A Phase III, Randomised,Double-Blind,Placebo-Controlled,Study of Durvalumab as Consolidation Therapy in Patients With Locally Advanced,Unresectable NSCLC, Who Have Not Progressed Following Definitive, Platinum-Based Chemoradiation Therapy
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: AstraZeneca

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
1
 
Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D933YC00001
Version
6.0
Date
28 Aug 2023
A Phase III, Randomised, Double-Blind, Placebo-Controlled, 
Multicentre Study of Durvalumab as Consolidation Therapy in 
Patients with Locally Advanced, Unresectable, Non-Small Cell 
Lung Cancer (Stage III) Who Have Not Progressed following 
Definitive, Platinum-Based, Chemoradiation Therapy (PACIFIC 5)
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): 
EudraCT number 2018-002294-22

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
3
 
U p date d t he descri pt i on of  parti ci pa nt wit hdra w fr o m  t he st u d y per C S P te m plate .
Secti o n 8. 3 – C ollecti o n of a d verse e ve nts

Cl arifie d N CI C T C A E versi o n 5. 0 will be ut ilise d f or all e ve nts wit h a n assi g ne d 
C T C A E gra di n g.

U p date t he list i n g of A d verse e ve nts of s pecial i nterest a n d t o i ncl u de rare/less A Es 
n o n- i nfecti o us e nce p halitis, n o n- i nfecti o us me ni n gitis a n d vasc ulit is p er l atest 
t e mplate .
Secti o n 8. 4 – S afet y re p orti n g a n d me dic al m a n a ge me nt
Cl arifie d a ll pre g na ncies i ncl u di n g pre g na nc y i n t he part ner of male partici pa nts.
Secti o n 8. 8. 3 – St or a ge, re use, a n d destr ucti o n of bi o m ar ker s a m ples
U p date d t he st ora ge d urati o n f or sa mples c o llecte d i n C hi na p er l o c al  practice.
Secti o n 1. 2 – S y n o psis, Secti o n 9. 2 – S a m ple size deter mi n ati o n a n d Secti o n 9. 5 –
St atistic al a n al yses T he D C Os f or P F S fi nal, O S i nteri m a n d fi nal a nal ysis are u p date d as 
f oll ows :

U p date d t hat P F S fi nal a nal ysis will  be perf or me d w he n reac hi n g a p pr o xi matel y  
 
BI C R P F S e ve nts or a p pr o xi matel y
 mo nt hs f oll o w-u p p ost last partici pa nt 
ra n d omiz at i on, w hic he ver occ urs first .

U p dat e d t hat O S fi nal a nal ysis will be perf or me d w he n reac hi n g a p pr o xi matel y  
 O S 
e ve nts or a p pr o xi matel y
 mo nt hs f oll ow- u p p ost last partici pa nt ra n d o miz at i on,
w hic he ver occ urs first.

U p date d t hat O S sec o n d i nteri m a nal ysis will be perf or me d at a p pr o xi matel y 1 2 m o nt hs 
after t he O S first i nteri m a nal ysis. If t he esti mate d D C O f or O S fi nal a nal ysis is wi t hi n 
2 4 m o nt hs after O S first i nteri m a nal ysis, t he O S sec o n d i nteri m a nal ysis ma y be 
r e mo ve d.   
A p pe n di x E- G ui deli nes f or e v al u ati o n of o bjecti ve t u m o ur res p o nse usi n g R E CI S T 
1. 1 Criteri a
A d de d “ Not A p plica ble” a n d c orres p o n di n g defi nit i on f or G uide li nes of e val uat i on of 
o bj ect i ve t u m o ur res p o nse usi n g R E CI S T 1. 1 Criteria.
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
6
 
Ta ble 1
Cl arifie d t hat
 s h o ul d be c ollecte d at C ycle 1 3.
Ta ble 2
C orrecte d P R O assess me nt i nf or mat i on t o ali g n wit h Ta ble 1.
Secti o n 1. 2 – S y n o psis 
Stati stical met h o ds
Ge nerall y, f o ll owi n g u p dates ha ve bee n ma de i n t his secti o n, a n d rele va nt s u bsect i ons i n 
secti on 9 (s pecificall y, sect i on 9. 2, secti o n 9. 5. 1, secti o n 9. 5. 7, secti o n 9. 6),
1) P F S i nteri m a nal ysis re m o ve d, mat urit y of  P F S fi nal a nal ysis i ncrease d fr om 6 8 % t o 
7 0 %, a d di tio n al  criteria t o e ns ure mi ni m u m f oll o w-u p ( 9 m o nt hs fr o m last s u bject 
ra n d omize d). T he c ha n ge has bee n ma de t o e ns ure s ufficie nt e ve nts ( ma t urit y) i n C hi na 
c o h ort at P F S fi nal a nal ysis, c o nsi deri n g a 1 year dela y i n e nr ol me nt i n C hi na t ha n o utsi de of 
C hi na.
2) M o dif y O S i nteri m a nal yses a n d O S fi nal a nal ysis, t o be i n li ne wit h t he c ha n ges t o P F S .
Secti o n 2. 3. 1 – P ote nti al be nefits of d ur v al u m a b
A d de d P A CI FI C 4 -year s ur vi val data.
Secti o n 3 – O bjecti ves a n d e n d p oi nts
A d de d f o ot n ote c ‘ E x pl orat or y  e n d p oi nts a n d a nal yses relate d t o P F S/ O R R a nal yses usi n g 
ir R E CI S T data ma y be prese nte d o utsi de of t he mai n C S R’.
Secti o n 4. 1 – O ver all desi g n
U p date d t he n u m ber of pat ient s w h o recei ve d pri or c C R T t o at least 6 0 %, a n d ca p t he 
n u m ber of patie nts wit h P D -L 1 < 1 % at a p pr o xi matel y 3 3 % o utsi de of C hi na. N u m ber
of  p atie nts wit h E G F R m utatio n or A L K rearra n ge me nt will be ca p pe d at a p pr o xi matel y  7 % 
of  t he t otal ra n d omisat i on.
Secti o n 4. 1. 1
C O VI D -1 9 mit i gati on g ui da nce is a d de d. 
Secti o n 4. 2. 2 – Pre dicti ve bi o m ar kers a n d r ati o n ale f or a n u nselecte d p o p ul ati o n i n 
St u d y D 9 3 3 Y C 0 0 0 0 1
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
7
 
Rational for PD-L1 negative cap is added.
Section 5.1 – Inclusion criteria – Part I Screening 
Updated inclusion criteria#7 by updating the cap of EGFR and ALK mutant patients to 7%.
Section 5.2 – Exclusion criteria
Updated exclusion criteria#7 by adding sarcomatoid variant.
Updated exclusion criteria#8 by adding ‘Grade 2 AE of laboratory abnormality for 
inclusion criteria 12 related lab parameters may be included as long as within the specified 
range in inclusion criteria 12’.
Updated exclusion criteria#20 by adding ‘Or the patient is not willing to/can not continue 
screening procedures during the screening period.’
Added exclusion criteria#21 Meet any of the study protocol specified capping criteria.
Updated other exclusions to clarify patient who is not willing to or not able to continue 
screening is considered as screen failure but not withdrawal.
Section 8.1.1 Central reading of scans
Updated ‘an exploratory analysis of PFS may be presented outside of the main CSR’.
Section 8.1.3 Second progression
Deleted ‘The follow up scan confirming an immediate prior RECIST 1.1 defined 
radiological progression is not to be considered as the second progression’.
Section 8.1.4.3 - Administration of patient-reported outcomes questionnaire.
Added back-up option of PRO data collection at the time of technical or other device-
related issues prohibit completion on the device.
Section 8.4.5.1 – Specific toxicity management and dose modification information -
durvalumab
Web portal of Toxicity Management Guidelines is removed.
Section 9.2 – Sample size determination
Update the relevant statistical calculations for PFS and OS analysis.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
8
 
Section 9.4.1.1 – RECIST 1.1-based endpoint
Removed ‘PFS and ORR by irRECIST 1.1 criteria using BICR assessments will also be 
performed for exploratory purpose.’
Section 9.4.1.2 – Primary endpoint
Removed ‘For exploratory purpose, PFS will also be assessed using irRECIST 1.1 data 
obtained from BICR’.
Section 9.4.1.5 – Objective response rate
Removed ‘For exploratory purpose, ORR by irRECIST 1.1 criteria using BICR assessments 
will also be reported’.
Section 9.4.1.8 - Time from randomisation to second progression
Update the definition of PFS2 and relevant analysis rules.
Section 9.5 - Statistical analyses
COVID-19 related data analysis is added.
Section 9.5.1 – Efficacy analyses
Removed ‘The analysis will be performed when (approximately) 245 PFS events have 
occurred across the durvalumab and placebo treatment arms (68% maturity)’.
Section 9.5.1.1– Primary endpoint: Progression-free survival
1% PD-L1 cut-off is added.
Table 13
Remove the exploratory endpoints and analyses related to PFS/ORR analyses using 
irRECIST data, as they may be presented outside of the main CSR.
Change the analysis method for landmarks (OS24, PFS12, PFS18).
Section 9.5.1.1– Primary endpoint: Progression-free survival
Removed ‘An exploratory analysis of PFS based on BICR assessments according to 
irRECIST 1.1 criteria will be performed. The stratified log rank test used for the primary 
analysis of PFS will be repeated’.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
9
 
Updated PD-L1 status (tumour cells [TCs] ≥ 1% vs TCs < 1%).
Section 9.5.1.3 – Proportion of patients alive at 24 months
The analysis of comparison of OS24, PFS12 and PFS18 were removed to be consistent with 
other durvalumab studies. Kaplan Meier estimates of APF12, OS24, PFS12 and PFS18 will 
still be provided for each treatment arm.  
Section 9.5.1.4 – Objective response rate
Removed ‘ORR by irRECIST 1.1 criteria using BICR assessments will also be reported’.
Section 9.5.7 – Methods for multiplicity control
Remove PFS IA, update the statistical calculations for PFS FA and OS analyses (OS IA1, 
OS IA2, OS FA), and make relevant updates for wordings of MTP.
Section 9.6 – Interim analyses
Remove PFS IA, update the statistical calculations for OS interim analyses 
Section 9.6.1 – Data monitoring committee
Updated the review period of IDMC to periodically in accordance with IDMC charter.
The details regarding whether IDMC to review the efficacy data for OS are removed.
Section 10 – References
Removed ‘Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a 
fixed point in time. Stat Med 2007; 26(24): 4505-19’.
2BAdded ‘Paz-Ares L 2020
Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 
expression in unresectable, Stage III non-small-cell lung cancer in the PACIFIC trial[J]. 
Annals of Oncology, 2020.’
Appendix E
Removed ‘and is the only lesion available’ from ‘A previously irradiated lesion may be 
selected as a Target Lesion provided that it fulfils the criteria for reproducible measurability 
and is the only lesion available.’

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
1 1
 
1. 2 S y n o psis
 test was d o w n gra de d fr om sec o n dar y o bject i ve t o e x pl orat or y o bject i ve.
T w o - part scree ni n g pr ocess relate d i nf or mati o n was u p date d. St u d y peri o d i nf or mat i on was 
u p date d.
S pecifie d se nsit izi n g E G F R m utati o n t ypes a n d o nl y  se nsitizi n g m utatio n w o ul d be 
e xcl u de d.
Treat me nt t hr o u g h pr o gressi o n relate d w or di n g was a d de d. e P R O w o ul d be f o ll owe d u ntil 
P F S 2.
S o m e statistical c o nsi derati ons were u p date d.
1. 3 Sc he ma
St u d y  Desi g n Fi g ure was u p date d t o i ncl u de t w o-part scree ni n g visit i nf or mat i on. 
2. 3. 1 P ote ntial be nefits of d ur val u ma b
Relate d w or di n g was u p date d wit h rece nt a vaila ble i nf or mat io n. 
3 O bject i ves a n d e n d p oi nts
 test was d o w n gra de d fr om sec o n dar y o bject i ve t o e x pl orat or y o bject i ve.
4. 1 O verall desi g n
S pecifie d se nsit izi n g E G F R m utati o n t ypes a n d o nl y  se nsitizi n g m utatio n w o ul d be 
e xcl u de d.
5. St u d y  P o p ulat i on
U p date d t he defi nit i on of e nr olle d pat ient s.
5. 1 I ncl usi o n  crit eria a n d 5. 2 E xclusi o n  crit eria
I ncl usi on cri t eria d uri n g scree ni n g visit part I were create d.
T he ori gi nal  incl usi o n  criteria i n C S P versi on 2. 0 are u n der scree ni n g visit part II. S o me of 
t he crit eria were m o ve d t o part I scree ni n g, b ut t he criteria n u m bers w o ul d n ot be assi g ne d 
a gai n t o ot her criteria.
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
1 2
 
I ncl usi on # 5 was u p date d t o reflect c orrect ra diat i o n t hera p y re q uire me nts.
5. 4 Scree n Fail ures 
Cl arifie d patie nts w h o d o n ot meet eli gi bilit y crit eria aft er sig ni n g part I scree ni n g I C F, or 
b ot h part I a n d part II scree ni n g I C Fs are b ot h scree n fail ures.
6 St u d y  Tr e at me nts
Bli n di n g re q uire me nts relate d w or di n g was u p date d.
6. 1. 3 D urati o n of treat me nt
Treat me nt t hr o u g h pr o gressi o n relate d w or di n g was a d de d. 
L o n g ter m  O S c ollecti on p ost Fi nal Data C ut off was a d de d.
6. 2. 1 Patie nt e nr o l me nt a n d ra n d o mizati o n 
P ati e nt scree ni n g a n d ra n d o mizat i on pr ocess was u p date d t o reflect t w o -part scree ni n g visit 
i nf or mat i on.
E m p hasize d 3 da ys wi n d o w fr o m ra n d o mizati o n t o 1st d ose.
6. 2. 4 Met h o d f or e ns uri n g bli n di n g 
W o r di n g a b o ut u n bli n d after treat me nt disc o nti n uati o n was u p date d.
8. St u d y  assess me nt a n d pr oce d ure 
Scree ni n g relate d w or di n gs were u p date d t o reflect t w o -part scree ni n g pr ocess.
8. 1. 4 . 3 A d mi nistrati o n of pati e nt -re p orte d o ut c o mes q uesti on naires 
U p date d w or di n g a b o ut e P R O c o m pleti o n re q uire me nts i n patie nts w h o are u na ble t o rea d.
8. 3. 2 Ti me peri o d a n d fre q ue nc y f or c ollect i on a d verse e ve nt a n d seri o us e ve nt i nf or mati o n 
Cl arifie d A E a n d S A E w o ul d be c ollecte d after part II scree ni n g I C F is si g ne d. 
8. 8 Bi o m ar ker 
Cl arifie d P D-L 1 will be teste d f or all e nr o lle d patie nts a n d  
 w o ul d be teste d f or all 
ra n d omize d patie nts .
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
1 4
 
Te xt c orrecte d t o state: 1) A recr uit me nt  perio d of  a p pr o xi matel y 2 2 mo n t hs a n d a f oll ow-
u p peri o d of 7 m o nt hs are e x pecte d f or t he P F S e n d p oi nt.  2) A recr uit me nt peri o d of 
a p pr o xi matel y 2 2 m o nt hs a n d a f o ll ow- u p peri o d of  4 3 mo n t hs are e x pecte d f or t he O S 
e n d p o i nt.  
Secti o n 1. 2 – S y n o psis a n d Sect i on 3 – O bjecti ves a n d E n d p o i nts
 testi n g was m ove d t o e x pl orat or y o bjecti ve.
Secti o n 1. 2 – S y n o psis a n d Sect i on 9 – Statist ical C o nsi derati o ns
Stati stical c o nsi derati ons were u p date d.
Secti o n 2. 1 – St u d y  r atio nale
State m e nts a b o ut C he m ora di ot hera p y as S o C f or u nresecta ble sta ge III N S C L C patie nts was 
r e mo ve d, a n d i nf or mat i on a b o ut P A CI FI C st u d y  P F S res ult was u p date d. S o me re d u n da nt 
descri pt i ons were re m o ve d.
Secti o n 4. 1 – O vera ll desi g n
Te xt c orrecte d t o state: patie nts ra n d o mize d s h o ul d be recei ve d c C R T or s C R T; a n d n u m ber 
of  p atie nts wit h E G F R m utatio n or A L K rearra n ge me nt will be ca p pe d at a p pr o xi matel y  
1 5 % of t he t otal ra n d o misat i on.
Secti o n 4. 2 – Scie nt ific rati onale f or st u d y desi g n
Rati o nale a b o ut usi n g place b o c o n tr ol was u p date d t o reflect m ost u p date d i nf or mati on.
Secti o n 4. 4 – E n d of st u d y  defi nitio n
T he w or di n g “rest of w orl d” i n st u d y  d uratio n para gra p h was re m o ve d t o a v oi d c o nf usi o n.
Secti o n 4. 4 – E n d of st u d y  defi niti on a n d Secti o n 6. 1. 3 – D urati o n of treat me nt
A d dit i onal f oll o w-u p f or l o n g- t er m efficac y assess me nt was a d de d.
Secti o n 5 – St u d y  P o p ulat i on
I ncl usi on cri t erio n # 7 a d de d as o ne i ncl usi o n cri teri o n of P D-L 1 stat us: T u m or P D -L 1 stat us, 
wi t h t he Ve nta na S P 2 6 3 P D -L 1 I H C assa y deter mi ne d b y a refere nce la b orat or y, must be 
k n o w n pri or t o ra n d o mizati o n. Patie nt wit h u n k n o w n P D -L 1 stat us i s n ot eli gi ble f or t he 
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
15
 
study.  “Unknown” refers to (1) insufficient sample which is not able to be analyzed, or (2) 
sample could be analyzed but results not interpretable.
Inclusion criterion #8 text corrected to state: “After approximately 15% EGFR or ALK 
mutant patients have been randomised”.
Exclusion criterion #15 was updated to clarify patients should not participate in another 
clinical study with an IP administered in the last 4 weeks prior to randomization.
Lifestyle restrictions’ contraception requirements was updated for male patients and female 
patients’ non-sterilised male partners, to require a male condom plus spermicide (or male 
condom in countries where spermicides are not approved).
Rescreen patients should sign a new ICF instead of re-sign on the original ICF, in order to 
avoid the risk of ICF update during re-screening period.
Section 1.2 – Synopsis and Section 6 – Study treatments
“Unblinded pharmacist” was updated to “unblinded pharmacist and/or other appropriate 
unblinded site staff” to reflect the local practice in some sites.
Section 6.4 – Concomitant Medication
Table 6 was updated to reflect palliative radiotherapy on non-target lesion is not applicable 
in this protocol as supportive care. 
Section 6.4.3 – Rescue medication
The description about dispensing rescue medications through IVRS/IWRS system was 
updated, this is only applicable when rescue medications are centrally provided by AZ.
Section 8 – Study assessments and procedures
Paragraph about maximum amount of blood collected from each patient was removed. No 
OS data will be recorded after final DCO was removed as it is incorrect.
Section 8.1.4 – Clinical outcome assessments
This section was updated to reflect most updated electronic patient reported outcome 
requirements.
Section 8.2.1 – Clinical safety laboratory assessments

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
1 6
 
Ta ble 7, Ta ble 8 a n d Ta ble 9 were u p date d t o re m o ve t he re q uire me nts a b o ut D M t o 
calc ulate t he la b testi n g res ults.
Secti o n 8. 2. 5 – Earl y pat ient  re vie w f or safet y
T his sect i on was re m o ve d t o kee p c o nsiste nc y  wit h P A CI FI C st u d y.
Secti o n 8. 3. 4 – A d verse e ve nt data c ollect i on a n d Secti o n 8. 4. 5 – Ma na ge me nt of I P -relate d 
t o xic ities
A E gra di n g scale g ui da nce has bee n u p date d fr o m C T C A E 4. 0 3 t o C T C A E 5. 0.
Secti o n 8. 4. 5. 1 – S pecific t o xicit y ma na ge me nt a n d d ose m o dificat i on i nf or mati on -
d ur val u ma b
Descri pt i on a b o ut T o xi cit y Ma na ge me nt G uideli nes has bee n u p date d as A p pe n di x G was
r e mo ve d.
Secti o n 8. 5 – P har mac o ki net ics
Bl o o d sa m pl e v ol u me was re m o ve d. Descri pt i on a b o ut sa m ple st ora ge d urati o n was 
u p date d.
Secti o n 8. 8. 1 – C ollect i on of patie nt select i on bi o mar ker data
T his sect i on was u p date d t o reflect ma n dat or y  tiss ue sa mple is n ot o nl y  us e d for 
 b ut 
als o tiss ue  
 a nal ysis.
Secti o n 8. 8. 2 – E x pl orat or y  bio m ar kers
 a n d e x pl orat or y t u mo ur m ar kers were u p date d as n ot a p plica ble t o C hi na.
 was m o ve d t o secti o n 8. 8. 1 – C o llecti o n of patient  select i on bi o mar ke r data.
 secti o n was a d de d t o pr o vi de m ore detail.
Secti o n 8. 8. 3 – St ora ge, re use, a n d destr ucti o n of bi o mar ker sa m ples
S a m ple st ora ge a n d dis p osal re q uire me nts was u p date d t o f oll o w l ocal la ws a n d re g ulati o ns, 
n ot j ust f or sa m ples c ollecte d i n C hi na.
Secti o n 8. 8. 5 – C hai n o f c ust o d y of biol o gi c al s a m ples
T his sect i on was u p date d t o reflect m ost u p date d A Z sa m ple ma na ge me nt re q uire me nts.
C CI
C CI
C CI
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
18
 
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY ........................................................................................................... 2
TABLE OF CONTENTS .................................................................................................... 18
1
PROTOCOL SUMMARY ................................................................................ 24
1.1
Schedule of activities (SoA).............................................................................. 24
1.2
Synopsis ........................................................................................................... 32
1.3
Schema............................................................................................................. 39
2
INTRODUCTION............................................................................................ 41
2.1
Study rationale.................................................................................................. 41
2.2
Background ...................................................................................................... 42
2.2.1
Immunotherapies .............................................................................................. 42
2.2.2
Durvalumab...................................................................................................... 43
2.3
Benefit/risk assessment..................................................................................... 44
2.3.1
Potential benefits of durvalumab....................................................................... 44
2.3.2
Overall risks ..................................................................................................... 45
2.3.2.1
Durvalumab...................................................................................................... 45
2.3.3
Overall benefit/risk ........................................................................................... 46
3
OBJECTIVES AND ENDPOINTS................................................................... 46
4
STUDY DESIGN ............................................................................................. 49
4.1
Overall design................................................................................................... 49
4.1.1
Study conduct mitigation during study disruptions due to cases of civil crisis, 
natural disaster, or public health crisis............................................................... 50
4.2
Scientific rationale for study design .................................................................. 51
4.2.1
Timing of treatment with durvalumab relative to concurrent or sequential 
chemoradiation therapy..................................................................................... 52
4.2.2
Predictive biomarkers and rationale for an unselected population in 
Study D933YC00001........................................................................................ 53
4.2.3
Rationale for study endpoints (efficacy)............................................................ 54
4.2.4
Rationale for study endpoints (other exploratory endpoints).............................. 55
4.3
Justification for dose......................................................................................... 55
4.3.1
Durvalumab monotherapy dose rationale .......................................................... 55
4.3.2
Rationale for fixed dosing................................................................................. 56
4.4
End of study definition...................................................................................... 57
5
STUDY POPULATION.................................................................................... 58
5.1
Inclusion criteria............................................................................................... 58
5.2
Exclusion criteria.............................................................................................. 61
5.3
Lifestyle restrictions ......................................................................................... 64
5.4
Screen failures .................................................................................................. 66

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
19
 
6
STUDY TREATMENTS................................................................................... 66
6.1
Treatments administered ................................................................................... 67
6.1.1
Investigational products.................................................................................... 67
6.1.1.1
Durvalumab (MEDI4736)................................................................................. 67
6.1.1.2
Placebo............................................................................................................. 68
6.1.2
Dose and treatment regimens ............................................................................ 69
6.1.2.1
Durvalumab (MEDI4736) monotherapy............................................................ 69
6.1.2.2
Placebo............................................................................................................. 69
6.1.3
Duration of treatment........................................................................................ 69
6.1.4
Storage ............................................................................................................. 70
6.2
Measures to minimise bias: randomisation and blinding.................................... 70
6.2.1
Participant enrolment and randomisation .......................................................... 70
6.2.2
Procedures for handling incorrectly enrolled or randomised participants........... 72
6.2.3
Methods for assigning treatment arms............................................................... 72
6.2.4
Methods for ensuring blinding .......................................................................... 73
6.3
Treatment compliance....................................................................................... 74
6.4
Concomitant therapy......................................................................................... 74
6.4.1
Other concomitant treatment............................................................................. 76
6.4.2
Durvalumab drug-drug interactions................................................................... 76
6.4.3
Rescue medication............................................................................................ 77
6.5
Dose modification............................................................................................. 77
6.6
Treatment after the end of the study.................................................................. 77
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL ... 78
7.1
Discontinuation of study treatment.................................................................... 78
7.1.1
Procedures for discontinuation of study treatment............................................. 79
7.2
Lost to follow-up .............................................................................................. 79
7.3
Withdrawal from the study................................................................................ 81
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 81
8.1
Efficacy assessments......................................................................................... 82
8.1.1
Central reading of scans.................................................................................... 83
8.1.2
Survival assessments......................................................................................... 84
8.1.3
Second progression........................................................................................... 84
8.1.4
Clinical outcome assessments ........................................................................... 84
8.1.4.1
EORTC QLQ-C30 and QLQ-LC13................................................................... 84
8.1.4.2
EQ-5D.............................................................................................................. 85
8.1.4.3
Administration of patient-reported outcomes questionnaires ............................. 86
8.2
Safety assessments............................................................................................ 87
8.2.1
Clinical safety laboratory assessments............................................................... 87
8.2.2
Physical examinations....................................................................................... 89
8.2.3
Vital signs......................................................................................................... 89
8.2.4
Electrocardiograms........................................................................................... 90
8.2.5
WHO/ECOG performance status ...................................................................... 90
8.2.6
Other safety assessments................................................................................... 91

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
20
 
8.3
Collection of adverse events ............................................................................. 91
8.3.1
Method of detecting adverse events and serious adverse events......................... 92
8.3.2
Time period and frequency for collecting adverse event and serious adverse 
event information.............................................................................................. 92
8.3.3
Follow-up of adverse events and serious adverse events.................................... 92
8.3.4
Adverse event data collection............................................................................ 93
8.3.5
Causality collection........................................................................................... 94
8.3.6
Adverse events based on signs and symptoms................................................... 94
8.3.7
Adverse events based on examinations and tests ............................................... 94
8.3.8
Hy’s Law.......................................................................................................... 95
8.3.9
Disease-under study.......................................................................................... 95
8.3.10
Disease progression .......................................................................................... 95
8.3.11
New cancers ..................................................................................................... 95
8.3.12
Deaths .............................................................................................................. 95
8.3.13
Adverse events of special interest ..................................................................... 96
8.3.14
Safety data to be collected following the final data cutoff of the study .............. 97
8.4
Safety reporting and medical management........................................................ 97
8.4.1
Reporting of serious adverse events .................................................................. 97
8.4.2
Pregnancy......................................................................................................... 98
8.4.2.1
Maternal exposure ............................................................................................ 98
8.4.2.2
Paternal exposure.............................................................................................. 99
8.4.3
Overdose ........................................................................................................ 100
8.4.4
Medication error ............................................................................................. 100
8.4.5
Management of IP-related toxicities................................................................ 101
8.4.5.1
Specific toxicity management and dose modification information – durvalumab
....................................................................................................................... 101
8.5
Pharmacokinetics............................................................................................ 102
8.5.1
Collection of samples...................................................................................... 102
8.5.1.1
Collection of samples to measure for the presence of antidrug antibodies........ 102
8.5.2
Storage and destruction of pharmacokinetic/antidrug antibody samples .......... 102
8.6
Pharmacodynamics......................................................................................... 103
8.6.1
Collection of samples...................................................................................... 103
8.6.2
Storage, reuse, and destruction of pharmacodynamic samples......................... 103
8.7
Genetics.......................................................................................................... 103
8.8
Biomarkers ..................................................................................................... 103
8.8.1
Collection of participant selection biomarker data........................................... 104
8.8.2
Exploratory biomarkers................................................................................... 105
8.8.3
Storage, reuse, and destruction of biomarker samples...................................... 107
8.8.4
Labelling and shipment of biological samples................................................. 107
8.8.5
Chain of custody of biological samples........................................................... 107
8.8.6
Withdrawal of informed consent for donated biological samples..................... 108
8.9
Health economics ........................................................................................... 108
9
STATISTICAL CONSIDERATIONS.............................................................. 108
9.1
Statistical hypotheses...................................................................................... 109

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
21
 
9.2
Sample size determination .............................................................................. 109
9.3
Populations for analyses.................................................................................. 110
9.3.1
Intent-to-treat set..............................................................................................111
9.3.2
Modified intent-to-treat set...............................................................................111
9.3.3
Safety analysis set............................................................................................111
9.3.4
PK analysis set.................................................................................................111
9.4
Outcome measures for analyses ...................................................................... 112
9.4.1
Calculation or derivation of efficacy variables ................................................ 112
9.4.1.1
RECIST 1.1-based endpoints .......................................................................... 112
9.4.1.2
Primary endpoint ............................................................................................ 113
9.4.1.3
Key secondary objective (Overall survival)..................................................... 114
9.4.1.4
Proportion of participants alive at 24 months after randomisation ................... 114
9.4.1.5
Objective response rate................................................................................... 114
9.4.1.6
Duration of response....................................................................................... 114
9.4.1.7
Progression-free survival at 12 and 18 months ................................................ 114
9.4.1.8
Time from randomisation to second progression ............................................. 115
9.4.1.9
Time to death or distant metastasis.................................................................. 115
9.4.1.10
Best objective response................................................................................... 115
9.4.2
Calculation or derivation of safety variables.................................................... 116
9.4.2.1
Adverse events................................................................................................ 116
9.4.2.2
Safety assessments.......................................................................................... 116
9.4.3
Calculation or derivation of patient-reported outcome variables...................... 117
9.4.3.1
EORTC QLQ-C30 and QLQ-LC13................................................................. 117
9.4.3.2
Calculation or derivation of patient-reported health state utility (EQ-5D-5L) .. 119
9.4.3.3
Analysis of EORTC QLQ-C30 and QLQ-LC13 .............................................. 119
9.4.4
Calculation or derivation of pharmacokinetic variables................................... 121
9.4.4.1
Population pharmacokinetics and exposure-response/safety analysis............... 121
9.4.4.2
Pharmacokinetic non-compartmental analysis................................................. 121
9.4.4.3
Immunogenicity analysis ................................................................................ 122
9.4.5
Calculation or derivation of biomarker variables............................................. 122
9.4.6
Calculation or derivation of health economic variables ................................... 122
9.5
Statistical analyses.......................................................................................... 122
9.5.1
Efficacy analyses ............................................................................................ 122
9.5.1.1
Primary endpoint: Progression-free survival.................................................... 124
9.5.1.2
Overall survival .............................................................................................. 126
9.5.1.3
Proportion of participants alive at 24 months .................................................. 127
9.5.1.4
Objective response rate................................................................................... 127
9.5.1.5
Duration of response....................................................................................... 127
9.5.1.6
Progression-free survival at 12 and 18 months ................................................ 127
9.5.1.7
Time from randomisation to second progression ............................................. 127
9.5.1.8
Time to death or distant metastasis.................................................................. 128
9.5.1.9
Patient-reported outcomes: EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L... 128
9.5.1.10
Health care resource use ................................................................................. 130
9.5.2
Safety analyses ............................................................................................... 130
9.5.3
Pharmacokinetic data...................................................................................... 130
9.5.4
Immunogenicity data ...................................................................................... 131

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
22
 
9.5.5
Pharmacokinetic/pharmacodynamic relationships ........................................... 131
9.5.6
Biomarker data ............................................................................................... 131
9.5.7
Methods for multiplicity control ..................................................................... 131
9.6
Interim analyses.............................................................................................. 133
9.6.1
Data monitoring committee............................................................................. 133
10
REFERENCES............................................................................................... 135
11
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 142
LIST OF FIGURES
Figure 1
Study design............................................................................................ 40
Figure 2
Durvalumab monotherapy dosing schedule.............................................. 69
Figure 3
Multiple testing procedure for controlling the type 1 error rate............... 133
LIST OF TABLES
Table 1
Schedule of activities for durvalumab/placebo treatment.......................... 25
Table 2
Schedule of activities for participants who have discontinued treatment 
with durvalumab /placebo........................................................................ 29
Table 3
Highly effective methods of contraception (<1% failure rate) .................. 66
Table 4
Study treatments ...................................................................................... 67
Table 5
Prohibited concomitant medications......................................................... 75
Table 6
Supportive medications............................................................................ 76
Table 7
Clinical chemistry.................................................................................... 87
Table 8
Haematology ........................................................................................... 88
Table 9
Coagulation Parameters ........................................................................... 88
Table 10
Urinalysis ................................................................................................ 88
Table 11
Summary of outcome variables and analysis populations ....................... 110
Table 12
Visit response for symptoms and HRQoL.............................................. 121
Table 13
Pre-planned statistical and sensitivity analyses to be conducted ............. 123
Table 14
Summary of imaging modalities for tumour assessment......................... 161
Table 15
Evaluation of target lesions.................................................................... 166
Table 16
Evaluation of non-target lesions............................................................. 167
Table 17
Overall visit response............................................................................. 168

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
2 3
 
LI S T O F A P P E N DI C E S
A p pe n di x A
Re g ulat or y , et hical a n d st u d y o versi g ht c o nsi derati o ns...........................1 4 3
A p pe n di x B
A d verse e ve nt defi nit i ons a n d a d dit i onal safety i nf or matio n ..................1 4 9
A p pe n di x C
Ha n dli n g of h u ma n bi o l ogical sa m ples ..................................................1 5 3
A p pe n di x D
Act i ons re q ui re d i n cases of i ncreases i n li ver bi oc he mistr y a n d 
e val uat i on of H y’s la w ...........................................................................1 5 6
A p pe n di x E
G ui deli nes f or e val uat i on of o bject i ve t u m o ur res p o nse usi ng R E CI S T 
1. 1 Cri teria ( Res p o nse E val uati on Cri t eria i n S oli d T u m ors) ..................1 6 0
A p pe n di x F
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on (I A T A) 6. 2 g uida nce 
d oc u m e nt ...............................................................................................1 7 3
A p pe n di x G
.....................1 7 4
A p pe n di x H
A b bre viat i ons ........................................................................................1 8 0
A p pe n di x I
C ha n ges R elate d t o Mitig ati o n of  St u d y Disr u ptio ns D ue t o Cases of 
Ci vil Crisis, Nat ural Disaster, or P u blic Healt h Crisis ............................1 8 5
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
24
 
1
PROTOCOL SUMMARY
1.1
Schedule of activities (SoA)
The procedures for the Screening and Treatment Periods in this study are presented in Table 1, 
and the procedures for the Follow-up Period are presented in Table 2.
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws.  The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, 
pharmacokinetic (PK) blood sample) to occur at the timepoints indicated in the Schedule of 
Activities (SoAs).  Whenever electrocardiograms (ECGs), vital signs, 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 timepoints indicated in the 
SoAs.  Safety assessments must be done prior to dosing.
For durvalumab monotherapy / placebo treatment

Participants may delay dosing under certain circumstances.

Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related adverse event (AE).

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.

Dosing intervals of subsequent cycles may be shortened as clinically feasible in order 
to gradually align treatment cycles with the schedule of tumour efficacy (Response 
Evaluation Criteria in Solid Tumors [RECIST]) and patient-reported outcome (PRO) 
assessments.  Subsequent time between 2 consecutive doses cannot be less than 21 
days, based on the half-life of durvalumab (see current Investigator Brochure [IB] for 
durvalumab).

If a participant has a delay to an infusion of study treatment, all tumour efficacy
assessments should still be conducted relative to date of randomisation, and PRO 
assessments should be conducted relative to the date of Cycle 1 Day 1 visit date (i.e. date 
of randomization/first dose).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
25
Table 1
Schedule of activities for durvalumab/placebo treatment 
Screening 
Visit Part 
I
Screening 
Visit Part 
II
C1
C2
C3
C4
C5 to PD
For details, 
see Section
Week
-12 to -1
-4 to -1
0
q4w ±3 days unless dosing needs to be held for toxicity reasons
Day
-84 to -1
-28 to -1
1b
q28d ±3 days unless dosing needs to be held for toxicity reasons
Informed consent
Informed consent: tumour sample 
collectionc (part I screening ICF)
X
5.1
Informed consent: study 
proceduresc (part II screening ICF)
X
5.1
Study procedures
Physical exam (full)
X
8.2.2
Targeted physical exam (based on 
symptoms)
X
X
X
X
X
8.2.2
Vital signs
X
X
X
X
X
X
8.2.3
Weight
X
X
X
X
X
X
8.2.3
ECGd
X
As clinically indicated
8.2.4
Concomitant medications
<----------------------------------------------------------------------------------------------------------------->
6.4
Demography
X
5.1
Tobacco use
X
5.1
Eligibility criteria
X
X
X
5.1, 5.2
Randomisation
X
6.2
Laboratory assessments
Clinical chemistrye
X
Xf
X
X
X
X
Table 7
Haematologye
X
Xf
X
X
X
X
Table 8

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
28
procedures, these can be used for screening purposes with consent of the participant. However, all screening laboratory and imaging results must have been obtained within 
28 days of randomisation.  
d
Any clinically significant abnormalities detected require triplicate ECG results.
e
Serum or plasma clinical chemistry (including LFT monitoring), haematology, and coagulation parameters may be performed more frequently if clinically indicated.
f
If part II screening clinical chemistry, haematology, and coagulation parameter assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need 
to be repeated at Day 1.
g
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
i
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  Women of childbearing potential are required to have a pregnancy test within 
7 days prior to the first dose of study treatment and then q4w.  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.  
j
Pre-dose same day as infusion 
k
Within 10 minutes of the end of infusion.
l
For AEs/SAEs reported during part II screening, additional information such as medical history and concomitant medications may be needed
m
Results for haematology, LFTs, electrolytes, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the treating physician or 
Investigator prior to dosing.
n
Will be administered using a site-based electronic device. It is preferred that PRO questionnaires are completed prior to any other study procedures (following informed 
consent) and before discussion of disease progression to avoid biasing the participant’s responses to the questions.
o        Documented EGFR and ALK status obtained from local lab uses a well-validated, local regulatory-approved kit is acceptable. EGFR and ALK status may also be tested in 
central lab at screening part I visit, if there’s no available documentation of EFGR and ALK status from local lab. 
p          Tumor assessment will be performed on images from CT (preferred) or MRI, each preferably with iv contrast, of the chest and abdomen (including the entire liver and both 
adrenal glands).  Additional anatomy, e.g. pelvis, should be imaged based on signs and symptoms of individual participants at Baseline and follow-up.  If a participant’s scan 
is assessed as a RECIST 1.1-defined radiological progression, a follow-up scan for confirmation of the prior radiological progression is collected no earlier than 4 weeks 
after and no later than the next regularly scheduled imaging visit after the prior RECIST 1.1-defined PD, and this scan is evaluated using the confirmation of radiological 
progression criteria outlined in Appendix E.  If the subsequent scan confirms the immediate prior radiological PD, no additional scans are required; however, if the 
subsequent scan does not confirm the immediate prior radiological PD, scanning should continue on the original imaging visit schedule until  the next clinical 
progression/deterioration or RECIST 1.1-defined PD, which in turn will require a subsequent scan evaluated using confirmation of radiological progression criteria outlined 
in Appendix E.  If an unscheduled assessment was performed and the participant has not progressed, every attempt should be made to perform the subsequent assessments at 
their next regularly scheduled visit.  See Section 6.1.3 and Section 8.1 for additional details relevant to tumour assessment.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
ADA Anti-drug antibody; AE Adverse event; ALK Anaplastic lymphoma kinase; C Cycle; CT Computed tomography; ECG Electrocardiogram; 
ECOG Eastern Cooperative Oncology Group; EGFR Epidermal growth factor receptor; EORTC QLQ-C30 European Organisation for Research and Treatment 
of Cancer 30-item core quality of life questionnaire; HIV Human immunodeficiency virus; ICF Informed consent form; IP Investigational Product; 
iv Intravenous; LFT Liver function test; miRNA Micro ribonucleic acid; MRI Magnetic resonance imaging; mRNA Messenger ribonucleic acid; 
NSCLC Non-small cell lung cancer; PD Progression of disease; PD-L1 Programmed death ligand 1; PK Pharmacokinetic; q4w Every 4 weeks; 
q8w Every 8 weeks; q12w Every 12 weeks; q28d Every 28 days; QLQ-LC13 13-item self-administered questionnaire for lung cancer; RNA Ribonucleic acid; 
SAE Severe Adverse Event; RECIST Response Evaluation Criteria in Solid Tumors; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; 
WHO World Health Organization; WT Body weight.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
29
Table 2
Schedule of activities for participants who have discontinued treatment with durvalumab /placebo
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months 
then  every 
2 months (±2 
weeks)a
For details, 
see Section
30
2
3
4
6
8
10
EORTC QLQ-C30, QLQ-LC13, 
and EQ-5D-5L as well as health 
resource use (HOSPAD)b
Participant questionnaires and information related to health resource use should be completed relative 
to the date of Cycle 1 Day 1 visit date(i.e. date of randomization/first dose) as follows: q4w (±1 week) 
for the first 8 weeks, every 8 weeks ±1 week thereafter for the first 48 weeks (per Table 1), then every 
12 weeks ±1 week thereafter until PFS2.
Physical examination (full)
X
8.2.2
Vital signs (temperature, 
respiratory rate, blood pressure, 
and pulse) 
X
8.2.3
Weight
X
X
X
8.2.3
Pregnancy testc
X
As clinically indicated
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.4
WHO/ECOG performance status
At timepoints consistent with tumour assessments; at 30, 60, and 90 days after treatment 
discontinuation; and then at initiation of subsequent anticancer therapyd
8.2.5
Subsequent anticancer therapye and 
second progression assessmentf, g
<------------------------------------------------------------------------------------------------------------------------>
8.1
Survival statush
X
X
X
X
X
X
X 
8.1.2
Haematology
X
X
X
Table 8
Clinical chemistry
X
X
X
Table 7
TSH (reflex free T3 or free T4i)
X
X
X
Table 7
PK assessment
X
8.5

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
31
lung cancer; PD Progression of disease; PFS2 Time from randomisation to second progression; PK Pharmacokinetic; q8w Every 8 weeks; q12w Every 
12 weeks; QLQ-LC13 13-item self-administered questionnaire for lung cancer; SAE Severe Adverse Event; RECIST Response Evaluation Criteria in Solid 
Tumors; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO World Health Organization

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
3 2
 
1. 2
S y n o psis
I nter nati o nal C o-or di nati n g I n vesti gat or
 1 0 6 Z h o n gs ha n 2 n d R d,
Y ue xi u, G ua n gz h o u, G ua n g d o n g 5 1 0 0 8 0 C hi na
Pr ot oc ol Title: 
A P hase III, Ra n d o mise d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, M ult ice ntre, St u d y of 
D ur val u ma b as C o ns o li dati on T hera p y i n Pat ient s wi t h L ocall y A d va nce d, U nresecta ble, N o n-
S m all Cell L u n g Ca ncer ( Sta ge III) W h o Ha ve N ot Pr o gresse d f oll o wi n g Defi niti ve, Plat i n u m-
Base d, C he m ora diat i on T hera p y ( P A CI FI C 5)
R ati o n ale: 
L u n g ca ncer has bee n t h e most c o m m o n  ca ncer i n t he w orl d f or se veral deca des, a n d t he 
maj orit y of  all lu n g ca ncers are n o n -s mall cell l u n g ca ncer. A p pr o xi matel y o ne-t hir d of t h ose 
patie nts wi t h n o n-s mall cell l u n g ca ncer prese nt wit h Sta ge III disease. C he m ora diati on has 
bee n t h e sta n dar d of care f or t hese patie nts f or a deca de, b ut pr o gressi o n-free s ur vi val is o nl y 
a b o ut 8 m o nt hs; ne w o pti o ns are nee de d.  T he P A CI FI C st u d y  has rece ntl y de m onstrate d t hat 
i m m u n o-o nc ol o g y  a ge nt d ur valu ma b as c o ns oli d ati o n  t hera p y wit h c o nc urre nt c he m ora diati o n 
t hera p y ca n pr olo n g pr o gressi o n -free s ur vi val t o a b o ut 
m o nt hs. T he P A CI FI C st u d y  
restricte d t he patie nt p o p ulatio n t o t h ose w h o ha ve recei ve d c o nc urre nt c he m ora diat i on 
t her a p y, b ut d ue t o t he n ote w ort h y t o xicit y of c o nc urre nt c he mor a di at i on t hera p y , ma n y 
patie nts ma y ha ve t o use a n ot her o pti o n, t hat is, se q ue nt ial c he m ora diati o n t hera p y. T his st u d y 
will e val uate if t he s uccess of c o nc urre nt c he m ora diat i on t hera p y  fol l owe d b y d ur val u ma b ca n 
be tra nslate d t o a br oa der p o p ulat i on i ncl u di n g t h ose w h o ha ve recei ve d se q ue ntial 
c he m ora diat i on t hera p y , w here a n u n met nee d re mai ns.  
O bjecti ves a n d E n d p oi nts
Pri m ar y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o assess t he efficac y of d ur val u ma b treat me nt 
c o m pare d wit h place b o i n ter ms of P F S i n 
ra n d o mise d partici pa nts wit h o ut se nsitizi n g 
E G F R m utati o ns or A L K rearra n ge me nts (i.e. 
mI T T p o p ulati o n)
P F S usi n g BI C R assess me nts acc or di n g t o 
R E CI S T 1. 1 a
Ke y sec o n d ar y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o f urt her assess t he efficac y of d ur val u ma b 
c o m pare d wit h place b o i n ter ms of O S i n t he 
mI T T
O S
P P D
P P D
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
33
 
Objectives and Endpoints
Secondary objective:
Endpoint/variable:
To further assess the efficacy of durvalumab 
treatment compared with placebo in terms of 
PFS in all randomised participants (i.e. ITT 
population)
PFS using BICR assessments according to 
RECIST 1.1a
To further assess the efficacy of durvalumab 
compared with placebo in terms of OS in the 
ITT 
OS
To further assess the efficacy of durvalumab 
compared with placebo in terms of OS24, ORR, 
DoR, PFS12, PFS18, PFS2, and TTDM in the 
mITT, and separately in ITT
OS24
ORR using BICR assessments according to 
RECIST 1.1b
DoR using BICR assessments according to 
RECIST 1.1b
PFS12 and PFS18 using BICR assessments 
according to RECIST 1.1
PFS2 as defined by local standard clinical practice
TTDM using BICR assessments according 
to RECIST 1.1b
To assess the PK of durvalumab
Concentration of durvalumab in blood and 
non-compartmental PK parameters (such as peak 
concentration and trough, as data allow) (sparse 
sampling)
To investigate the immunogenicity of 
durvalumab
ADA (confirmatory results: positive or negative; 
titres [ADA neutralising antibodies will also be 
assessed])
To assess symptoms and health-related quality 
of life in participants treated with durvalumab 
compared with placebo using EORTC QLQ-C30 
v3 and QLQ-LC13 in the mITT, and separately 
in the ITT
Change in patient-reported symptoms, functioning 
and global health status/QoL 
To investigate the relationship between a 
participant’s baseline tumour PD-L1 expression 
and efficacy outcomes with durvalumab 
compared with placebo in the mITT, and 
separately in the ITT
IHC analysis of tumoural PD-L1 expression and 
spatial distribution within the tumour 
microenvironment relative to efficacy outcomes 
(OS, PFS, and ORR)
Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab compared with placebo
AEs, physical examinations, vital signs, 
electrocardiograms, and laboratory findings
Exploratory objective:
Endpoint/variable:

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
3 5
 
pr o gressi o n free at 1 2 m o nt hs fr o m ra n d o misati o n; P F S 1 8
Pr o p orti o n of par tici pa nts ali ve a n d pr o gressi o n 
free at 1 8 m o nt hs fr o m ra n d o misati o n; P K P har mac o ki netic(s); Q L Q -L C 1 3
1 3- ite m self-a d mi nistere d 
q uesti o n naire f or l u n g ca ncer; Q o L Q ualit y of Life; R E CI S T
Res p o nse E val uati o n Criteria I n S oli d 
T u m o rs; 
; T T D M Ti me t o deat h or dista nt 
metastasis.
O ver all desi g n:
T his is a P hase III, ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d, m ult ice ntre st u d y assessi n g 
t he efficac y a n d safety of  d ur valu ma b c o m pare d wi t h place b o, as c o ns oli dati on t hera p y  in 
parti ci pa nts wi t h locall y a d va nce d, u nresecta ble, n o n -s mall c ell lu n g ca ncer ( Sta ge III), w h o 
ha ve n ot pr o gresse d f o ll owi n g defi nit i ve, plat i n u m-base d, c he m ora diati o n t hera p y.
P arti cip a nts will be re q uire d t o u n der g o a t w o -part scree n i n g pr ocess. I n scree ni n g visit part I, 
parti ci pa nts will be as ke d t o c o nse nt f or pr o vi di n g arc hi ve d or ne wl y ac q uire d t u m o ur sa m ples 
t o perf or m pr os pecti ve t u m o ur bi o mar ker assess me nt (f or P D-L 1; E G F R m utati o n a n d A L K 
m utati o n will be teste d, if t here's n o a vaila ble res ult fr o m l o cal la b orat ories). C o nse nt f or 
pr os pecti ve testi n g of t he arc hi ve d or ne wl y ac q uire d t u m o ur sa m ples c o ul d be gi ve n bef ore, 
d uri n g or after c he m ora diat i on. H o we ver, a n y  irra diate d sa mple is n ot acce pta bl e a n d a bi o ps y 
pr oce d ure d ur i n g scree ni n g peri o d is n ot all o we d. T he p ur p ose of scree ni n g visit part I is t o 
all o w m ore ti me f or t he t u m o ur sa m ple a nal ysis t o be c o n d ucte d.  Scree ni n g visit part II 
c o nse nt m ust be pr o vi de d after parti ci pa nts c o mplete C R T. A p pr o xi matel y 4 0 0 parti ci pa nts
( w h o are i n c o m plete res p o nse, partial res p o nse, or ha ve sta ble disease f oll owi n g defi nit i ve, 
pl at i n u m-base d, c o nc urre nt or se q ue ntial c he m ora diat i on t hera p y ) will be ra n d o mise d 
gl o ball y .
T he st u d y  will be c o n d ucte d i n a d o u ble- bli n d ma n ner. T he parti ci pa nt , t he I n vesti gat or, a n d 
t he st u d y site staff will be bli n de d t o st u d y treat me nt all o cat i on. T he st u d y  site p har macist 
a n d/ or ot her a p pr o priate site staff will be u n bli n de d t o st u d y  tr e at me nt.
Ra n d o misat i on will be stratifie d b y t he le vel o f P D- L 1 e x pressi o n ( P D - L 1 < 1 % vers us P D-
L 1 ≥1 %) a n d pri or t hera p y  (c o nc urre nt vers us se q ue ntial c he m ora diati o n t hera p y).
St u d y Peri o d:
Esti mate d date of first partici pa nt e nr olle d: Q uarter 4 2 0 1 8 rest of w orl d, Q uarter 4 2 0 1 9 C hi na
Esti mate d date of last partic i pa nt c o mplete d: ap pr o xi matel y Q uarter 1 2 0 2 7
N u m ber of p artici p a nts :
A p pr o xi matel y  4 0 0 parti ci pa nts w h o recei ve d c o nc urre nt c he m ora diat i on t hera p y  or 
se q ue ntial c h e m or a diat i on t hera p y  will be ra n d o mise d 2: 1 t o d ur valu ma b or pl ace b o.  T he 
n u m ber of parti cipa nts wi t h se nsitizi n g E G F R mut ati o n (e. g., e x o n 1 9 del etio n or e x o n 2 1 
L 8 5 8 R, e x o n 2 1 L 8 6 1 Q, e x o n 1 8 G 7 1 9 X, or e x o n 2 0 S 7 6 8I m utati o n) or A L K rearra n ge me nt 
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
36
 
randomised will be capped at approximately 7%.  In order to reflect global clinical practice, 
study will recruit at least 60% of participants who received prior cCRT. The majority of 
participants will be recruited in China. 
Screen failures are participants who do not fulfil the eligibility criteria for the study and 
therefore must not be randomised. Withdrawn participants will not be replaced. 
Treatments and treatment duration:
The study includes the two-part screening process (part I up to 84 days; part II up to 28 days), 
Treatment Period (until treatment discontinuation criterion is met), and Follow-up Period.
Durvalumab monotherapy

Durvalumab 1500 mg via intravenous infusion every 4 weeks, starting on Week 0, until 
confirmed radiological progression or other discontinuation criterion (Section 7.1) is met.  
(Please note, if a participant’s weight falls to 30 kg or below (≤30 kg), then the participant
should receive weight-based dosing equivalent to 20 mg/kg of durvalumab every 4 weeks 
after consultation between the Investigator and Study Physician, until the weight 
improves to above 30 kg (>30 kg), at which point the participant should start receiving 
the fixed dosing of durvalumab 1500 mg every 4 weeks).
Placebo

Intravenous infusion bags of normal saline (0.9% [w/v] sodium chloride) injection via 
intravenous infusion every 4 weeks, starting on Week 0, until confirmed radiological 
progression or other discontinuation criterion (Section 7.1) is met
Duration of treatment
Unless specific treatment discontinuation criteria (Section 7.1) are met, participants in the 
durvalumab and placebo treatment arms will continue therapy until confirmed radiological 
progression (defined in Appendix E).
Progression during treatment
During the Treatment Period, participants who are clinically stable at an initial Response 
Evaluation Criteria in Solid Tumors 1.1-defined radiological progression of disease may 
continue to receive study treatment at the discretion of the Investigator and participants.  A 
follow-up scan is to be collected after the initial Response Evaluation Criteria in Solid 
Tumors 1.1-defined radiological progression of disease, no less than 4 weeks after the prior 
assessment of progression of disease and no later than the next regularly scheduled imaging 
visit, and this scan is evaluated using the Confirmation of Radiological Progression criteria 
outlined in Appendix E.  Participants with confirmed PD who continue to receive study 
treatment at the discretion of the Investigator and participant (following consultation with 
AstraZeneca) can receive treatment until no longer having clinical benefit, and tumor 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
37
 
assessments should continue on their regular imaging schedule for the duration of treatment. If 
the subsequent scan does not confirm the immediate prior radiological progressive disease, 
scanning should continue until the next Response Evaluation Criteria in Solid Tumors 1.1-
defined radiological progression of disease, which in turn will require a subsequent scan 
evaluated using the Confirmation of Radiological Progression criteria outlined in Appendix E. 
Follow-up of participants post discontinuation of study treatment
Participants who have discontinued study treatment due to toxicity or symptomatic 
deterioration, clinical progression, or who have commenced subsequent anticancer therapy 
will be followed up with tumour assessments until Response Evaluation Criteria in Solid 
Tumors 1.1-defined radiological progression of disease plus an additional follow-up scan or 
until death (whichever comes first) and followed for survival. PRO questionnaires will be 
followed up until PFS2. 
Survival
All participants randomised in the study should be followed up for survival.
Independent Data Monitoring Committee:
The Independent Data Monitoring Committee will meet periodically in accordance with the 
IDMC charter to review safety assessments and make recommendations to continue, amend, 
or stop the study based on safety findings.  
Full details of the Independent Data Monitoring Committee procedures and processes can be 
found in the Independent Data Monitoring Committee Charter.
Statistical methods
The primary aim of the study is to compare the efficacy of durvalumab with placebo in terms 
of progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1 
(RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) in the modified 
intent-to-treat (mITT) population. Progression-free survival will be defined as the time from 
the date of randomisation until the date of objective disease progression or death by any cause, 
regardless of whether the participant withdraws from randomised therapy or receives another 
anticancer therapy prior to progression.
Secondary efficacy objectives include evaluation of overall survival in the mITT (key 
secondary), PFS and OS in the intent-to-treat (ITT), the proportion of participants alive at 24 
months from randomisation, objective response rate, duration of response, the proportion of 
participants alive and progression free at 12 months from randomisation, the proportion of 
participants alive and progression free at 18 months from randomisation, the time from 
randomisation to second progression, and time to death or distant metastasis. Other secondary 
objectives include an assessment of safety and tolerability, durvalumab pharmacokinetic 

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
3 8
 
e x p os ure, i m m u n o ge nicit y, a n d pat ient -re p orte d o utc o mes.  E x pl orat or y o bjecti ves are als o 
i ncl u de d.
Efficac y data will be s u m marise d a n d a nal yse d base d o n t he mI T T ( pri mar y p o p ulat i on), a n d 
se paratel y base d o n t he I T T p o p ulat i on, a n d t he treat me nt ar ms will be c o m pare d o n t he basis 
of  ra n d omise d treat me nt, re gar dless of t he treat me nt act uall y recei ve d.  Parti ci pa nts w h o were 
ra n d omise d b ut di d n ot s u bse q ue nt l y g o o n t o recei ve i n vesti gati onal pr o d uct are i ncl u de d i n 
t he mI T T/I T T p o p ulat i on. Ot her p o p ulati o ns i ncl u de p har mac o ki net ics a n d safety.
A p pr o xi matel y  4 0 0 parti ci pa nts w h o recei ve d c o nc urre nt c he m ora diat i on t hera p y  or 
se q ue ntial c h e m or a diat i on t hera p y  will be ra n d o mise d 2: 1 t o d ur valu ma b or pl ace b o.  Of t he 
4 0 0 ra n d o mise d parti cipa nts , a p pr o xi matel y 3 7 5 parti ci pa nts wi t ho ut se nsit izi n g e pi der mal 
gr o wt h fact or rece pt or ( E G F R) m utati o ns or a na plastic l y m p h o ma ki nase ( A L K) 
rearra n ge me nts will be i ncl u de d i n t he mI T T p o p ulati o n.
T he fi nal ( pri mar y) P F S a nal ysis f or s u peri orit y will  be p erf or m e d i n t he mI T T w he n 
w hic he ver of  t he f oll owi n g c o n di tio ns ha ve bee n met first:

R eac hi n g a p pr o xi matel y  
 BI C R pr o gressi o n -free s ur vi val e ve nts i n t he  
 acr oss 
t he d ur val u ma b a n d place b o treat me nt ar ms (a p pr o xi matel y  
 mat urit y)
O R

A p pr o xi ma t el y  
mo n t hs fol l ow- u p f r o m last partici pa nt ra n d o mize d t o t he st u d y. 
T he fi nal O S a nal ysis will be perf or me d w he n reac hi n g a p pr o xi matel y  
 deat h e ve nts
 
mat urit y)  or a p pr o xi matel y 
 m o nt hs f o ll ow- u p fr o m  t h e last parti ci pa nt ra n d o mizati on i n t he 
mI T T acr oss t he d ur val u ma b a n d place b o treat me nt ar ms, w hic he ver occ urs first.
T he st u d y  will ra n d o mise a p pr o xi matel y 4 0 0 partici pa nts w h o recei ve d c o nc urre nt 
c he m ora diat i on t hera p y  or se q ue ntial c h e m or a diat i o n t hera p y. Of t he 4 0 0 ra n d o mise d 
parti ci pa nts, a p pr o xi matel y 3 7 5 part ici pa nts wi t ho ut se nsit izi n g E G F R m utati o ns or A L K 
rearra n ge me nts will be i ncl u de d i n t he mI T T p o p ulati o n.  If t he tr ue pr o gressi o n-free s ur vi val 
hazar d rati o is  
 wit h a n est i mate d 
BI C R P F S e ve nts i n t he mI T T, t he st u d y  will 
pr o vi de at l east  
 p o wer t o de m o nstrate a statisticall y si g nifica nt differe nce f or 
pr o gressi o n -free s ur vi val with a 
 t his tra nslates t o a n 
a p pr o xi matel y
m o nt h be nefit i n me dia n pr o gressi o n- free s ur vi val o ver 
m o nt hs o n pl ace b o. 
T he s mallest treat me nt differe nce t hat w o ul d be statist icall y si g nifica nt is a hazar d rati o of 
 
T he o verall al p ha le vel f or c o m paris o n of t he sec o n dar y ke y  e n d p oi nt of o verall s ur vi val 
 will be 
. T he fi nal o verall 
a nal ysis f or s u peri orit y will be perf or me d w he n reac hi n g a p pr o xi matel y  
 deat h e ve nts 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
3 9
 
 mat urit y) or a p pr o xi matel y  
m o nt hs f o ll ow- u p fr o m t he last partici pa nt
ra n d omizat i on , w hic he ver occ urs first. If t he tr ue overall s ur vi val hazar d rati o is  
, wit h a n 
esti mate d  
 O S e ve nts, t his st u d y will pr o vi de 
 p o wer t o de mo nstrate a stati sticall y 
sig nifica nt differe nce f or o verall s ur vi val, ass u mi n g a  
 2 -side d si g nifica nce le vel ( wit h 
o verall 2 -si de d al p ha f or O S as 
. T his tra nslates t o a 
-m o nt h be nefit i n me dia n o verall 
s ur vi val o ver
m o nt hs o n place b o. T he s mallest treat me nt differe nce t hat w o ul d be 
statisticall y si g nifica nt is a hazar d ratio of  
U p t o t w o i nteri m a nal yses f or O S will be 
c o n d ucted: 1) at t he sa me ti me as pri mar y P F S a nal ysis a n d 2) at a p pr o xi matel y 
 m o nt hs 
after t he O S first i nteri m a nal ysis, wit h a p pr o xi matel y 
 of t he tar get e ve nts 
res pecti vel y. If t he e x pecte d D C O f or O S fi nal a nal ysis is withi n 
 m o nt hs after t he O S first 
i nteri m a nal ysis, t he O S sec o n d i nteri m a nal ysis ma y be re mo ve d. 
If t he i nteri m res ults d o n ot meet t he criteri o n of st o p pi n g f or s u peri ority f or a gi ve n 
h y p ot hesis, t he n f o ll ow- u p will c o nti n ue u nt il t he fi nal a nal ysis, fol l owi n g w hic h t he 
h y p ot hesis will be re- teste d.
Pr o gressi o n -free s ur vi val will be a nal yse d usi n g a stratifie d l o g-ra n k test (stratifie d f or t he 
le vel of P D-L 1 e x pressi o n [ P D -L 1 < 1 % or P D -L 1 ≥1 %] a n d pri or t hera p y  [c o nc urre nt or 
se q ue ntial c h e m or a diat i on t hera p y ]).  T he effect of treat me nt will be est i mate d b y t he hazar d 
r atio t o get her wit h c orres p o n di n g 9 5 % c o nfi de nce i nter val a n d p -val ue.
S af et y a n d t olera bilit y data will be prese nte d b y  tr e at me nt ar m usi n g t he safety p o p ul at i on.  
1. 3
Sc he m a
T he ge neral st u d y  desi g n is s u m marise d i n 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI AL A N D P R O P RI E T A R Y
4 0
 
