Staining description
Positive for PD-L1
≥25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control
OR
≥25% tumor associated immune cell positivity for PD-L1 at any intensity 
above background staining as noted on the corresponding negative control
Negative for PD-L1
<25% tumor cell membrane positivity for PD-L1 at any intensity above 
background staining as noted on the corresponding negative control
AND
<25% tumor associated immune cell positivity for PD-L1 at any intensity 
above background staining as noted on the corresponding negative control
IHC Immunohistochemistry; PD-L1 Programmed cell death ligand 1.
[...]
Reason for Amendment: 
The table was included to increase the visibility of the cutoff utilized for PDL1.
Persons who initiated the Amendment:
AstraZeneca, Sponsor
Change 9
Section of protocol affected:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.1 
Inclusion criteria
Previous text:
Section 3.1 Inclusion criteria
3.
Patients with histologically or cytologically documented, unresectable, Stage IV 
(ie, T4b, any N; or any T, N2-N3; or M1) transitional cell carcinoma (transitional 
cell and mixed transitional/non-transitional cell histologies) of the urothelium 
(including renal pelvis, ureters, urinary bladder, and urethra), who have not been 

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previously treated with first-line chemotherapy.  (Patients who have received prior 
definitive chemoradiation for locally advanced disease, adjuvant treatment, or 
neoadjuvant treatment are eligible, provided that progression has occurred 
>6 months from last therapy [for chemoradiation and adjuvant treatment] or 
>6 months from last surgery [for neoadjuvant treatment].)
[...]
Revised text:
Section 3.1 Inclusion criteria
3.
Patients with histologically or cytologically documented, unresectable, Stage IV 
(ie, T4b, any N; or any T, N2-N3 (Note: The Investigators will use their 
discretion to confirm the cause of N2 disease [reactive or inflammatory]); or 
M1) transitional cell carcinoma (transitional cell and mixed 
transitional/non-transitional cell histologies) of the urothelium (including renal 
pelvis, ureters, urinary bladder, and urethra), who have not been previously treated 
with first-line chemotherapy.  (Patients who have received prior definitive 
chemoradiation for locally advanced disease, adjuvant treatment, or neoadjuvant 
treatment are eligible, provided that progression has occurred >6 months from last 
therapy [for chemoradiation and adjuvant treatment] or >6 months from last surgery 
[for neoadjuvant treatment].)
[...]
Reason for Amendment: 
This correction was made based on comments from the FDA in its review of the protocol.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 10
Sections of protocol affected:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.1 
Inclusion criteria
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 procedures
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 procedures

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Previous text:
Section 3.1 Inclusion criteria
8.
Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be 
known prior to randomization.  As such, all patients must be able to undergo a fresh 
tumor biopsy during screening or to provide an available tumor sample taken 
<3 months prior to screening.  When a tumor sample taken <3 months prior to 
screening is not available for any reason, a sample <6 months old may be 
provided, only after Sponsor approval.  Tumor lesions used for fresh biopsies 
should not be target lesions, unless there are no other lesions suitable for biopsy.  
Fine needle aspirate specimens are not acceptable.  Specimens from metastatic bone 
lesions are typically unacceptable unless there is a significant soft tissue component.  
The tumor specimen submitted to establish eligibility should be of sufficient 
quantity to allow for PD-L1 IHC and other exploratory biomarker analyses and is 
preferred in formalin-fixed paraffin embedded blocks.
[...]
Revised text:
Section 3.1 Inclusion criteria
8.
Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be 
known prior to randomization.  As such, all patients must be able provide a newly 
acquired tumor biopsy during screening (preferred) or provide an available 
tumor sample taken <3 years prior to screening.  Tumor lesions used for newly 
acquired biopsies should not be target lesions, unless there are no other lesions 
suitable for biopsy.  Samples with limited tumor content and fine needle aspirate 
specimens are not acceptable. Specimens from metastatic bone lesions are typically 
unacceptable unless there is a significant soft tissue component.  The tumor 
specimen submitted to establish PD-L1 status  should be of sufficient quantity to 
allow for PD-L1 IHC and other exploratory biomarker analyses and is preferred in 
formalin-fixed paraffin embedded blocks.
[...]
Reason for Amendment: 
The text was amended to provide clarification of tumor biopsy sampling.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor