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
41
 
2
INTRODUCTION
Investigators should be familiar with the durvalumab IB.
2.1
Study rationale
By 2012 there were an estimated 1.8 million new cases of lung cancer, representing 12.9% of 
all new cancers.  It was also the most common cause of death from cancer, with 1.59 million
deaths (19.4% of the total) (GLOBOCAN 2012).  NSCLC represents approximately 80% to 
85% of all lung cancers, and 30% of patients present with Stage III disease.  Standard 
treatment for patients with a good performance status and unresectable Stage III NSCLC is 
platinum-based doublet chemotherapy and radiotherapy administered cCRT).  However, the 
median PFS among patients who have received chemoradiotherapy is poor (approximately 8 
months), and only 15% of patients are alive at 5 years.  The PACIFIC study has recently 
demonstrated that immuno-oncology agent durvalumab as consolidation therapy with 
concurrent chemoradiation therapy (cCRT) can prolong PFS to about 17 months (Antonia et al 
2017).  
Chemoradiotherapy often induces initial tumour shrinkage and systemic control followed by 
eventual relapse.  The initial tumour shrinkage observed in some patients following 
chemoradiotherapy is the result of cell death and tumour damage.  Chemoradiotherapy-
induced cell death can enhance the ability of the immune system to recognise and respond to 
the tumour through enhanced antigen release and presentation.  Triggering or augmenting an 
antigenic antitumour response with chemoradiotherapy, followed by an anti-programmed 
death ligand 1 (PD-L1) therapy, could enhance antitumour activity by improving local control 
and decreasing systemic spread.
Both chemotherapy and radiotherapy can up-regulate the expression of PD-L1 (Zhang et al 
2008b, Butts et al 2014, Deng et al 2014) due to the release of cytokines and other 
inflammatory molecules, which could therefore make such tumours sensitive to a PD-L1 
directed therapy.  The study by Deng et al showed that therapeutic blockade of PD-L1 could 
enhance thymus gland lymphocyte (T cell) effector function when PD-L1 is expressed in 
chronically inflamed tissues and tumours (Deng et al 2014).  The study demonstrated that PD-
L1 was upregulated in the tumour microenvironment after ionizing radiation and that 
administration of anti–PD-L1 enhanced the efficacy of radiation through a cytotoxic T 
lymphocyte (T cell)-dependent mechanism.  Concomitant with radiation-mediated tumour 
regression, it was also observed that radiation and anti–PD-L1 synergistically reduced the 
local accumulation of tumour-infiltrating myeloid-derived suppressor cells that suppress T 
cells and alter the tumour immune microenvironment (Butts et al 2014, Deng et al 2014).  
Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction 
with programmed death 1 (PD-1) and cluster of differentiation (CD)80 (B7.1).  Durvalumab 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
42
 
following cCRT has shown promise in the PACIFIC study, an ongoing, randomised, double-
blind, placebo-controlled, Phase III study to evaluate the efficacy and safety of durvalumab 
consolidation therapy in patients with locally advanced, unresectable Stage III NSCLC, who 
have not progressed following definitive, platinum-based, cCRT. The durvalumab treatment 
demonstrated a median PFS improvement of 11.2 months when compared with placebo, and 
durvalumab reduced risk of death and progression by 48% compared to placebo. Consistent 
OS and PFS benefit with durvalumab was observed across all prespecified subgroups with the 
exception of the EGFR-positive subgroup, for which survival benefit was uncertain (Faivre-
Finn et al 2021). Therefore, in this study, participants harbouring EGFR mutations and ALK 
alterations will be removed from the primary objective and key secondary objective. 
Other endpoints such as proportion of participants alive and progression free at 12 months 
from randomisation (PFS12), proportion of participants alive and progression free at 
18 months from randomisation (PFS18), objective response rate (ORR), time to death or 
distant metastasis (TTDM), and duration of response (DoR) also provided support of the 
clinical benefit seen from durvalumab in this population (see Section 2.3.1 for details).
These combined data led to the hypothesis underlying this study: that durvalumab added after 
definitive chemoradiation therapy would provide clinical benefit by potentiating the pro-
inflammatory effects of the definitive therapy.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the IB.
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognised by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumours 
(Dunn et al 2004).
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation.  The programmed death 1 (PD-1) receptor (CD279) is expressed on the 
surface of activated T cells (Keir et al 2008).  It has 2 known ligands: PD-L1 (B7-H1; CD274) 
and programmed death ligand 2 (PD-L2; B7-DC; CD273) (Okazaki and Honjo 2007).  PD-1 
and PD-L1/PD-L2 belong to a family of immune checkpoint proteins that act as co-inhibitory 
factors, which can halt or limit the development of T-cell response.  When PD-L1 binds to 
PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production 
and suppresses T-cell proliferation.  Tumour cells exploit this immune checkpoint pathway as 
a mechanism to evade detection and inhibit immune response.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
43
 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016).  Importantly, PD-L1 is commonly over-expressed on tumour cells or on 
non-transformed cells in the tumour microenvironment (Pardoll 2012).  PD-L1 expressed on 
the tumour cells binds to PD-1 receptors on the activated T cells, leading to the inhibition of 
cytotoxic T cells.  These deactivated T cells remain inhibited in the tumour microenvironment.  
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is 
exerted by tumour cells in response to endogenous anti-tumour activity.
The inhibitory mechanism described above is co-opted by tumours that express PD-L1 as a 
way of evading immune detection and elimination.  The binding of an anti-PD-L1 agent to the 
PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on immune cells.  This activity overcomes PD-L1-mediated inhibition of anti-tumour 
immunity.  While functional blockade of PD-L1 results in T-cell reactivation, this mechanism 
of action is different from direct agonism of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers.  Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance anti-tumour immune responses in patients
with cancer.  Results of pre-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance anti-tumour immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 
2008a) with responses that tend to be more pronounced in patients with tumours that express 
PD-L1 (Powles et al 2014, Rizvi et al 2015a, Segal et al 2015).  In addition, high mutational 
burden (eg, in bladder carcinoma; Alexandrov et al 2013) may contribute to the responses 
seen with immune therapy.
Pre-clinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as CTLA-4 and PD-L1 has promising clinical 
activity.  Ipilimumab was first granted United States (US) Food and Drug Administration 
(FDA) approval for the treatment of metastatic melanoma and is currently under investigation 
for several other malignancies.  Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and 
atezolizumab, an anti-PD-L1 agent, have been granted approvals by agencies for the treatment 
of a number of malignancies including metastatic melanoma, squamous and non-squamous 
cell NSCLC, squamous cell carcinoma of the head and neck, and urothelial carcinoma.  In 
addition, there are data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a 
wide range of tumour types.
2.2.2
Durvalumab
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 4
 
P D -1 o n T cells a n d C D 8 0 ( B 7. 1) o n i m m u ne cells. It is bei n g de vel o pe d b y Astra Ze neca f or 
use i n t he treat me nt of ca ncer.  ( Me dI m m u ne is a w h oll y o w ne d s u bsi diar y of Astra Ze neca; 
Astra Ze neca/ Me dI m m u ne will be referre d t o as Astra Ze neca t hr o u g h o ut t his d oc u me nt.) T he 
pr o p ose d m ec ha nis m o f actio n f or d ur val u ma b is i nterfere nce i n t he i nteracti o n of P D -L 1 wi t h 
P D - 1 a n d C D 8 0 ( B 7. 1).  Bl ocka de of P D -L 1/ P D -1 a n d P D -L 1/ C D 8 0 i nteracti o ns releases t he 
i n hi biti on o f i m m u ne res p o nses, i ncl u di n g t h ose t hat ma y res ult i n t u m o ur eli mi nati on.  I n 
vit r o stu dies de m o nstrate t hat d ur val u ma b a nta g o nises t he i n hi bit or y effect of P D -L 1 o n 
pri mar y  hu ma n T cells res ult i n g i n t he rest ore d pr oliferati on of i nterfer o n (I F N) -γ (Ste wart et 
al 2 0 1 5).  I n vi v o st u dies ha ve s h o w n t hat d ur val u ma b i n hi bit s t u mo ur g r o wt h i n xe n o graft 
m o dels via a T -cell-de pe n de nt m ec ha nis m (Ste wart et al  2 0 1 5).  Base d o n t hese data, 
d ur val u ma b is e x pecte d t o sti m ulate t he pati e nt ’s a nti-t u mo ur i m m u ne res p o nse b y bi n di n g t o 
P D -L 1 a n d s hift i n g t he bala nce t o war ds a n a nti-t um o ur res p o nse.  D ur val u ma b has bee n 
e n gi neere d t o re d uce a nti b o d y-de pe n de nt cell ular c y t ot o xicit y a n d c o mple me nt -de pe n de nt 
c yt ot o xicit y.
T o date, d ur val u ma b has b ee n gi ve n t o more t ha n  
 pati e nts as part of o n g oi n g st u dies 
eit her as mo n ot hera p y  or i n c o m bi nati on wi t h ot her a ntica ncer a ge nts.  Details o n t he safet y 
pr ofile of d ur val u ma b m o n ot hera p y  are s u m marise d i n Secti on  4. 3. 1 a n d Secti o n 8. 3. 1 3 .  
Refer t o t he c urre nt d ur val u ma b I B f or a c o mplete s u m mar y of pre -cli nical a n d cli nical 
i nf or mat i on i ncl u di n g safety,  efficac y, a n d P K.
2. 3
Be nefit/ris k assess me nt
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d a d verse e ve nts ( A Es) of d ur val u ma b ma y be f o u n d i n t he I B.
See Secti o n  9. 6. 1 a n d A p pe n di x A f or i nf or mati o n re gar di n g t he Data M o nit ori n g C om mittee.
2. 3. 1
P ote nti al be nefits of d ur v al u m a b
D ur val u ma b, a h u ma n m o n ocl o nal a nt i b o d y directe d a gai nst h u ma n P D-L 1, ma y  offer be nefit 
t o t his pati e nt p o p ul atio n. I n t he P A CI FI C st u d y , d ur val u ma b treat me nt de m o nstrate d a 
statisticall y si g nifica nt ( hazar d rati o [ H R]: 0. 5 2; 9 8. 9 % c o nfi de nce i nter val [ CI]: 0. 3 9, 0. 7 0; p-
val ue less t ha n 0. 0 0 0 1) a n d cli nicall y mea ni n gf ul pr ol o n gati o n o f P F S (acc or di n g t o Bli n de d 
I n de pe n de nt Ce ntral Re vie w [ BI C R] assess me nt of R E CI S T 1. 1) c o m pare d wit h place b o i n 
patie nts wi t h locall y a d va nce d, u nresecta ble N S C L C w h ose disease ha d n ot pr o gresse d after 
pl at i n u m-base d c C R T. T he ris k of pr o gressi o n or deat h was re d uce d b y  4 8 % o n t he 
d ur val u ma b treat me nt c o m pare d wit h place b o. T he d ur val u ma b treat me nt de m o nstrate d a 
me dia n P F S i m pr o ve me nt of 1 1. 2 m o nt hs w he n c o m pare d wit h place b o (t he me dia n P F S was 
1 6. 8 m o nt hs i n t he d ur val u ma b gr o u p a n d 5. 6 m o nt hs i n t he place b o gr o u p). T he P F S b e nefit 
i n fa v o ur of d ur val u ma b was o bser ve d irres pecti ve of P D-L 1 e x pressi o n ( H R: 0. 5 9; 9 5 % CI: 
0. 4 3, 0. 8 2 f or less t ha n 2 5 % a n d H R: 0. 4 1; 9 5 % CI: 0. 2 6, 0. 6 5 f or at least 2 5 %).  
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
45
 
The improvement of PFS is supported by the clinically meaningful incremental ORR of 12% 
over placebo (28.4% in the durvalumab group vs 16.0% in the placebo group; nominal p-value 
less than 0.001). The responses were durable with the median DoR not reached in the 
durvalumab group, compared to 13.8 months in the placebo group. TTDM was longer for the 
durvalumab group compared to the placebo group (HR: 0.52; 95% CI: 0.39, 0.69; nominal 
p-value <0.0001).  The median TTDM was 23.2 months in the durvalumab group, compared 
to 14.6 months in the placebo group.
In addition, durvalumab treatment demonstrated a statistically significant OS benefit with 
clinically meaningful improvement compared to placebo (stratified HR for death, 0.68; 
99.73% CI, 0.469 to 0.997; p=0.0025). The 4-year survival update demonstrated a long-term 
clinical benefit with durvalumab after chemoradiotherapy. Median OS were 47.5 months in 
durvalumab arm, compared to 29.1 months in placebo arm, with 18.4 months prolongation. 
The OS rate remains higher for durvalumab compared to placebo at 36 month (56.7% vs 
43.6%, respectively) and 48 month (49.6% vs 36.3%, respectively) landmarks.
Please refer to the current IB for clinical experience with durvalumab.
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against tumour cells.  By stimulating the immune system, however, there is the potential for 
adverse effects on normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues.  These risks are 
generally events with a potential inflammatory or immune mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ
system, and are most commonly seen as gastrointestinal AEs such as colitis and diarrhoea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypo- and hyper-
thyroidism.  
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhoea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis, adrenal insufficiency, hyper- and hypo-
thyroidism, and type I diabetes mellitus), hepatitis/increases in transaminases, 
nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, rash/dermatitis, 
myocarditis, myositis/polymyositis, other rare or less frequent inflammatory events including 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
46
 
neurotoxicities, infusion-related reactions, hypersensitivity reactions, and infections/serious 
infections.
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs reported very commonly include events such as fatigue, 
diarrhoea, nausea and vomiting, decreased appetite, and muscle and joint pain.  A total of 5% 
to 10% of participants discontinued the drug due to an AE.  Please see the current version of 
the IB for a detailed summary of the monotherapy data including AEs, severe adverse events 
(SAEs), and Common Toxicity Criteria (CTC) Grade 3 to 5 events reported across the 
durvalumab program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
2.3.3
Overall benefit/risk
In summary, the potential for clinical benefit associated with inhibition of the PD-1/PD-L1 
pathway, as supported by objective responses observed in earlier studies in participants with 
NSCLC and demonstrated in terms of PFS by a Phase III study in participants with locally 
advanced unresectable Stage III NSCLC after cCRT, outweighs the known and potential risks 
based on the AEs reported in participants treated with durvalumab and other PD-1/PD-L1 
inhibitors.  Thus, the benefit/risk assessment favours the conduct of this proposed study.
The safety of participants in this study will be assessed by an Independent Data Monitoring 
Committee (IDMC) via ongoing safety assessments periodically in accordance with the IDMC 
charter.
3
OBJECTIVES AND ENDPOINTS
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab treatment 
compared with placebo in terms of PFS in 
randomised participants without sensitizing 
EGFR mutations or ALK rearrangements (i.e. 
mITT)
PFS using BICR assessments according to 
RECIST 1.1a

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
47
 
Objectives and Endpoints
Key secondary objective:
Endpoint/variable:
To further assess the efficacy of durvalumab 
compared with placebo in terms of OS in the
mITT
OS
Secondary objective:
Endpoint/variable:
To further assess the efficacy of durvalumab 
treatment compared with placebo in terms of 
PFS in all randomised participants (i.e. ITT)
PFS using BICR assessments according to 
RECIST 1.1a
To further assess the efficacy of durvalumab 
compared with placebo in terms of OS in the 
ITT
OS
To further assess the efficacy of durvalumab 
compared with placebo in terms of: OS24, ORR, 
DoR, PFS12, PFS18, PFS2, and TTDM in the 
mITT, and separately in the ITT
OS24
ORR using BICR assessments according to 
RECIST 1.1b
DoR using BICR assessments according to 
RECIST 1.1b
PFS12 and PFS18 using BICR assessments 
according to RECIST 1.1
PFS2 as defined by local standard clinical practice
TTDM using BICR assessments according 
to RECIST 1.1b
To assess the PK of durvalumab
Concentration of durvalumab in blood and 
non-compartmental PK parameters (such as peak 
concentration and trough, as data allow) (sparse 
sampling)
To investigate the immunogenicity of 
durvalumab
ADA (confirmatory results: positive or negative; 
titres [ADA neutralising antibodies will also be 
assessed])
To assess symptoms and health-related quality 
of life in participants treated with durvalumab 
compared with placebo using EORTC QLQ-C30 
v3 and QLQ-LC13 in the mITT, and separately 
in the ITT
Change in patient-reported symptoms, functioning 
and global health status/QoL 
To investigate the relationship between a 
participant’s baseline tumour PD-L1 expression 
and efficacy outcomes with durvalumab 
compared with placebo in the mITT, and 
separately in the ITT
IHC analysis of tumoural PD-L1 expression and 
spatial distribution within the tumour 
microenvironment relative to efficacy outcomes 
(OS, PFS, and ORR)
Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab compared with placebo
AEs, physical examinations, vital signs, 
electrocardiograms, and laboratory findings 

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 9
 
q uesti o n naire; I H C I m m u n o hist oc he mical; ir R E CI S T I m m u ne-relate d Res p o nse E val uati o n Criteria I n 
S oli d T u m ors; O R R O bjecti ve res p o nse rate; O S
O verall s ur vi val; O S 2 4
Pr o p orti o n of partici pa nts ali ve 
at 2 4 m o nt hs fr o m ra n d o misati o n; P D -L 1
Pr o gr a m me d deat h li ga n d 1; P F S Pr o gressi o n free s ur vi val; 
P F S 2 Ti me fr o m ra n d o misati o n t o sec o n d pr o gressi o n; P F S 1 2 Pr o p orti o n of partici pa nts ali ve a n d 
pr o gressi o n free at 1 2 m o nt hs fr o m ra n d o misati o n; P F S 1 8 Pr o p orti o n of partici pa nts ali ve a n d pr o gressi o n 
free at 1 8 m o nt hs fr o m ra n d o misati o n; P K P har mac o ki netic(s); Q L Q -L C 1 3
1 3- ite m self-a d mi nistere d 
q uesti o n naire f or l u n g ca ncer; Q o L Q ualit y of Life; R E CI S T Res p o nse E val uati o n Criteria I n S oli d 
T u m o rs; T T D M Ti me t o deat h or dista nt metastasis; 
; T cell T 
l ym p h oc y t e.
4
S T U D Y D E SI G N
4. 1
O ver all desi g n
T his st u d y  is a P hase III, ra n d omise d, d o u ble -bli n d, pl ace b o -c o ntr olle d, m ult ice ntre st u d y 
assessi n g t he efficac y a n d safet y of  d ur val u ma b c o m pare d wit h place b o as c o ns oli dati on 
t hera p y in partici p a nts wit h l ocall y a d va nce d, u nresecta ble N S C L C ( Sta ge III) w h o ha ve n ot 
pr o gresse d f o ll owi n g defi nit i ve, plati n u m-base d, c he m ora diat i on t hera p y .
A p pr o xi matel y  4 0 0 parti ci pa nt s wit h l ocall y a d va nce d, u nresecta ble N S C L C ( Sta ge III) w h o 
recei ve d c C R T or s C R T will be ra n d omise d gl o ball y . T hese partici p a nts will be i n c o m p lete 
res p o nse ( C R), partial res p o nse ( P R), or ha ve sta ble disease ( S D) f oll owi n g defi nit i ve, 
pl at i n u m-base d, c o nc urre nt or se q ue ntial c he m ora diat i on t hera p y .
P arti cip a nts m u st ha ve hist ol o gicall y or c yt olo gi call y d oc u me nte d N S C L C a n d prese nt wit h 
l ocall y a d va nce d, u nresecta ble ( Sta ge III) disease (acc or di n g t o Versi o n 8 of t he I nter nati o nal 
Ass oci at i on f or t he St u d y of L u n g Ca ncer [I A S L C] Sta gi n g Ma n ual i n T h oracic O nc ol og y . 
T he n u m ber of parti ci pa nts wi t h a se nsitizi n g E G F R m utati o n (e. g., e x o n 1 9 delet i on or e x o n 
2 1 L 8 5 8 R, e x o n 2 1 L 8 6 1 Q, e x o n 1 8 G 7 1 9 X, or e x o n 2 0 S 7 6 8I m utati o n) or A L K 
rearra n ge me nt will be ca p pe d at a p pr o xi matel y 7 % of t he t otal n u m ber of parti ci pa nts
ra n d omise d. I n or der t o reflect gl o bal cli nical practice, st u d y will rec r uit at least 6 0 % of 
parti ci pa nts w h o recei ve d pri or c C R T. T he maj orit y of  parti ci pa nts will be recr uite d i n C hi na. 
P arti cip a nts will be ra n d o mise d i n a 2: 1 rati o ( d ur val u ma b t o place b o) t o 1 of 2 ar ms:

D ur val u ma b ( 1 5 0 0 m g e ver y 4 wee ks [ q 4 w] i ntra ve n o usl y [iv] u ntil c o nfir me d 
r a diol o gical  pr o gressio n , or ot her disc o nti n uati on cri t erio n is met)

Pl ace b o ( matc hi n g place b o f or i nf usi o n q 4 w i v u ntil c o nfir me d ra di o l ogi cal pr o gressio n , 
or ot her disc o nt i n uati on cri t erio n is met)
Ra n d o misat i on will be stratifie d b y t he l e v el of P D-L 1 e x pressi o n ( P D -L 1 < 1 % or P D -
L 1 ≥1 %] a n d pri or t hera p y  (c C R T or s C R T).  Parti cipa nts m ust n ot ha ve pr o gresse d f o ll owi n g 
defi nit i ve, plati n u m-base d, c o nc urre nt or se q ue nt ial C R T (see Secti o n 5. 1 f or details).  F or 
t hose partici pa nts ra n d o mise d t o t he place b o ar m, n o cr oss o ver t o t he d ur val u ma b ar m is 
per mitte d; si milarl y , t h ose partici pa nts ra n d o mise d t o t he d ur val u ma b ar m ca n n ot cr oss o ver t o 
t he place b o ar m.
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
50
 
Administration of study treatment (ie, investigational product [IP] durvalumab or placebo) 
will commence on Day 1 following randomisation to durvalumab or placebo after 
confirmation of eligibility and will continue on a q4w schedule until confirmed radiological 
progression, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent, or other reasons which reaching the discontinuation criteria (Section 7.1). 
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) 
will be performed at the times specified in Table 1 and Table 2.  RECIST 1.1 measurements 
(using BICR assessments) will be used to derive the primary variable of PFS and secondary 
variables of ORR, DoR, PFS12, and PFS18.
Once a participant has had objective radiological progression recorded and has discontinued 
study treatment, the participant will be followed up for survival status monthly at the first 4
months, and then every 2 months until death, withdrawal of consent, or the end of the study.
Once the planned statistical analyses have been performed, the analysis portion of the clinical 
study will have been completed.  See Section 4.4 for more information on study completion. 
In the event that a roll-over or safety extension study is available at the time of the final data 
cutoff (DCO) and database closure, participants currently receiving treatment with 
durvalumab may be transitioned to such a study, and the current study would reach its end.  
The roll-over or safety extension study would ensure treatment continuation with visit 
assessments per its protocol.  Any participant who would be proposed to move to such a study 
would be given a new informed consent.
For an overview of the study design see Figure 1, Section 1.3.  For details on treatments given 
during the study, see Section 6.1 Treatments Administered.  Guidelines for the management of 
toxicities are described in Section 8.4.5.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.
4.1.1
Study conduct mitigation during study disruptions due to cases of civil 
crisis, natural disaster, or public health crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS- CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study Sponsor to discuss whether the mitigation 
plans below should be implemented.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
51
 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent, 
the Informed Consent Form (ICF) should be signed at the participant’s next contact with 
the study site).

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix I.
4.2
Scientific rationale for study design
The current SoC for unresectable Stage III disease is cCRT.  The rationale for combining 
chemotherapy and radiotherapy is to combine the benefits of radiotherapy in terms of local 
regional control with the benefits of chemotherapy in terms of reducing the risks of metastatic 
disease.  With CRT, there is the potential for chemotherapy, given during a course of 
radiotherapy, to enhance the effectiveness of radiotherapy (i.e. radiosensitisation) (O'Rourke 
et al 2010).  
For patients with unresectable Stage III disease, combined modality therapy (chemoradiation) 
is superior to radiation alone, and cCRT is superior to sequential therapy (National 
Comprehensive Cancer Network [NCCN Guidelines 2014). cCRT regimens that may be used 
for all histologies for initial treatment include cisplatin/etoposide, cisplatin/vinblastine, or 
carboplatin/paclitaxel (TAXOL®).  For non-squamous NSCLC, other cCRT regimens include 
cisplatin/pemetrexed (ALIMTA®) (NCCN Guidelines 2014).  The guidelines for the 
treatment of patients with unresectable Stage III NSCLC in Europe (Vansteenkiste et al 2013) 
and Japan (Saijo et al 2010) are in line with those used in the US.  The best survival outcomes 
can be achieved in patients with Stage III NSCLC with concurrent chemoradiation instead of 
sequential; however, cCRT also has a higher rate of Grade 3 or 4 esophagitis than sCRT.  
Consequently, cCRT is only given to patients with minimal or no comorbidities, a good 
general condition, and who are relatively young.  Decelerated approaches such as sCRT may 
be a valuable alternative for patients who are not eligible for cCRT (De Ruysscher et al 2009).
Despite longer survival benefit comparing with sCRT, the majority of patients who receive 
cCRT inevitably progress (PFS is usually short; approximately 8 months), and 5-year OS is 
approximately 15% (Butts et al 2014).  Though advances have been made in improving 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
52
 
survival from Stage III NSCLC by optimising local control, evidence suggests that cCRT also 
does not reduce the risk of distant relapse.  
With fewer cycles and, in some cases, lower doses of chemotherapy being delivered in the 
concurrent setting, several studies have assessed whether delivering induction or consolidation 
treatment will improve survival.  A pooled analysis of 41 Phase II/III trials confirmed that 
there remains no evidence to suggest that consolidation chemotherapy after cCRT improves 
survival for patients with Stage III NSCLC, and current guidelines continue to recommend 
cCRT alone for the treatment of inoperable Stage III NSCLC (Bayman et al 2014).  However, 
intensification of both radiotherapy and concurrent chemotherapy may result also into 
excessive toxicity or incomplete treatment. There is still, therefore, a significant unmet 
medical need for additional treatment options for use in this patient population to improve on 
PFS and OS (see Section 2.2).
The consolidation setting post CRT may be ideal to evaluate the efficacy of immunotherapy, 
which is aimed at boosting the ability of the patient’s immune system to eliminate cancer 
cells.  Both chemotherapy and radiotherapy can up-regulate the expression of PD-L1 (Zhang 
et al 2008b, Deng et al 2014) due to the release of cytokines and other inflammatory 
molecules, which could therefore make such tumours sensitive to a PD-L1-directed therapy.  
Durvalumab, an antibody that blocks the interaction between PD-L1 and its receptors, may 
relieve PD-L1-dependent immunosuppressive effects and therefore enhance the cytotoxic 
activity of antitumour T cells.  Emerging clinical data from the PACIFIC study have proven 
this concept (see Section 2.3.1) by providing early, statistically significant evidence of clinical 
activity and a manageable safety profile.  This study will further evaluate durvalumab in 
patients with unresectable Stage III NSCLC in both cCRT and sCRT to ascertain if the 
success of cCRT can also be applied to sCRT.  
Durvalumab will be compared against placebo in this study as although durvalumab 
demonstrated a PFS benefit in this setting, it is not yet available (i.e approved and/or 
reimbursed) as a treatment option in countries where this study is conducted. Furthermore the 
2:1 randomised allocation ensures there is more opportunity for participants to receive 
durvalumab than placebo in this study. 
4.2.1
Timing of treatment with durvalumab relative to concurrent or 
sequential chemoradiation therapy
Non-clinical data show that both chemotherapy and ionising radiation up-regulate PD-L1 
expression (Deng et al 2014, Zhang et al 2008b).  In addition, chemotherapy and radiotherapy 
both release new antigens, leaving the cancer to act as an in situ vaccine that can elicit 
tumour-specific T cells.  The PACIFIC study showed that the subset of patients who started 
durvalumab <14 days after CRT had superior results than the subset of patients who started 14 
to 42 days after CRT.  Thus, starting durvalumab as close as possible to the completion of the 