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Study Code D419BC00001
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Change 11
Section of protocol affected:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.2 
Exclusion criteria
Previous text:
Section 3.2 Exclusion criteria
4.
Prior exposure to immune-mediated therapy, including but not limited to, other 
anti-CTLA 4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including 
therapeutic anticancer vaccines
12
Other malignancy within 5 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal 
carcinoma in situ of the breast that has been surgically cured.  Cancer patients with 
incidental histologic findings of prostate cancer (tumor/node/metastasis stage of T1a 
or T1b or prostate specific antigen <10) who have not received hormonal treatment 
may be included, pending a discussion with the Study Physician
17
Known history of clinical diagnosis of tuberculosis
22.
Known allergy or hypersensitivity to IP or any IP excipient
23.
No medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy
[...]
Revised text:
Section 3.2 Exclusion criteria
4.
Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette 
Guerin, BCG), including but not limited to, other anti-CTLA-4, anti-PD-1, 
anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines
12
Other malignancy within 5 years except for noninvasive malignancies such as 
cervical carcinoma in situ, non-melanomatous carcinoma of the skin, localized 
prostate cancer treated with curative intent  and absence of PSA relapse or 
ductal carcinoma in situ of the breast that has been surgically cured.  Cancer 
patients with incidental histologic findings of prostate cancer 
(tumor/node/metastasis stage of T1a or T1b or prostate specific antigen <10) who 

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have not received hormonal treatment may be included, pending a discussion with 
the Study Physician
17
Active tuberculosis
22.
Known allergy or hypersensitivity to IP or any IP excipient, or to other humanized 
mAbs
23.
Any medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy
24.
Patient <30 kg in weight
[...]
Reason for Amendment: 
The criteria were amended for clarity and completeness.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 12
Section of protocol affected:
1.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL, Section 3.8 
Restrictions, Table 1
Previous text:
Table 1
Effective methods of contraception
Barrier/Intrauterine methods
Hormonal methods

Male or female condom with or without
spermicidea,b,c 

Cap, diaphragm, or sponge with spermicidea,b,c

Copper T intrauterine device

Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)d

Implants

Hormone shot or injection

Combined pill

Minipillb

Patch
[...]

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Revised text:
Table 2
Effective methods of contraception
Barrier/Intrauterine methods
Hormonal methods

Male or female condom with spermicidea,b,c 

Cap, diaphragm, or sponge with spermicidea,b,c

Copper T intrauterine device

Levonorgesterel-releasing intrauterine system 
(eg, Mirena®)d

Progesterone Td

Implants

Hormone shot or injection

Combined pill

Minipillb

Patch
[...]
Reason for Amendment:
The protocol contraceptive language was reviewed and updated to be consistent with similar 
AstraZeneca clinical trials.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 13
Sections of protocol affected:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnote d
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnotes 
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 footnotes
4.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 footnotes
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 footnotes
Previous text:
Table 2, footnote d
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
[...]

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Revised text:
Table 3, footnote d
For women of childbearing potential are required to have a pregnancy test within 7 days 
prior to the first dose of study drug.  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.
[...]
Reason for Amendment: 
The pregnancy language was modified to provide clarity.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 14
Section of protocol affected:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 and Table 4 footnotes

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Previous Text: Table 3
Schedule of assessments for cisplatin + gemcitabine 28-day cycle treatment period
Screening
C1
C2
C3, C4, C5, and C6
For details 
see CSP 
Section
(±3 days, tumor assessment ±7 days)
Week
-4 to -1
0
0
1
2
4
4
5
6
8
8
9
10
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Informed consent
Written informed consent
Xa
3.3
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical exam (based on symptoms)
X
X
X
5.2.2
ECGb
X
As clinically indicated
5.2.3
Vital signs
X
X
Xc,d
5.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including medical and surgical history and 
history of tobacco use
X
4.1
Laboratory assessments
Serum chemistry (complete clinical chemistry panel) and 
hematologye
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Liver enzyme panele
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and fT4)f
X
Xc
5.2.1
Urinalysisc, hepatitis B and C, and HIV
X
5.2.1
Urine hCG or serum β-hCGg and coagulation parameterse
X
As clinically indicated
5.3.3
Monitoring 
ECOG PS
X
X
X
X
5.3.3
AE/SAE assessment
Xh
All visits
6.3
IP administration

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Screening
C1
C2
C3, C4, C5, and C6
For details 
see CSP 
Section
(±3 days, tumor assessment ±7 days)
Week
-4 to -1
0
0
1
2
4
4
5
6
8
8
9
10
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Cisplatin
X
X
X
7.2.1
Gemcitabine
X
X
X
X
X
X
X
X
X
7.2.1
Quality of life assessments
FACT-BLi
X
q8w
5.3.1
PRO-CTCAEi
X
X
X
X
X
q4w from Week 
8
5.3.1
PGICi
Weeks 8, 16, 32, and 48
5.3.1
EQ-5D-5Li
X
q8w
5.3.1
Other laboratory assessments and assays
Serum PD-L1 concentration
X
Xc
5.5
Circulating soluble factors, PBMCs, and miRNA/mRNA
X
X
Xc,j
5.5
Urine for exploratory biomarkersk
X
X
Xc
5.5
SNP genotyping
X
5.5
MDSCs
X
5.5
Tumor biopsy (recently acquired (within 3 months) or 
archival <3 years old)
Xa
5.5
Tumor biopsy (archival if available, for patients who 
submit a (recently acquired (within 3 months) biopsy at 
screening for PD-L1 status)
X
5.5
Tumor assessment (CT or MRI)l
X
q8w relative to the date of randomization until confirmed progression
5.1
PGx sample (optional [DNA element])
X
5.6
Health economics assessments
Health resource use (HOSPAD module)m
X
To be completed at each hospitalization
8.5.10

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
257 (275)
a
Informed consent includes consent for study procedures, biopsy for PD-L1 status, and optional genetic sampling and analysis.  Informed consent may be obtained prior to 
the 28-day screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization.  When a tumor sample taken 
<3 months prior to screening is not available for any reason, a sample <6 months old may be provided, only after Sponsor approval.   
b
Any clinically significant abnormalities detected require triplicate ECG results.
c
Day 1 of Cycle 4 only.
d
Day 1 of Cycle 6 only.
e
If screening laboratory assessments are performed within 3 days prior to Day 1, then tests do not need to be repeated at Day 1, if applicable as per local routine practice.  
Hematology and serum chemistry results should be available and reviewed prior to chemotherapy administration on each dosing day and as per local routine practice.  
LFT results should be available and reviewed by the treating physician or Investigator prior to the start of each chemotherapy cycle and as per local routine practice.  
Serum chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.  Coagulation tests include activated partial 
thromboplastin time and international normalized ratio.
f
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
h
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
i
PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the 
PGIC, the EQ-5D-5L, and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides 
with a scheduled site visit; otherwise, patients will complete PROs at home.  
j
Circulating soluble factors only.
k
Urine for exploratory biomarkers will be obtained only in patients who have not undergone a full cystectomy and who have tumor lesion(s) present in the urothelium.
l
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  Baseline assessments, ideally, should be performed as close as possible prior to the start of study treatment.  The confirmatory 
scans should preferably be performed at the next scheduled visit (relative to the date of randomization) and no less than 4 weeks after the initial assessment of PD (in the 
absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform 
the subsequent assessments at his or her scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the database.   
m
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit.
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments on treatment days are to be performed pre-infusion unless otherwise indicated.
β-hCG Beta-human chorionic gonadotropin; C Cycle; CSP Clinical study protocol; EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional 
Assessment of Cancer Therapy-Bladder Cancer; fT3 Free triiodothyronine; fT4 Free thyroxine; hCG Human chorionic gonadotropin; LFT Liver function test; MDSC Myeloid-
derived suppressor cells; miRNA Micro-ribonucleic acid; mRNA Messenger ribonucleic acid; PBMC Peripheral blood mononuclear cells; PGIC Patient Global Impression of 
Change; PGx Pharmacogenetic; PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; q8w Every 8 weeks; SNP Single 
nucleotide polymorphism; TSH Thyroid-stimulating hormone.
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
258 (275)
Revised text:
Table 4
Schedule of assessments for cisplatin + gemcitabine 28-day cycle treatment period
Screening
C1
C2, C3, C4, and C5
C6
For 
details see 
CSP 
Section
(±3 days, tumor assessment ±7 days)
Week
-4 to -1
0
0
1
2
4
4
5
6
20
20
21
22
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Informed consent
Written informed consent
Xa
3.3
Study procedures
Physical examination (full)
X
5.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
5.2.2
ECGb
X
As clinically indicated
5.2.3
Vital signs
X
X
Xc
Xd
5.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography, including medical and 
surgical history and history of tobacco 
use
X
4.1
Laboratory assessments
Serum or plasma chemistry (complete 
clinical chemistry panel) and 
hematologye
X
X
X
X
X
X
X
X
X
X
X
X
X
5.2.1
Liver enzyme panele
X
X
X
X
5.2.1
Thyroid function tests (TSH, fT3, and 
fT4)f
X
Xc
5.2.1
Urinalysisc, hepatitis B and C, and HIV
X
5.2.1

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
259 (275)
Screening
C1
C2, C3, C4, and C5
C6
For 
details see 
CSP 
Section
(±3 days, tumor assessment ±7 days)
Week
-4 to -1
0
0
1
2
4
4
5
6
20
20
21
22
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Urine hCG or serum β-hCGg and 
coagulation parameterse
X
As clinically indicated
5.2.1
Monitoring 
ECOG PS
X
X
X
X
5.3.3
AE/SAE assessment
Xh
All visits
6.3
IP administration
Cisplatin
X
X
X
7.2.1
Gemcitabine
X
X
X
X
X
X
X
X
X
7.2.1
Quality of life assessments
FACT-BLi
X
q8w
5.3.1
PRO-CTCAEi
X
X
X
Xr
X
5.3.1
PGICi
Weeks 8 and 16 
5.3.1
EQ-5D-5Li
X
q8w
5.3.1
Other laboratory assessments and assays
Serum PD-L1 concentration
X
Xc
5.5
Circulating soluble factors, PBMCs, 
and miRNA/mRNA
X
Xl,
m
5.5
Urine for exploratory biomarkersn
X
Xl
5.5
SNP genotyping
X
5.5
MDSCs
X
5.5
Tumor biopsy (newly acquired or 
archival <3 years old)
Xa
5.5