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 3
 
C R T w he n a nti ge n release a n d P D- L 1 e x pressi o n are m ost li kel y t o be at t heir ma xi m u m will 
h y p ot h eti call y r es ult in t he m ost o pti mal  be nefit.
4. 2. 2
Pre dicti ve bi o m ar kers a n d r ati o n ale f or a n u nselecte d p o p ul ati o n i n 
St u d y D 9 3 3 Y C 0 0 0 0 1
F or t hi s st u d y, we pr o p ose n ot t o e xcl u de a n y bi omar ker -defi ne d s u b p o p ulat i on a n d, w here 
p ossi ble, t o caref ull y assess t h ese pati e nt c haracterist ics i n t he c o nte xt of t his st u d y, a n d ot her 
st u dies.
T u m o ur bi o psies a n d via ble ti ss ue ma y be diffic ult t o o btai n p ost C R T.  T u m o urs e v ol ve with 
ti me a n d i n res p o nse t o treat me nt, a n d P D-L 1 e x pressi o n is li kel y t o be differe nt, p ost C R T.  
I n a d diti on, n o n- cli nical data s h o w t hat bot h c he m ot hera p y  a n d io nisi n g ra diati o n u p- re g ulate 
P D -L 1 e x pressi o n ( De n g et al  2 0 1 4, Z ha n g et al 2 0 0 8 b ).  T heref ore, P D-L 1 e x pressi o n fr o m a 
bi o ps y sa m ple pri or t o C R T ma y  not acc uratel y reflect t he state of disease at t he ti me t he 
parti ci pa nt e nr ols i n t his st u d y a n d is ra n d o mise d t o eit her d ur val u ma b or place b o.  I n 
a d ditio n, t u m o urs t hat are p o orl y  i m m u n o ge nic or t hat ha ve bec o me i m m u n os u p pressi ve ca n 
li kel y b e ma de i m m u n o ge nic t hr o u g h a d mi nistrati o n of pr o -i m m u n o ge nic t hera pies desi g ne d 
t o i ncrease a nt i ge n release fr om t he ca ncer cell T heref ore, as state d, we pr o p ose n ot t o restrict 
i ncl usi on i n t his st u d y base d o n P D-L 1 e x pressi o n fr o m tiss ue sa m ples a vaila ble pri or t o C R T, 
b ut t o pr os pecti vel y e val uate t he rele va nce of P D -L 1 e x pressi o n t o o utc o me .  
Fi n di n gs fr o m t he P A CI FI C st u d y c o mpari n g d ur val u ma b a n d pl ace b o i n a n all-c o mers 
p o p ul at i on of parti ci pa nts wi t h Sta ge III N S C L C di d n ot de m o nstrate P D-L 1 t o be a pre dict i ve 
mar ker. Parti ci pa nts wi t h hi g h (≥2 5 %) or l o w ( < 2 5 %) or ne gati ve ( < 1 %) P D -L 1 e x pressi o n 
e x perie nce d cli nical mea ni n gf ul i m pr o ve d P F S o ver place b o ( P D -L 1 hi g h: H R 0. 4 1 [ 9 5 % CI: 
0. 2 6, 0. 6 5]; P D -L 1 l o w: H R, 0. 5 9 [ 9 5 % CI: 0. 4 3, 0. 8 2]; P D -L 1 ne gati ve: H R 0. 7 3 [ 9 5 % CI: 
0. 4 8, 1. 1 1]) (Paz- Ares L 2 0 2 0 ).  In li g ht of t hese res ults, t his st u d y  tar get t o recr uit all c o mer 
p o p ul at i on reflect i n g nat ural P D- L 1 pre vale nce. 
Astra Ze neca has c o m mitte d t o i de nt if yi n g t he ri g ht dr u g f or t he ri g ht patie nt ; t heref ore, 
e x pl orat or y a nal yses of e mer gi n g i m m u n o-o nc ol o g y  bi o mar kers are crit ical t o t his fiel d.  
Rece nt st u di es ha ve s h o w n t hat t u m o urs wit h hi g her 
 
res p o n d t o c hec k p oi nt i n hi biti on.  T he h y p ot hes is is t hat t u m o urs wit h 
 
 t hat ca n be rec o g nize d b y t he i mm u ne s y st e m.  I mpr o ve d O R R, P F S, a n d d ura ble 
cli nical be nefit were o bser ve d i n pat ient s wit h hi g h s o mat ic n o ns y n on y m o us m utati o n b ur de n 
i n N S C L C patie nts w h o recei ve d pe m br oliz u ma b (Ri z vi et al 2 0 1 5 b).  Rece ntl y,  
 was 
e xa mi ne d as part of a n e x pl orat or y a nal ysis of t he C hec k mate 0 2 6 st u d y, w hic h c o mpare d 
ni v o l u ma b wit h plati n u m d o u blet c he m ot hera p y i n first-li ne metastatic N S C L C.  F or patie nts 
wi t h a hi g h  
, t he resp o nse rate was hi g her i n t h ose w h o recei ve d ni v o l uma b vers us 
c he m ot hera p y ( 4 7 % vers us 2 8 %), a n d P F S was i m pr o ve d ( 9. 7 vers us 5. 8 m o nt hs) (Car b o ne et 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 4
 
al 2 0 1 7).  D ue t o t hese o bser vati o ns, we will be e val uat i n g  
 i n relati o n t o cli nical 
res p o nse i n t his st u d y.
4. 2. 3
R ati o n ale f or st u d y e n d p oi nts (effic ac y)
T he pri mar y  ai m of t his st u d y is t o deter mi ne t he efficac y of d ur val u ma b ( 1 5 0 0 m g q 4 w via i v 
i nf usi on) c o m pare d wi t h place b o i n ter ms of P F S ( mI T T).  P F S ma y ser ve as a s urr o gate 
e n d p o i nt for O S w he n differe nces bet wee n treat me nt ar ms are of s ufficie nt ma g nit u de a n d are 
cli nicall y i m p orta nt (F D A G ui da nce 2 0 1 1 , Paz d ur 2 0 0 8 ).  I n certai n setti n gs, t he utility of  
s ur vi val as a n e n d p oi nt ma y p ote ntiall y be c o nf o u n de d b y su bse q ue nt t hera pi es.  S pecificall y, 
a n u m ber of a ge nts tar geti n g t he P D- 1/ P D -L 1 pat h wa y i n a d va nce d N S C L C ha ve bee n 
a p pr o ve d a n d are a vaila ble o n t he mar ket w hile t his st u d y is o n g oi n g.  T his p oses c halle n ges 
i n bei n g a ble t o f ull y  c haracterise effects o n O S if parti ci pa nts s u bse q ue ntl y recei ve t hese 
i m m u n ot hera pe utic a ge nts.  T heref ore, P F S ( mI T T) will be t he pri mar y e n d p oi nt.  Gi ve n t hat 
t u mo ur res p o nse t o i m m u n ot hera p y  ma y differ fr o m t ypi c al  res p o nses, O S ( mI T T) will be a 
k e y  sec o n dar y e n d p oi nt.
A nt itu m o ur acti vit y will  be assesse d acc or di n g t o R E CI S T 1. 1 g ui deli nes, wit h t he 
u n dersta n di n g t hat i n t he c o nte xt of p ost -ra diati on c ha n ges, t u m o ur assess me nt ma y be 
diffic ult a n d ma y nee d t o be re peate d o ver ti me t o reac h a clear deter mi nat i on re gar di n g 
res p o nses a n d P D (see Secti o n 8. 1 ).  T he pri mar y a nal ysis of P F S will be base d o n 
pr o gra m mat icall y deri ve d P F S base d o n BI C R assess me nts.  Se nsit i vity a nal yses will als o be 
perf or m e d usi n g st u d y site I n vestigat or’s t u m o ur data fr o m  all sca ns base d o n R E CI S T 1. 1.  
E x pl or at or y  a nal ysis ma y als o be perf or me d f or data o btai ne d fr o m t he BI C R usi n g ir R E CI S T 
(Ni s hi n o et al 2 01 3 ), w hic h ma y be prese nte d o utsi de t he mai n C S R.
Res p o nse t o i m m u n ot hera p y  ma y differ fr o m t ypi c al  res p o nses o bser ve d wit h c yt ot o xic 
c he m ot hera p y, i ncl u di n g t he f o ll owi n g differe nces ( per W o lch o k et al 2 0 0 9 ):
1
Res p o nse t o i m m u n ot hera p y  ma y be dela ye d.
2
Res p o nse t o i m m u n ot hera p y  ma y occ ur after P D b y c o n v e ntio nal  criteria.
3
S D w hile o n i m m u n ot hera p y  ma y be d ura ble a n d re prese nt cli nical be nefit.
Use of  C o nfir mati on of Ra di o l ogical  Pr o gressio n cri t eria as descri be d (A p pe n di x E ) ma y 
di sc o ura ge t he earl y disc o nti n uatio n of  st u d y dr u g a n d pr o vide a m o re c o mplete e val uat i on of 
its a ntitu m o ur acti vit y t ha n w o uld be see n wi t h c o n ve nti onal res p o nse criteria.  N o net heless, 
t he efficac y a nal ysis will be c o n d ucte d b y pr o gra m maticall y deri vi n g eac h efficac y e n d p oi nt 
base d o n R E CI S T 1. 1 criteria.
N ota bl y, cl i nicall y si g nifica nt deteri orati o n is c o nsi dere d t o be a ra pi d t u m o ur pr o gressi o n t hat 
necessitates treat me nt wit h a nt ica ncer t hera p y ot her t ha n d ur val u ma b or wit h s y m pt o matic 
pr o gressi o n t hat re q uires ur ge nt me dical i nter ve nt i o n (e g, ce ntral ner v o us s ystem metastasis, 
res pir at or y fail ure d ue t o t u m o ur c o m pressi o n, a n d s pi nal c or d c o m pressi o n).
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 5
 
T he sec o n dar y  s y m pt o ms a n d o verall health rel ate d q ualit y of life ( H R Q o L) e n d p oi nts 
assesse d usi n g t he E ur o pea n Or ga nisat i on f or Researc h a n d Treat me nt of Ca ncer 3 0-ite m c ore 
q ualit y- of -life q uesti o n naire ( E O R T C Q L Q-C 3 0), versi o n 3 a n d t he c o m ple me ntar y  1 3-ite m 
self- a d mi nistere d q uesti o n naire f or l u n g ca ncer ( Q L Q-L C 1 3), will s h o w t he o verall i nfl ue nce 
of  t he be nefits a n d t o xicity of  t he treat me nt fr o m t he parti ci pa nt ’s pers pecti ve a n d will ai d i n 
u n dersta n di n g t he be nefit/ris k e val uat i on.  T hese P R O q uesti o n naires are well -esta blis he d 
i nstr u me nts t hat ha ve bee n pre vi o usl y i ncl u de d i n ca ncer cli nical st u dies.
4. 2. 4
R ati o n ale f or st u d y e n d p oi nts ( ot her e x pl or at or y e n d p oi nts)
B i ol ogi cal sa m ples will be use d t o e x pl ore p ote ntial 
 
, w hic h ma y i nfl ue nce t he pr o gressi o n of ca ncer (a n d ass ociate d cli nical 
c haracterist ics) a n d/ or res p o nse t o treat me nt.
T he assess me nt of healt h ec o n o mic r es o urce use data a n d deri vat i on of healt h state utilit y will 
pr o vi de i m p orta nt i nf or mat i on f or p a yers a n d will be use d wit hi n ec o n o mic e val uat i ons of 
d ur val u ma b.
4. 3
J u stific ati o n f or d ose
4. 3. 1
D ur v al u m a b m o n ot her a p y d ose r ati o n ale
A d ur val u ma b d ose of 2 0 m g/ k g q 4 w is s u p p orte d b y i n vitr o data, pre-cli nical acti vit y, 
cli nical P K/ p har mac o d y na mics, bi o mar kers, a n d acti vit y d at a f r o m St u d y C D -O N -
M E DI 4 7 3 6 -1 1 0 8 ( hereafter referre d t o as St u d y 1 1 0 8) i n parti ci pa nts wi t h a d va nce d s oli d 
t u mo urs a n d fr o m  a P hase I st u d y perf or me d i n Ja pa nese parti ci pa nts wi t h a d va nce d s oli d 
t u mo ur 
P K/ p h ar m ac o d y n a mic d at a
Base d o n a vaila ble P K/ p har mac o d y na mic data fr o m o n g o i n g St u d y 1 1 0 8 wit h d oses ra n gi n g 
fr om 0. 1 t o 1 0 m g/ k g e ver y 2 wee ks ( q 2 w) or 1 5 m g/ k g e ver y  3 wee ks ( q 3 w) , d ur valu ma b 
e x hi bite d n o n-li near ( d ose-de pe n de nt) P K c o nsiste nt wit h tar get -me d iate d dr u g dis p ositi on.  
T he P K a p pr oac he d li nearit y at ≥3 m g/ k g q 2 w, s u g gesti n g near -c o m p lete tar get sat urati o n 
( me m bra ne-b o u n d a n d s o l uble pr o gra m me d deat h li ga n d 1 [s P D -L 1]) , a n d f urt her s h o ws t hat 
t he d ur val u ma b d osi n g fre q ue nc y ca n be a da pte d t o a partic ular re gi me n gi ve n t he li nearity 
see n at d oses hi g her t ha n 3 m g/ k g. T he e x pecte d half- life wit h d oses ≥3 m g/ k g q 2 w is 
a p pr o xi matel y 2 1 da ys.  A d ose -de pe n de nt s u p pressi o n i n peri p heral  s P D-L 1 was o bser ve d 
o ver t he d ose ra n ge st u die d, c o nsiste nt wit h e n ga ge me nt of d ur val u ma b wit h P D -L 1. A l o w 
le vel of i m m u n o ge nicity has bee n o bser ve d. N o partici pa nts ha ve e x perie nce d i m m u ne -
c o mple x disease f o ll owi n g e x p os ure t o d ur val u ma b. ( F o r furt her i nf or mat i on o n 
i m m u n o ge nicity,  please see t he c urre nt d ur val u ma b I B.) 
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 6
 
A p o p ulati o n P K m o del was de vel o pe d usi n g t he data fr o m St u d y 1 1 0 8 ( d oses = 0. 1 t o 
1 0 m g/ k g q 2 w or 1 5 m g/ k g q 3 w;  Fair ma n et al 2 0 1 4 ). M ultiple si m ulati o ns i n dicate t hat a 
si milar o verall e x p os ure is e x pecte d f o ll owi n g b ot h 1 0 m g/ k g q 2 w a n d 2 0 m g/ k g q 4 w 
re gi me ns, as re prese nte d b y area u n der t he c o nce ntrati o n-ti me c ur ve at stea d y state ( 4 wee ks). 
Me dia n ma xi m u m c o nce ntrati o n at stea d y  state is e x pecte d t o be hi g her wit h 
 
( ~ 1. 5-f ol d), a n d me dia n tr o u g h c o nce ntrati o n at stea d y state is e x pecte d t o be hi g her wit h 
1 0 m g/ k g q 2 w ( ~ 1. 2 5 -f ol d). Cli nical acti vity wi t h t he 2 0 m g/ k g q 4 w d osi n g re gi me n is 
a nt ici pate d t o be c o nsiste nt wit h 1 0 m g/ k g q 2 w, wit h t he pr o p ose d si milar d ose of 2 0 m g/ k g 
q 4 w e x pecte d t o (a) ac hie ve c o m plete tar get sat urati o n i n maj orit y of  parti ci pa nts; ( b) acc o u nt 
f or a ntici pate d varia bility i n P K, p har mac o d y na mics, a n d cli nical act i vity i n di verse ca ncer 
p o p ul at i ons; (c) ma i ntai n s ufficie nt P K e x p os ure i n case of a nt i-dr u g a nt i b o d y ( A D A) i m pact; 
a n d ( d) ac hie ve P K e x p os ure t hat yiel de d ma xi mal a nti-t u mo ur acti vit y i n a ni mal m o dels.
Gi ve n t he si milar area u n der t he ser u m dr u g c o nce ntrati o n -ti me c ur ve a n d m o dest differe nces 
i n me dia n pea k a n d tr o u g h le vels at stea d y  state, t he o bser vati on t hat b ot h re gi me ns mai ntai n 
c o mplete s P D -L 1 s u p pressi o n at tr o u g h, a n d t he a vaila ble cli nical data, t he 2 0 m g/ k g q 4 w a n d
1 0 m g/ k g q 2 w re gi me ns are e x pecte d t o ha ve si milar efficac y a n d safet y pr ofiles, s u p p orti n g 
f urt her de vel o p me nt wit h a d ose of 
  
Cli nic al d at a
Refer t o t he c urre nt d ur val u ma b I B f or a c o mplete s u m mar y of cli nical i nf or mati o n i ncl u di n g 
safety , efficac y, a n d P K at t he 
 re gi me n.
4. 3. 2
R ati o n ale f or fi xe d d osi n g
A p o p ulati o n P K m o del was de vel o pe d f or d ur val u ma b usi n g m o n ot hera p y data St u d y 1 1 0 8 
( N = 2 9 2; d oses = 0. 1 t o 
; s oli d t u m o urs). P o p ulati o n P K 
a nal ysis i n dica te d o nl y mi n or i m pact of b o d y wei g ht ( W T) o n t he P K of d ur val u ma b 
(c oefficie nt of ≤0. 5).  T he i m pact of b o d y  WT- base d (
 a n d fi xe d d osi n g  
 
 of d ur val u ma b was e val uate d b y c o mpari n g pre di cte d stea d y state P K c o nce ntrati o ns 
( 5t h, me dia n, a n d 9 5t h perce nt iles) usi n g t he p o p ulati o n P K m o del. A fi xe d d ose of  
 
was selecte d t o a p pr o xi mate 
 ( base d o n me dia n b o d y W T of ~ 7 5 k g). A t otal of 
1 0 0 0 partici pa nts were si m ulate d usi n g b o d y  W T distri b uti on of 4 0 t o 1 2 0 k g. Si m ulat i on 
res ults de mo nstrate t hat b o d y  WT- base d a n d fi xe d d osi n g re gi me ns yiel d si milar me dia n 
stea d y state P K c o nce ntrati o ns with sli g ht l y less o verall bet wee n-parti ci pa nt varia bilit y wi t h 
fi xe d d osi n g re gi me n.
Si milar fi n di n gs ha ve bee n re p orte d b y  ot hers (Nar wal  et al 2 0 1 3, N g et al 2 0 0 6 , Wa n g 
et al 2 0 0 9 , Z ha n g et al 2 0 1 2 ). Wa n g a n d c ollea g ues in vest i gate d 1 2 m o n ocl o nal a nti b o dies 
a n d f o u n d t hat fi xe d a n d b o d y size-base d d osi n g perf or m si milarl y, wit h fi xe d d osi n g bei n g 
better f or 7 of 1 2 a nti b o dies (Wa n g et
al 2 0 0 9 ). I n a d ditio n, t he y  in vest i gate d 1 8 t hera pe utic 
pr otei ns a n d pe pti des a n d s h o we d t hat fi xe d d osi n g perf or me d better f or 1 2 of 1 8 i n ter ms of 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 7
 
re d uci n g t he bet wee n-parti ci pa nt varia bilit y i n P K/ p har mac o d y na mic para meters (Z ha n g 
et al 2 0 1 2 ).
A fi xe d d osi n g a p pr oac h is preferre d b y t he prescri bi n g c o m m u nity d ue t o ease of use a n d 
re d uce d d osi n g err ors. Gi ve n e x pectati o n of si milar P K e x p os ure a n d varia bilit y,  Astra Ze neca 
c o nsi dere d it feasi ble t o s witc h t o fi xe d d osi n g re gi me ns. Base d o n a vera ge b o d y  W T of 7 5 
k g, a fi xe d d ose of 1 5 0 0 m g q 4 w d ur val u ma b (e q ui vale nt t o 
) is i ncl u de d i n t he 
c urre nt st u d y.
4. 4
E n d of st u d y defi niti o n
F or t he p ur p ose of Cli nical Trial Tra ns pare nc y ( C T T) t he defi nit i on of t he e n d of t he st u d y 
differs u n der F D A a n d E U re g ulat or y re q uire me nts:
E ur o pea n U ni o n re q uire me nts defi ne st u d y c o mpl eti o n as t he last visit of t h e last s u bject f or 
a n y pr ot oc ol  relate d activit y.
F o o d a n d Dr u g A d mi nistrati o n re q uire me nts defi nes t w o c o m plet i on dates:
Pri mar y C o m p leti on Date – t he date t hat t he fi nal parti ci pa nt is e xa mi ne d or recei ves a n 
i nter ve nt i on f or t he p ur p oses of fi nal c ollecti on of data f or t he pr i mary o ut c o m e meas ure, 
w het her t he cli nical st u d y  c o ncl u de d acc or di n g t o t he pre-s pecifie d pr ot oc ol or was 
ter mi nate d. I n t he case of cli nical st u dies wit h m ore t ha n o ne pri mar y o utc o me meas ure wit h 
differe nt c o m plet i on dates, t his ter m refers t o t he date o n w hic h data c ollect i on is c o m plete d 
f or all of t he pri mar y o ut c o mes.
St u d y  C o mplet i on Date – t he date t he fi nal part ici pa nt is e xa mi ne d or recei ves a n i nter ve nti on 
f or p ur p oses of fi nal c ollecti o n of data f or t he pri mar y  a n d sec o n dar y o ut c o me meas ures a nd 
A Es (f or e xa m ple, last partici pa nt ’s last visit), w het her t he cli nical st u d y c o nclu des acc or di n g 
t o t he pre-s pecifie d pr ot oc ol or is ter mi nate d.
A partici pa nt i s c o nsidere d t o ha ve c o m plete d t he st u d y  if t he y ha ve c o mplete d all  p hases of 
t he st u d y incl u d i n g t he last sc he d ule d pr oce d ure s h o w n i n t he S o A.
T he st u d y  ma y be ter mi nate d at i n di vi d ual st u d y sites if t he st u d y pr oce d ures are n ot bei n g 
perf or m e d acc or di n g t o G o o d Cli nical Pract ice, if recr uitme nt  is sl o w, or w he n t here are n o 
l on ger a n y part ici pant s bei n g treate d or if t he O S F oll o w -u p Peri o d bef ore t he fi nal D C O f or 
t he st u d y has occ urre d a n d all q ueries at t hat st u d y site ha ve bee n res ol ve d.  
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
58
 
Participants may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, participants are placed at undue risk because of 
clinically significant findings.
See Appendix A 6 for guidelines for the dissemination of study results.
Treatment after final DCO for the study
The final DCO is the latest DCO for any of the planned analyses. For further details about 
treatment and participant management after the final DCO for the study, see Section 6.6.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be assigned/randomised to a study intervention. Under no circumstances 
can there be exceptions to this rule. Participants who do not meet the entry requirements are 
screen failures; refer to Section 5.4.
In this protocol, “enrolled” participants are defined as those who sign informed consent of 
tumour sample collection (part I screening ICF). “Randomised” participants are defined as 
those who undergo randomisation and receive a randomisation number.
For procedures for withdrawal of incorrectly enrolled participants, see Section 6.2.2.
5.1
Inclusion criteria
Part I screening
Participants are eligible to be included in the study only if all of the following inclusion 
criteria apply and none of the Part II screening exclusion criteria numbers 1-5, 7, 10, 16-20 
apply:
Informed consent
1
Capability to give signed informed consent of tumour sample collection that includes 
compliance with the requirements and restrictions listed in the pre-screening informed 
consent form (part I screening ICF) and in this protocol
2
Provision of signed and dated written part I screening ICF prior to any mandatory 
study-specific procedures, sampling, and analyses
The ICF consenting process is described in Appendix A 3.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
59
 
Age
3
Age ≥18 years at the time of Screening
Type of participant and disease characteristics
4
Histologically or cytologically documented NSCLC and present with locally advanced, 
unresectable (Stage III) disease (according to Version 8 of the (IASLC Staging Manual in 
Thoracic Oncology]).  Positron emission tomography/CT, MRI of the brain, and 
endobronchial ultrasound with biopsy are highly encouraged at diagnosis.
5
Tumour sample requirements are as follows: Provision of a tumour tissue sample (newly 
acquired sample < 3 months old is preferred; an archived sample < 6 months old is 
acceptable) in a quantity sufficient to allow for analysis. (refer to Section 8.8.1 and the 
Laboratory Manual for details). A biopsy procedure during screening period is not 
allowed. Study subject should not have received any intervening systemic therapy other 
than chemoradiotherapy for Stage III disease as described above.
6
Tumor PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a 
reference laboratory, must be known prior to randomization. Participant with unknown 
PD-L1 status is not eligible for the study. “Unknown” refers to (1) insufficient sample 
which is not able to be analyzed, or (2) sample could be analyzed but results not 
interpretable.
7
Documented EGFR and ALK status (locally or centrally) at screening visit part I. If the 
local laboratory will perform the test, a well-validated, local regulatory-approved kit must 
be used.
EGFR and ALK status must be available prior to randomisation. After approximately 7% 
sensitizing EGFR (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 
G719X, or exon 20 S768I mutation) or ALK mutant participants have been randomised, 
the incoming participants with sensitizing EGFR (e.g., exon 19 deletion or exon 21 
L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation) or ALK mutation 
will not be enrolled. 
Part II screening
Participants are eligible to be included in the study only if all the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1
Capability to give signed informed consent of study procedure that includes compliance 
with the requirements and restrictions listed in the Main informed consent form (Part II 
screening ICF) and in this protocol
2
Provision of signed and dated written Part II screening ICF prior to any mandatory 
study-specific procedures, sampling, and analyses
The ICF consenting process is described in Appendix A 3.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
60
 
Type of participant and disease characteristics
4
Histologically or cytologically documented NSCLC and present with locally advanced, 
unresectable (Stage III) disease (according to Version 8 of the (IASLC Staging Manual in 
Thoracic Oncology]).  Positron emission tomography/CT, MRI of the brain, and 
endobronchial ultrasound with biopsy are highly encouraged at diagnosis.
5
Receipt of concurrent or sequential chemoradiation therapy, which must be completed 
within 1 to 28 days prior to first dose of IP in the study.

For cCRT, participants must have received at least 2 cycles of platinum-based 
chemotherapy concurrent with radiation therapy.  The last dose of chemotherapy 
must be prior to, or concurrent with, the final dose of radiation.  Consolidation 
chemotherapy after radiation is not permitted, but no more than 2 cycles of induction 
chemotherapy prior to cCRT is acceptable.

For sCRT, participants must have received at least 2 cycles of platinum-based 
chemotherapy before radiation therapy.  The interval between administration of the 
last dose of chemotherapy regimen and start of RT must be no more than 6 weeks.  
Consolidation chemotherapy after radiation is not permitted.  
o
Note: If a participant receives only 1 cycle of platinum-based chemotherapy 
concurrent with radiation treatment, this participant will be eligible for the study 
to participate in the sCRT stratum.

The platinum-based chemotherapy regimen must contain cisplatin or carboplatin and 
1 of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or 
docetaxel), or pemetrexed, according to the local SoC regimens.  (Gemcitabine is not 
included.)

Participants must have received a total dose of radiation of 60 Gy ±10% (54 to 
66 Gy) to be randomised as part of the chemoradiation therapy.  Study sites are 
encouraged to adhere to the following mean organ radiation dosing:
o
Mean lung dose must be <20 Gy, and/or V20 must be <35%
o
Mean oesophagus dose must be <34 Gy
o
Heart V45 must be <35%, or V30 must be <50% 

Study sites should be aware of the recent RTOG 0617 Trial data demonstrating that 
doses higher than 60 Gy may be associated with greater toxicity and worse efficacy.
6
No progression following definitive, platinum-based, concurrent or sequential 
chemoradiation therapy
7
World Health Organization (WHO) PS of 0 or 1 at enrolment
8
No prior exposure to any anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, 
excluding therapeutic anticancer vaccines

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
61
 
9
Adequate organ and marrow function as defined below.  Absolute neutrophil count, 
platelet count, and haemoglobin criteria cannot be met with transfusion or growth factor 
support administered within 14 days before randomisation.

Haemoglobin ≥9 g/dL

Absolute neutrophil count >1.5 × 109/L (1500 per mm3)

Platelet count >100 × 109/L (100000 per mm3)

Serum bilirubin ≤1.5× the upper limit of normal (ULN).  This will not apply to 
participants with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of 
haemolysis or hepatic pathology), who will be allowed in consultation with their 
primary physician.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5× ULN

Serum creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of 
creatinine CL
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)
10 Life expectancy of at least 12 weeks at Day 1
11 WT >30 kg
5.2
Exclusion criteria 
Part I screening: Participants should not enter the study, if any of 1-5, 7, 10, and 16-20 
exclusion criteria are fulfilled. 
Part II screening: Participants should not enter the study if any of the following exclusion 
criteria are fulfilled. 
Medical conditions
1
History of allogeneic organ transplantation
2
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g. colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
62
 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]).  The following are exceptions to this criterion:

Participants with vitiligo or alopecia

Participants with hypothyroidism (e.g. following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Participants without active disease in the last 5 years may be included but only after 
consultation with the Study Physician

Participants with celiac disease controlled by diet alone
3
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially increase risk 
of incurring AEs, or compromise the ability of the participant to give written informed 
consent
4
History of another primary malignancy except for

Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of investigation product (IP) and of low potential risk for 
recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease
5
History of active primary immunodeficiency 
6
Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] 
result), hepatitis C (HCV), or human immunodeficiency virus (positive human 
immunodeficiency virus [HIV] 1/2 antibodies).  Participants with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are 
eligible.  Participants positive for HCV antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA.
7
Mixed small cell and NSCLC histology, sarcomatoid variant
8
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Grade ≥2 from the prior chemoradiation therapy.  
Participants with irreversible toxicity that is not reasonably expected to be exacerbated by 
study treatment may be included (eg, hearing loss) after consultation with the 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
63
 
AstraZeneca Study Physician. Grade 2 AE of laboratory abnormality for inclusion criteria 
12 related lab parameters may be included as long as within the specified range in 
inclusion criteria 12.
9
Participants with Grade ≥2 pneumonitis from prior chemoradiation therapy
10 Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients
Prior/concomitant therapy
11 Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer 
treatment other than those under investigation in this study
12 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.  
Note: Participants, if enrolled, should not receive live vaccine whilst receiving IP and up 
to 30 days after the last dose of IP.
13 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 and placement of 
vascular access are acceptable.
14 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab.  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)

Systemic steroid administration required as prophylaxis against or to manage 
toxicities arising from chemotherapy and/or radiotherapy delivered as part of the 
chemoradiation therapy for locally advanced NSCLC
Prior/concurrent clinical study experience
15 Participation in another clinical study with an IP administered in the last 4 weeks prior to 
randomization.
16 Previous IP assignment in the present study
17 Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the Follow-up Period of an interventional 
study
18 Prior randomisation or treatment in a previous durvalumab ± tremelimumab clinical study 
regardless of treatment arm assignment 
Other exclusions

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
64
 
19 Female participants who are pregnant or breastfeeding or male or female participants of 
reproductive potential who are not willing to employ effective birth control from 
Screening to 90 days after the last dose of durvalumab monotherapy
20 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements. Or 
the participant is not willing to/can not continue screening procedures during the 
screening period. 
21 Meet any of the study protocol specified capping criteria.
Procedures for withdrawal of incorrectly enrolled participants are provided in Section 6.2.2.
Participant who is not willing or not able to continue screening is considered as screen failure 
but not withdrawal.
5.3
Lifestyle restrictions
The following restrictions apply while the participant is receiving IP and for the specified 
times before and after:
1
Female participant of childbearing potential

Female participants of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilised male partner must use at least 1 highly effective 
method of contraception (Table 3) from the time of screening throughout the total 
duration of the drug treatment and the drug washout period (90 days after the last 
dose of durvalumab monotherapy).  Non-sterilised male partners of a female 
participant of childbearing potential must use a male condom plus spermicide (or 
male condom in countries where spermicides are not approved) throughout this 
period.  Cessation of birth control after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception.  Female participants should 
refrain from breastfeeding throughout this period.  
2
Male participants with a female partner of childbearing potential

Non-sterilised male participants who are not abstinent and intend to be sexually 
active with a female partner of childbearing potential must use a male condom plus 
spermicide (or male condom in countries where spermicides are not approved) from 
the time of screening throughout the total duration of the drug treatment and the drug 
washout period (90 days after the last dose of durvalumab monotherapy).  Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception.  Male participants should refrain from sperm donation 
throughout this period.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
65
 

Female partners (of childbearing potential) of male participants must also use a 
highly effective method of contraception throughout this period (Table 3).
Please note, females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinising hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago.

Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible.
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 3.  
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper-containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel, which is considered highly effective]; and triphasic combined oral 
contraceptive pills).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
66
 
Table 3
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
•
Implants: Etonogestrel-releasing implants (eg, 
Implanon® or Norplant®)
•
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Injection: Medroxyprogesterone injection (eg, 
Depo-Provera®)
•
Combined Pill: Normal and low-dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Minipill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently 
the only highly effective progesterone based pill 
a
This is also considered a hormonal method.
3
All participants: Participants should not donate blood or blood components while 
participating in this study and through 90 days after receipt of the final dose of 
durvalumab or until alternate anticancer therapy is started.
4
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Screen failures
Screen failures are participants who have signed the part I screening ICF or part I screening 
ICF plus part II screening ICF and do not fulfil the eligibility criteria for the study. These 
participants should have the reason for study withdrawal recorded as “eligibility criteria not 
fulfilled” (i.e. participant does not meet the required inclusion/exclusion criteria).  This reason 
for study withdrawal is only valid for screen failures (i.e. not randomised participants).  
Participants may be re-screened a single time, but they may not be re-randomised.  
If a participant who has failed screening is re-screened, a new E-code must be assigned. 
Participants will reconfirm their consent to participate in the study by signing and dating a 
new consent form(s).
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs.
6
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.  Study treatment in this study refers to durvalumab or placebo.