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
260 (275)
Screening
C1
C2, C3, C4, and C5
C6
For 
details see 
CSP 
Section
(±3 days, tumor assessment ±7 days)
Week
-4 to -1
0
0
1
2
4
4
5
6
20
20
21
22
Day
-28 to -1
1
2
8
15
1
2
8
15
1
2
8
15
Tumor biopsy (archival, if available, for 
patients who submit a  newly acquired
biopsy at screening for PD-L1 status
X
5.5
Tumor assessment (CT or MRI)o
X
q8w relative to the date of randomization until progressionp
5.1
PGx sample (optional [DNA element])
X
5.6
Health economics assessments
Health resource use (HOSPAD 
module)q
To be completed at each hospitalization
8.5.10
a
Informed consent includes consent for study procedures, biopsy for PD-L1 status, and optional genetic sampling and analysis.  Informed consent may be obtained prior to 
the 28-day screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to randomization. 
b
Any clinically significant abnormalities detected require triplicate ECG results.
c
Day 1 of Cycle 4 only.
d
Day 1 of Cycle 6 only.
e
If screening laboratory assessments are performed within 3 days prior to Day 1, then tests do not need to be repeated at Day 1, if applicable as per local routine practice.  
Hematology and chemistry results should be available and reviewed prior to chemotherapy administration on each dosing day and as per local routine practice.  LFT 
results should be available and reviewed by the treating physician or Investigator prior to the start of each chemotherapy cycle and as per local routine practice.  
Chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.  Coagulation tests include activated partial thromboplastin time 
and international normalized ratio.
f
fT3 and fT4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  Pregnancy test may occur on the day of dosing, but results must be 
available and reviewed by the physician prior to the first dose of study drug.
h
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed.
i
PRO-CTCAE will only be administered in those countries where a linguistically validated version exists.  The FACT-BL will be administered first, followed by the 
PGIC, the EQ-5D-5L, and then the PRO-CTCAE.  Patients will complete PROs using handheld electronic devices at study sites if the assessment timepoint coincides 
with a scheduled site visit; otherwise, patients will complete PROs at home.  
j
Starting at Cycle 3; every 4 weeks
k
For Cycle 3 and 4 only
l
Day 1 of Cycle 2 and 4 only; 
m
Circulating soluble factors only for Cycle 4
n
Urine for exploratory biomarkers will be obtained only in patients who have not undergone a full cystectomy and who have tumor lesion(s) present in the urothelium.
o
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of the chest, abdomen, and pelvis.  Additional anatomy may be imaged based on 
signs and symptoms of individual patients.  Baseline assessments, ideally, should be performed as close as possible prior to the start of study treatment.  The confirmatory 

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
261 (275)
scans should preferably be performed at the next scheduled visit (relative to the date of randomization) and no less than 4 weeks after the initial assessment of PD (in the 
absence of clinically significant deterioration).  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform 
the subsequent assessments at his or her scheduled visits (relative to the date of randomization).  All confirmatory scans should be recorded on the database.   
p         Patients enrolled in the SOC arm will discontinue study drug at the first assessment of disease progression.
q
HOSPAD module should be completed by site staff whenever the patient has attended or been admitted in to the hospital.  A reminder will be provided at each clinic 
visit.
r     Week 2 only
Note: Assessments to be performed at the times stipulated in the table and as clinically required in the management of the patient.
Note: All assessments on treatment days are to be performed pre-infusion unless otherwise indicated.
β-hCG Beta-human chorionic gonadotropin; C Cycle; CSP Clinical study protocol; EQ-5D-5L EuroQol five-dimensional descriptive system; FACT-BL Functional 
Assessment of Cancer Therapy-Bladder Cancer; fT3 Free triiodothyronine; fT4 Free thyroxine; hCG Human chorionic gonadotropin; LFT Liver function test; MDSC Myeloid-
derived suppressor cells; miRNA Micro-ribonucleic acid; mRNA Messenger ribonucleic acid; PBMC Peripheral blood mononuclear cells; PGIC Patient Global Impression of 
Change; PGx Pharmacogenetic; PRO-CTCAE Patient-reported outcomes version of the Common Terminology Criteria for Adverse Events; q8w Every 8 weeks; SNP Single 
nucleotide polymorphism; TSH Thyroid-stimulating hormone.
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
262 (275)
Reason for Amendment: 
Table header was reorganized for clarity, as a result, C3, C4, and C5 that had been previously 
grouped with C6 were regrouped with C2. As a result some of the operations at various 
timepoints shifted, resulting in updates to superscript lettering and footnotes. In addition, 
language regarding tissue biopsies was clarified and updated in the table.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 15
Sections of protocol affected:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 3 footnote c
3.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 
4.
STUDY PLAN AND TIMING OF PROCEDURES, Table 4 footnote e
5.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 
6.
STUDY PLAN AND TIMING OF PROCEDURES, Table 5 footnote c
7.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 
8.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 
9.
STUDY ASSESSMENTS, Section 5.2 Safety assessments
Previous text:
Serum chemistry (complete clinical chemistry panel) and hematology
[...]
Revised text:
Serum or plasma chemistry (complete clinical chemistry panel) and hematology
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
263 (275)
Reason for Amendment: 
Text was revised to indicate that serum or plasma could be used for chemistry analyses.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 16
Sections of protocol affected:
1.
STUDY PLAN AND TIMING OF PROCEDURES, Table 6 
2.
STUDY PLAN AND TIMING OF PROCEDURES, Table 7 
Previous text:
X
and 
q8w relative to the date of randomization until confirmed progression
Revised text:
q8w up to Month 6 after disease progression
and
q8w (±7 days) relative to the date of randomization until confirmed progression
Reason for Amendment: 
Text was revised and updated to clarify timepoints for post-disease progression assessments.
Persons who initiated the Amendment:
AstraZeneca, Sponsor

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
264 (275)
Change 17
Section of protocol affected:
1.
STUDY ASSESSMENTS, Section 5.1 Efficacy assessments
Previous text:
Section 5.1 Efficacy assessments
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months (8 weeks) as outlined in the study plan (Table 5 and Table 6).  An exception is 
patients with PD who continue to receive IP at the discretion of the Investigator (after 
consultation with AstraZeneca); these patients will have scans for RECIST 1.1 assessments 
q8w (per Table 2, Table 3, and Table 4) until confirmed progression.  In addition, all patients 
will be contacted in the week following data cutoff to confirm survival status.
[...]
Revised text:
Section 5.1 Efficacy assessments 
Following confirmed progression, patients should continue to be followed up for survival 
every 2 months (8 weeks) as outlined in the study plan (Table 6 and Table 7).  Patients 
enrolled in the SOC arm will discontinue study drug at the first assessment of disease 
progression).  An exception is patients with PD who continue to receive MEDI4736 
monotherapy or MEDI4736 + tremelimumab combination arms at the discretion of the 
Investigator (after consultation with AstraZeneca); these patients will have scans for RECIST 
1.1 assessments q8w (per Table 3, Table 4, and Table 5) until confirmed progression.  In 
addition, all patients will be contacted in the week following data cutoff to confirm survival 
status.
[...]
Reason for Amendment: 
Text was updated to provide clarity with regards to medication referred to as IP in paragraph.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
265 (275)
Change 18
Section of protocol affected:
1.
STUDY ASSESSMENTS, Section 5.5.1 Evaluation of candidate, predictive 
markers - tumor PD-L1
Previous text:
Provision of tissue for PD-L1 IHC is as follows: 

MANDATORY – Provision of a recent tumor biopsy formalin fixed and embedded 
in paraffin.  A freshly collected tumor biopsy is strongly preferred; however, if not 
clinically feasible, an archival muscle invasive tumor biopsy sample taken 
<3 months prior to screening may be submitted.  When a tumor sample taken 
<3 months prior to screening is not available for any reason, a sample 
<6 months old may be provided, only after Sponsor approval. 
Samples should be collected via an image-guided core needle (18 gauge or larger) 
or be collected as an excisional or incisional tumor biopsy sample.
When tissue is newly obtained for the purpose of entry into the study, 2 cores 
should be placed in formalin and processed to a single paraffin embedded block, as 
described in the Laboratory Manual.
The tumor specimen submitted to establish eligibility should be of sufficient 
quantity to allow for PD-L1 IHC analyses (see the Laboratory Manual).  Newly 
acquired or archival specimens with limited tumor content and fine needle aspirates 
are inadequate for defining tumor PD-L1 status.
Tumor lesions used for fresh biopsies should not be the same lesions used as 
RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.  If a 
RECIST 1.1 target lesion is used for biopsy, the lesion must be ≥2 cm in the longest 
diameter and must be biopsied outside of the screening period.  