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 7
 
6. 1
Tre at me nts a d mi nistere d
6. 1. 1
I n vesti g ati o n al pr o d ucts
Astra Ze neca will s u p pl y  d ur val u ma b ( M E DI 4 7 3 6).  T he sali ne s ol uti on f or t he place b o will be 
s u p plie d l ocall y.  See Ta ble 4 St u d y  treat me nts f or st u d y treat me nt details.
Ta ble 4
St u d y tr e at me nts
Tre at me nt 1
Pl ace b o
St u d y tre at me nt n a me:
D ur val u ma b ( M E DI 4 7 3 6)
Sali ne s ol uti o n
D os a ge f or m ul ati o n:
5 0 0- m g vial s ol uti o n f or 
i nf usi o n after dil uti o n, 
5 0 m g/ m L
Sterile s ol uti o n of 0. 9 % ( w/ v) 
s o di u m c hl ori de f or i njecti o n
R o ute of a d mi nistr ati o n 
i v
i v
D osi n g i nstr ucti o ns:
i v i nf usi o n o ver a p pr o xi matel y 
6 0 mi n utes ( ± 5 mi n utes), q 4 w 
(see Secti o n 6. 1. 2 )
i v i nf usi o n o ver a p pr o xi matel y 
6 0 mi n utes ( ± 5 mi n utes), q 4 w (see 
Secti o n 6. 1. 2)
P ac k a gi n g a n d l a belli n g
St u d y treat me nt will be
la belle d i n acc or da nce wit h 
G M P A n ne x 1 3 a n d per 
c o u ntr y re g ulat or y 
re q uire me nta
S o urce d l ocall y b y site
Pr o vi der
Astra Ze neca
S o urce d l ocall y b y site
a
La bel te xt pre pare d f or d ur val u ma b ( M E DI 4 7 3 6) will s h o w t he pr o d uct na me as “ M E DI 4 7 3 6” or “ d ur val u ma b 
( M E DI 4 7 3 6)” de pe n di n g u p o n t he a gree d pr o d uct na me use d i n t he a p pr o ve d st u d y master la bel d oc u me nt.  All na mi n g 
c o n ve nti o ns are c orrect d uri n g t his tra ns iti o nal peri o d.  
G M P
G o o d Ma n ufact uri n g Practice; i v
I ntra ve n o us; q 4 w E ver y 4 wee ks.
6. 1. 1. 1
D ur v al u m a b ( M E DI 4 7 3 6)
D ur val u ma b ( M E DI 4 7 3 6) will be s u p plie d b y Astra Ze neca as a 5 0 0 -m g vial s o l uti on f or 
i nf usi on after dil ut i on.  T he s ol ut i on c o ntai ns 5 0 m g/ m L d ur val u ma b ( M E DI 4 7 3 6),  
 
hist i di ne/ histi di ne-h y dr oc hl ori de,  
 tre hal ose di h y drate, a n d 
 
 p ol ys or bate 8 0; it has a  
.  T he n omi nal fill v o l ume is 1 0. 0 m L. I P vials are 
st ore d at 2° C t o 8° C ( 3 6° F t o 4 6° F) a n d m ust n ot be fr oze n.  Dr u g pr o d uct s h o ul d be ke pt i n 
sec o n dar y pac ka gi n g u ntil use t o pre ve nt e xcessi ve li g ht e x p os ure.
Pre p ar ati o n of d ur v al u m a b ( M E DI 4 7 3 6) d oses f or a d mi nistr ati o n wit h a n i v b a g
T he d ose of d ur val u ma b ( M E DI 4 7 3 6) f or a d mi nistrati o n m ust be pre pare d b y  t he 
I n vesti gat or’s or st u d y site’s desi g nate d I P ma na ger usi n g ase pt ic tec h ni q ue.  T otal ti me fr om 
nee dle p u nct ure of t he d ur val u ma b ( M E DI 4 7 3 6) vial t o t he start of a d mi nistrati o n s h o ul d n ot 
e xcee d: 

2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F)
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 8
 

4 h o urs at r o o m  t e mperat ure
A d ose of 1 5 0 0 m g (f or partici pa nts > 3 0 k g i n wei g ht) will be a d mi nistere d usi n g a n i v ba g 
c o ntai ni n g 0. 9 % ( w/ v) sali ne or 5 % ( w/ v) de xtr ose, wit h a fi nal d ur val u ma b ( M E DI 4 7 3 6) 
c o nce ntrati o n ra n gi n g fr o m 1 t o
, a n d deli vere d t hr o u g h a n i v a d mi nistrati o n set 
wi t h a 0. 2- or 0. 2 2 -μ m  in- li ne filter. A d d 3 0. 0 m L of  d ur val u ma b ( M E DI 4 7 3 6) (ie, 1 5 0 0 m g 
of  d ur val u ma b [ M E DI 4 7 3 6]) t o t he i v ba g. T he i v ba g size s h o ul d be selecte d s uc h t hat t he 
fi nal c o nce ntrati o n is wit hi n 1 t o  
 Mi x t he ba g b y ge nt l y i n verti n g t o e ns ure 
h o m o ge neit y of t he d ose i n t he ba g. T he I V ba g s h o ul d be c o vere d wit h a tra nsl uce nt c ol ore d 
or o pa q ue slee ve after pre parati o n b y  t he u n bli n de d p har macist prior t o dis pe nsi n g t o ot her 
st u d y pers o n nel, slee ve c o ver s h o ul d be sec ure d (e. g. usi n g sta pli n g, heat -seali n g), t o mai ntai n 
d o u bl e- bli n d c o n dit i ons.
If wei g ht falls t o ≤3 0 k g, wei g ht -base d d osi n g at  
 will be a d mi nistere d usi n g a n i v 
ba g c o ntai ni n g 0. 9 % ( w/ v) sali ne or 5 % ( w/ v) de xtr ose, wit h a fi nal d ur val u ma b ( M E DI 4 7 3 6) 
c o nce ntrati o n ra n gi n g fr o m 1 t o 
, a n d deli vere d t hr o u g h a n i v a d mi nistrati o n set 
wi t h a 0. 2- or 0. 2 2 -μ m  in- li ne filter.
Sta n dar d i nf usi o n ti me is 1 h o ur.  I n t he e ve nt t hat t here are i nterr u pti o ns d uri n g i nf usi o n, t he 
t otal allo we d i nf us i on ti me s h o ul d n ot e xcee d 8 h o urs at r o o m te m perat ure.  
D o n ot c o -a d mi nister ot her dr u gs t hr o u g h t he sa me i nf usi o n li ne.
T he i v li ne will be fl us he d wit h a v o l ume of i v dil ue nt e q ual t o t he pri mi n g v o l ume of t he 
i nf usi on set use d, after t he c o nte nts of t he i v ba g are f ull y a d mi nistere d, or c o m plete t he 
i nf usi on acc or di n g t o i nstit uti o nal p o lic y t o e ns ure t he f ull d ose is a d mi nistere d a n d d oc u me nt 
if t he li ne was n ot fl us he d.
If either pre parati o n ti me or i nf usi o n ti me e xcee ds t he ti me li mit s a ne w d ose m ust be 
pre pare d fr o m ne w vials.  D ur val u ma b ( M E DI 4 7 3 6) d oes n ot c o ntai n preser vati ves, a n d a n y 
u n use d p orti o n m ust be discar de d.
6. 1. 1. 2
Pl ace b o 
Steril e s o l uti on of 0. 9 % ( w/ v) s o di u m c hl ori de f or i nject i on will be a d de d t o a n i v ba g 
c o ntai ni n g 0. 9 % ( w/ v) sali ne or 5 % ( w/ v) de xtr ose.  T he v o l ume of sali ne s o l uti on a d de d will 
be 3 0. 0 m L f or d ur valu ma b place b o.  T he i v ba g s h o ul d be c o vere d wit h a tra nsl uce nt 
c olo ure d or o pa q ue sl ee ve after pre parati o n b y t he u n bli n de d p har macist a n d/ or ot her 
a p pr o priate u n bli n de d sit e staff prior t o di s pe nsi n g t o ot her st u d y pers o n nel, slee ve c o ver 
s h o uld be sec ure d (e. g. usi n g sta pli n g, heat -seali n g), t o mai ntai n d o u ble-bli n d c o n dit i ons. 
I nf usi on ti me is 1 h o ur a n d s h o ul d be deli vere d t hr o u g h a n i v a d mi nistrati o n set wit h a 0. 2 - or 
0 . 2 2-μ m  in- li ne filter.
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 9
 
6. 1. 2
D ose a n d tre at me nt re gi me ns
6. 1. 2. 1
D ur v al u m a b ( M E DI 4 7 3 6) m o n ot her a p y 
P arti cip a nts i n t he d ur val u ma b m on ot hera p y  treat me nt ar m will recei ve 1 5 0 0 m g d ur val u ma b 
via i v i nf usi o n q 4 w u nt il c o nfir me d ra di ol ogical pr o gressi o n u nless t here is u nacce pta ble 
t o xicit y, wit hdra wal  of c o nse nt, or a n ot her disc o nti n uati on cri t erio n ( Secti o n 7. 1) i s met.  See 
Fi g ure 2 .  ( Please n ote, if a parti ci pa nt ’s wei g ht falls t o 3 0 k g or bel o w t he partici pa nt s h o uld 
recei ve wei g ht-base d d osi n g e q ui vale nt t o 
 of d ur val u ma b q 4 w after c o ns ultati o n 
bet wee n t he I n vest i gat or a n d St u d y P h ysicia n, u ntil t he wei g ht i m pr o ves t o > 3 0 k g, at w hic h 
p oi nt t he parti ci pa nt s h o ul d start recei vi n g t he fi xe d d osi n g of d ur val u ma b 1 5 0 0 m g q 4 w).
T he sta n dar d i nf usi o n ti me is 6 0 mi n utes.  I n t he e ve nt t hat t here are i nterr u pti o ns d uri n g 
i nf usi on, t he t otal all o we d ti me s h o ul d n ot e xcee d 8 h o urs at r o o m te m perat ure.
Fi g ure 2
D ur v al u m a b m o n ot her a p y d osi n g sc he d ule
q 4 w E ver y 4 wee ks.
6. 1. 2. 2
Pl ace b o
T he treat m e nt re gi me n f or place b o is t he sa me as descri be d f or d ur val u ma b m o n ot hera p y  
( Sectio n  6. 1. 2. 1 ), i ncl u di n g t he d osi n g sc he d ule s h o w n i n Fi g ure 2 .
6. 1. 3
D ur ati o n of tre at me nt
All treat me n t will be a d mi nistere d be gi n ni n g o n Da y 1 u ntil c o nfir me d ra di o l ogi cal 
pr o gressi o n (refer t o  A p pe n di x E ), u nless t here is u nacce pta ble t o xicity, wi t hdra wal of 
c o nse nt, or a n ot her disc o nt i n uati on cri t erio n ( Secti o n  7. 1 ) is met.
D uri n g t he Treat me nt Peri o d, partici pa nts w h o are cli nicall y sta ble at a n i nit ial R ECI S T 1. 1 -
defi ne d ra di o l ogi cal P D ma y c o nt i n ue t o recei ve st u d y treat me nt at t he discreti on of t he 
I n vesti gat or a n d parti ci pa nt .  A f oll ow- u p sca n is t o be c ollecte d after t he i nit ial R E CI S T 1. 1-
defi ne d ra di o l ogi cal P D, n o less t ha n 4 wee ks after t he pri or assess me nt of P D a n d n o later 
t ha n t he ne xt re g ularl y sc he d ule d i ma gi n g visit, a n d t his f o ll ow- u p sca n is e val uate d usi n g t he 
C o nfir mati o n o f Ra di ol o gi c al Pr o gressio n cri t eria o utli ne d i n  A p pe n di x E .  Parti ci pa nts wi t h 
r a pid t u m o ur pr o gressi o n or wi t h s y m pt o matic pr o gressi o n t hat re q uires ur ge nt me dical 
i nter ve nt i on (e g, ce ntral ner v o us s yste m metastasis, res pirat or y  fail ure d ue t o t u m o ur 
c o mpressi o n , or s pi nal c or d c o m pressi o n) will n ot be eli gi ble f or c o nti n ui n g st u d y  treat me nt.  
C y cl e
W e e k
1 
2 
3 
4
5 t o P D
0 
2 
4 
6 
8
1 0
1 2
1 4
q 4 w ± 3 d a y s
D ur v al u m a b 1 5 0 0 m g D o s e q 4 w
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
70
 
At the request of the Investigator, following discontinuation of IP and RECIST 1.1- defined 
progression of disease plus the additional regularly scheduled follow-up scan participant can 
be unblinded.  Participants may not receive any further study treatment (durvalumab or 
placebo) after this point and they will be counselled on other anticancer therapy options. 
For all participants who are treated through progression, the Investigator should ensure that 
participants do not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing would not further benefit the participant.  
Participants in placebo arm will no longer receive any further placebo treatment after the 
study is unblinded. 
Crossover within the study will not be permitted.
The participant ICF will specify that treatment beyond initial evidence of PD during follow up 
is not the SoC and that alternative treatment options, either locally licensed treatments or other 
clinical trials, are available for this participant population.
Participants with confirmed PD who continue to receive study treatment at the discretion of 
the Investigator and participant (following consultation with AstraZeneca) can receive 
treatment until no longer having clinical benefit, and tumour assessments should continue on 
their regular imaging schedule for the duration of treatment.
6.1.4
Storage
The Investigator, or an approved representative (e.g., 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.
6.2
Measures to minimise bias: randomisation and blinding
6.2.1
Participant enrolment and randomisation
All participants will be centrally assigned to randomised study treatment using an interactive 
voice response system (IVRS)/interactive web response system (IWRS).  Before the study is 
initiated, the telephone number and call-in directions for the IVRS and/or the log-in 
information and directions for the IWRS will be provided to each study site.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
71
 
If a participant withdraws from the study, then his/her enrolment/randomisation code cannot 
be reused.  Withdrawn participants will not be replaced.
Investigators should keep a record (i.e. the participant screening log) of participants who 
entered Screening.
At Screening part I visit (Days -84 to -1), the investigator or suitably trained delegate will:

Obtain signed informed consent form of use of tumour sample. A biopsy procedure 
during screening period is not allowed, and an irradiated sample is not acceptable.

Obtain a unique 7-digit enrolment number (E-code), through the IVRS/IWRS in the 
following format (ECCNNXXX: CC being the country code, NN being the centre 
number, and XXX being the participant enrolment code at the centre). This number is the 
participant’s unique identifier and is used to identify the participant on the electronic case 
report forms (eCRFs).

Obtain tumour sample and send for centralised PD-L1 testing. Obtaining the tumour 
biopsy samples should be given the highest priority and, as such, the sample may be 
obtained and sent for PD-L1 expression status evaluation.  If EGFR and ALK status is 
unknown, the archived or newly acquired tumour sample can be used for central EGFR 
and ALK mutation testing along with PD-L1 testing. However, the EGFR and ALK result 
from the local laboratory is also acceptable, if it is accessed by a well-validated, local 
regulatory-approved kit.

Determine participant eligibility (see Sections 5.1 and 5.2)
At Screening part II visit/Baseline (Days -28 to -1), the Investigator or suitably trained 
delegate will:

After participants complete CRT, obtain signed informed consent of study procedures 
before any study specific procedures are performed.  If laboratory or imaging procedures 
were performed for alternate reasons prior to signing inform consent of study procedure, 
these can be used for screening purposes with consent of the participant.  However, all 
screening laboratory and imaging results must have been obtained within 28 days of 
randomisation. For participants with a single target lesion, if screening biopsy is collected 
prior to screening imaging for baseline tumour assessment, allow approximately 2 weeks 
before imaging scans are acquired.

Determine participant eligibility (see Sections 5.1 and 5.2).
At randomisation, once the participant is confirmed to be eligible, the Investigator or suitably 
trained delegate will perform the following:

A unique randomisation number will be generated via the IVRS/IWRS, when 
randomization transaction is completed.  Numbers will start at 001 and will be assigned 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
72
 
strictly sequentially by IVRS/IWRS as participants are eligible for entry into the study.  
The system will randomise the eligible participant to 1 of the 2 treatment arms.  (PD-L1 
expression status results need to be received from the central laboratory by the 
IVRS/IWRS prior to randomisation.)

If the participant is ineligible and not randomised, the IVRS/IWRS should be contacted to 
terminate the participant in the system.
Participants will begin treatment on Day 1. Treatment should start no more than 3 days after 
being randomised. Participants must not be randomised and treated unless all eligibility 
criteria have been met.
6.2.2
Procedures for handling incorrectly enrolled or randomised 
participants
Participants who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication. There can be no exceptions to this 
rule.  Participants who are enrolled, but subsequently found not to meet all the eligibility 
criteria must not be randomised or initiated on treatment, and must be withdrawn from the 
study.
Where a participant does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the participant
from treatment.  The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented and that the potential benefit: risk profile remains positive for the participant.  
6.2.3
Methods for assigning treatment arms
The actual treatment given to participants will be determined by the randomisation scheme in 
the IVRS/IWRS.  The randomisation scheme will be produced by a computer software 
program that incorporates a standard procedure for generating randomisation numbers.  
One randomisation list will be produced for each of the randomisation strata.  A blocked 
randomisation will be generated, and all centres will use the same list in order to minimise any 
imbalance in the number of participants assigned to each treatment arm.
Participants will be identified to the IVRS/IWRS per country regulations.  Randomisation 
codes will be assigned strictly sequentially, within each stratum, as participants become 
eligible for randomisation.  The IVRS/IWRS will provide the kit identification number to be 
allocated to the participant at the randomisation visit and subsequent treatment visits.
Participants will be randomised in a 2:1 ratio to either durvalumab (1500 mg q4w) or placebo.  
Participants will be stratified at randomisation based on the level of PD-L1 expression (PD-L1 
<1% or PD-L1 ≥1%) and prior therapy (cCRT or sCRT).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
73
 
Every effort should be made to minimise the time between randomisation and starting study 
treatment.  It is recommended that participants commence study treatment as soon as possible 
after randomisation (ie, on the same day after randomisation in the IVRS system).
The IVRS/IWRS may not be available after the final DCO for the study.  In this case, a 
manual process will need to be followed.
6.2.4
Methods for ensuring blinding
The study will be conducted in a double-blind manner.  The reconstituted durvalumab solution 
and its matching placebo will be identical in colour, and the iv bags used for administration 
will be identical with regards to size.  All study treatment will be blinded using a translucent 
colored or opaque sleeve, after preparation by the unblinded pharmacist prior to dispensing to 
other study personnel, sleeve cover should be secured (e.g. using stapling, heat-sealing), to 
maintain double-blind conditions.
The IVRS/IWRS will provide to the pharmacists and/or other appropriate site staff the kit 
identification number to be allocated to the participant at the dispensing visit.  Blinded and 
unblinded access and notifications will be controlled using the IVRS/IWRS.  Investigators 
will remain blinded to each participant’s assigned study treatment until the time of final 
analysis of the primary endpoint.  To maintain this blind, a pharmacist and/or other 
appropriate site staff will be unblinded and responsible for the reconstitution and dispensation 
of all study treatment and will endeavour to ensure that there are no differences in time taken 
to dispense following randomisation. The unblinded pharmacist and/or other appropriate site 
staff will be monitored by unblinded study monitors all of whom will have no further role in 
the management of study participants or data collection and will not have access to the study 
database. All other site personnel will be blinded for the dispensation of all study treatments.
In the event that the treatment allocation for a participant becomes known to the Investigator 
or other study staff involved in the management of participants, or needs to be known to treat 
an individual participant for an AE, the Sponsor must be notified promptly by the Investigator 
and if possible, before unblinding.
The IVRS/IWRS will be programmed with blind-breaking instructions.  The treatment code 
should not be broken except in medical emergencies when the appropriate management of the 
participant requires knowledge of the treatment randomisation. Additionally, at the request of 
the Investigator, following discontinuation of IP and RECIST 1.1-defined progression of 
disease plus the additional regularly scheduled follow-up scan the participant can be 
unblinded. In the setting of rapid clinical progression, unblinding should be discussed with the 
AstraZeneca Global Study Physician and Study Statistician.
The Sponsor must be notified before the blind is broken unless identification of the study 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
74
 
treatment is required for a medical emergency in which the knowledge of the specific blinded 
study treatment will affect the immediate management of the participant’s condition (eg, 
antidote available). In this case, the Sponsor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and eCRF, as applicable.  
Study unblinding should not occur until database lock and all decisions on the evaluability of 
the data from each individual participant have been made and documented. AstraZeneca 
retains the right to break the code for SAEs that are unexpected and are suspected to be 
causally related to an IP and that potentially require expedited reporting to regulatory 
authorities.
The IDMC will be provided with unblinded data for their review, but AstraZeneca and 
designee staff and Investigators involved in the study will remain blinded.
6.3
Treatment compliance
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations 
should be recorded in the eCRF.  Treatment compliance will be assured by study site 
reconciliation of medication dispensed.
The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP.  The Investigator(s) is 
responsible for ensuring that the participant has returned all unused IP.
The administration of all study treatments (including IPs) should be recorded in the 
appropriate sections of the eCRF.  The Investigator or pharmacy must retain records of all 
study treatments administered.  The Study Monitor will check these records to confirm the 
compliance with the protocol administration schedule.  
Use of IP in doses in excess of that specified in the protocol is considered to be an overdose.  
Refer to Section 8.4.3 for procedures in case of overdose.
6.4
Concomitant therapy
The Investigator must be informed as soon as possible about any medication taken from the 
time of part II screening until the end of the clinical treatment phase of the study including the 
90-day safety Follow-up Period following the last dose of study drug.
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the participant is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
75
 

Dates of administration including start and end dates

Dosage information including dose, unit, and frequency
Participants 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 (Table 5 and Table 6).  Refer also to the Dosing Modification and Toxicity 
Management Guidelines (see Section 8.4.5).
Table 5
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
For all treatment arms
Any investigational anticancer therapy other than 
those under investigation in this study
Should not be given concomitantly whilst the participant
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly whilst the participant
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic, or hormonal therapy 
for cancer treatment other than those under 
investigation in this study
Should not be given concomitantly whilst the participant
is on study treatment.  (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable.  
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the study treatment infusions.  
The following are allowed exceptions:

Use of immunosuppressive medications for the 
management of study treatment-related AEs

Short-term premedication for participants
receiving SoC CRT, in which the prescribing 
information or local guidance for the agent 
requires the use of steroids for documented 
hypersensitivity reactions, nausea/vomiting, or 
prophylaxis

Use in participants with contrast allergies
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.  A temporary period of 
steroid treatment will be allowed if clinically indicated 
and considered to be essential for the management of 
non-immunotherapy-related events experienced by the 
participant (eg, chronic obstructive pulmonary disease, 
radiation, or nausea).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
76
 
Prohibited medication/class of drug:
Usage:
EGFR TKIs 
Should not be given concomitantly.  
Should be used with caution in the 90 days after the last 
dose of durvalumab.  
Increased incidences 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.
Herbal and natural remedies that may have 
immune-modulating and/or anticancer effects
Should not be given concomitantly unless agreed by the 
Sponsor
AE Adverse event; EGFR Epidermal growth factor receptor; mAb Monoclonal antibody; PD-1 Programmed 
death 1; PD-L1 Programmed death ligand 1; TKI Tyrosine kinase inhibitors.
Table 6
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management 
Should be used, when necessary, for all participants
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
6.4.1
Other concomitant treatment
Medications other than those described above that are considered necessary for the 
participant’s safety and well-being, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the eCRF.
6.4.2
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-
clinically or in participants.  As durvalumab is a monoclonal antibody and therefore a protein, 
it will be degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance.  It is therefore not expected that durvalumab will induce or 
inhibit the major drug-metabolising cytochrome P450 pathways.  As a result, there are no 
expected PK drug-drug interactions.  The mechanism of action of durvalumab involves 
binding to PD-L1, and therefore, significant pharmacodynamic drug-drug interactions with the 
commonly administered concomitant medications are not expected.  Despite this, appropriate 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
77
 
clinical monitoring in all of the planned clinical studies will be conducted to evaluate any 
potential drug-drug interactions.
6.4.3
Rescue medication
As a result of immune-mediated adverse events (imAEs) that could potentially be experienced 
by participants on durvalumab, steroids and other immunosuppressant rescue medication has 
to be made available to this participant population.  The 2 products that fall into the category 
of immunosuppressants are infliximab (eg, for colitis) and mycophenolate (eg, for hepatitis).  
AstraZeneca supply chain will only be responsible for sourcing these 2 rescue medications to 
the study sites if local regulations prevent the use of infliximab and mycophenolate in this 
indication, as they are considered off-label for management of immunotherapy-related 
toxicities.  These rescue medications must be receipted, controlled, and administered by the 
unblinded pharmacist and/or other appropriate unblinded site staff and stored according to the 
labelled storage conditions, with temperature excursions reported accordingly by the 
unblinded pharmacist and/or other appropriate unblinded site staff.  If required for use as a 
result of an imAE, then the IVRS/IWRS will provide to the unblinded pharmacists and/or 
other appropriate unblinded site staff the kit identification number to be allocated to the 
participant at the time, when the rescue medication is centrally supplied by AstraZeneca 
supply chain.  Blinded and unblinded access and notifications will be controlled using the 
IVRS/IWRS.
6.5
Dose modification
Dose delays are permitted for immuno-oncology therapy (see Dosing Modification and 
Toxicity Management Guidelines in Section 8.4.5).  However, dose reduction is not 
permitted.
6.6
Treatment after the end of the study
After the final DCO for this study, AstraZeneca will continue to supply open-label 
durvalumab monotherapy to participants who received durvalumab monotherapy until PD 
occurs as judged by the investigator. Tumour assessment scans will be performed in 
accordance with local clinical practice.
For participants continuing to receive durvalumab treatment following the final DCO and 
database closure, it is  recommended that the participants continue the scheduled site visits 
and investigators monitor the participants’ safety laboratory results prior to and periodically 
during treatment with durvalumab in order to manage AEs in accordance with the durvalumab  
Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
78
 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment may be transitioned to such a 
study, and the current study would reach its end. The roll-over or extension study would 
ensure treatment continuation with visit assessments per its protocol, as applicable. Any 
participant who would be proposed to move to such a study would be given a new informed 
consent, as applicable.
Dependent on the analysis results of the study, a decision may be made to continue further 
data collection for a longer period with intent to analyse long-term OS and safety data to fulfil 
any other potential Health Authority requirements. Any additional long-term analysis may be 
further clarified through addendum to main statistical analysis plan, which will be developed 
before DCO for the long-term analysis.  
7
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
An individual participant will not receive any further IP (durvalumab or placebo) if any of the 
following occur in the participant in question:

Withdrawal of consent from further treatment with IP.  The participant is, at any time, 
free to discontinue treatment, without prejudice to further treatment.  A participant who 
discontinues treatment is normally expected to continue to participate in the study (eg, for 
safety and survival follow up) unless they specifically withdraw their consent to all 
further participation in any study procedures and assessments (see Section 7.3).

An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing

Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (see Section 8.4.5)

Pregnancy or intent to become pregnant

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits)

Initiation of alternative anticancer therapy including another investigational agent

Confirmed radiological progression (refer to Appendix E) or Clinical progression and 
Investigator determination that the participant is no longer benefiting from treatment with 
IP
Withdrawal of consent for biological sampling is included in Section 8.8.6.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
79
 
7.1.1
Procedures for discontinuation of study treatment
Discontinuation of study treatment, for any reason, does not impact the participant’s 
participation in the study.  A participant who decides to discontinue IP will always be asked 
about the reason(s) for discontinuation and the presence of any AE.  The participant should 
continue attending subsequent study visits, and data collection should continue according to 
the study protocol.  If the participant does not agree to continue in-person study visits, a 
modified follow-up must be arranged to ensure the collection of endpoints and safety 
information.  This follow-up could be a telephone contact with the participant, a contact with a 
relative or treating physician, or information from medical records.  The approach taken 
should be recorded in the medical records.  A participant who agrees to modified follow-up is 
not considered to have withdrawn consent or to have withdrawn from the study.
Participants who are permanently discontinued from further receipt of IP, regardless of the 
reason, will be identified as having permanently discontinued treatment.  Participants who are 
permanently discontinued will enter Follow-up (see the SoAs).
Participants who permanently discontinue drug for reasons other than objective RECIST 1.1 
disease progression should continue to have RECIST 1.1 scans performed every 8 weeks 
(q8w) ±1 week for the first 48 weeks (relative to the date of randomisation), and then every 
12 weeks (q12w) ±1 week thereafter until RECIST 1.1-defined radiological PD plus an 
additional follow-up scan or death (whichever comes first) regardless of whether or not the 
participants started a subsequent anticancer therapy as defined in the SoAs.
If a participant is discontinued for RECIST 1.1-defined progression, then the participant
should have 1 additional follow-up scan performed preferably at the next (and no later than 
the next) scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD.
All participants will be followed for survival until the end of the study.
Participants who decline to return to the study site for evaluations should be contacted by 
telephone as indicated in the SoAs as an alternative.
Participants who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
7.2
Lost to follow-up
Participants will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4), such that there is insufficient information to 
determine the participant’s status at that time.  Participants 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-

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
80
 
establish contact with missing participants throughout the study period.  If contact with a 
missing participant is re-established, the participant should not be considered lost to follow-up 
and evaluations should resume according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
·        The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.
·        Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record.
·        Should the participant continue to be unreachable, he/she will be considered to have 
been lost to follow-up.
·        Site personnel, or an independent third-party, will attempt to collect the vital status of 
the participant during survival follow-up within legal and ethical boundaries for all 
participants randomised, including those who did not get study intervention. Public sources 
may be searched for vital status information. If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. Sponsor personnel 
will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
In order to support key endpoints of PFS and OS analyses, the survival status of all 
participants in the intent-to-treat and the safety analysis sets (SAS) should be re-checked; this 
includes those participants who withdrew consent or are classified as “lost to follow-up.”

Lost to Follow-up – study site personnel should check hospital records, the participants’ 
current physician, and a publicly available death registry (if available) to obtain a current 
survival status.  (The applicable eCRF modules will be updated.)