If available and accessible, archived tumor tissue block greater than 6 months old 
(formalin-fixed paraffin-embedded) is requested, where such samples exist in a 
quantity sufficient to allow for analysis.  Tumor tissue block is preferred.  If a tissue 
block is unavailable, unstained sections from the tissue block may be submitted.  
An archived tumor tissue block or sections may be delivered at any time during the 
study.  Please consult the Laboratory Manual for specific instructions and 
guidelines regarding sections.

The collection of tumor biopsies at the time of progression and prior to retreatment 
is strongly encouraged.  The biopsy procedure at retreatment should be omitted only 
if there is unacceptable clinical risk or the procedure is otherwise considered not 

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
266 (275)
feasible.  The Investigator must consult with the Study Physician prior to making 
the decision not to biopsy at retreatment.

The collection of additional biopsies upon progression of patients in the MEDI4736 
+ tremelimumab combination therapy and MEDI4736 monotherapy arms is 
strongly encouraged.  
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses or 
upon PD) may be submitted for exploratory analyses.
Please review the Laboratory Manual for further details of requirements including sample QC 
and shipping.
A brief description of exploratory tumor markers likely to be explored by IHC or RNA 
analysis is provided in Section 5.5.1.1.
The Ventana PD-L1 IHC assay will be used to determine PD-L1 IHC status in this study for 
stratification.  The Ventana PD-L1 IHC analysis will be performed at a Ventana approved 
College of American Pathologists/Clinical Laboratory Improvement Act laboratory using the 
Ventana assay.  No other assays will be accepted in lieu of results obtained from the Ventana 
test using specimen submitted at screening.  Details regarding the assay and algorithm to 
be used for determination of the PD-L1 IHC status (positive or negative) in this study 
will be finalized and fully documented prior to enrollment of any patients in this study.
To meet the requirement of Food and Drug Administration (FDA) approval of a companion 
diagnostic, sections of the tumor will be retained at Ventana for potential additional studies, as 
requested by the FDA, to support potential test approval.
[...]
Revised text:
Provision of tissue for PD-L1 IHC is as follows: 

MANDATORY – Provision of a newly acquired tumor sample (preferred) OR 
formalin fixed and paraffin embedded archival tissue obtained within 3 years 
prior to screening.  ONLY 1 sample (either newly acquired or archival tissue) 
will be used to determine PD-L1 status.  Where multiple samples have been 
submitted for the same patient, the initial result will determine a patient’s 
PD-L1 status.

Samples should be collected via an image-guided core needle (18 gauge or larger) 
or be collected as an excisional or incisional tumor biopsy sample.

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
267 (275)
Where institutional practice, in this setting, uses a smaller gauge needle, 
samples should be submitted in sufficient number to ensure that a valid result 
can be achieved.
When tissue is acquired for this study, effort should be made to maximize 
material for downstream analyses. 2 cores using an 18 gauge or larger needle
are required for establishing PD-L1 status.  These should be placed in formalin 
and processed to a single paraffin embedded block, as described in the Pathology 
Manual.  When a smaller gauge needle is used the number of cores rises to 3 or 4. 
That written, and as a guidance, it is anticipated that 4 passes of a core needle 
will provide sufficient tissue for establishing PD-L1 status and for delivering 
protocol-defined exploratory objectives.  Whenever feasible, additional cores 
(beyond those required to establish PD-L1 status) should be obtained and 
immediately frozen as described in the laboratory manual.
The tumor specimen submitted to establish PD-L1 status should be of sufficient 
quantity to allow for PD-L1 IHC analyses (see the Laboratory Manual.  Samples 
with limited tumor content and fine needle aspirates are inadequate for defining 
tumor PD-L1 status.
Tumor lesions used for biopsies acquired during screening should not be the same 
lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable 
for biopsy.  If a RECIST 1.1 target lesion is used for biopsy, the lesion must be 
≥2 cm in the longest diameter and must be biopsied outside of the screening period.  

If a newly acquired tumor sample is submitted to determine PD-L1 status 
during screening, archived tumor tissue block greater (formalin-fixed paraffin-
embedded) is requested, when available and accessible, and where such samples 
exist in a quantity sufficient to allow for analysis.  Tumor tissue block is preferred.  
If a tissue block is unavailable, unstained sections from the tissue block may be 
submitted.  An archived tumor tissue block or sections may be delivered at any time 
during the study (when newly acquired tissue was used to establish PD-L1 
status). Please consult the Laboratory Manual for specific instructions and 
guidelines regarding sections.

The collection of tumor biopsies at the time of progression and prior to retreatment 
is strongly encouraged.  The biopsy procedure at retreatment should be omitted only 
if there is unacceptable clinical risk or the procedure is otherwise considered not 
feasible.  The Investigator must consult with the Study Physician prior to making 
the decision not to biopsy at retreatment.

The collection of additional biopsies upon progression of patients in the MEDI4736 
+ tremelimumab combination therapy and MEDI4736 monotherapy arms is 
strongly encouraged.  

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
268 (275)
Tumor biopsies collected after determination of PD-L1 status for stratification will be 
used only for exploratory analyses.  
Please review the Laboratory Manual for further details of requirements including sample QC 
and shipping.
A brief description of exploratory tumor markers likely to be explored by IHC or RNA 
analysis is provided in Section 5.5.1.1.
To meet the requirement of Food and Drug Administration (FDA) approval of a companion 
diagnostic, sections of the tumor will be retained at Ventana for potential additional studies, as
requested by the FDA, to support potential test approval.
[...]
Reason for Amendment: 
The text was updated to provide clarity on tumor biopsy sampling.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 19
Section of protocol affected:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.6.Paternal 
exposure
Previous text: 
Male patients must refrain from fathering a child or donating sperm during the study and for 
180 days  
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
269 (275)
Revised text:
Male patients must refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 
90 days after the last dose of MEDI4736 monotherapy.  For patients receiving standard 
of care agents for chemotherapy, please follow the local prescribing information relating 
to contraception and the time limit for such precautions.
[...]
Reason for Amendment: 
The text was reviewed against other similar AstraZeneca protocols and amended to provide 
consistency between trials.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 20
Section of protocol affected:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.7 
Management of IP-related toxicities
Previous text: 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care.  If medically appropriate, dose modifications are permitted (see the Dosing Modification 
and Toxicity Management Guidelines).
[...]
Revised text:
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care.  If medically appropriate, dose modifications are permitted (see the Dosing Modification 
and Toxicity Management Guidelines [MEDI4736 and MEDI4736 + tremelimumab, only; 
for SOC refer to Section 6.7.2]).
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
270 (275)
Reason for Amendment: 
The text was revised to provide clarity with regards to medications and applicable guidelines.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 21
Section of protocol affected:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.7.1 
MEDI4736 and MEDI4736 + tremelimumab
Previous text: 
Information on MEDI4736 and MEDI4736 + tremelimumab adverse events of special 
interest and guidelines for the management of immune-mediated reactions, infusion-related 
reactions, and non-immune-mediated reactions for MEDI4736 and MEDI4736 + 
tremelimumab are provided in the Dosing Modification and Toxicity Management Guidelines.
[...]
Revised text:
Adverse events of special interest (AESIs) are events of scientific and medical interest 
specific to the further understanding of the MEDI4736 and tremelimumab safety profile 
and require close monitoring and rapid communication by the Investigator to 
AstraZeneca.  MEDI4736 and tremelimumab AESIs may be serious or non-serious.  The 
rapid reporting of these AESIs allows ongoing analysis of these events in order to 
characterize and understand them in association with the use of these IPs. 
Information on MEDI4736 and MEDI4736 + tremelimumab AESIs and guidelines for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune-
mediated reactions for MEDI4736 and MEDI4736 + tremelimumab are provided in the 
Dosing Modification and Toxicity Management Guidelines.
[...]
Reason for Amendment: 
Text was added to provide information on AESIs.

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
271 (275)
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 22
Section of protocol affected:
1.
SAFETY REPORTING AND MEDICAL MANAGEMENT, Section 6.8 Study 
governance and oversight
Previous text: 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC will be established and comprised of independent experts.  The committee will 
meet approximately 6 months after the study has started or after the randomization of 
30 patients, whichever happens first, then on a regular basis thereafter to perform an 
interim assessment of the safety of MEDI4736 monotherapy and MEDI4736 + tremelimumab 
combination therapy in this population.  Following the meeting, the IDMC will report to
AstraZeneca and may recommend changes in the conduct of the study.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
[...]
Revised text:
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC will be established to perform an interim assessment of the safety of MEDI4736 
monotherapy and MEDI4736 + tremelimumab combination therapy in this population.  The 
IDMC will be comprised of independent experts.  The committee will meet 
approximately 6 months after the study has started or after the randomization of 
30 patients, whichever happens first.  The second IDMC meeting will occur 3 months 
after the first IDMC meeting or when 90 patients are enrolled, whichever occurs first.  A 
subsequent IDMC meeting will occur 3 months after 90 patients are enrolled.  Further 
IDMC meetings will occur every 6 months, unless otherwise requested by the IDMC.  