In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by study site personnel 
from publicly available death registries (if available) where it is possible to do so under 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
81
 
applicable local laws to obtain a current survival status.  (The applicable CRF modules 
will be updated.)
7.3
Withdrawal from the study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, compliance, 
or administrative reasons.
A participant who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options to ensure the collection of endpoints and safety information 
including new AEs and follow-up on any ongoing AEs and concomitant medications (eg, 
telephone contact after study intervention is discontinued, a contact with a relative or treating 
physician, or information from medical records).
A participant who withdraws consent will always be asked about the reason(s) for withdrawal 
and the presence of any AE.  The Investigator will follow up AEs outside of the clinical study.
If a participant withdraws consent, they will be specifically asked if they are withdrawing 
consent to:

All further participation in the study including any further follow-up (eg, survival contact 
telephone calls)

Withdrawal to the use of any samples (see Section 8.8.6)
Withdrawn participants will not be replaced.
Vital status (ie, whether a participant is dead or alive), based on public available sources, will 
be investigated at the scheduled study end.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoAs (Table 1 and Table 2).
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture system will be used for data collection and query handling.  
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
82
 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood count 
and imaging assessments) and obtained before signing of the ICF may be utilised for 
screening or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
Whenever feasible, participants must first be confirmed to have documented PD-L1 
expression status (<1% or ≥1%), EGFR and ALK status before proceeding with the rest of 
screening procedures. Screening/baseline evaluations may be performed over more than 1 
visit.
Inform consent form of tumour samples collection should be signed in order to permit tumour 
biopsy samples acquisition.
8.1
Efficacy assessments 
This study will evaluate the primary endpoint of PFS (mITT). Efficacy assessments of PFS, 
ORR, DoR, PFS12, PFS18, and time to death or distant metastasis (TTDM) will be derived 
(by AstraZeneca) using BICR RECIST 1.1 assessments. Time from randomisation to second 
progression (PFS2) will be assessed by the Investigator according to local standard clinical 
practice. OS and proportion of participants alive at 24 months from randomisation (OS24) will 
also be assessed.
Tumour assessments utilise images from CT (preferred) or MRI, each preferably with iv 
contrast, of the chest and abdomen (including the entire liver and both adrenal glands), 
collected during part II screening/Baseline and at regular (Follow-up) intervals during the 
study. Pelvic imaging is recommended only when primary or metastatic disease in the pelvic 
region is likely. Any other areas of disease involvement should be additionally imaged based 
on the signs and symptoms of individual participants. It is important to follow the tumour 
assessment schedule as closely as possible (refer to the SoAs). If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has 
not progressed, every attempt should be made to perform the subsequent assessments at the 
next scheduled visit. Treatment continues until confirmed radiological progression (refer to 
Appendix E) or other discontinuation criterion (Section 7.1) is met; and scanning/tumour 
assessments continue until RECIST 1.1-defined radiological progression plus 1 or more 
additional follow-up scans for confirmation of progression (if clinically feasible).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
83
 
The RECIST 1.1 guidelines (Appendix E) provide a method of assessment of change in 
tumour burden in response to treatment. Part II screening/baseline imaging should be 
performed no more than 28 days before start of study treatment, and ideally should be 
performed as close as possible to and prior to the start of study treatment.  The RECIST 1.1 
assessments of baseline images identify TLs (defined as measurable) and Non-Target Lesions 
(NTLs).  On-study images are evaluated for TLs and NTLs chosen at Baseline, and for New 
Lesions (NLs) when they appear.  This allows determination of follow-up TL response, NTL 
lesion response, the presence of unequivocal NLs, and overall timepoint responses (CR, PR, 
SD, PD, or Not Evaluable [NE]).
A follow-up scan is to be collected after the initial RECIST 1.1-defined radiological PD, no 
less than 4 weeks after the prior assessment of PD and no later than the next regularly 
scheduled imaging visit and; this follow-up scan is evaluated using the Confirmation of 
Radiological Progression criteria outlined in Appendix E.  If the subsequent scan confirms the 
immediate prior radiological PD, no additional scans are required; however, if the subsequent 
scan does not confirm the immediate prior radiological PD, scanning should continue until the 
next RECIST 1.1-defined radiological PD, which in turn will require a subsequent scan 
evaluated using the Confirmation of Radiological Progression criteria outlined in Appendix E.
If a participant has initial progression but changes to another anticancer treatment before that 
progression is confirmed, the follow-up scan should still be acquired on the regular imaging 
schedule.  
8.1.1
Central reading of scans
The primary analysis for this study will be based on PFS (mITT) from BICR using assessment 
of tumours using RECIST 1.1.  All images, including unscheduled visit scans, will be 
collected on an ongoing basis and sent to an AstraZeneca-appointed contract research 
organisation for QC and storage.  Guidelines for image acquisition, de-identification, storage 
at the investigative study site as source data, and transfer to the imaging contract research 
organisation will be provided in a separate document.  A BICR of images will be performed at 
the discretion of AstraZeneca.  Results of these independent reviews will not be 
communicated to Investigators, and results of Investigator RECIST 1.1 assessments will not 
be shared with the central reviewers.  The management of participants will be based in part on 
the results of the RECIST 1.1 assessment conducted by the Investigator.  Further details of the 
BICR will be documented in the Independent Review Charter (also referred to as “Imaging 
Charter”).
In addition, an exploratory analysis of PFS from BICR by assessment of tumours using 
immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 (Wolchok et al 
2009, Nishino et al 2013) may be presented outside of the main CSR.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
84
 
8.1.2
Survival assessments
Assessments for survival must be made once a month in the first four months following 
treatment discontinuation, and then every two months thereafter.  Survival information may be 
obtained via telephone contact with the participant or the participant’s family, or by contact 
with the participant’s current physician.  The details of first and subsequent therapies for 
cancer, after discontinuation of treatment, will be collected.
In addition, participants on treatment or in survival Follow-up will be contacted following the 
DCO for the primary analysis and all subsequent survival analyses to provide complete 
survival data.  These contacts should generally occur within 7 days of the DCO.
8.1.3
Second progression
Following the first progression event used for the primary variable, PFS (the first 
progression), the site will be asked on a regular basis (q8w ±1 week for the first 48 weeks 
[relative to the date of randomisation], and then q12w ±1 week) if the participant has had a 
second progression event.   A participant’s progression status is defined according to local 
standard clinical practice and may involve any of the following: objective radiological 
progression, symptomatic progression, or death. The date of PFS2 assessment and 
Investigator’s opinion of progression status (progressed or non-progressed) at each assessment 
will be recorded in the PFS2 eCRF.
8.1.4
Clinical outcome assessments
A Clinical Outcome Assessment (COA) is any assessment that may be influenced by human
choices, judgement, or motivation and may support either direct or indirect evidence of
treatment benefit. Patient Reported Outcomes (PROs) is one of the types of COAs. PROs is an 
umbrella term referring to all outcomes that are directly reported by the participant. The 
following PRO instruments will be administered in this study: EORTC QLQ-C30 v3 (core 
questionnaire), EORTC QLQ-LC13 (lung cancer module), and EQ-5D-5L; see Appendix G.
Timings of the assessments for PRO are presented in Table 1 (Screening and the Treatment 
Period) and Table 2 (Follow-up).  
If participants have scans at an outside facility or missed a scheduled data collection, PRO 
questionnaires need to be administered at the next visit.  
8.1.4.1
EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ-C30 is a 30-item self-administered questionnaire (Appendix G).  There are 
9 multiple item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, 
emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a 
global health status/quality of life (QoL) scale.  There are 5 single-item measures assessing 
additional symptoms commonly reported by cancer participants (dyspnoea, loss of appetite, 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
85
 
insomnia, constipation, and diarrhoea) and a single item concerning perceived financial 
impact of the disease.  
For NSCLC participants, a disease-specific, 13-item, self-administered questionnaire for lung 
cancer was developed (QLQ-LC13; Appendix G) to be used in conjunction with the EORTC 
QLQ-C30 (Bergman et al 1994).  It comprises both multi-item and single-item measures of 
lung cancer-associated symptoms (ie, coughing, haemoptysis, dyspnoea, and pain) and side 
effects from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore 
mouth, and dysphagia).  
All but 2 questions have 4-point scales: “Not at all,” “A little,” “Quite a bit,” and “Very 
much.” The 2 questions concerning global health status/QoL have 7-point scales with ratings 
ranging from “Very poor” to “Excellent.” Final scores are transformed such that they range 
from 0 to 100, where higher scores indicate greater functioning, greater health status/QoL, or 
greater level of symptoms (Aaronson et al 1993).  
8.1.4.2
EQ-5D
The EuroQoL 5-dimension utility index (EQ-5D) is a standardised measure of health status 
developed by the EuroQol Group in order to provide a simple, generic measure of health for 
clinical and economic appraisal (EuroQoL 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 unable to/extreme problems) that reflect 
increasing levels of severity (EuroQoL 2013).
Since 2009, the EuroQoL group has been developing a more sensitive version of the EQ-5D 
(the EuroQoL 5-dimension, 5-level health state utility index [EQ-5D-5L]), which 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 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 participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions.  The questionnaire also includes a visual 
analogue scale, where the participant will be asked to rate current health status on a scale of 0 
to 100, with 0 being the worst imaginable health state.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
86
 
The assessment of health state utility will provide important information for payers and will 
be used within economic evaluations of durvalumab.
8.1.4.3
Administration of patient-reported outcomes questionnaires
Participants will perform the PRO assessments using an electronic tablet (ePRO) during clinic 
visits and will take approximately 10 minutes to complete.
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. The PRO questionnaires must be administered 
and completed at the clinic as per the SoAs. 
It is important that the site staff explains the value and relevance of PRO data: to hear directly 
from participants how they feel. The following best practice guidelines should be followed:

It is preferred that PRO questionnaires are completed prior to any other study procedures 
(following informed consent) and before discussion of disease progression to avoid 
biasing the participant’s responses to the questions.

PRO questionnaires must be completed in private by the participant.

Participant should be given sufficient time to complete the PRO questionnaires at their 
own speed. 

If the participant is unable to read the questionnaire (e.g. is blind or illiterate), that 
participant should be exempted from completing PRO questionnaires but may still 
participate in the study. Participants exempted in this regard should be flagged 
appropriately by the site staff in the source documents.

The research nurse or appointed site staff should stress that the information is 
confidential. Therefore, if the participant has any medical problems, he or she should 
discuss them with the doctor or research nurse separately from the ePRO assessment.

The research nurse or appointed site staff must train the participant on how to use the 
ePRO device using the materials and training provided in the ePRO device. 

The research nurse or appointed site staff must remind participants that there are no right 
or wrong answers and avoid introducing bias by not clarifying items. The participant
should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. 

All PRO questionnaires are to be completed using an ePRO device. If technical or other 
device-related issues prohibit completion on the device, an appropriate back-up option 
may be considered with prior approval from the study team.
A key aspect of study success is to have high PRO compliance. Therefore it is essential to 
follow SoA and that sites make sure the device is charged and fully functional at all times in 
order to minimize missing data.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
87
 
8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoAs.
8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
the SoAs).
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 study site.  
Pregnancy tests may be performed at the study 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 7 (clinical chemistry), Table 8
(haematology), and Table 10 (urinalysis).
Other safety tests to be performed at part II screening include assessment for HBsAg, HCV 
antibodies, and HIV antibodies.
The following laboratory variables will be measured:
Table 7
Clinical chemistry
Albumin
Lipasea,b
Alkaline phosphatasec
Magnesiumd
ALTc
Potassium
Amylasea,b
Sodium
ASTc
Total bilirubinc
Bicarbonated
Total protein
Calcium 
TSHe
Chlorided
T3 freef (reflex)
Creatinined
T4 freef (reflex)
Gamma glutamyltransferased
Urea or blood urea nitrogen, depending on local practice
Glucose
Uric acidb
Lactate dehydrogenase

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
88
 
a
It is preferable that both amylase and lipase parameters are assessed.  For study sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable.
b
Amylase, lipase, and uric acid are tested at Screening, Day 1 (unless part II screening laboratory 
assessments are performed within 3 days prior to Day 1) and every 4 weeks thereafter.
c
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin.
d
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at Baseline, on Day 1 (unless all part II screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
e
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 
1.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
AE Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; T3 Triiodothyronine; 
T4 Thyroxine; TSH Thyroid-stimulating hormone; WT Body weight.
Table 8
Haematology
Absolute neutrophil counta
Absolute lymphocyte counta
Haemoglobin
Platelet count
Total white blood cell count
a
Should be recorded as absolute counts other than percentages.
Table 9
Coagulation Parameters
Activated partial thromboplastin timea
International normalised ratioa
a
Can be recorded as absolute counts or as percentages.  Total white blood cell count therefore has to be 
provided.
Note: For coagulation parameters, activated partial thromboplastin time and international normalised ratio are to 
be assessed at part II screening and as clinically indicated.
Table 10
Urinalysis
Bilirubin
Ketones
Blood
pH
Colour and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at Baseline (part II screening), and then as clinically indicated.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red and white blood cells.
If a participant shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer 
to Appendix D for further instructions on cases of increases in liver biochemistry and 
evaluation of Hy’s Law.  These cases should be reported as SAEs if, after evaluation, they 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
89
 
meet the criteria for a Hy’s Law case or if any of the individual liver test parameters fulfil any 
of the SAE criteria.
All participants should have further chemistry profiles performed at 30 days (±3 days), 2 
months (±1 week), and 3 months (±1 week) after permanent discontinuation of IP (see the 
SoAs).
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 8.3.7.
All participants with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from IP 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.
8.2.2
Physical examinations
Physical examinations will be performed according to the assessment schedules (see the 
SoAs).  Full physical examinations will include assessments of the head, eyes, ears, nose, and 
throat and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 
measured at part II screening only.  Targeted physical examinations are to be utilised by the 
Investigator on the basis of clinical observations and symptomatology.  Situations in which 
physical examination results should be reported as AEs are described in Section 8.3.7.
8.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. WT is also recorded at each visit along with vital signs.
First infusion
On the first infusion day, participants will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of IP as presented in the bulleted list below.
BP and pulse will be collected from participants before, during, and after each infusion at the 
following times (based on a 60-minute infusion):

Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])

Approximately 30 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 60 minutes ±5 minutes)

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
90
 
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.  A 1-hour 
observation period is recommended after the first infusion of durvalumab.
Subsequent infusions
BP, pulse, and other vital signs should be measured and collected/recorded in the eCRF prior 
to the start of the infusion.  Participants should be carefully monitored, and BP and other vital 
signs should be measured during and post infusion as per institution standard and as clinically 
indicated.  Any clinically significant changes in vital signs should be entered onto an 
unscheduled vital signs CRF page.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7.  For any AEs of infusion reactions, the vital signs values should be entered into 
the CRF.
8.2.4
Electrocardiograms
Resting 12-lead ECGs will be recorded at part II screening and as clinically indicated 
throughout the study (see the SoAs).  ECGs should be obtained after the participant has been 
in a supine position for 5 minutes and recorded while the participant remains in that position.
In case of clinically significant ECG abnormalities, including a QT interval corrected for heart 
rate using Fridericia’s formula (QTcF) value >470 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (eg, 30 minutes) to confirm the finding.
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.5
WHO/ECOG performance status
WHO/Eastern Cooperative Oncology Group (ECOG) PS will be assessed at the times 
specified in the assessment schedules (see the SoAs) based on the following:
1
Fully active; able to carry out all usual activities without restrictions
2
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work)
3
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours
4
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
5
Completely disabled; unable to carry out any self-care and totally confined to bed or chair
6
Dead
Any significant change from Baseline or part II screening must be reported as an AE.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
91
 
WHO/ECOG PS should also be collected at other study site visits that the participant attends, 
if appropriate study site staff are available to collect such information.  In addition, 
WHO/ECOG PS should be provided when information on subsequent anticancer therapy is 
provided, where possible.
8.2.6
Other safety assessments
If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease (ILD) is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5) will be applied.  The results of the full diagnostic workup (including high-
resolution computed tomography [HRCT], blood and sputum culture, haematological 
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 oedema, or pulmonary haemorrhage.  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 should be followed.
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis.  The results of the 
assessment will be collected.

Physical examination

Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
o
ILD Markers (KL-6 and surfactant-associated protein) and β-D-glucan
o
Tumour markers: Particular tumour markers that are related to disease 
progression
o
Additional Clinical chemistry: C-reactive protein, lactate dehydrogenase 
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
92
 
The definitions of an AE or SAE can be found in Appendix B.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow up AEs, 
see Section 8.3.3.
8.3.1
Method of detecting adverse events and serious adverse events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event information 
AEs and SAEs will be collected from the time of the participant signing the ICF of study 
procedure (part II screening) until the Follow-up Period is completed (90 days after the last 
dose of study drug).  If an event that starts post the defined safety Follow-up Period noted 
above is considered to be due to a late onset toxicity to study drug, then it should be reported 
as an AE or SAE as applicable.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants.  
However, if the Investigator learns of any SAE, including a death, at any time after a 
participant’s last visit and he/she considers the event to be reasonably related to the study 
treatment or study participation, the Investigator should notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be followed until resolution,
stabilisation, the event is otherwise explained, or the participant is lost to follow-up.
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
Investigator for as long as medically indicated (this may be beyond the 90 days after the last 
dose of durvalumab), but without further recording in the eCRF.  AstraZeneca retains the right 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
93
 
to request additional information for any participant with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar day)

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria 

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 8.3.5

Description of the SAE
The grading scales found in the revised NCI CTCAE version 5.0 will be utilised for all events 
with an assigned CTCAE grading.  For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used.  A copy of the CTCAE version 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
Any non-serious AE that is ongoing at the time of the final DCO is to be followed up at the 
discretion of the Investigator, per local practice, and in alignment with the toxicity 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
94
 
management guidelines (refer to Section 8.4.5) of this protocol. Data will not be captured for 
the purposes of this study outside of being recorded in the participants’ source documents.
8.3.5
Causality collection
The Investigator will assess causal relationship between IP 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?”
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 B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff, “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.
8.3.7
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarised in the 
Clinical Study Report (CSR).  Deterioration as compared to Baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP.
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, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Asymptomatic Grade 3 or 4 increases in amylase or lipase resulting in interruption of dosing 
(refer to Section 8.4.5) should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
95
 
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 unless unequivocally 
related to the disease under study; see Section 8.3.8 and Section 8.3.9.
8.3.8
Hy’s Law
Cases in which a participant shows elevations in liver biochemistry may require further 
evaluation, and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN 
may need to be reported as SAEs.  Please refer to Appendix D for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law.
8.3.9
Disease-under study
Symptoms of disease under study are those that might be expected to occur as a direct result 
of lung cancer.  Events that are unequivocally due to disease under study should not be 
reported as an AE during the study unless they meet SAE criteria or lead to discontinuation of 
the IP.
8.3.10
Disease progression
Disease progression can be considered as a worsening of a participant’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.  Events that are unequivocally due to 
disease progression should not be reported as an AE during the study.
8.3.11
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 IP and have been identified 
after the participant’s inclusion in this study.
8.3.12
Deaths
All deaths that occur during the study Treatment Period, or within the protocol-defined 
Follow-up Period after the administration of the last dose of study drug, must be reported as 
follows:

Death clearly resulting from disease progression should be documented in the eCRF in 
the Statement of Death page.  It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours.  It should also be 
documented in the Statement of Death page in the eCRF.  The report should contain a 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
96
 
comment regarding the co-involvement of PD, if appropriate, and should assign main and 
contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE, and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death.  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 
Participant Safety or its representative within the usual timeframes.
Deaths occurring after the protocol-defined safety Follow-up Period after the administration of 
the last dose of study drug should be documented in the Statement of Death page.  If the death 
occurred as a result of an event that started after the defined safety Follow-up Period and the
event is considered to be due to a late onset toxicity to study drug, then it should also be 
reported as an SAE.
8.3.13
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.  An AESI may be serious or 
non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in 
order to characterise and understand them in association with the use of this IP.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy.  
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy.  An imAE is defined as an AESI that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is 
no clear alternate aetiology.  Serologic, immunologic, and histologic (biopsy) data, as 
appropriate, should be used to support an imAE diagnosis.  Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the 
imAE.
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs/imAEs observed with anti PD-1/PD-L1 agents such as durvalumab include:

Diarrhoea/colitis and intestinal perforation

Pneumonitis/ILD

Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism, and type I diabetes mellitus)

Hepatitis/transaminase increases

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
97
 

Nephritis/blood creatinine increases

Pancreatitis/serum lipase and amylase increases

Rash/dermatitis

Myocarditis

Myositis/polymyositis

Other inflammatory responses that are rare/less frequent with a potential immune-
mediated aetiology include, but are not limited to, haematological events, 
neuropathy/neuromuscular toxicity (eg, Guillain-Barré and myasthenia gravis), non-
infectious encephalitis, non-infectious meningitis, pericarditis, rheumatological events, 
sarcoidosis, skin events, uvetitis [and other events involving the eye] and vasculitis.
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 durvalumab IB.  More specific guidelines for their evaluation and treatment are 
described in detail in the Dose Modification and Toxicity Management Guidelines (see 
Section 8.4.5).  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.
8.3.14
Safety data to be collected following the final data cutoff of the study
For participants continuing to receive durvalumab treatment after final DCO and database 
closure, it is recommended that the participants continue the scheduled study site visits and 
Investigators monitor the participant’s safety laboratory results prior to and periodically 
during treatment with durvalumab in order to manage AEs in accordance with the durvalumab 
Dose Modification and Toxicity Management Guidelines (see Section 8.4.5).  All data post 
the final DCO and database closure will be recorded in the participant notes but, with the 
exception of SAEs, will not otherwise be reported for the purposes of this study.
All SAEs that occur in participants still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) after the final DCO and database closure 
must be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s).  All SAEs will be recorded in the CRF.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
98
 
If any SAE occurs in the course of the study, then Investigators or other study site personnel 
inform the appropriate AstraZeneca representatives within 1 day (ie, 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 the 
necessary information is provided to the AstraZeneca Participant 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 study site personnel inform 
AstraZeneca representatives 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.
The reference document for definition of expectedness/listedness is the IB for durvalumab.
After the final DCO for the study, any SAEs occurring in the 90-day safety Follow-up Period 
after receiving the last dose of durvalumab are to be recorded in a paper CRF and reported 
directly to the AstraZeneca Participant 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 further guidance on the definition of a SAE, see Appendix B.
8.4.2
Pregnancy
All pregnancies including pregnancy in the partner of male participants and outcomes of 
pregnancy should be reported to AstraZeneca representative except:

If the pregnancy is discovered before the patient has received any study treatment
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.
Following the final DCO for the study, Investigators or other study site personnel shall report 
all pregnancy outcomes to AstraZeneca Participant Safety.
8.4.2.1
Maternal exposure
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately and the pregnancy reported to AstraZeneca.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
99
 
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 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other study site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
or no later than 24 hours of when he or she becomes aware of it).
If any pregnancy occurs after the final DCO for the study, Investigators or other study site 
personnel must inform AstraZeneca Participant Safety 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 Participant Safety data entry site within 
1 or 5 calendar days for SAEs (see Section 8.4.1) 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.  Paper-based modules will be available to study 
sites following final DCO for the study.
8.4.2.2
Paternal exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 90 days after the last dose of durvalumab monotherapy.
Pregnancy of the participant’s partner is not considered to be an AE.  However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the date of the first dose until 90 days after 
the last dose of durvalumab monotherapy should, if possible, be followed up and documented 
in the medical record and provided to the AstraZeneca Participant Safety data entry site. 
Consent from the partner must be obtained before the information is collected and reported to 
AstraZeneca.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the participant’s partner.  Therefore, the local study 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
100
 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.
Participants who are permanently discontinued from further receipt of IP, regardless of the 
reason, will enter Follow-up (see the SoAs).
8.4.3
Overdose
Use of durvalumab in doses in excess of that specified in the protocol is considered to be an 
overdose.  There is currently no specific treatment in the event of overdose of durvalumab, 
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 CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study treatment occurs in the course of the study, then the 
Investigator or other study site personnel informs 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 Participant Safety data entry site within 
one or 5 calendar days for overdoses associated with an SAE (see Section 8.4.1) and within 30 
days for all other overdoses.
If an overdose on an AstraZeneca study treatment occurs after the final DCO for the study, 
then Investigators or other study site personnel shall inform AstraZeneca Participant Safety 
immediately, or no later than 24 hours of when he or she becomes aware of it.
8.4.4
Medication error
If an event of medication error occurs during the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within one calendar day, ie, 
immediately but no later than 24 hours of when they become aware of it. The designated 
AstraZeneca representative works with the Investigator to ensure that all relevant information 
is completed within 1 (initial Fatal/Life-Threatening or follow-up Fatal/Life-Threatening) or 5 
(other serious initial and follow-up) calendar days if there is an SAE associated with the 
medication error(see Section 8.3.2) and within 30 days for all other medication errors.
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix B 4.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
101
 
8.4.5
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 5.0.
8.4.5.1
Specific toxicity management and dose modification information –
durvalumab 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab monotherapy are provided in the Dosing 
Modifications and Toxicity Management Guidelines. The most current version of these 
guidelines is to be maintained within the Site Master File. 
Participants 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 aetiology, events should be considered 
potentially immune related.
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines).
Following the first dose of IP, subsequent administration of durvalumab 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 durvalumab monotherapy by the 
reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
102
 
Dose modifications will not be required for AEs that are clearly not attributed to study 
treatment (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant.  Dosing may continue despite concurrent vitiligo of any AE grade.
8.5
Pharmacokinetics
Drug concentration information that may unblind the study will not be reported to 
investigative study sites or blinded personnel until the study has been unblinded.
8.5.1
Collection of samples
Blood samples for determination of durvalumab concentration in serum will be obtained 
according to the SoAs.  
Samples for determination of durvalumab concentration in serum will be analysed by a 
designated third party on behalf of AstraZeneca.  Samples will be collected, labelled, 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.
8.5.1.1
Collection of samples to measure for the presence of antidrug antibodies
The presence of ADAs will be assessed in serum samples taken according to the SoAs.  
Samples will be measured for the presence of ADAs and ADA-neutralising antibodies using 
validated assays. Tiered analysis will be performed to include screening, confirmatory, and 
titre assay components, and positive-negative cut points previously statistically determined 
from drug-naïve validation samples will be employed.
8.5.2
Storage and destruction of pharmacokinetic/antidrug antibody samples
PK and ADA samples collected in China will be destroyed after the finalisation of the 
Bioanalytical Reports.  PK/ADA samples collected will be stored and disposed of according 
to local laws and regulations.
Durvalumab PK and ADA samples collected in rest of world may be disposed of or destroyed 
and anonymised by pooling. Additional analyses may be conducted on the anonymised, 
pooled PK samples to further evaluate and validate the analytical method. Results from such 
analyses may be reported separately from the CSR. Durvalumab PK samples collected in the 
rest of the world will be disposed of 6 months after final study Bioanalytical report.   
Durvalumab ADA samples collected in the rest of the world will be destroyed within 5 years 
of CSR finalization.
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 
separately in a Bioanalytical Validation Report.

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 3
 
8. 6
P h ar m ac o d y n a mics
P har mac o d y na mic para meters are n ot e val uate d i n t his st u d y .
8. 6. 1
C ollecti o n of s a m ples
P har mac o d y na mic sa m ples will n ot be ta ke n d uri n g t he st u d y .
8. 6. 2
St or a ge, re use, a n d destr ucti o n of p h ar m ac o d y n a mic s a m ples
P har mac o d y na mic sa m ples will n ot be ta ke n d uri n g t he st u d y .
8. 7
Ge netics
N ot a p plica ble.
8. 8
Bi o m ar kers
B y  partici pati n g i n t his st u d y t he parti ci pa nt c o nse nts t o t he ma n dat or y c ollecti on a n d use of 
d o nate d bi ol o gical  s a m ples as descri be d here.  
Pre -treat me nt t u mo ur P D -L 1 e x pressi o n will be e val uate d i n all scree ni n g partici p a nts , a n d 
 will be e val uate d i n all ra n d omise d parti ci pa nts. F or ra n d o mise d parti ci pa nts, data will 
be c o m pare d bet wee n ar ms t o deter mi ne if baseli n e P D-L 1 stat us a n d  
 is pr o g n ostic 
a n d/ or pre dict i ve of o utc o mes ass ociate d wit h d ur val u ma b.  Baseli ne t u m o ur re q uire me nts are 
br iefl y descri be d i n Secti on  8. 8. 1 . 
Base d o n a vaila bilit y of tiss ue, a d diti o nal e x pl orat or y  bio m ar kers ma y be e val uate d as 
descri be d i n Secti o n  8. 8. 2 .  Als o, descri pti ons o f e x pl orat or y, p erip heral  meas ures are 
descri be d i n t his sect i on.  Sa m ples will be o btai ne d acc or di n g t o t he assess me nt sc he d ules 
pr o vi de d i n t he S o As.
Details o n t he c ollecti o n, v o l umes, st ora ge, a n d s hi p me nt of bi o l ogi c s a mples are prese nte d i n 
a se parate La b orat or y  Ma n ual.
All sa m ples c ollecte d f or bi omar ker a nal yses will be st ore d at t he st u d y  site, a refere nce 
la b orat or y, or at Astra Ze neca facilities a n d ma y be use d f or s u bse q ue nt researc h rele va nt t o 
e val uat i n g bi o l ogical  a n d/ or cli nical res p o nse t o i m m u n ot hera p y as descri be d i n t he 
e x pl orat or y a nal yses sectio n.
T he res ults ma y be p o ole d wit h bi o mar ker data fr o m ot her d ur val u ma b ± tre meli m u ma b 
st u dies t o e valuate bi ol o gi c al  res p o nses acr oss i n dicati o ns a n d t o c o m pare res ults i n 
m o n ot hera p y  vers us c o m bi nati o n setti n gs.
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 4
 
8. 8. 1
C ollecti o n of p artici p a nt selecti o n bi o m ar ker d at a
At  part I scree ni n g, t here is 1 ma n dat or y pr o visio n  of tiss ue t o be use d f or deter mi nati on of 
P D -L 1 ( E G F R m utati o n a n d A L K m utati o n assess me nts will be teste d, if t here’s n o a vaila ble 
res ult fr o m lo c al  la b orat ories).  After P D-L 1 is teste d a n d parti ci pa nts are eli gi ble a n d 
ra n d omize d, t he re mai ni n g sa m ple will be use d t o assess  
:

M A N D A T O R Y: Pr o visi o n of a t u m o ur bi o ps y , for mali n fi xe d a n d e m be d de d i n paraffi n, 
f or t he p ur p ose of P D-L 1 e x pr essio n  a nal yses (a n d f or e na bli n g 
 a nal yses, if 
t he partici pa nts are ra n d o mize d). A ne wl y ac q uire d t u m o ur bi o ps y sa m ple < 3 m o nt hs ol d 
is str o n gl y preferre d; h o we ver, if n ot feasi ble wit h a n acce pta ble cli nical ris k, a n arc hi val 
sa m ple ta ke n ≤ 6 m o nt hs pri or t o part I scree ni n g ca n be s u b mitte d. A bi o ps y  pr oce d ure 
d uri n g scree ni n g peri o d is n ot all o we d. Arc hi ve d or ne wl y ac q uire d t u m o ur sa m ple m ust 
be o btai ne d bef ore C R T. A n y  irra diate d sa mple is n ot acce pta ble. 

S a m ples s h o ul d be c ollecte d vi a a n i ma ge-g ui de d c ore nee dle (at l east 1 8 ga u ge) or b y 
e xcisi o n.  W here i nst ituti o nal  practice, i n t his setti n g, uses a s maller ga u ge nee dle, 
sa m ples s h o ul d be s u b mitte d wit h tiss ue a de q uate t o e ns ure t hat a vali d res ult ca n be 
ac hie ve d (i.e. t otal tiss ue q uant ity s u b mitte d s h o ul d be si milar t o c ore nee dle or e xcisi onal 
bi o ps y re q uire me nts descri be d briefl y  here a n d o utli ne d i n t he la b ma n ual).

Eff ort s h o ul d be ma de t o ma xi mize material f or d o w nstrea m a nal yses. Sa m ple ac q uire d 
bef ore scree ni n g peri o d is e x pect e d t o be c ollecte d i n t w o c ores, usi n g a n 1 8 -ga u ge or 
lar ger nee dle, f or deter mi ni n g P D-L 1 e x pressi o n. U nstai ne d tiss ue sect i ons will be 
c ollecte d f or P D-L 1 e x pressi o n. It i s ma n date d t hat s ufficie nt tiss ue f or b ot h P D-L 1 
a nal yses a n d  
 a nal ysis s h o ul d be o btai ne d a n d pr ocesse d as descri be d i n t he 
La b orat or y  Ma n ual/ Pat h olo g y  Ma n ual.
T he t u m o ur s peci me n s u b mitte d s h o ul d be of s ufficie nt q ua nt ity t o all o w f or P D-L 1 
i m m u n o hist oc he mistr y (I H C) a nal yses a n d deter mi nati on of  
 (see t he La b orat or y  
Ma n ual).  Ne wl y ac q uire d or arc hi ve d s peci me ns wit h li mite d t u m o ur c o n te nt a n d fi ne nee dle 
as pirates are i na de q uate f or defi ni n g t u m o ur P D-L 1 stat us. 
 is a n o pti o nal test i n 
C hi na .
T u m o ur lesi o n s use d f or fres h bi o psies s h o ul d n ot be t he sa me lesi ons use d as R E CI S T 1. 1 
tar get lesi ons, u nless t here are n o ot her lesi o ns s uit a ble f or bi o ps y, a n d i n t his i nsta nce o nl y 
c ore nee dle ( n ot e xcisi o nal/i ncisi o n al ) bio ps y  is all o we d. F or partici pa nts wi t h a si n gle tar get 
lesio n, if scree ni n g bi o ps y  is c ollecte d pri or t o scree ni n g i ma gi n g f or baseli ne t u m o ur 
assess me nt, all o w a p pr o xi matel y 2 wee ks bef ore i ma gi n g sca ns are ac q uire d.
A d dit i onal t u m o ur bi o psies c o llecte d as part of cli nical care (e. g. f or mi xe d res p o nses or u p o n 
P D) ca n be s u b mitte d f or f urt her a nal ysis. T his sa m ple will n ot be c ollecte d i n C hi na.
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 5
 
See t he La b orat or y  Ma n ual for f urt her details of re q uire me nts i ncl u di n g sa m ple q ualit y 
c o ntr ol a n d s hi p pi n g.
T he Ve nta na P D -L 1 ( S P 2 6 3) I H C assa y will be use d t o deter mi ne P D -L 1 stat us i n all 
s peci me ns.
A pa nel o f ge nes, s uc h as t he 
, will be utilize d t o assess 
 
 i n t he s u bject s peci me ns fr o m t he trial. 
T o m eet t he re q uire me nt of gl o bal re g ulat or y a p pr o val of  a dia g n ost ic, secti o ns of t he t u m o ur 
will be retai ne d i n all re gi o ns t hat all o w t his f or p ote ntial a d dit i onal st u di es, as re q ueste d b y 
t he re g ulat or y a ge ncies, t o s u p p ort p ote ntial test a p pr o val.  
8. 8. 2
E x pl or at or y bi o m ar kers 
Bl o o d a n d t u m o ur s a m ples f or e x pl or at or y  bio m ar ker a nal yses will be o btai ne d acc or di n g t o 
t he sc he d ules prese nte d i n t he S o As.  Details f or c ollect i on, v o l umes, st ora ge, a n d s hi p me nt of 
bi o l ogic sa m ples are prese nte d i n a se parate La b orat or y  Ma n ual.  
Baseli ne meas ures will be c orrelate d wi t h o ut c o mes.  N ote t hat sa mples will be o btai ne d fr o m 
parti ci pa nts ra n d o mise d t o eac h treat me nt ar m.  C o m paris o ns will be ma de bet wee n baseli ne 
meas ures t o deter mi ne if bi o mar kers ( or c o m bi nati o n of mar kers) are pr o g n ostic or pre dict i ve 
of  o utc o mes associate d wi t h d ur val u ma b t hera p y.
A d dit i onal sa m ple c ollecti ons a n d a nal yses ma y be c o m plete d at select st u d y  sites b y sit e-
s pecific a me n d me nt.  All sa m ples c o llecte d f or s uc h e x pl orat or y a nal yses will be st ore d at t he 
st u d y site, a refere nce la b orat or y, or at Astra Ze neca’s facilit ies a n d ma y be use d f or 
s u bse q ue nt researc h rele va nt t o e val uat i n g res p o nse t o i m m u n ot hera p y.  
T he e x pl orat or y  bio m ar ker pla n is descri be d b y sa m ple t ype bel o w.
 
 
 
 
T his sa m ple will n ot be c ollecte d i n C hi na.
 
 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
M a n a ge me nt of bi o m ar ker d at a
T he bi o mar k er data will ha ve u n k n o w n cli nical si g nifica nce.  Astra Ze neca will n ot pr o vi de 
bi o mar ker researc h res ults t o partici pa nts , t heir fa mil y me m bers, a n y ins ura nce c o m pa n y, a n 
e mpl o y er, cli nical st u d y I n vestigat or, ge neral  p h ysicia n, or a n y ot her t hir d part y, unless 
re q uire d t o d o s o b y la w.  T he partici pa nt ’s sa m ples will n ot be use d f or a n y p ur p ose ot her 
t ha n t h ose descri be d i n t he st u d y pr ot oc ol.
I n di vi d ual part ici pa nts will n ot be i de nt ifie d i n a n y re p ort or p u blicati o n res ulti n g fr om t his 
w or k.  T he data a n d res ul ts of t his researc h ma y b e r e vie we d wit h c olla b orat ors a n d p u blis he d, 
b ut neit her t he partici pa nt ’s na me n or a n y ot her pers o nal i de nt ifiers will a p pear i n a n y 
p u blicat i on or re p ort.
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
107
 
8.8.3
Storage, reuse, and destruction of biomarker samples
Samples collected in China will be disposed of according to local laws and regulations. . 
Samples collected in the rest of the world will be stored for a maximum of 15 years from the 
end of study, after which they will be destroyed. Summaries and analyses for exploratory 
biomarkers will be documented in a separate analysis plan and will be reported outside the 
CSR in a separate report. The results of this biomarker research may be pooled with 
biomarker data from other studies involving durvalumab ± tremelimumab to generate 
hypotheses to be tested in future research.
Biological samples collected will be stored and disposed of according to local laws and 
regulations.
8.8.4
Labelling and shipment of biological samples
The Principal Investigator will ensure that samples are labelled 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 C “International Airline Transportation Association (IATA) 6.2 Guidance 
Document.”
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved participants unless agreed upon with AstraZeneca and 
appropriate labelling, shipment, and containment provisions are approved.
8.8.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each study site will keep full traceability of collected biological 
samples from the participants while in storage at the study site until shipment or disposal 
(where appropriate) and will keep documentation of sample shipments.
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, auditing or process checks, and contractual requirements of external 
laboratory providers.
Except in China, samples retained for further use will be registered in the AstraZeneca-
assigned Biobank during the entire life cycle.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
108
 
8.8.6
Withdrawal of informed consent for donated biological samples
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of or destroyed and the action documented.  If samples have already been 
analysed, AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:

Ensure that AstraZeneca is immediately notified of the participant’s withdrawal of 
informed consent to the use of donated samples

Ensure that biological samples from that participant, if stored at the study site, are 
immediately identified, disposed of or destroyed and the action documented

Ensure that the organisation(s) holding the samples is/are immediately informed about the 
withdrawn consent and that samples are disposed of or destroyed, the action is 
documented, and the site informed.
Ensure that the participant and AstraZeneca are informed about the sample disposal.
8.9
Health economics
For the purposes of economic evaluation, it is necessary to capture health care resource use 
related to the treatment and the underlying disease.  Within the study, the following will be 
captured:

Hospital episodes including the type of contact (hospitalisations, outpatient, or day case), 
reason, length of stay by ward type (including intensive care unit), and concomitant 
medications and procedures

Treatment related to AEs (including the method of delivery of the treatment)

Treatment not related to the study
The above resource use data will mainly come from the participant’s medical record and will 
be captured in the eCRF.
The assessment of health economic resource use data will provide important information for 
payers and will be used in economic evaluations of durvalumab.
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information.
9
STATISTICAL CONSIDERATIONS 
The primary aim of the study is to compare the efficacy of durvalumab compared with 
placebo in terms of BICR PFS (mITT).

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 9
 

All pers o n nel i n v o l ve d with t he a nal ysis o f t he st u d y will re mai n bli n de d u ntil data base 
l oc k for t he fi nal  a nal ysis a n d pr ot oc ol de viatio ns i de nt ifie d.

A nal yses will be perf or me d b y Astra Ze neca or its re prese ntati ves.

Refer t o t he statist ical a nal ysis pla n ( S A P) f or details.
T he m I T T, IT T a n d t he Safet y A nal ysis Set descri be d bel o w will be a p plie d t o t he ra n d o mise d 
parti ci pa nts.
9. 1
St atistic al h y p ot heses
T he f or mal statist ical a nal ysis will be perf or me d t o test t he mai n h y p ot heses: 

H 0: N o differe nce bet wee n d ur val u ma b a n d place b o

H 1: Diffe re nce bet wee n d ur val u ma b a n d place b o 
T he researc h h y p ot hesis f or t his st u d y  is t hat d ur val u ma b ( 1 5 0 0 m g q 4 w via i v i nf usi o n) will 
s h o w i m pr o ve d efficac y c o m pare d wit h place b o w he n gi ve n as c o ns o li dati on t hera p y  t o 
parti ci pa nts wi t h locall y a d va nce d, u nres ecta ble N S C L C ( Sta ge III) w h o ha ve n ot pr o gresse d 
f oll owi n g defi nit i ve, plati n u m-base d, c o nc urre nt or se q ue nt ial c he mor a di at i on t hera p y .
T his will be assesse d via t he pri mar y  o bjecti ve of t his st u d y, w hic h is t o assess t he efficac y of 
d ur val u ma b treat me nt c o m pare d wit h place b o i n ter ms of BI C R P F S ( m I T T).  I n or der t o 
str o n gl y c o ntr ol t h e t ype I err or at 5 % ( 2 si de d), P F S ( mI T T) will be tes te d first wit h a 
sig nifica nce l e vel of 5 % a n d t he st u d y will be c o nsi dere d p ositive (a s uccess) if t he P F S 
( mI T T) a nal ysis res ult is statisticall y si g nifica nt.  T he sec o n dar y efficac y e n d p oi nts i ncl u de d 
i n t he m ulti ple testin g pr oce d ure are (i n or der): O S ( mI T T), P F S (I T T) a n d O S (I T T). T he 
details o n t he m ult i ple testin g pr oce d ure f or c o ntr olli n g t he t y pe I err or rate ca n be f o u n d i n 
Secti o n  9. 5. 7 . Ot her sec o n dar y efficac y o bjecti ves i ncl u de e val uati on of O S 2 4, O R R, D o R, 
P F S 1 2 a n d P F S 1 8, P F S 2, a n d T T D M.  Ot her sec o n dar y o bjecti ves i ncl u de a n assess me nt of 
safety a n d t olera bilit y,  d ur val u ma b P K e x p os ure, i m m u n o ge nicity,  a n d P R Os.  E x plorat or y  
o bj ect i ves are als o i ncl u ded.
9. 2
S a m ple size deter mi n ati o n 
T he st u d y  will ra n d o mise a p pr o xi matel y 4 0 0 partici pa nts i n t he I T T p o p ulati on a n d 
a p pr o xi matel y 3 7 5 partici p a nts i n t he mI T T p o p ulati o n.  Parti ci pa nts w h o recei ve d pri or 
c C R T or s C R T a n d ha ve n ot pr o gresse d f o ll owi n g defi nit i ve c he m ora diat i on t hera p y  will be 
ra n d omise d i n a 2: 1 rati o t o recei ve d ur val u ma b a n d place b o. St u d y will recr uit at least 
 
of  parti ci pa nts w h o recei ve d pri or c C R T wit h t he maj orit y of  parti ci pa nts t o be recr uite d i n 
C hi na.
T he fi nal ( pri mar y) P F S ( mI T T) a nal ysis f or s u peri orit y will be perf or me d w he n eit her of  t he 
f oll owi n g c o n dit i ons ha ve bee n met first:
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 0
 

R eac hi n g a p pr o xi matel y 
BI C R pr o gressi o n -free s ur vi val e ve nts acr oss t he 
d ur val u ma b a n d place b o treat me nt ar ms (a p pr o xi matel y  
 mat urit y)  in t he m I T T 
p o p ul at i on
O R

A p pr o xi matel y  
m o nt hs f oll ow- u p f r o m last partici pa nt ra n d o mize d t o t he st u d y
If t he tr ue P F S H R is 
, wit h a n esti mate d 
BI C R P F S e ve nts i n t he mI T T, t he st u d y  
will pr o vi de at least  
 p o wer t o de m o nstrate a statist icall y si g nifica nt differe nce f or P F S 
wi t h a 2-side d si g nifica nce le vel o f 5 %; t his tra nslates t o a n a p pr o xi matel y 3 -m o nt h be nefit i n 
me dia n P F S o ver  m o nt hs o n place b o.  T he s mallest treat me nt differe nce t hat w o ul d be 
statisticall y si g nifica nt is a H R of  
.  A recr uit me nt peri o d of a p pr o xi matel y 
m o nt hs 
a n d a f o ll ow- u p peri o d of  
m o nt hs are e x pecte d f or t he P F S ( mI T T) fi nal a nal ysis.  
T he o verall al p ha le vel f or t he statist ical testi n g of t he sec o n dar y ke y e n d p oi nt O S  
 f or 
d ur val u ma b vers us place b o will be  
 if P F S ( mI T T) a nal ysis is si g nifica nt.  T he fi nal 
pl a n ne d o verall s ur vi val a nal ysis data c ut off will occ ur w he n reac hi n g a p pr o xi matel y  
 
deat h e ve nts ( 
 mat urit y) or a p pr o xi matel y 
 mo n t hs fol l ow- u p f r o m t h e last partici pa nt 
ra n d omizat i on i n t he mI T T, w hic he ver occ urs first . If t he tr ue O S H R is  
 wit h a n 
esti mate d  
 O S e ve nts, t his st u d y will pr o vi de  
 p o wer t o de mo nstrate a stati sticall y 
sig nifica nt differe nce f or O S, ass u mi n g a  
2 -side d si g nifica nce le vel ( wit h o verall 2 -
side d alp ha f or O S as 
T hi s tra nslates t o a -m o nt h be nefit i n me dia n O S o ver 
 m o nt hs 
o n place b o.  T he s mallest treat me nt differe nce t hat w o ul d be statist icall y si g nifica nt is a H R of 
U p t o t w o i nteri m a nal yses f or O S will be c o n d ucte d: 1) at t he sa me ti me as pri mar y 
P F S a nal ysis a n d 2) at a p pr o xi matel y  
 mo nt hs after t he O S first i nteri m a nal ysis, wit h 
a p pr o xi matel y  
 a n d  
 of t he tar get e ve nts res pecti vel y. If t he e x pecte d D C O f or O S 
fi nal a nal ysis is wit hi n 
 m o nt hs after t he O S first i nterim a nal ysis, t he O S sec o n d i nteri m 
a nal ysis ma y be r e mo v e d.  A recr uit me nt perio d of a p pr o xi matel y 
m o nt hs a n d a f o ll ow- u p 
p eri o d of  
m o nt hs are e x pecte d f or t he fi nal a nal ysis o f O S e n d p o i nt. 
9. 3
P o p ul ati o ns f or a n al yses
Defi nit i ons of t he a nal ysis sets f or eac h o utc o m e v aria ble are pr o vide d i n  Ta ble 1 1 .
Ta ble 11
S u m m ar y of o utc o me v ari a bles a n d a n al ysis p o p ul ati o ns
O utc o me v ari a bl e
P o p ul ati o ns
Effic ac y d at a
P F S
mI T T a n d I T T
a
O S, O S 2 4, O R R, D o R, P F S 1 2, P F S 1 8, P F S 2, P R O e n d p oi nts, 
a n d T T D M
mI T T a n d I T T
a
De m o gra p h y
mI T T a n d I T T
a
P K data
P K a nal ysis set
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C CI
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
111
 
Outcome variable
Populations
Safety data
Exposure
Safety analysis set
Adverse events
Safety analysis set
Laboratory measurements
Safety analysis set
Vital Signs
Safety analysis set
a  ITT is the secondary population for efficacy analysis, and the analysis to be performed in the ITT population 
will be detailed in the SAP.
DoR Duration of response; ITT Intent-to-treat; mITT Modified Intent-to-treat set; ORR Objective response 
rate; OS Overall survival; OS24 Proportion of participants alive at 24 months from randomisation; 
PFS Progression-free survival; PFS2 Time from randomisation to second progression; PFS12 Proportion of 
participants alive and progression free at 12 months from randomisation; PFS18 Proportion of participants alive 
and progression free at 18 months from randomisation; PK Pharmacokinetic; PRO Patient-reported outcomes; 
TTDM Time to death or distant metastasis.
9.3.1
Intent-to-treat set
The ITT will include all randomised participants.  The ITT will be used as secondary 
population for efficacy analyses (including PROs).  Treatment arms will be compared on the 
basis of randomised study treatment, regardless of the treatment actually received.  
Participants who were randomised but did not subsequently go on to receive study treatment 
are included in the analysis in the treatment arm to which they were randomised.  
9.3.2
Modified intent-to-treat set
The mITT will include all randomised participants in the ITT who are without sensitizing 
EGFR mutations or ALK rearrangements.  Unless otherwise specified, the mITT will be used 
as primary population for all efficacy analyses (including PROs). Treatment arms will be 
compared based on randomized study treatment, regardless of the treatment actually received.
9.3.3
Safety analysis set
The SAS will consist of all participants who received at least 1 dose of study treatment 
(durvalumab or placebo).  Safety data will not be formally analysed but summarised using the 
SAS according to the treatment received; that is, erroneously treated participants (eg, those 
randomised to treatment A but actually given treatment B) will be summarised according to 
the treatment they actually received.
When assessing safety and tolerability, summaries will be produced based on the SAS.
9.3.4
PK analysis set
All participants who receive at least 1 dose of durvalumab per the protocol for whom any 
post-dose data are available and who do not violate or deviate from the protocol in ways that 
would significantly affect the PK analyses will be included in the PK analysis set.  The 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
112
 
population will be defined by the Study Physician, Pharmacokineticist, and Statistician prior 
to any analyses being performed.
9.4
Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
9.4.1.1
RECIST 1.1-based endpoints
The analysis of the primary endpoint PFS (mITT), and the analyses of the secondary 
endpoints, PFS (ITT), ORR, DoR, PFS12, PFS18, and TTDM, will be based on BICR 
assessments using RECIST 1.1.  In addition, the other secondary endpoints, OS, OS24, and 
PFS2, will also be evaluated.
Blinded Independent Central Review
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a participant discontinues study treatment or 
receives another anticancer therapy.
All images will be collected centrally.  The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required.  For each participant, the 
BICR will define the overall visit response data (CR, PR, SD, PD, or NE) and the relevant 
scan dates for each timepoint (ie, for visits where response or progression is/is not identified).  
If a participant has had a tumour assessment that cannot be evaluated, then the participant 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, ORR, and DoR) 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.
Investigator RECIST 1.1-based assessments
An Investigator assessment of radiological scans will be performed on all participants to 
confirm the robustness of the PFS endpoint.  
At each visit, participants 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 before the day of 
randomisation.  If a participant has had a tumour assessment that cannot be evaluated, then the 
participant will be assigned a visit response of not evaluable (NE; unless there is evidence of 
progression in which case the response will be assigned as PD).
Please refer to Appendix E for the definitions of CR, PR, SD, and PD.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
113
 
9.4.1.2
Primary endpoint
The primary endpoint is PFS (mITT). PFS (per RECIST 1.1 as assessed by the BICR) will be 
defined as the time from the date of randomisation until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
participant withdraws from randomised therapy or receives another anticancer therapy prior to 
progression (ie, [date of event or censoring – date of randomisation] + 1).  Participants 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 
participant progresses or dies after 2 or more missed visits, the participant will be censored at 
the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits.  If the 
participant 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, which then will be treated as an event with date 
of death as the event date.
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 within the imaging visit window.  The following rules will be applied:

For BICR assessments, date of progression will be determined based on the earliest of the 
dates of the component that triggered the progression on the first set of scans that 
indicates progression for the adjudicated reviewer selecting PD, or where both reviewers 
select PD as a timepoint response and there is no adjudication, then the assessments of the 
reviewer who completed their baseline assessments first are used for the PD timepoint.

For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST 1.1 assessment/scan dates of the component that indicates 
progression.

When censoring a participant for PFS, the participant will be censored at the latest of the 
scan dates contributing to a particular overall visit assessment.
Note: At each imaging visit, an overall timepoint response is algorithmically derived 
according to assessments of target lesions, non-target lesions, and new lesions (refer to 
Appendix E).  For target lesions, only the latest scan date is recorded in the RECIST 1.1 eCRF 
out of all scans performed within an imaging visit window used for the assessment of target 
lesions, and similarly for non-target lesions only the latest scan date is recorded out of all 
scans performed within an imaging visit window used for the assessment of non-target 
lesions.  For new lesions, only the first scan date is recorded in the RECIST eCRF out of all 
scans performed within an imaging visit window used for the assessment of new lesions.
A sensitivity analysis of PFS will be performed using Investigator assessments according to 
RECIST 1.1.  If applicable, another sensitivity analysis will be performed by excluding sCRT 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
114
 
participants with 1 concurrent chemotherapy and radiation cycle using BICR tumour data 
(RECIST 1.1).
9.4.1.3
Key secondary objective (Overall survival)
OS (mITT) is a key secondary endpoint of this study.  OS is defined as the time from the date 
of randomisation until death due to any cause.  Any participant not known to have died at the 
time of analysis will be censored based on the last recorded date on which the participant was 
known to be alive.
Note: Survival calls will be made in the week following the date of DCO for the analysis 
(these contacts should generally occur within 7 days of the DCO).  If participants are 
confirmed to be alive or if the death date is after the DCO date, these participants will be 
censored at the date of DCO.  Death dates may be found by checking publicly available death 
registries.
9.4.1.4
Proportion of participants alive at 24 months after randomisation
The OS24 will be defined as the Kaplan-Meier (KM) estimate of OS at 24 months after 
randomisation.
9.4.1.5
Objective response rate
ORR (per RECIST 1.1 as assessed by BICR) is defined as the number (%) of participants with 
at least 1 visit response of CR or PR. Data obtained up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR. 
Participants who go off treatment without progression, receive a subsequent therapy, and then 
respond will not be included as responders in the ORR.
9.4.1.6
Duration of response
DoR (per RECIST 1.1 as assessed by BICR) 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 (ie, date of PFS event or censoring – date of first response + 1).  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 participant does not progress following a response, 
then his or her DoR will be censored at the PFS censoring time.  DoR will not be defined for 
those participants who do not have documented response.
9.4.1.7
Progression-free survival at 12 and 18 months
The PFS12 and PFS18 will be defined as the KM estimate of PFS (per RECIST 1.1 as 
assessed by BICR) at 12 and 18 months, respectively.  

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
115
 
9.4.1.8
Time from randomisation to second progression
Time from randomisation to second progression or death (PFS2) will be defined as the time 
from the date of randomisation to the earliest of the progression event subsequent to first 
subsequent therapy, or death. The date of second progression will be recorded by the 
Investigator in the eCRF and defined according to local standard clinical practice and may 
involve any of the following: objective radiological imaging, symptomatic progression, or 
death. Second progression status will be reviewed (q8w ±1 week for the first 48 weeks 
[relative to the date of randomisation], and then q12w ±1 week (the first progression)) and 
status will be recorded. Censoring details for this endpoint will be defined in the SAP. 
9.4.1.9
Time to death or distant metastasis
TTDM will be defined as the time from the date of randomisation until the first date of distant 
metastasis or death in the absence of distant metastasis.  Distant metastasis is defined as any 
new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy.  
Participants who have not developed distant metastasis 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 participant has distant metastasis or dies after 2 or more missed 
visits, the participant will be censored at the time of the latest evaluable RECIST 1.1 
assessment prior to the 2 missed visits.  If the participant 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, 
which then will be treated as an event with date of death as the event date.
9.4.1.10
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST 1.1 assessment, as described in Appendix E.  It is the best response a participant has 
had during their time in the study up until RECIST 1.1 progression or the last evaluable 
assessment in the absence of RECIST 1.1 progression.
Categorisation of BoR will be based on RECIST 1.1 (Appendix E) using the following 
response categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST 1.1 using all BICR assessments 
up until the first progression event.  For participants whose progression event is death, BoR 
will be calculated based on all evaluable RECIST 1.1 assessments prior to death.
For participants who die with no evaluable RECIST 1.1 assessments, if the death occurs 
≤17 weeks (ie, 16 weeks + 1 week to allow for a late assessment within the assessment 
window) after randomisation, then BoR will be assigned to the progression (PD) category.  
For participants who die with no evaluable RECIST 1.1 assessments, if the death occurs >17 
weeks (ie, 16 weeks + 1 week) after the date of randomisation, then BoR will be assigned to 
the NE category.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
116
 
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure.  These will be collected for all participants.  Data from 
all cycles of treatment will be combined in the presentation of safety data.  “On treatment” 
will be defined as assessments between date of start dose and 90 days following 
discontinuation of IP (ie, the last dose of durvalumab monotherapy or placebo).  For AEs, on 
treatment (or treatment-emergent AEs) will be defined as any AEs that started after dosing or 
prior to dosing and which worsens following exposure to the treatment.
AEs observed up until 90 days following discontinuation of IP or until the initiation of the 
first subsequent therapy following discontinuation of treatment (whichever occurs first) will 
be used for the reporting of the AE summary tables. This will more accurately depict AEs 
attributable to study treatment only, as a number of AEs up to 90 days following 
discontinuation of treatment are likely to be attributable to subsequent therapy. However, to 
assess the longer-term toxicity profile, AE summaries will also be produced containing AEs 
observed up until 90 days following discontinuation of IP (ie, without taking subsequent 
therapy into account). Any events in this period that occur after a participant has received 
further therapy for cancer (following discontinuation of study treatment) will be flagged in the 
data listings.
The SAS will be used for reporting of safety data.
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.
Any AE occurring before treatment with study treatment will be included in the data listings 
but will not be included in the summary tables of AEs.
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examinations, 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) using the following formula:
QTcF = QT/RR^ (1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using the 
following formula:

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
117
 
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – Albumin (G/L)] × 0.02)
The denominator used in laboratory summaries will only include evaluable participants, ie, 
those who had sufficient data to have the possibility of an abnormality.
For example:

If a CTCAE criterion involves a change from Baseline, evaluable participants would have 
both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from Baseline to be evaluable, the 
participant need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those participants with recorded data.
9.4.3
Calculation or derivation of patient-reported outcome variables
All PRO questionnaires will be scored according to published scoring guidelines or the 
developer’s guidelines, if published guidelines are not available.  All PRO analyses will be 
based on the mITT (primary population), and separately on the ITT population.
9.4.3.1
EORTC QLQ-C30 and QLQ-LC13
Symptoms and overall quality of life will be assessed using EORTC QLQ-C30 and QLQ-
LC13 (secondary endpoints).
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnoea, insomnia, appetite loss, constipation, and 
diarrhoea), and a global measure of health status.  The QLQ-LC13 is a lung cancer-specific 
module from the EORTC for lung cancer comprising 13 questions to assess lung cancer 
symptoms (cough, haemoptysis, dyspnoea, and site-specific pain), treatment-related 
symptoms (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication.  
With the exception of a multi-item scale for dyspnoea, all are single items.  The dyspnoea 
scale will only be used if all 3 items have been scored; otherwise, the items are treated as 
single-item measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales, and the global health status/QoL scale 
according to the EORTC QLQ-C30 Scoring Manual (EORTC QLQ-C30 Scoring Manual, 
Third Edition) and EORTC QLQ-LC13 instructions.
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom 
severity.  Changes in score compared with baseline will be evaluated.  For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
118
 
of non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2001).  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 minimised.
Definition of clinically meaningful changes
Changes in score compared with Baseline will be evaluated.  A minimum clinically 
meaningful change is defined as an absolute change in the score from Baseline of ≥10 for 
scales/items from the EORTC QLQ-C30 (Osoba et al 1998).  For example, a clinically 
meaningful improvement in physical function (as assessed by EORTC QLQ-C30) is defined 
as an increase in the score from Baseline of ≥10, whereas a clinically meaningful deterioration 
is defined as a decrease in the score from Baseline of ≥10.  At each post-baseline assessment, 
the change in symptoms/functioning from Baseline will be categorised as improvement, no 
change, or deterioration, as shown in Table 12 in Section 9.4.3.3.
Time to symptom deterioration (QLQ-C30 and QLQ-LC13)
Time to deterioration in symptoms, functioning and global health status/QoL will be
evaluated, more details will be specified in the SAP.
Symptom improvement rate (QLQ-C30 and QLQ-LC13)
The symptom improvement rate will be defined as the number (%) of participants with 2 
consecutive assessments, at least 14 days apart, that show a clinically relevant improvement (a 
decrease ≥10) in that symptom from Baseline.
The denominator will consist of a subset of the mITT/ITT who have a baseline symptom score 
of ≥10.
QoL/function improvement rate (QLQ-C30)
The QoL/function improvement rate will be defined as the number (%) of participants with 
2 consecutive assessments, at least 14 days apart, that show a clinically relevant improvement 
(an increase score ≥10) in that scale from Baseline.
The denominator will consist of a subset of the mITT/ITT who have a baseline QoL/function 
score of ≤90.
CHANGE FROM BASELINE
Change from baseline in key symptom scores of dyspnea, cough, chest pain, fatigue and 
appetite loss will be analysed using a mixed model for repeated measures (MMRM) analysis.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
119
 
9.4.3.2
Calculation or derivation of patient-reported 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 5 possible options of increasing levels of 
severity (no problems, slight problems, moderate problems, severe problems, and unable 
to/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 value sets are not available, the EQ-5D-5L to EuroQoL 5-dimension, 3-level health 
state utility index crosswalk will be applied (van Hout et al 2012, van Reenen and Janseen 
2015).  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.
9.4.3.3
Analysis of EORTC QLQ-C30 and QLQ-LC13
Symptoms and overall quality of life will be assessed using EORTC QLQ-C30 and QLQ-
LC13 (secondary endpoints). Questionnaires will be scored according to published guidelines 
or the developer’s guidelines, if published guidelines are not available. PRO analyses will be 
based on the mITT (primary population), and separately on the ITT. Further details of the 
statistical analyses including details of Mixed effect Models for Repeated Measures (MMRM) 
modelling and the analysis to be performed in the ITT will be given in the SAP.
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a global measure of health status. The QLQ-LC13 is a lung cancer-specific 
module from the EORTC for lung cancer comprising 13 questions to assess lung cancer 
symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related symptoms 
(sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication. With the 
exception of a multi-item scale for dyspnea, all are single items. The dyspnea scale will only 
be used if all 3 items have been scored; otherwise, the items are treated as single-item 
measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales and the global health status/QoL scale 
according to the EORTC QLQ-C30 Scoring Manual (EORTC QLQ-C30 Scoring Manual, 
Third Edition) and EORTC QLQ-LC13 instructions.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
120
 
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom 
severity. Changes in score compared with baseline will be evaluated. For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 
of non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2001). 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.
Definition of compliance and evaluability rates
Compliance rates for the PRO questionnaires should be 85%, this rate will be monitored as the 
trial goes on. Compliance with the EORTC QLQ-C30 and EORTC QLQ-LC13 will be 
calculated, separately for each questionnaire:
Compliance rate = 
× 100
Evaluability rates for the EORTC QLQ-C30 and EORTC QLQ-LC13 will also be calculated, 
separately for each questionnaire:
Evaluability rate = 
	 
  forms
	 
 	 
	 × 100
An expected form = a questionnaire that is expected to be completed at a scheduled 
assessment time, i.e. a questionnaire from a participant who has not withdrawn from the study 
at the scheduled assessment time but excluding participants in countries with no available 
translation.
An evaluable form = a questionnaire with a completion date and at least one subscale that is 
non-missing.
A received form = a questionnaire that has been received and has a completion date and at 
least one individual item completed.
Definition of clinically meaningful changes
Changes in score compared to baseline will be evaluated. A minimum clinically relevant 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-C30 and the QLQ-LC13 (Osoba et al 1998). For example, a clinically relevant 
deterioration or worsening in chest pain (as assessed by QLQ-LC13) is defined as an increase 
in the score from baseline (defined as Day 1, pre-dose) of ≥10. A clinically relevant 
improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the score from 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
121
 
baseline of ≥10. At each post-baseline assessment, change in symptoms/functioning from 
baseline will be categorized as improved, stable, or worsening as shown in Table 11. 
Participants with no baseline data will be excluded from analyses.
Table 12
Visit response for symptoms and HRQoL
Score 
Change from baseline 
Visit response
QLQ-C30/QLQ-LC13 symptom 
scales/items
≥+10
≤-10
Otherwise
Worsened
Improved
Stable
QLQ-C30 functional scales and 
global health status/QoL
≥+10
≤-10
Otherwise
Improved
Worsened
Stable
HRQoL Health-related quality of life; QLQ-C30 30-item core quality of life questionnaire; QLQ-LC13 13-item 
lung cancer quality of life questionnaire.
Time to symptom and HRQL/function deterioration (QLQ-C30 and QLQ-LC13)
Time to deterioration in symptoms, functioning and global health status/QoL will be 
evaluated, more details will be specified in the SAP.
Improvement in symptom and HRQL (QLQ-C30 and QLQ-LC13)
Improvement in symptoms, functioning and global health status/QoL will be evaluated, more 
details will be specified in the SAP.
9.4.4
Calculation or derivation of pharmacokinetic variables
9.4.4.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modelling 
approach in participants with NSCLC.  The impact of physiologically relevant participant
characteristics (covariates) and disease on PK will be evaluated.  The relationship between the 
PK exposure and the effect on safety and efficacy endpoints will be evaluated.  The results of 
such an analysis 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.
9.4.4.2
Pharmacokinetic non-compartmental analysis
The actual sampling times will be used in the PK calculations.  PK concentration data and 
summary statistics will be tabulated.  Individual and mean blood concentration-time profiles 
will be generated.  PK parameters will be determined using standard non-compartmental 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
122
 
methods.  The following PK parameters will be determined after the first and steady-state 
doses: peak concentration and trough concentration (as data allow).  Samples below the lower 
limit of quantification will be treated as missing in the analyses.
9.4.4.3
Immunogenicity analysis
Immunogenicity results will be analysed descriptively by summarising the number and 
percentage of participants who develop detectable ADAs against durvalumab.  The 
immunogenicity titre and presence of neutralising 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.
9.4.5
Calculation or derivation of biomarker variables
Biomarker(s) will be assessed for evaluable participants in each treatment arm according to 
prespecified criteria that will be detailed in the SAP.
9.4.6
Calculation or derivation of health economic variables
Frequency and estimates of resource use, including length of stay and number of hospital 
admissions, will be derived from the health resource use information.
9.5
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.
Analyses will be performed by AstraZeneca or its representatives.  A comprehensive 
statistical analysis plan will be developed and finalised before database lock and will describe 
the participant populations to be included in the analyses and the procedures to account for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.  Any deviations from this plan will be 
reported in the CSR.
Depending on the extent of any impact, summaries of data relating to participants diagnosed 
with COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, 
delayed or discontinued IP, and other protocol deviations) may be generated. Relevant listings 
will be generated as needed. More details will be provided in the SAP.
9.5.1
Efficacy analyses
The study has been sized to characterise the PFS benefit of durvalumab versus placebo.  
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarised by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
123
 
summarised 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 randomisation.
All data collected will be listed.  Efficacy and PRO data will be summarised and analysed 
based on the mITT (primary population), and separately on the ITT, more details will be 
specified in the SAP.  PK data will be summarised and analysed based on the PK analysis set.  
Safety data will be summarised on the SAS.
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated.
Table 13 details which endpoints are to be subjected to formal statistical analysis, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as primary 
for that endpoint.  Note, all endpoints compare durvalumab versus placebo in randomised 
participants in the mITT/ITT, unless otherwise indicated.
Table 13
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analysed
Notes
Progression-free survival
Stratified log-rank tests for:
Primary analysis using BICR tumour RECIST 1.1 assessments
Sensitivity analyses using BICR tumour data (RECIST 1.1)
1
Interval censored analysis – evaluation time bias
2
Analysis using alternative censoring rules – attrition bias
3
Analysis by excluding sCRT participants with 1 concurrent 
chemotherapy and radiation cycle
Sensitivity analysis stratified log-rank test using study site Investigator 
tumour data (RECIST 1.1) – ascertainment bias 
Overall survival
Stratified log-rank test
Proportion of participants alive at 
24 months from randomisation
Kaplan-Meier estimates of survival at 24 months 
Objective response rate
Logistic regression for:
Secondary analysis using BICR tumour data (RECIST 1.1)
Sensitivity analysis using study site Investigator tumour data (RECIST 1.1)
Duration of response
Analysis following the method described by Section 9.5.1.5 using BICR 
tumour data (RECIST 1.1)

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
124
 
Endpoints analysed
Notes
Progression-free survival at 
12 and 18 months from 
randomisation
Kaplan-Meier estimates of progression-free survival at 12 and 18 months 
Time from randomisation to 
second progression
Stratified log-rank test
Time to death or distant 
metastasis
Stratified log-rank test using BICR tumour data
(RECIST 1.1)
Symptom improvement rate 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Logistic regression
HRQoL/Function improvement 
rate (EORTC QLQ-C30 
endpoints)
Logistic regression
Time to HRQoL/Function 
deterioration (EORTC QLQ-C30 
endpoints)
Stratified log-rank test
Time to symptom deterioration 
(EORTC QLQ-C30 and 
QLQ-LC13 endpoints)
Stratified log-rank test
Change from Baseline in key 
symptoms (EORTC QLQ-C30 
and QLQ-LC13)
Mixed model repeated measures analysis
BICR Blinded Independent Central Review; EORTC QLQ-C30 European Organisation for Research and 
Treatment of Cancer 30-item core quality of life questionnaire; EQ-5D-5L EuroQoL 5-dimension, 5-level health 
state utility index; HR Hazard ratio; KM Kaplan-Meier; QoL Quality of Life; QLQ-LC13 13-item self-
administered questionnaire for lung cancer; RECIST 1.1 Response Evaluation Criteria In Solid Tumors Version 
1.1.
All outputs will be summarised by treatment arm for randomised participants in the 
mITT/ITT.
9.5.1.1
Primary endpoint: Progression-free survival
The primary PFS analysis will be based on the programmatically derived RECIST 1.1 using 
the BICR tumour assessments in the mITT.  The analysis will be performed using a stratified 
log-rank test adjusting for the level of PD-L1 expression (PD-L1<1% or PD-L1≥1%) and 
prior therapy (cCRT or sCRT).  The effect of durvalumab versus placebo treatment will be 
estimated by the HR together with its corresponding 95% CI and p-value.
KM plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of participants experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
125
 
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints.  The midpoint 
between the time of progression and the previous evaluable RECIST 1.1 assessment will be 
analysed using a log-rank test.  For participants whose death was treated as PFS event, the 
date of death will be used to derive the PFS time used in the analysis.  This approach has been 
shown to be robust even in highly asymmetric assessment schedules (Sun and Chen 2010).
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of participants who progressed or died in the absence of 
progression immediately following 2 or more non-evaluable tumour assessments will be 
included.  In addition, participants who take subsequent therapy prior to progression or death 
will be censored at their last evaluable assessment prior to taking the subsequent therapy.  
This analysis will be supported by a KM plot of the time to censoring where the censoring 
indicator of the PFS analysis is reversed.
A sensitivity analysis will be performed by analysing the Investigator assessments. The 
stratified log-rank test will be repeated on these data. The HR and 95% CI will be presented.  
If applicable, a sensitivity analysis will be performed by excluding sCRT participants with 
1 concurrent chemotherapy and radiation cycle using BICR tumour data (RECIST 1.1). The 
stratified log-rank test will be repeated on these data. The HR and 95% CI will be presented.  
The assumption of proportionality will be assessed first by examining plots of complementary 
log-log (event times) versus log (time) and, if these raise concerns, by fitting a time-dependent 
covariate to assess the extent to which this represents random variation.  If a lack of 
proportionality is evident, the variation in treatment effect will be described by presenting 
piecewise HR calculated over distinct time-periods.  In such circumstances, the HR can still 
be meaningfully interpreted as an average HR over time unless there is extensive crossing of 
the survival curves.  If lack of proportionality is found, this may be a result of treatment-by-
covariate interactions, which will be investigated.  In addition, the KM curve along with 
landmark analyses (eg, 1-year PFS rate) will also help in understanding the treatment benefit.
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using BICR 
assessments) between durvalumab versus placebo in the following (but not limited to) 
subgroups:

Prior therapy (cCRT or sCRT)

Sex (male versus female)

Age at randomisation (<65 versus ≥65 years)

Stage (IIIA versus IIIB/C)

Time from last dose of radiation to randomisation (<14 days versus ≥14 days)

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
126
 

PD-L1 status (tumour cells [TCs]  ≥ 1% vs TCs < 1%)

Histology (squamous versus non-squamous)

Smoking (smoker versus non-smoker [never smoker])

Race (Asian versus non-Asian)

EGFR/ALK status (positive vs negative) (only applicable for analyses in the ITT 
population)
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 PFS.
Cox proportional hazards modelling will be employed to assess the effect of covariates on the 
HR estimate.  A model will be constructed, containing treatment and the stratification factors, 
to ensure that any output from the Cox modelling is likely to be consistent with the results of 
the stratified log-rank test.
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
For each subgroup, the HR (durvalumab:placebo) and 95% CI will be calculated from a Cox 
proportional hazards model with treatment as the only covariate.  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 PFS will not be formally analysed.  In 
this case, only descriptive summaries will be provided.
The analysis of PFS will be performed in the mITT (primary population), and separately in the 
ITT, more details will be specified in the SAP.
9.5.1.2
Overall survival
The key secondary endpoint of OS (mITT) will be analysed using stratified log-rank tests, 
using the same methodology as described for the primary PFS endpoint.  The effect of 
durvalumab versus placebo will be estimated by the HR together with its corresponding CI 
and p-value.  KM plots will be presented by treatment arm.  Summaries of the number and 
percentage of participants 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.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
127
 
The analysis of OS will be performed in the mITT (primary population), and separately in the 
ITT, more details will be specified in the SAP.
9.5.1.3
Proportion of participants alive at 24 months 
OS24 will be summarised (using the KM curve) and presented by treatment arm based on the 
mITT (primary population), and separately on the ITT.
9.5.1.4
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using the BICR tumour 
data.  The ORR will be compared between durvalumab versus placebo using logistic 
regression models adjusting for the same factors as the primary endpoint (the level of PD-L1 
expression [PD-L1<1% or PD-L1≥1%] and prior therapy [cCRT or sCRT]).  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).   This analysis will be performed in the mITT 
(primary population), and separately in the ITT.
This analysis of ORR will be repeated using the results of the programmatically derived site 
Investigator data from all scans based upon RECIST 1.1 as a sensitivity analysis to confirm 
the results of the primary analysis derived from the BICR data. 
Summaries will be produced that present the number and percentage of participants with a 
tumour response (CR/PR).  Overall visit response data will be listed for all participants (ie, the 
ITT).  For each treatment arm, BoR will be summarised by n (%) for each category (CR, PR, 
SD, PD, and NE).  No formal statistical analyses are planned for BoR.
9.5.1.5
Duration of response
Descriptive data will be provided for the DoR based on BICR assessments according to 
RECIST 1.1 in responding participants, including the associated KM curves (without any 
formal comparison of treatment arms or p-value attached).   This analysis will be performed in 
the mITT (primary population), and separately in the ITT.
9.5.1.6
Progression-free survival at 12 and 18 months
The PFS12 and PFS18, will be summarised (using the KM curve) and presented by treatment 
arm.  
These analyses will be performed in the mITT (primary population), and separately in the 
ITT.
9.5.1.7
Time from randomisation to second progression
Second progression (PFS2) will be analysed using a stratified log-rank tests, using the same 
methodology as described for the primary PFS endpoint.  The effect of durvalumab versus 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
128
 
placebo will be estimated by the HR together with its corresponding 95% CI and p-value.  KM 
plots will be presented by treatment arm.  Summaries of the number and percentage of 
participants who have an event as well as those who were censored will be provided along 
with the medians for each treatment.
For supportive purposes, the time to the start of subsequent therapy will be analysed using the 
same methodology and model.  The HR for the treatment effect together with its 95% CI will 
be presented.  In addition, a KM 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, if applicable.
This analysis will be performed in the mITT (primary population), and separately in the ITT.
9.5.1.8
Time to death or distant metastasis
TTDM will be analysed using identical methods as outlined for the analysis of PFS and 
adjusting for the same set of covariates, but no subgroup analysis will be performed.  Medians 
and KM plots will be presented to support the analysis.  The sensitivity analysis outlined in 
Section 9.5.1.1 will not be repeated for TTDM, with the exception of a KM plot of the time to 
censoring where the censoring indicator of TTDM is reversed.  This analysis will be 
performed in the mITT (primary population), and separately in the ITT.
9.5.1.9
Patient-reported outcomes: EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L
PRO is a secondary objective. PRO analyses will be based on the mITT (primary population), 
and separately on the ITT, more details will be provided in the SAP. 
Five symptoms have been identified as primary PRO endpoints:

Dyspnoea: multi-item scale based on 3 questions (“Were you short of breath when you 
rested; walked; climbed stairs?” – QLQ-LC13)

Cough: 1 item (“How much did you cough?” – QLQ-LC13)

Chest pain: 1 item (“Have you had pain in your chest?” – QLQ-LC13)

Fatigue: multi-item based on 3 questions (“Did you need rest?; Have you felt weak?; 
Were you tired?” – QLQ-C30)

Appetite loss: 1 item (“Have you lacked appetite?” – QLQ-C30)
The physical functioning and overall health status domains of the EORTC QLQ-C30 are 
furthermore pre-specified endpoints of interest.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
129
 
Mixed models repeated measures (MMRM) analysis 
Change from baseline in dyspnea, cough, and chest pain scores as assessed by the EORTC 
QLQ-LC13 and fatigue and appetite loss as assessed by the EORTC QLQ-C30 will be the 
primary analysis and assessment of PRO outcome measures. The analysis will be performed 
using a linear mixed model for repeated measures (MMRM) analysis of change from baseline 
in the scores for each assessment timepoint and the Bonferroni-Holm procedure for adjusting 
the significance level will be used to aid interpretation. Therefore, the 5 endpoints will be 
tested at a 1% significance level.  
Time to deterioration
Time to symptom and function/HRQoL deterioration will be analysed for each of the 
symptom scales/items, function scales, and global health status/QoL in EORTC QLQ-C30 and 
QLQ-LC13. This will be achieved by comparing between treatment arms using a stratified 
log-rank test as described for the primary analysis of PFS. The HR and 95% CI for each 
scale/item will be presented graphically on a forest plot.
For each of the symptom scales/items, functional scales, and global health status/QoL, time to 
deterioration will be presented using a KM plot.  Summaries of the number and percentage of 
participants experiencing a clinically relevant deterioration or death and the median time to 
deterioration will also be provided for each treatment arm.
Symptom and function/HRQoL improvement rate
A summary of the symptom improvement rate for all symptom scales/items in EORTC 
QLQ-C30 and QLQ-LC13 will be produced.  Similarly, a summary of function/HRQoL
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced.
Symptom improvement rates will be analysed by comparing between treatment arms using a 
logistic regression model.  The odds ratio and 95% CI for each scale/item will be presented 
graphically on a forest plot.  If there are very few responses in 1 treatment arm, a Fisher’s 
exact test will be considered.
Change from baseline
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score, and each functional domain will be reported by assessment timepoint 
for each treatment arm. Graphical presentations may also be produced as appropriate. 
Summaries of the number and percentage of participants in each response category at each 
assessment timepoint for each ordinal item (in terms of the proportion of participants in the 
categories of improvement, stable, and deterioration as defined in Table 12) will also be 
produced for each treatment arm. 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
130
 
EuroQol-5-Dimension 5-Level questionnaire
The change from Baseline in health state utility values and the visual analogue scale will be 
compared between treatment arms at each visit using a mixed model repeated measures 
analysis, which adjusts for the same factors as the primary analysis and also the baseline 
health state utility value/visual analogue scale as appropriate.  Adjusted mean differences 
between treatments and 95% CIs from these analyses will be presented, but, as this analysis is 
exploratory in nature, p-values will not be calculated.
Descriptive statistics will be reported for the health state domain (eg, proportion in each 
domain) and the visual analogue scale by visit, as well as the change in the visual analogue 
scale value and the derived utility index value from Baseline.  To support future economic 
evaluations, additional appropriate analyses may be undertaken, for example, mean health 
state utility pre- and post-treatment, and pre- and post-progression.
9.5.1.10
Health care resource use
An exploratory health economic analysis of hospital episodes including type of contact 
(hospitalisation, 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 durvalumab, 
and will be outlined in the payer analysis plan.  This would include providing descriptive 
statistics as appropriate, including means, median, and ranges.
9.5.2
Safety analyses
Safety is a secondary objective.  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 Medical Dictionary for Regulatory Activities preferred terms and CTCAE 
grade) will be listed individually by participant.  The number of participants experiencing 
each AE will be summarised by treatment arm and CTCAE grade.  Additionally, data 
presentations of the rate of AEs per person-years at risk may be produced.  
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
haematology, vital signs, and ECGs.  Exposure to durvalumab and placebo will be 
summarised.  Time on study, durvalumab and placebo dose delays will also be summarised.  
At the end of the study, appropriate summaries of all safety data will be produced, as defined 
in the SAP.
9.5.3
Pharmacokinetic data
PK concentration data will be listed for each participant and each dosing day, and a summary 
will be provided for all evaluable participants.

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 1
 
9. 5. 4
I m m u n o ge nicit y d at a
I mm u n o ge nicit y res ults will be liste d b y part ici pa nt, a n d a s u m mar y will be pr o vide d b y  t he 
n u m ber a n d perce nta ge of parti ci pa nts w h o de vel o p detecta ble a nt i-d ur val u ma b a nti b o dies.  
T he i m m u n o ge nicit y titre a n d ne utralisi n g A D A data will be liste d f or sa m ples c o nfir me d 
p osi tive f or t he prese nce of a nti-d ur v al u ma b a nt i b o dies.
T he effect of i m m u n o ge nicit y as well as t he effect of its ne utralisi n g pr o perties o n P K, 
p har mac o d y na mics, efficac y , a n d safety will be e val uate d, if t he data all o w.  A detaile d pla n 
will be writte n b y t he Astra Ze neca Cli nical P har mac ol o g y  gr o u p or desig nee.
9. 5. 5
P h ar m ac o ki netic/ p h ar m ac o d y n a mic rel ati o ns hi ps
If t he data are s uita ble, t he relati o ns hi p bet wee n P K e x p os ure a n d efficac y/safet y para meters 
ma y be i n vest i gate d gra p hicall y or usi n g a n a p pr o priate data m o delli n g a p pr oac h.
9. 5. 6
Bi o m ar ker d at a
T he rel at i ons hi p of P D -L 1 e x pressi o n a n d, if a p plica ble, of e x pl orat or y  bio m ar kers t o cli nical 
o utc o m es (i ncl u di n g b ut n ot restricte d t o) of P F S, O S, O R R, a n d D o R will be prese nte d.
P D -L 1 e x pressi o n deter mi ne d b y I H C will be re p orte d i n t he C S R.  S u m mari es a n d a nal yses 
f or e x plor at or y  bio m ar kers will be d oc u me nte d i n a se parate a nal ysis pla n a n d will be re p orte d 
o utsi de t he C S R i n a se parate re p ort.
9. 5. 7
Met h o ds f or m ulti plicit y c o ntr ol
T he m ul tiple testi n g pr oce d ure (as s h o w n i n  Fi g ure 3 ) will defi ne w hic h si g nifica nce le vels 
s h o uld be a p plie d t o t he i nter pretati o n of t he ra w p -val ues f or t he pri mar y  e n d p oi nt of P F S 
( mI T T) a n d t he ke y sec o n dar y e nd p oi nt O S ( mI T T), a n d 
 
T here will be u p t o 3 D C O ti me p o i nts i n t he st u d y.  
T he fi nal ( pri mar y) P F S a nal ysis (first a nal ysis) f or s u peri orit y will be perf or me d i n t he mI T T 
p o p ul at i on w he n w hic he ve r of  t he f oll owi n g c o n diti o ns ha ve bee n met first:

R eac hi n g a p pr o xi matel y  
 BI C R pr o gressi o n -free s ur vi val e ve nts acr oss t he 
d ur val u ma b a n d place b o treat me nt ar ms (a p pr o xi matel y  
 mat urit y)
O R

A p pr o xi matel y  
 mo n t hs fol l ow -u p f r o m last partici pa nt ra n d o mize d t o t he st u d y. 
T he first O S i nteri m a nal ysis i n t he mI T T will be c o n d ucte d at t he sa me ti me as pri mar y P F S 
a nal ysis ( wit h a p pr o xi matel y  
O S e ve nts,  
mat urit y) .  T he D C O f or t he sec o n d i nteri m 
O S a nal ysis i n t he mI T T will be perf or me d at ap pr o xi matel y 
 m o nt hs after t he O S first 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 2
 
i nteri m a nal ysis (a p pr o xi matel y  
O S e ve nts i n t he  
wit h  
 mat urity) , w hic h ma y
be r e mo ve d as s pecifie d i n secti on  9. 2 .  T he D C O f or t he fi nal O S a nal ysis i n t he  
 will 
be perf or m e d w he n reac hi n g a p pr o xi matel y  
 O S e ve nts ( 
 mat urity)  or a p pr o xi matel y 
 mo nt hs f ol l ow- u p f r o m t h e last partici pa nt ra n d o mizati on , w hic he ver occ urs first. 
If t he n ull h y p ot hesis is rejecte d i n P F S ( mI T T) fi nal a nal ysis,  
al p ha le vel will be rec ycle d 
t o O S ( 
) a nal ysis.  T he  
 al p ha le vel all ocate d t o O S will be c o ntr olle d at t he i nteri m 
a n d fi nal a nal ysis b y usi n g t he La n De Mets (La n a n d D e Mets 1 9 8 3) s pe n di n g f u ncti on t hat 
a p pr o xi mates a n O’ Brie n Fle mi n g a p pr oac h. If  
 of t he O S e ve nts re q uire d at t he 
ti me of t he fi nal O S a nal ysis is a vaila ble at t he ti me of t he i nteri m a nal ysis (ie,  
 or 
 O S e ve nts ha ve occ urre d), t he 2-side d si g nifica nce le vel t o be a p plie d f or t he O S 
i nteri m a nal ysis w o ul d be  
 a n d  
, res pecti vel y, a n d t he 2- side d si g nifica nce l e vel 
t o be a p plie d f or t he fi nal O S a nal ysis wo ul d be  
. N ote t hat t he act ual all ocati o n of 
alp ha acr oss t he t hree a nal ysis t i mes will be dri ve n b y t he act ual i nf or mati o n fracti o n 
ass ociat e d wit h t he a nal ysis a n d alp ha all o c ati o n f or O S first i nteri m a nal ysis will  ass u me t hat 
t he O S sec o n d i nteri m a n d fi nal a nal ysis will ta ke pl ace. If sec o n d i nteri m a nal ysis is re m ove d
after t he first i nteri m a nal ysis is c om p lete, t he alp ha has bee n s pe nt f or first i nteri m a nal ysis 
will n ot be c ha n ge d, t he re mai ni n g al p ha will be calc ulate d base d o n act ual i nf or mati o n 
fracti o n a n d allocate d f or O S fi nal a nal ysis.
If t he n ull h y p ot hesis is rejecte d i n either O S  
 i nteri m or fi nal a nal yses, 
 al p ha le vel 
will be f urt her rec ycle d t o P F S  
 a nal ysis. T o str o n gl y c o ntr ol t he t ype I err or rate, t he 
D C O f or P F S  
 a nal ysis will be fi xe d at t he sa me ti me as t hat of pri mar y  P F S (
 
a nal ysis a n d a p pr o xi matel y 
BI C R P F S e ve nts are e x pecte d i n t he 
p o p ulat i on at t his 
ti me. 
If t he n ull h y p ot hesis is rejecte d i n P F S  
 a nal ysis,  
 al p ha le vel will be fi nall y rec ycle d 
t o O S  
a nal ysis. T he  
 al p ha le vel will be c o ntr olle d at t he i nteri m a n d fi nal a nal yses 
b y usi n g t he La n De Mets met h o d descri be d as a b o ve. At t he ti me o f i nteri m a n d fi nal a nal yses 
(sa me ti me as t he O S ( mI T T) a nal ysis), t he n u m ber of O S e ve nts is e x pecte d t o be 
a p pr o xi matel y  
 mat urit y),  
 mat urit y), a n d  
 mat urit y), 
res pecti vel y, w hic h c orres p o n ds t o a n i nf or mati o n fracti o n of a p pr o xi matel y 
 
 at eac h a nal ysis, t he res ulti n g al p ha was calc ulate d t o be 
 
at s u bse q ue nt a nal yses. T he alp ha allo c ati o n f or O S i nt eri m a n d fi nal a nal ysis i n t he I T T 
p o p ul at i on will f oll ow t he sa me r ule a n d c o nsi deratio n a b o ve f or t he a nal ysis i n t h e mI T T 
p o p ul at i on . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 3
 
9. 6
I nteri m a n al yses 
T he Stati stical A nal ysis Pla n will descri be t he pla n ne d i nteri m a nal yses i n greater detail.
U p t o t w o i nteri m a nal yses of O S will be perf or me d. T he D C O f or t he first i nteri m a nal ysis of 
O S will occ ur at t he sa me ti me as pri mar y  P F S a nal ysis. T he sec o n d i nteri m a nal ysis of O S 
will be c o n d ucte d at a p pr o xi matel y 
 m o nt hs after t he first O S i nteri m a nal ysis 
(a p pr o xi matel y 
O S e ve nts i n t he  
 wit h
 mat urit y), w hic h ma y be r e mo ve d as 
s pecifie d i n secti on  9. 2 . 
If t he i nteri m res ults d o n ot meet t he criteri o n of st o p pi n g f or s u peri ority f or a gi ve n 
h y p ot hesis, t he n f o ll ow- u p will c o nti n ue u nt il t he fi nal a nal ysis, fol l owi n g w hic h t he 
h y p ot hesis wi ll be re-teste d.
T he m ul tiplici t y int r o d uce d b y incl u di n g O S i nteri m a nal yses f or s u peri orit y has bee n 
acc o u nte d f or, usi n g t he met h o d as s pecifie d i n secti o n  9. 5. 7 .
9. 6. 1
D at a m o nit ori n g c o m mittee
T his st u d y  will use a n e xter nal I D M C t o assess o n g oi n g safety a nal yses:

T he I D M C will re vie w t he safet y data peri o di call y i n acc or da nce wit h t he I D M C c harter.

A d dit i onal re vie ws of t he safet y d at a m a y be re q ueste d b y t he I D M C at a d ditio nal  p oi nts 
d uri n g t he st u d y .
T his c o m mittee will be c o m p ose d of t hera pe utic area e x perts a n d bi o st atisticia ns, w h o are n ot 
e mpl o y e d b y Astra Ze neca a n d d o n ot ha ve a n y major c o nflict of i nterest.
C CI
C CI
C CI
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
134
 
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way.  Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca.  The report will include the 
recommendation and any potential protocol amendments and will not contain any unblinding 
information.  The final decision to modify or stop the study will rest with the sponsor.
A separate IDMC charter will be developed, which will contain details of the IDMC members 
and clearly define the responsibilities of the IDMC.
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with the Participant Safety Department.  Issues 
identified will be addressed; this could involve, for instance, amendments to the clinical study 
protocol and letters to Investigators.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
135
 
10
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’
Aaronson et al 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
Alexandrov et al 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature 2013;500:415-21.
Antonia et al 2017
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after 
chemoradiotherapy in Stage III non–small-cell lung cancer. N Engl J Med 2017;377:1919-29.
Aupérin et al 2010
Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of 
concomitant versus sequential radiochemotherapy in locally advanced non-small cell lung 
cancer. J Clin Oncol 2010;28(13):2181-90.
Bayman et al 2014
Bayman N, Blackhall F, McCloskey P, Taylor P, Faivre-Finn C. How can we optimise 
concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer? Lung 
Cancer 2014;83(2):117-25. [Epub ahead of print]
Bergman et al 1994
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in 
lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 
1994;30A(5):635-42.
Brahmer et al 2012
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-
65.
Butts et al 2014
Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al, on behalf of 
the START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for 
stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. 
Lancet Oncol 2014;15(1):59-68.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
136
 
Carbone et al 2017
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-line nivolumab in 
stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376(25):2415-26.
Cockcroft and Gault 1976
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
De Ruysscher et al 2009
De Ruysscher D, Botterweck A, Dirx M, Pijls-Johannesma M, Wanders R, Hochstenbag M, 
et al. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung 
cancer patients: a prospective, population-based study. Ann Oncol 2009;20(1):98-102.
Deng et al 2014
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and 
anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 
2014;pii:67313. [Epub ahead of print]
Dunn et al 2004
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60.
EORTC QLQ-C30 Scoring Manual, Third Edition
EORTC QLQ-C30 Scoring Manual, Third Edition. 2001, EORTC, Brussels.
EuroQoL 1990
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208.
EuroQoL 2013
EuroQol Group. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L 
instrument, Version 2.0, October 2013. Available from: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_
EQ-5D-5L_v2.0_October_2013.pdf. Accessed 21 November 2013.
Fairman et al 2014
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics 
of durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced 
solid tumours. ASCO Annual Meeting Abstracts [abstract 2602]. J Clin Oncol 2014;32(Suppl 
5). 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
137
 
Faivre-Finn et al 2021
Faivre-Finn C, Vincente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste J, et al. Four-
year survival with durvalumab after chemoradiotherapy in stage III NSCLC – an update from 
the PACIFIC trial. J Thorac Oncol 2021;16(5) :860-67.
Fayers et al 2001
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A; EORTC Quality 
of Life Group. The EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: European 
Organisation for Research and Treatment of Cancer; 2001.
FDA Guidance 2011
FDA Guidance for Industry (issued June 2011) ‘Clinical trial endpoints for the approval of 
non-small cell lung cancer drugs and biologics’. Available from URL: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM259421.pdf. Accessed 08 January 
2014.
Gail and Simon 1985
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985;41(2):361-72.
GLOBOCAN 2012
GLOBOCAN 2012: Lung cancer estimated incidence, mortality, and prevalence worldwide in 
2012. Available from URL: http://globocan.iarc.fr/factsheets/cancers/lung.asp. Accessed 
28 February 2017.
Herdman et al 2011
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 
2011;20(10):1727-36.
Hirano et al 2005
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
2005;65(3):1089-96.
Iwai et al 2002
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99:12293-7.
Janssen et al 2008a
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level 
system with a five-level version. Value Health 2008;11(2):275-84.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
138
 
Janssen et al 2008b
Janssen MF, Birnie E, Bonsel GJ. Quantification of the level descriptors for the standard 
EQ-5D three-level system and a five-level version according to two methods. Qual Life Res 
2008;17(3):463-73.
Keir et al 2008
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity 
Annu Rev Immunol 2008;26:677-704.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63.
Narwal et al 2013
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferonalpha monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet 2013;52:1017–27.
NCCN Guidelines 2014
National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology 
(NCCN Guidelines): Non-Small Cell Lung Cancer. Version 1.2014. Available from URL: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed 
10 January 2014.
NCCN 2017
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. NCCN clinical 
practice guidelines in oncology: non–small cell lung cancer, version 6.2017. National 
Comprehensive Cancer Network May 12, 2017.
Ng et al 2006
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab 
in cancer patients based on population pharmacokinetic analysis. Pharm Res 
2006;23(6):1275–84.
Nishino et al 2013
Nishino M, Biobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 2013;19(14):3936-43.
Okazaki and Honjo 2007
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol 2007;19(7):813-24.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
139
 
Okudaira et al 2009
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-
H1 or B7-DC induces an antitumor effect in a mouse pancreatic cancer model. Int J Oncol 
2009;35(4):741-9.
O'Rourke et al 2010
O'Rourke N, Roqué I, Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy 
in non-small cell lung cancer. Cochrane Database Syst Rev 2010;16(6):CD002140.
Osoba et al 1998
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
Pardoll 2012
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12:252-64.
Paz-Ares L 2020
Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 expression 
in unresectable, Stage III non-small-cell lung cancer in the PACIFIC trial[J]. Annals of 
Oncology, 2020..
Pazdur 2008
Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 
2008;13(Suppl 2):19-21.
Pickard et al 2007
Pickard AS, De Leon MC, Kohlmann T, Cella D, Rosenbloom S Psychometric comparison of 
the standard EQ-5D to a 5 level version in cancer patients  Med Care 2007;45(3):259-63.
Powles et al 2014
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558-
62.
Qin et al 2016
Qin, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current status 
of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 2016; 9:2169–70.
Rizvi et al 2015a
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with 
nonsmall cell lung cancer (NSCLC) [abstract 8032]. J Clin Oncol 2015;33.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
140
 
Rizvi et al 2015b
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational 
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
2015;348(6230):124-8.
Saijo et al 2010
Nagahiro Saijo, Fukuoka M, Thongprasert S, Ichinose Y, Mitsudomi T, Mok TS, et al. Lung 
Cancer Working Group Report. Jpn J Clin Oncol 2010;40(Suppl 1):i7-12.
Segal et al 2015
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma 
of the head and neck (SCCHN) expansion cohort [abstract 3011]. J Clin Oncol 2015;33.
Stewart et al 2015
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification 
and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3(9):1052-62.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein's method with the conventional approach for 
interval-censored data analysis. Stat Biopharm Res 2010;2(1):97-108.
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366:2443-54.
van Hout et al 2012
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim 
scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health 
2012;15(5):708-15.
van Reenen and Janseen 2015
van Reenen M, Janssen B. EQ-5D-5L user guide: basic information on how to use the 
EQ-5D-5L instrument V2.1 [Internet]. EuroQoL.org. 2015 [cited 2016Apr13]. Available 
from: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. 
Vansteenkiste et al 2013
Vansteenkiste J, De Ruysscher D, Eberhardt WE, Lim E, Senan S, Felip E, Peters S; ESMO 
Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 
2013;24(Suppl 6):vi89-98.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab
CONFIDENTIAL AND PROPRIETARY
141
 
Wang et al 2009
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012–24.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of 
randomized clinical trials. Stat Med 1991;10(11):1665-77.
Wolchok et al 2009
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009;15(23):7412-20.
Zhang et al 2008a
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Antitumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10(7):711-9.
Zhang et al 2008b
Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 
1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell 
apoptosis. Mol Immunol 2008;45(5):1470-6. [Epub ahead of print].
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28.

SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 9 3 3 yc 0 0 0 0 1-cs p- v 6
D oc u me nt Title:
D 9 3 3 Y C 0 0 0 0 1 Cli nical St u d y Pr ot oc ol versi o n 6
D oc u me nt I D:
Versi o n L a bel:
7. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
3 0- A u g- 2 0 2 3 1 6: 0 3 U T C
C o nte nt A p pr o val
3 0- A u g- 2 0 2 3 1 1: 2 4 U T C
C o nte nt A p pr o val
0 5- Se p- 2 0 2 3 1 3: 0 6 U T C
C o nte nt A p pr o val
C CI
C CI
P P D
P P D
P P D