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
272 (275)
IDMC members will be consulted to ensure appropriate frequency.  Following each
meeting, the IDMC will report to AstraZeneca and may recommend changes in the conduct of 
the study.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
[...]
Reason for Amendment: 
This revision was made based on comments from the Food and Drug Administration (FDA) in 
its review of the protocol
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 23
Section of protocol affected:
1.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS, Section 7.7 
Concomitant and other treatments
Previous text: 
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given during the study
mAbs against CTLA-4, PD-1, or PD-L1 
through 90 days after the last dose during the 
study (including SoC)
Should not be given during the study
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment
Should not be given during the study.  (Concurrent 
use of hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.  Local treatment of isolated 
lesions, excluding target lesions, for palliative intent 
is acceptable [eg, by local surgery or radiotherapy])

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
273 (275)
Prohibited medication/class of drug:
Usage:
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 during the study.  (Use of 
immunosuppressive medications for the 
management of IP-related AEs, premedication for 
patients randomized to the SoC arm, or in patients 
with contrast allergies is acceptable).  In addition, 
use of inhaled, topical, and intranasal 
corticosteroids is permitted.  
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC)
[...]
Revised text:
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given during the study
mAbs against CTLA-4, PD-1, or PD-L1 
through 90 days after the last dose during the 
study (including SoC)
Should not be given during the study
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment
Should not be given during the study.  (Concurrent 
use of hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement
therapy] is acceptable.  Local treatment of isolated 
lesions, excluding target lesions, for palliative intent 
is acceptable [eg, by local surgery or radiotherapy])
Immunosuppressive medications including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given during the study.  (Use of 
immunosuppressive medications for the 
management of IP-related AEs, premedication for 
patients randomized to the SoC arm, or in patients 
with contrast allergies is acceptable).  In addition, 
use of inhaled, topical, and intranasal corticosteroids 
is permitted.  
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC)
Sunitinib
Should not be given to patients within 3 months 
of a dose of tremelimumab, as acute renal failure 
has been reported with combination therapy of 
tremelimumab and sunitinib
Drugs with laxative properties and herbal 
or natural remedies for constipation 
Should be avoided through 90 days after the last 
dose of tremelimumab during the study, if 
possible.  In case of strong medical need, should 
be used with caution.
[...]

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
274 (275)
Reason for Amendment: 
This revision was made based on comments from the Food and Drug Administration (FDA) in 
its review of the protocol.
Persons who initiated the Amendment: 
AstraZeneca, Sponsor
Change 24
Section of protocol affected:
1.
STATISTICAL ANALYSIS BY ASTRAZENECA, Section 8.4.1.2 Primary 
endpoint
Previous text: 
Additionally, PFS will be obtained using the algorithm described above, but following a 
modification whereby any objective disease progression must be confirmed by the next 
scheduled scan.  The confirmatory scan must be no sooner than 4 weeks after the initial 
suspected progression.  If disease progression is confirmed (or disease progression occurs and 
no further scans are recorded) then the date of progression will be when it was originally 
observed.  Patients with a single disease progression and no further tumor assessment scans 
will be treated as PD in the analysis.  In the absence of significant clinical deterioration, the 
investigational site is advised to continue the patient on their randomized MEDI4736 + 
tremelimumab combination therapy or MEDI4736 monotherapy until progression has been 
confirmed.  If progression is not confirmed, the patient should continue their randomized 
MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy treatment and 
on-treatment assessments.  Treatment through PD in the SoC group is at the 
Investigator’s discretion; however, a confirmatory scan is required for all patients in the 
SoC group, even if a subsequent treatment is started.
[...]
Revised text:
Additionally, PFS will be obtained using the algorithm described above, but following a 
modification whereby any objective disease progression must be confirmed by the next 
scheduled scan.  The confirmatory scan must be no sooner than 4 weeks after the initial 
suspected progression.  If disease progression is confirmed (or disease progression occurs and 
no further scans are recorded) then the date of progression will be when it was originally 
observed.  Patients with a single disease progression and no further tumor assessment scans 
will be treated as PD in the analysis.  In the absence of significant clinical deterioration, the 
investigational site is advised to continue the patient on their randomized MEDI4736 + 

Clinical Study Protocol Appendix H
Drug Substance MEDI4736 + Tremelimumab  
Study Code D419BC00001
Version 9
Date 03 December  2019
275 (275)
tremelimumab combination therapy or MEDI4736 monotherapy until progression has been 
confirmed.  If progression is not confirmed, the patient should continue their randomized 
MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy treatment and 
on-treatment assessments. A confirmatory scan is required for all patients in the SoC group, 
even if a subsequent treatment is started.
[...]
Reason for Amendment: 
The change was made to increase the opportunity for patients to have access to alternative 
treatments.
Persons who initiated the Amendment:
AstraZeneca, Sponsor

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d419bc00001-csp-v9
Document Title:
D419BC00001 Clinical Study Protocol version 9
Document ID:
Doc ID-004053077
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
02-Jan-2020 13:54 UTC
Content Approval
31-Dec-2019 17:29 UTC
Content Approval
07-Jan-2020 17:10 UTC
Content Approval
02-Jan-2020 14:07 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD