A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Maintenance Olaparib Monotherapy in Patients With gBRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy
Phase: PHASE3
Conditions: Germline BRCA1/2 Mutations and, Metastatic Adenocarcinoma of the Pancreas
Sponsor: AstraZeneca

P P D
P P D
P P D
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
2( 1 3 3)
P R O T O C O L S Y N O P SI S
A P h ase III, R a n d o mise d, D o u ble Bli n d, Pl ace b o C o ntr olle d, M ultice ntre 
St u d y of M ai nte n a nce Ol a p ari b M o n ot her a p y i n P atie nts wit h g B R C A
M u t ate d Met ast atic P a ncre atic C a ncer w h ose Dise ase H as N ot Pr o gresse d 
o n First Li ne Pl ati n u m B ase d C he m ot her a p y
I nter n ati o n al C o-o r di n ati n g I n vesti g at or: 
 M D 
 M D 
St u d y ce ntre(s) a n d n u m ber of p atie nts pl a n ne d: A p pr o xi matel y 8 0 ce ntres w orl d wi de will 
be i nitiate d t o ra n d o mise a p pr o xi matel y 1 4 5 patie nts wit h ger mli ne B R C A 1/ 2 m ut atio ns a n d 
metastati c a de n ocarci n o ma of t he pa ncreas ( hereafter referre d t o as pa ncreas ca ncer).  
A d dit i onal c o u ntries a n d ce ntres ma y be a d de d de pe n de nt o n recr uitme nt  rates.
St u d y peri o d
P h ase of de vel o p me nt
Esti mate d date of first patie nt e nr olle d
Q 2 2 0 1 4
III
Esti mate d date of last patie nt c o m plete d
Q 1 2 0 2 1
 
 
 
O bjecti ves
P ri m ar y O bjecti ve:
O utc o me Me as ure:

T o deter mi ne t he efficac y o f Ola pari b 
mai nte na nce m o n ot hera p y  c o mpare d t o 
pl ace b o b y pr o gressio n  free s ur vi val 
( P F S)

Pr o gressi o n Free S ur vi val ( P F S) b y BI C R 
usi n g m o difie d R E CI S T 1. 1
P P D
P P D
P P D
P P D
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E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
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Sec o n d ar y O bjecti ve:
O utc o me Me as ure:

T o deter mi ne t he efficac y o f Ola pari b 
mai nte na nce m o n ot hera p y  c o mpare d t o 
pl ace b o

O verall S ur vi val ( o bser ve d a n d pre dicte d 
usi n g o bser ve d P F S a n d O S data)

Ti me fr o m ra n d o misati on t o sec o n d 
pr o gressi o n ( P F S 2)

Ti me fr o m ra n d o misati on t o first s u bse q ue nt 
t hera p y or deat h ( T F S T)

Ti me fr o m ra n d o misati on t o sec o n d 
s u bse q ue nt t hera p y or deat h ( T S S T).

Ti me fr o m ra n d o misati on t o st u d y  treat me nt 
di sc o nti n uati on or deat h ( T D T)

O bject i ve Res p o nse Rate b y BI C R usi n g 
m o difie d R E CI S T 1. 1 cri t eria for e val ua ble 
patie nts

Di sease C o ntr ol Rate at 1 6 wee ks b y BI C R 
usi n g m o difie d R E CI S T 1. 1 criteria

T o assess t he effect of Ola pari b o n t he 
Heal t h-relate d Q uality of  Life 
( H R Q o L) as meas ure d b y E O R T C 
Q L Q -C 3 0 gl o bal Q o L scale.

A d j uste d mea n c ha n ge fr o m baseli ne i n 
gl o bal  Q o L sc ore fr o m t he E O R T C-Q L Q -
C 3 0 q uesti o n naire
S afet y O bjecti ve:
O utc o me Me as ure:

T o assess t he safet y a n d t olera bilit y of 
Ol a pari b mai nte na nce m o n ot hera p y

A d verse e ve nt ( A E), p h y sical e xa mi nati on, 
vit al si g ns i ncl u di n g bl o o d press ure ( B P), 
p ul se, electr ocar dio gra m  ( E C G) a n d 
la b orat or y fi n di n gs i ncl u di n g cli nical 
c he mistr y a n d hae mat olo g y
E x pl or at or y O bjecti ve:
O utc o me Me as ure:

 
 

 
 
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Re vise d Cli nic al St u d y Pr ot o c ol _ Gl o b al
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
 
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
 

 
 
 

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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
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E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5( 1 3 3)
 
 
 
 
 
 
 
 
 
 

 

T he e x pl orat or y  a nal yses ma y n ot be re p orte d i n t he cli nical st u d y re p ort ( C S R).  If n ot, t he y 
will be re p orte d se paratel y .
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
6(133)
Study Flow Chart 

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
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St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
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T ar get P atie nt p o p ul ati o n
All patie nts ra n d o mise d i n t he st u d y  will be selecte d base d o n t he f oll o wi n g 2 pri nci ples: 

Ge netic selecti o n :  D oc u me nte d ger mli ne m utati o n i n B R C A 1 or B R C A 2 t hat is 
pre di cte d t o be deleterio us or s us pecte d deleteri o us ( k n o w n or pre dicte d t o be 
detri me ntal /lea d t o loss of f u nct i on).  Pati e nts wit h gB R C A 1 a n d/ or g B R C A 2 m ut at i ons 
t hat are c o nsi dere d t o be n o n detri me ntal (e g, “ Varia nts of u ncertai n c li nical 
sig nifica nce” or “ Varia nt of u n k n o w n si g nifica nce” or “ Varia nt, fa v or p ol y m or p his m” 
or “ be ni g n p o l y m or p his m,” etc) will n ot be eli gi ble f or t he st u d y.

Tre at me nt setti n g: All eli gi ble pat ient s must ha ve metastatic g B R C A m pa ncreas 
ca ncer, m ust ha ve recei ve d a mi ni m u m of 1 6 wee ks of plat i n u m base d treat me nt a n d 
m ust ha ve n o e vi de nce of pr o gressi o n base d o n i n vesti gat or’s o pi ni o n. St u d y  treat me nt 
will be starte d after ra n d o misat i on as s o o n as p ossi ble b ut n o less t ha n 4 a n d n o m ore 
t ha n 8 wee ks after last d ose of first li ne c he m ot hera p y. T u mo ur res p o nse d uri n g st u d y  
treat me nt will be assesse d usi n g m o difie d R E CI S T 1. 1.  Baseli ne assess me nts will be 
perf or m e d usi n g C T or M RI sca ns of t he c hest, a b d o me n a n d pel vis a n d s h o ul d be 
perf or m e d n o more t ha n 2 8 d a ys prior t o start of st u d y  treat me nt, a n d as close as 
p ossi ble t o ra n d o misat i on. F oll o w -u p assess me nts s h o ul d be perf or me d e ver y  8 wee ks 
( ± 1 wee k) f or 4 0 wee ks a n d t he n e ver y 1 2 wee ks ± 1 wee k relati ve t o date of 
ra n d omisat i on, u nt il o bjecti ve disease pr ogressi o n as defi ne d b y  mo difie d R E CI S T 1. 1.
 
 
 
After c o nfir mat i on o f eli gi bilit y, pati e nts will be ra n d o mise d ( usi n g a n I V R S) i n a 3: 2 rati o 
( Ola pari b: place b o) t o t he treat me nts as s pecifie d bel o w:

Ol a pari b ta blets p o. 3 0 0 m g t wice dail y

Pl ace b o ta blets t wice dail y
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n
Ol a pari b is a vaila ble as a gree n fil m- c oate d ta blet c o ntai ni n g 1 5 0 m g or 1 0 0 m g of Ola pari b.  
P ati e nts will be a d mi nistere d st u d y treat me nt orall y at a d ose of 3 0 0 mg t wi ce dail y ( bi d). T he 
pl a n ne d d ose of 3 0 0 m g bi d will be ma de u p of t w o x 1 5 0 m g ta blets bi d wi t h 1 0 0 mg ta blets 
use d t o m a na ge d ose re d ucti o ns. 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
8( 1 3 3)
C o m p ar at or, d os a ge a n d m o de of a d mi nistr ati o n
Pl ace b o will be a vaila ble as gree n fil m-c oate d ta blets matc hi n g t he Ola pari b ta blets. T hese 
s h o uld be ta ke n as per i nstr ucti o ns f or Ola pa rib ta blets.
D ur ati o n of tre at me nt
P ati e nts s h o uld c o nt i n ue t o recei ve st u d y treat me nt u ntil o bjecti ve ra di ol ogi cal disease 
pr o gressi o n per m o difie d R E CI S T 1. 1 as assesse d b y t he i n vesti gat or or u nacce pta ble t o xicit y 
a n d t he y d o n ot meet a n y ot h er disc o ntin uat i on cri t eria.  Patie nts w h o are deter mi ne d t o ha ve 
pr o gresse d acc or di n g t o m o difie d R E CI S T 1. 1 criteria b y t he I n vest i gat or will ha ve sca ns 
ce ntrall y re vie we d f or c o nfir mat i on of o bject i ve disease pr o gressi o n. If disease pr o gressi o n is 
n ot c o nfir me d at ce ntral re vie w o ne a d dit i on al  R E CI S T assess me nt will be re q ueste d 
prefera bl y at t he ne xt sc he d ule d R E CI S T visit. O nce patie nts ha ve bee n disc o nt i n ue d fr om 
st u d y tr e at me nt, ot her treat me nt o ptio ns will  be at t he discret i on of t he i n vesti gat or. Patie nts 
a n d i n vesti gat ors will n ot be r o uti nel y u n bli n de d t o st u d y treat me nt pri or t o t he 
 
. It is e x pecte d t hat ma n y if not m ost pati e nts will be restarte d o n a 
pl at i n u m base d re gi me n at pr o gressi o n o n st u d y  t hera p y. W hate ver t he re gi me n, t he y will be 
assesse d f or P F S 2 a n d f o ll owe d f or s ur vi val.  
St atistic al met h o ds
A p pr o xi matel y  1 4 5 p atie nts will be ra n d o mise d ( 3: 2 rati o of Ola pari b: place b o) a n d t he 
pri mar y  P F S a nal ysis will occ ur o nce a p pr o xi matel y 8 7 P F S e ve nts (c o nfir me d via a ce nt r al 
re vie w, D C O 1) ha ve occ urre d.  A si n gle i nteri m P F S a nal ysis f or f utility will  be perf or me d 
w he n 5 0 % of t he fi nal n u m ber of pr o gressi o n e ve nt s nee de d f or t he pri m ar y P F S a n al ysis 
has bee n reac he d (a p pr o xi matel y 4 4 P F S e ve nts).  T he i nteri m a nal ysis wi ll be perf or m e d b y 
a n I n de pe n de nt Data Ma na ge me nt C o m mittee (I D M C) a n d f ull details will be pr o vi de d i n t he 
I D M C c harter.  
T he st u d y  is size d ass u mi n g a tr ue treat me nt effect is a P F S Hazar d Rati o ( H R) of 0. 5 4, 
ass u mi n g 8 0 % p o wer a n d 2. 5 % al p ha ( 1 -si de d), wit h 3: 2 ra n d o misat i on ( Ol a pari b: place b o). 
Ass u mi n g P F S is e x p o ne nt iall y distri b ute d, a P F S H R of 0. 5 4 e q uates t o a 3. 4 m o nt h 
i m pr o ve me nt i n me dia n P F S o ver a n ass u me d 4 m o nt h me dia n P F S f or place b o. 
Ass u mi n g t hat t he st u d y  accr ual p erio d will  be a p pr o ximatel y 1 5 m o nt hs, 8 7 pr o gressi o n 
e ve nts are a nt ici pate d t o be o bser ve d a p pr o xi matel y 1 8-1 9 m o n t hs after t he first patie nt is 
ra n d omise d i n t he st u d y. It is esti mate d t hat 4 4 P F S e ve nts will occ ur a p pr o xi matel y 1 3 t o 1 4 
m o nt hs after t he first patie nt e nter s t he trial.
P ati e nts are t o be f o ll owe d f or t he fi nal a nal ysis of O S ( w he n a p pr o xi matel y  1 0 6 deat h e ve nts 
ha ve occ urre d, D C O 2).  Wit h 1 0 6 O S e ve nts t he st u d y  has 8 0 % p o wer t o s h o w a statisticall y 
sig nifica nt differe nce i n O S at t he 2. 5 % le vel ( 1 -si de d) if t he ass u me d tr ue treat me nt effect is a 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
9( 1 3 3)
H R 0. 5 7; t hi s tra nslates t o a n a p pr o xi mate 6 m o nt h i m pr o ve me nt i n me dia n O S o ver a n 
ass u me d 8 m o nt h me dia n O S o n place b o, ass u mi n g O S is e x p o ne nt iall y distri b ute d. 
 
 
T he pri mar y  statistical a nal ysis of t he efficac y of Ol a pari b will i ncl u de all ra n d o mise d patie nts 
( F ull A nal ysis Set; F A S) a n d will c om p are t he treat me nt gr o u ps o n t he basis of ra n d o mise d 
treat me nt, re gar dless o f t he treat me nt act uall y recei ve d. I n a d diti on, ke y  se nsitivit y a nal yses of 
efficac y e nd p oi nts will be perf or me d i n t he s u b gr o u p of pat ient s i n t he F A S t hat ha ve a 
g B R C A m ut atio n c o nfir me d b y  t he M yria d test. W he n assessi n g safet y a n d t olera bilit y, 
s um mar ies will be pr o d uce d base d o n t he Safety A nal ysis Set.  T his will i ncl u de all patie nts 
w h o recei ve at least o ne d ose of ra n d o mise d treat me nt ( Ola pari b or place b o).  T he safet y data 
will be s u m marise d descri pt i vel y a n d will n ot be f or mall y a nal yse d.
P F S will be a nal yse d usi n g a l o g ra n k test .  T he H R t o get her wit h its 9 5 % c o nfi de nce 
i nter val ( CI) a n d p-val ue will be prese nte d (a H R less t ha n 1 will fa v o ur Ola pari b).  T he 
pri mar y  a nal ysis will be base d o n a bli n de d i n de pe n de nt ce ntral re vie w ( BI C R) of disease 
pr o gressi o n b y  mo difie d R E CI S T 1. 1; h o we ver, a se nsit i vity a nal ysis will be perf or me d usi n g 
t he i n vest i gat or-rec or de d assess me nt.
S u b gr o u p a nal yses will be c o n d ucte d t o assess c o nsiste nc y of treat me nt effect acr oss p ote ntial 
pr o g n osti c fact ors (see Sectio n 8. 8. 2 f or all pre defi ne d s u b gr o u ps). A n a nal ysis will n ot be 
perf or m e d if t here are t o o fe w e ve nts a vaila ble f or a mea ni n gf ul a nal ysis o f a partic ular 
s u b gr o u p (ie, if t here are less t ha n 2 0 e ve nts i n a s u b gr o u p).
O S a nal yses will be perf or me d at t he sa me ti me as t he pri m ar y a nal ysis o f P F S a n d will use 
t he sa me met h o d olo g y  a n d mo d el  as P F S.  A fi nal for m al a nal ysis o f O S will  be perf or me d 
w he n a p pr o xi matel y  1 0 6 deat h e ve nts ha ve occ urre d ( D C O 2) a n d a m ulti plicity a dj ust me nt 
will be ma de t o acc o u nt f or t he differe nt a nal yses.
 
At  t he ti me of t he P F S a nal ysis ( D C O 1), 
 
 at t he fi nal a nal ysis will be deri ve d usi n g a wei g hte d s u m of t he 
o bser ve d O S data a n d t he pre dicte d O S val ue usi n g pri mar y P F S data a vaila ble at D C O 1. 
 
 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
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St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0( 1 3 3)
P F S 2 a nal yses will be perf or me d at t he sa me t i me as t he pri mar y a nal ysis of P F S, at t he ti me 
of  the fi nal O S a nal ysis, P F S 2 will be a nal yse d usi n g t he sa me met h o d ol o g y a n d m o del as 
P F S. 
I n or der t o descri be t he nat ure of t he be nefits of Ola pari b mai nte na nce treat me nt, P F S, P F S 2 
a n d O S will be teste d at a 1 -si de d sig nifica nce l e vel of 2. 5 %. H o we ver, in or der t o str o n gl y 
c o ntr ol t h e t ype I err or, a m ult i ple testi n g pr oce d ure will als o be e m pl oye d w here P F S is teste d 
first usi n g t he f ull test mass a n d O S will be teste d if t he n ull h y p ot hesis f or P F S is rejecte d.
Sec o n dar y  a nal yses of ti me t o treat me nt disc o nti n uati o n, ti me t o first s u bse q ue nt t hera p y or 
deat h, a n d ti me t o sec o n d s u bse q ue nt t hera p y  or deat h will be pr o vi de d, usi n g t he sa me 
met h o d ol o g y  as s pecifie d f or t he pri mar y a nal yses of P F S; h o we ver n o m ulti plicity 
a djust m e nt will be a p plie d as t hese are vie we d as s u p p ortive e n d p o i nts.
O bject i ve t u m o ur res p o nse rates a n d disease c o ntr ol rates ( base d o n ce ntral re vie w) will be 
s u m marise d f or t he t w o treat me nt ar ms.  I n a d dit i on, t he i n vest i gat or re p orte d res p o nse rates 
will als o be s u m marise d. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1( 1 3 3)
 
 
 
 
 
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
12(133)
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL SYNOPSIS...................................................................................................... 2
TABLE OF CONTENTS.................................................................................................... 12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 19
1.
INTRODUCTION............................................................................................ 24
1.1
Background and rationale for conducting this study .......................................... 24
1.1.1
Pancreas cancer and its treatment...................................................................... 24
1.1.2
Chemotherapy use in advanced pancreas cancer................................................ 25
1.1.3
PARP inhibition as a target for BRCA mutation positive cancer ........................ 26
1.1.4
Pre-clinical experience...................................................................................... 26
1.1.5
Toxicology and safety pharmacology summary................................................. 26
1.1.6
Clinical experience with Olaparib ..................................................................... 27
1.1.6.1
Olaparib monotherapy studies in pancreas cancer patients................................. 27
1.2
Research hypothesis.......................................................................................... 27
1.3
Rationale for study design, doses and control group.......................................... 28
1.3.1
Rationale for using Myriad Genetics................................................................. 29
1.4
Benefit/risk and ethical assessment ................................................................... 29
1.4.1
Important potential risks ................................................................................... 30
1.4.1.1
Myelodysplastic syndrome/acute myeloid leukaemia ........................................ 30
1.4.1.2
Pneumonitis...................................................................................................... 31
1.4.1.3
New Primary Malignancies............................................................................... 32
1.4.2
Potential benefit................................................................................................ 33
1.5
Study Design .................................................................................................... 34
2.
STUDY OBJECTIVES..................................................................................... 39
2.1
Primary objective.............................................................................................. 39
2.2
Secondary objectives ........................................................................................ 39
2.3
Safety objectives............................................................................................... 40
2.4
Exploratory objectives ...................................................................................... 40
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................... 41
3.1
Inclusion criteria............................................................................................... 42
3.2
Exclusion Criteria ............................................................................................. 43
3.3
Patient enrolment and randomisation ................................................................ 45
3.4
Procedures for handling incorrectly enrolled or randomised patients................. 46
3.5
Methods for assigning treatment groups............................................................ 46
3.6
Methods for ensuring blinding .......................................................................... 47
3.7
Methods for unblinding..................................................................................... 47

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 3( 1 3 3)
3. 7. 1
Met h o ds f or e ns uri n g bli n di n g ..........................................................................4 7
3. 7. 2
Met h o ds f or u n bli n di n g t he st u d y ......................................................................4 7
3. 8
Restricti o ns .......................................................................................................4 8
3. 8. 1
C o ntrace pti o n ...................................................................................................4 8
3. 8. 2
Ol a pari b a n d C Y P 3 A 4/ 5 ...................................................................................4 8
3. 9
Di sc o nti n uatio n of  in vesti gat i onal pr o d uct ........................................................4 8
3. 9. 1
Pr oce d ures f or disc o nt i n uati on of a patie nt fr o m i n vesti gati o nal pr o d uct...........4 9
3. 1 0
Cri teria f or wit hdra wal ......................................................................................4 9
3. 1 0. 1
Scree n fail ures ..................................................................................................5 1
3. 1 0. 2
Wit h dra wal o f t he i nf or me d c o nse nt ................................................................. 5 1
3. 1 1
Di sc o nti n uatio n of  t he st u d y .............................................................................5 1
4.
S T U D Y P L A N A N D TI MI N G O F P R O C E D U R E S .........................................5 1
4. 1
E nr ol me nt/scree ni n g peri o d ..............................................................................5 9
4. 2
Treat me nt peri o d ...............................................................................................6 0
4. 3
F o ll ow- u p peri o d ..............................................................................................6 2
4. 3. 1
Treat me nt disc o nt i n uati on visit d ue t o o bjecti ve ra di o l ogi cal disease 
pr o gressi o n .......................................................................................................6 2
4. 3. 2
Treat me nt disc o nt i n uati on visit d ue t o a n y  ot her disc o nti n uati o n criteria...........6 2
4. 3. 3
P ati e nts w h o ha ve o bjecti ve ra di o l ogical  disease pr o gressio n b ut c o nti n ue o n 
st u d y tr e at me nt ................................................................................................. 6 2
4. 3. 4
F o ll ow- u p 3 0 da y  aft er last d ose of st u d y treat me nt (fol l ow- u p visit) ................6 3
4. 3. 5
S ur vi val ............................................................................................................6 3
4. 3. 6
Sec o n d Pr o gressi o n ...........................................................................................6 3
4. 3. 7
S u bse q ue nt Treat me nt .......................................................................................6 4
4. 4
P ati e nt ma na ge me nt p ost fi nal a nal ysis .............................................................6 4
5.
S T U D Y A S S E S S M E N T S .................................................................................6 5
5. 1
Efficac y assess me nts .........................................................................................6 5
5. 1. 1
C T a n d M RI sca ns T u m o ur assess me nts ( M o difie d R E CI S T 1. 1) ......................6 5
5. 1. 2
T u m o ur E val uat i on ...........................................................................................6 6
5. 1. 3
Ce ntral  rea di n g of sca ns....................................................................................6 8
5. 2
S af et y assess me nts ............................................................................................6 8
5. 2. 1
La b orat or y  safety assess me nts ..........................................................................6 8
5. 2. 2
P h ysical e xa mi nat i on ........................................................................................6 9
5. 2. 4
E C G .................................................................................................................7 0
5. 2. 4. 1
Rest i n g 1 2-lea d E C G ........................................................................................7 0
5. 2. 5
Vi t al si g ns.........................................................................................................7 0
5. 2. 5. 1
P ul se a n d blo o d press ure ...................................................................................7 1
5. 2. 5. 2
B o d y  t e mperat ure .............................................................................................7 1
5. 2. 6
Ot her safet y assess me nts ...................................................................................7 1
5. 2. 6. 1
S er u m  or uri ne pre g na nc y test...........................................................................7 1
5. 2. 7
B o ne m arr o w or blo o d c y t o ge netic sa m ples ......................................................7 1
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 4( 1 3 3)
5. 3
Ot her assess me nts .............................................................................................7 2
 
5. 6
Bi ol o gi cal sa m pli n g pr oce d ures ........................................................................7 7
5. 6. 1
V ol u me of bl o o d ...............................................................................................7 7
5. 6. 2
Ha n dli n g, st ora ge a n d destr ucti o n of bi o l ogical sa m ples ...................................7 8
5. 6. 3
La belli n g a n d s hi p me nt of bi o hazar d sa m ples ...................................................7 8
5. 6. 4
C hai n o f c ust o d y of biol o gical sa m ples .............................................................7 9
5. 6. 5
Wit h dra wal o f i nf or me d c o nse nt f or d o nate d bi ol ogi cal sa m ples .......................7 9
6.
S A F E T Y R E P O R TI N G A N D M E DI C A L M A N A G E M E N T ............................8 0
6. 1
Defi nit i on o f a d verse e ve nts ..............................................................................8 0
6. 2
Defi nit i ons of seri o us a d verse e ve nt ..................................................................8 0
6. 3
Rec or di n g of a d verse e ve nts .............................................................................8 1
6. 3. 1
Ti me peri o d f or c ollect i on of a d verse e ve nts .....................................................8 1
6. 3. 1. 1
A d verse e ve nts after t he 3 0 da y  fol l ow u p peri o d ..............................................8 2
6. 3. 2
F o ll ow- u p of  u nres ol ve d a d verse e ve nts............................................................8 2
6. 3. 3
V ari a bles ..........................................................................................................8 2
6. 3. 4
Ca usalit y c o llecti o n...........................................................................................8 4
6. 3. 5
A d verse e ve nts base d o n si g ns a n d s y m pt o ms ...................................................8 4
6. 3. 6
A d verse e ve nts base d o n e xa mi nat i ons a n d tests ...............................................8 4
6. 3. 7
H y’s La w ..........................................................................................................8 5
6. 3. 8
Di sease pr o gressio n ..........................................................................................8 5
6. 4
Re p orti n g of seri o us a d verse e ve nts ..................................................................8 6
6. 4. 1
Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es..................................................8 7
6. 5
O ver d ose ..........................................................................................................8 8
6. 6
Pre g na nc y .........................................................................................................8 8
6. 6. 1
Mater nal e x p os ure
............................................................................................8 8
6. 6. 2
Pater nal  e x p os ure..............................................................................................8 9
6. 7
Ma na ge me nt of t o xicit y of  Ola pari b..................................................................8 9
6. 7. 1. 1
Ma na ge me nt of a nae mia ...................................................................................9 0
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
15(133)
6.7.1.2
Management of neutropenia, leukopenia and thrombocytopenia........................ 91
Management of prolonged haematological toxicities while on study treatment.................... 91
6.7.2
Management of non-haematological toxicity Olaparib ...................................... 92
6.7.2.1
Management of new or worsening pulmonary symptoms.................................. 92
6.7.2.2
Management of nausea and vomiting ................................................................ 92
6.7.2.3
Interruptions for intercurrent non-toxicity related events................................... 93
6.7.3
Management of toxicity on placebo .................................................................. 93
6.7.4
Renal impairment ............................................................................................. 94
6.8
Study governance and oversight........................................................................ 94
6.8.1
Data Monitoring Committee ............................................................................. 94
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................. 94
7.1
Identity of investigational product(s)................................................................. 94
7.2
Dose and treatment regimens ............................................................................ 95
7.3
Labelling .......................................................................................................... 95
7.4
Storage ............................................................................................................. 96
7.5
Compliance....................................................................................................... 96
7.6
Accountability .................................................................................................. 96
7.7
Concomitant and other treatments..................................................................... 97
7.7.1
Medications that may NOT be administered...................................................... 97
7.7.2
CYP3A4/5 restrictions...................................................................................... 97
7.7.3
Other concomitant treatment............................................................................. 98
7.7.4
Anti-emetics/ Anti-diarrhoeals .......................................................................... 98
7.7.5
Anticoagulant Therapy...................................................................................... 98
7.7.6
Administration of other anti-cancer agents........................................................ 98
7.7.7
Subsequent therapies for cancer ........................................................................ 99
8.
STATISTICAL ANALYSIS AND SAMPLE SIZE DETERMINATION BY 
PAREXEL........................................................................................................ 99
8.1
Statistical considerations................................................................................... 99
8.2
Definitions of analysis sets................................................................................ 99
8.2.1
Full analysis set ................................................................................................ 99
8.2.2
Safety analysis set........................................................................................... 100
8.2.3
PRO analysis set ............................................................................................. 100
8.3
Calculation or derivation of efficacy variable(s).............................................. 101
8.3.1
Primary endpoint (PFS) .................................................................................. 101
8.3.2
Secondary endpoints....................................................................................... 102
8.3.2.1
Overall Survival.............................................................................................. 102
8.3.2.2
Best overall RECIST response (BoR) ............................................................. 102
8.3.2.3
Time from randomisation to second progression (PFS2) ................................. 103
8.3.2.4
Time to first subsequent therapy or death (TFST) ........................................... 103
8.3.2.5
Time to second subsequent therapy or death (TSST)....................................... 103
8.3.2.6
Time to study treatment discontinuation or death (TDT)................................. 104
8.3.2.7
Disease Control Rate (DCR)........................................................................... 104

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 6( 1 3 3)
8. 4
Calc ulati o n or deri vat i on of safet y varia ble(s) .................................................1 0 4
8. 4. 1
Ot her si g nifica nt a d verse e ve nts ( O A E) ..........................................................1 0 4
8. 5
Calc ulati o n or deri vat i on of patie nt re p orte d o utc o me varia bles ......................1 0 5
C o m plia nce .......................................................................................................................1 0 7
8. 6
Calc ulati o n or deri vat i on of p har mac o ge net ic varia bles ..................................1 0 8
8. 7
Calc ulati o n or deri vat i on of healt h ec o n o mic varia bles ...................................1 0 8
8. 8
Met h o ds f or statist ical a nal yses.......................................................................1 0 9
8. 8. 1
M ul tiplici t y str at e g y for pri m ar y a n d ke y sec o n dar y e nd p oi nts ........................1 1 1
8. 8. 2
A nal ysis of t he pri mar y  varia ble (s) ................................................................1 1 2
8. 8. 3
Se nsit i vity a nal ysis f or t he pri mar y e n d p oi nt...................................................1 1 4
8. 8. 3. 1
E val uat i on- Ti me bias ......................................................................................1 1 4
8. 8. 3. 2
At tritio n bias ...................................................................................................1 1 5
8. 8. 3. 3
Ascertai n me nt bias ..........................................................................................1 1 5
8. 8. 3. 4
De viat i on bias (if mea ni n gf ul t o d o) ................................................................1 1 5
8. 8. 4
A nal ysis of t he sec o n dar y v ari a ble(s) ..............................................................1 1 6
8. 8. 4. 1
A nal ysis of O S e n d p o i nt .................................................................................1 1 6
8. 8. 4. 2
A nal ysis of P F S 2 e n d p o i nt..............................................................................1 1 6
8. 8. 4. 3
A nal ysis of T D T e n d p oi nt ...............................................................................1 1 7
8. 8. 4. 4
A nal ysis of T F S T e n d p o i nt .............................................................................1 1 7
8. 8. 4. 5
A nal ysis of T S S T e n d p oi nt .............................................................................1 1 7
8. 8. 4. 6
A nal ysis of P R O e n d p oi nts .............................................................................1 1 8
8. 8. 4. 7
S u m mar y  of Best o verall R E CI S T Res p o nse ( B o R) a n d O R R.........................1 1 9
8. 8. 4. 8
S u m mar y  of D C R...........................................................................................1 1 9
8. 8. 5
E x pl or at or y  a nal ysis .......................................................................................1 1 9
 
8. 9
S a m ple Si ze Deter mi nat i on .............................................................................1 2 1
8. 9. 1
I nteri m a nal ysis ..............................................................................................1 2 2
9.
S T U D Y A N D D A T A M A N A G E M E N T B Y P A R E X E L ................................1 2 2
9. 1
Trai ni n g of st u d y  site pers o n nel ......................................................................1 2 2
9. 2
M o ni t ori n g of t he st u d y...................................................................................1 2 3
9. 2. 1
S o urce data .....................................................................................................1 2 3
9. 2. 2
St u d y  a gree me nts ............................................................................................1 2 3
9. 2. 3
Arc hi vi n g of st u d y  d oc u me nts ........................................................................1 2 4
9. 3
St u d y  ti meta ble a n d e n d of st u d y ....................................................................1 2 4
9. 4
Data m a na ge me nt b y P A R E X E L....................................................................1 2 4
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 7( 1 3 3)
1 0.
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S ....................................1 2 5
1 0. 1
Et hical c o n d uct of t he st u d y ............................................................................1 2 5
1 0. 2
P ati e nt data pr otectio n .....................................................................................1 2 5
1 0. 3
Et hics a n d re g ulat or y  re vie w...........................................................................1 2 6
1 0. 4
I nf or me d c o nse nt ............................................................................................1 2 7
1 0. 5
C ha n g es t o t he pr ot oc ol a n d i nf or me d c o nse nt f or m ........................................1 2 7
1 0. 6
A u dits a n d i ns pect i ons ....................................................................................1 2 8
1 1.
LI S T O F R E F E R E N C E S ................................................................................1 2 8
LI S T O F T A B L E S
Ta ble 1
St u d y  Sc he d ule – Scree ni n g, O n St u d y  Treat me nt, Disc o nti n uatio n a n d 
F o ll ow- u p ................................................................................................5 2
Ta ble 2
La b orat or y  S afet y Varia bles .....................................................................6 8
Ta ble 5
V ol u me of bl o o d t o be dra w n fr o m  eac h patie nt .......................................7 8
Ta ble 6  
Ma na ge me nt of a nae mia ..........................................................................9 0
Ta ble 7
Ma na ge me nt of ne utr o pe nia, le u k o pe nia a n d t hr o m b oc yt o pe nia
..............9 1
Ta ble 8
D ose re d ucti o ns f or st u d y  treat me nt .........................................................9 3
Ta ble 9
S u m mar y  of O utc o me Varia bles a n d A nal ysis P o p ulat i ons ....................1 0 0
Ta ble 1 2
Ti mi n g of statistical a nal yses ................................................................. 1 0 9
Ta ble 1 3
F or mal Stati stical A nal yses t o be C o n d ucte d a n d Pre -Pl a n ne d Se nsit i vity 
A nal yses ................................................................................................1 1 0
LI S T O F FI G U R E S
Fi g ure 1
St u d y  Flo w C hart .....................................................................................3 5
Fi g ure 2
M ul tiple Te sti n g Pr oce d ures ..................................................................1 1 1
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 8( 1 3 3)
LI S T O F A P P E N DI C E S
A p pe n di x A
Si g nat ures
A p pe n di x B
A d dit i onal Safet y I nf or matio n  
A p pe n di x C
I A T A 6. 2 G ui da nce D oc u me nt
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
A p pe n di x E
Acce pta ble Birt h C o ntr ol Met h o ds
A p pe n di x F
G ui deli nes f or E val uati o n of O bject i ve T u m o ur Res p o nse Usi n g M o difie d 
R E CI S T 1. 1 ( Res p o nse E val uat i on Cri t eria i n S oli d T u m o urs)
A p pe n di x H
C Y P 3 A 4/ 5 Restrict i ons
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
19(133)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
20(133)
Abbreviation or 
special term
Explanation
AE
Adverse event (see definition in Section 6.1)
ALP
Alkaline phophatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukaemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboblastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
Baseline
Refers to the most recent assessment of any variable prior to dosing with 
study treatment
BICR
Blinded Independent Central Review
bid
Bis in die (twice daily)
BoR
Best Overall RECIST Response
BP
Blood pressure
gBRCA
germline Breast Cancer susceptibility gene
BRCA mutation or 
BRCAm
Breast Cancer susceptibility gene mutation (see gBRCA mutation or 
gBRCAm)
BUN
Blood urea nitrogen
CHO
Chinese hamster ovary
CI
Confidence Interval 
CR
Complete Response
CRF
Case Report Form (electronic/paper)
CRO
Clinical Research Organisation
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
DCIS
ductal carcinoma in situ
DCO
Data Cut Off
DCO1
Data Cut Off for primary PFS analysis
DCO2
Data Cut Off for final formal OS analysis

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
2 1( 1 3 3)
D C R
Disease c o ntr ol r at e
D N A
De o x yri b o n ucleic aci d 
D S B
D o u ble stra n d brea k
E C G
Electr ocar di o gra m
E C
Et hics C o m mittee, s y n o n y m o us t o I nstit uti o nal Re vie w B oar d (I R B) a n d 
I n de pe n de nt Et hics C o m mittee (I E C)
E -c o de
E nr ol me nt c o de (all ocate d b y I V R S/I W R S)
 
e C R F
Electr o nic Case Re p ort f or m
E O R T C Q L Q -C 3 0
T he E O R T C Q L Q -C 3 0 is a q uesti o n naire de vel o pe d t o assess t he q ualit y 
of life of ca n cer patie nts
 
 
 
i n de x
F A S
F ull A nal ysis Set
F D A
F o o d a n d Dr u g A d mi nistrati o n
F F P E
F or mali n Fi xe d Paraffi n E m be d de d
F S H
F ollicle sti m ulati n g h or m o ne
g B R C A m utati o n or 
g B R C A m
T he ter m " g B R C A m utati o n" is use d t o refer t o a ger mli ne B R C A 1 or 
B R C A 2 m utati o n classifie d as " deleteri o us" or "s us pecte d deleteri o us" i n 
acc or da nce wit h t he A merica n C olle ge of Me dical Ge netics a n d 
Ge n o mics rec o m me n dati o ns f or sta n dar ds f or i nter pretati o n a n d re p orti n g 
of se q ue nce varia nts 
g B R C A wt
g B R C A wil dt y pe ( patie nts wit h o ut e vi de nce of B R C A 1 or B R C A 2
deleteri o us or s us pecte d deleteri o us m utati o ns)
G C P
G o o d Cli nical Practice
G- C S F
Gra n ul oc yte c ol o n y -sti m ulati n g fact or
G G T
Ga m ma gl uta m yl tra nsferase
G M P
G o o d Ma n ufact uri n g Practice
G Ra n d
A Z Gl o bal Ra n d o misati o n s yste m
H b
Hae m o gl o bi n 
H D P E
Hi g h- de nsit y p ol yet h yle ne
C CI
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
22(133)
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRD
Homologous recombination repair deficiencies
HRQoL
Health-related Quality of Life
IATA
International Air Transport Association 
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-
ordinating Investigator is the Investigator co-ordinating the investigators 
and/or activities internationally. 
IDMC   
Independent Data Monitoring Committee
INR
International Normalised Ratio
IPCW
Inverse Probability of Censoring Weighting
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan Meier
LDH
Lactic dehydrogenase
LH
Luteinizing hormone
LIMS
Laboratory Information Management System
m
Metre
MCH
Mean cell haemoglobin
MCHC
Mean cell haemoglobin concentration
MCV
Mean cell volume
MDS
Myelodysplastic syndrome
mg
Milli-gram
MRI
Magnetic resonance imaging
nab
nanoparticle albumen bound
NCI
National Cancer Institute
NE
Not evaluable
NTL
Non-target lesions
OAE
Other Significant Adverse Event (see definition in Section 8.4.1)
ORR
Objective response rates
OS
Overall survival

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
2 3( 1 3 3)
P D
Pr o gressi ve disease
P F S
Pr o gressi o n Free S ur vi val
p. o.
Per os ( b y m o ut h, orall y)
P R
Partial res p o nse
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 urs.  T his st u d y will use 
m o difie d R E CI S T versi o n 1. 1
R P S F T
Ra n k Preser vi n g Str uct ural Fail ure Ti me
S A E
Seri o us a d verse e ve nt (see defi niti o n i n Secti o n 6. 2
S A P
Statistical A nal ys is Pla n
S D
Sta ble disease
S S B
Si n gle stra n d brea k
S U S A Rs
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns
St u d y treat me nt
Ola pari b or c o ntr ol ar m c he m ot hera p y
 
 
 
 
T L
Tar get lesi o ns
U S
U nite d States
W B C
W hite bl o o d cells
W B D C
We b Base d Data Ca pt ure
wt
Wil dt y pe ( patie nts wit h o ut e vi de nce of B R C A 1 or B R C A 2 deleter i o us or 
s us pecte d deleteri o us m utati o ns)
C CI
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
24(133)
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
1.1.1
Pancreas cancer and its treatment 
Pancreas cancer is a life-threatening disease and is the fourth leading cause of cancer death in 
the West.  In 2013, it is estimated that there were 45,220 newly diagnosed pancreas cancer 
cases in the US, and approximately 38,460 people deaths from pancreas cancer (American 
Cancer Society 2013).  Worldwide, it was estimated that 266,000 people died of pancreas 
cancer in 2008 (.
Fitzsimmons D et al 1999
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality of life 
(QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the 
QLQ-C30 in patients with pancreatic cancer. Eur. J. Cancer 35: 939-941, 1999.
Fong et al 2009
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of 
poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 
2009;361(2):123-34.
Fowble et al 2001 
Fowble B, Hanlon A, Freedman G, Nocolaou N, Anderson P. Second cancers after 
conservative surgery and radiation for stages I-II breast cancer : identifying a subset of women 
at increased risk. Int J Radiat Oncol, Biol, Phys. 2001; 51 (3);679-690.
Gaymes et al 2008
Gaymes TJ, Shall S, MacPherson LJ, Twine NA, Lea NC, Farzaneh F, and Mufti GJ. 
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic 
cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. 
Haematologica 2009; 94:638-646. doi:10.3324/haematol.2008.00193
Ginsburg et al 2010
Ginsburg et al BRCA1 and BRCA2 families and the risk of skin cancer Springer 
Science+Business Media B.V. 2010
Goggins M. et al 1996
Germline M et al BRCA2 gene mutations in patients with apparently sporadic pancreatic 
carcinomas. Cancer Res. 1996 Dec 1;56(23):5360-4
Hay et al 2009
Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) 
polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary 

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Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 
2009;69(9):3850-5.
Hahn et al 2003
Hahn et al BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 
2003 Feb 5;95(3):214-21.
Helleday 2011
Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing 
up the misunderstandings. Molecular Oncology 2011; 5: 387-393.
Jemal A et al 2011).
The poor prognosis of pancreas cancer (~90% of patients who are diagnosed will die of the 
disease) is a function of late presentation of the disease when inoperable/ locally advanced or 
metastatic. Furthermore treatment of metastatic pancreas cancer even with the most “active” 
regimens such as FOLFIRINOX (Conroy et al 2011) or gemcitabine + nab paclitaxel (Von 
Hoff et al 2013) is associated with median survivals of less than one year, and for single agent 
treatments at best only 6 months. Unfortunately the toxicity of the most active combination 
chemotherapy regimens limits the duration of exposure to patients even if benefiting from the 
treatment. The neurotoxicity of both FOLFIRINOX and gemcitabine + nab paclitaxel in the 
former case generally leads to discontinuation of some or all of the drugs at or before 6 
months of treatment and in the later case dose attenuation.  The FOLFIRINOX study 
recommended no more than a total of 6 months of chemotherapy for patients who had a 
response (Conroy et al 2011).Furthermore there are few if any established second line 
regimens available (American Cancer Society 2013) and benefit if any, is at most a few 
months of survival (Rahma et al 2013). Despite the development of more “active” regimens 
for first treatment of metastatic pancreatic cancer in the last decade, their limited absolute 
benefit and significant toxicity strongly suggest that improving the results of initial therapy of 
metastatic pancreas cancer constitutes an unmet medical need. Furthermore to date there has 
been no marker, clinical or molecular that would predict for increased likelihood of benefit 
from systemic therapies for pancreas cancer. 

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Although carriers of deleterious germline mutations of the BRCA1 and particularly BRCA2 gene 
are known to have an increased risk of developing pancreas cancer (The Breast Cancer Linkage 
Consortium 1999, Goggins M. et al 1996), the prevalence of  gBRCAm in the unselected cases of 
pancreas cancer is unclear but likely less than 5 % In a tissue based study, 7% of patients with 
resected pancreas cancer or human xenografts had “germline” mutations in their tumour 
(Goggins M. et al 1996) but this cohort may not represent the typical unselected cases and the 
prevalence is likely somewhat lower.  There are specific populations, however, where the 
association is much stronger. In Ashkenazi Jewish patients with pancreas cancer, the prevalence 
of gBRCAm is 6-10% in unselected patients (Fayers et al 2001
Fayers et al. EORTC QLQ-C30 Scoring Manual (Third Edition). Belgium: EORTC Quality of 
Life Group, 2001.
Ferrone CR et al 2009, Ozcelik et al 1997) and 15% in patients with a family history of the 
disease (Sadler ZK. 2012). In pancreas cancer patients with a family history of the disease, 
reported prevalence of carrying a germline BRCA2 mutation may be as high as 17-19% 
(Murphy KM et al 2002, Hahn et al 2003).Given the small size of the gBRCAm subpopulation in 
pancreas cancer, information comparing the natural history of this group with the overall 
pancreas cancer population is minimal. One study of the natural history of Ashkenazi Jews with 
pancreas cancer treated with surgery (most of whom eventually died of the disease) could find no 
difference in survival between those who had germline BRCAm (n=8) vs. those who did not 
(n=137). The study however did not extend beyond 2004 and did not include patients treated 
with more modern chemotherapies (Fayers et al 2001
Fayers et al. EORTC QLQ-C30 Scoring Manual (Third Edition). Belgium: EORTC Quality of 
Life Group, 2001.
Ferrone CR et al 2009). In a large study of the natural history of BRCAm associated pancreas 
cancer, the median all–stage overall survival (OS) for 58 patients was 14 months (95% CI 10-
23 months). Median OS for patients with stage 1-2 disease has not been reached at 60 months. 
Median OS for stage 3-4 was 12 months (95% CI 6-15). Superior OS was observed for 
patients with stage III and IV disease treated with platinum versus those treated with non-
platinum chemotherapies (22 vs 9 months; p=0.039 (Golan et al unpublished data). There are 
no approved treatments for patients with germline BRCA1/2 mutations and these patients are 
treated with regimens used for standard advanced pancreas (Lowery M et al 2011).
Recent data suggest there may also be a number of pancreas cancer patients’ tumours with 
ATM defects or a gBRCA-like or HRD phenotype (Cowley et al 2013). The development of a 
test to identify such tumours may broaden the patient population which could benefit from 
PARP inhibitors. Obtaining tumour tissue to look for the prevalence these other potential
markers of drug sensitivity is another unmet need in advancing therapy of this serious illness.
1.1.2
Chemotherapy use in advanced pancreas cancer 
Chemotherapy for metastatic pancreas cancer has modest, at best, impact on PFS and OS. The 
“best” regimens for use as initial treatment of metastatic disease, FOLFIRINOX or 

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Edition Number 3
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gemcitabine + nab paclitaxel have respectively PFS’s of 6.4 and 5.5 mos. and OS’s of 11.1 
and 8.5 mos. (Conroy et al 2011, Von Hoff et al 2013). Toxicity particularly on the platinum
based regimen was substantial (80% had hematologic toxicity, 45% ≥grade 3; 70% had 
peripheral neurotoxicity, 9% ≥grade 3) and led to dose reductions and treatment 
discontinuations. It is of note that median number of FOLFIRINOX cycles given was 10 (ie. 
~5 months of treatment) but the median PFS was 6.4 months suggesting some discontinuation 
prior to the planned 12 cycles and evidence of progression. Nevertheless platinum based 
regimens are widely used as first line therapy of metastatic pancreas cancer. 
1.1.3
PARP inhibition as a target for BRCA mutation positive cancer
Investigators should be familiar with the current Olaparib (AZD2281) Investigator Brochure 
(IB).
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an 
oral therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anti-cancer agents.
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to DNA double 
strand breaks (DSBs) during the process of DNA replication.  During the process of cell 
division, DSBs can be efficiently repaired in normal cells by homologous recombination 
repair.  Tumours with homologous recombination deficiencies (HRD), such as ovarian cancers 
in patients with gBRCA1/2 mutations, cannot accurately repair the DNA damage, which may 
become lethal to cells as it accumulates.  In such tumour types, Olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available 
chemotherapy regimens. 
gBRCA1 and gBRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in 
tumour models in vivo Rottenberg et al 2008, Hay et al 2009) and in the clinic (.
Fitzsimmons D et al 1999, Fong et al 2009, Fowble et al 2001). The mechanism of action for 
Olaparib results from the trapping of inactive PARP onto the single-strand breaks preventing 
their repair (Helleday 2011, Murai et al 2012).  Persistence of SSBs during DNA replication 
results in their conversion into the more serious DNA DSBs that would normally be repaired 
by homologous repair.  Olaparib has been shown to inhibit selected tumour cell lines in vitro 
and in xenograft and primary explant models as well as in genetic BRCA knockout models, 
either as a stand-alone treatment or in combination with established chemotherapies.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
2 8( 1 3 3)
1. 1. 4
Pre -cli nic al e x perie nce
T he pre -cli nical e x perie nce is f ull y descri be d i n t he c urre nt versi o n of t he Ola pari b I B.
1. 1. 5
T o xic ol o g y a n d s afet y p h ar m ac ol o g y s u m m ar y
Ol a pari b has bee n teste d i n a sta n dar d ra n ge of safet y p har ma c olo g y  st u dies e g, d o g 
car dio vasc ular a n d res pirat or y  fu n cti o n tests, a n d t he rat Ir wi n test.  T here were n o n oticea ble 
effects o n t he car di o vasc ular or res pirat or y para meters i n t he a naest hetise d d o g or a n y 
be ha vi o ural, a ut o n o mic or m ot or effects i n t he rat at t he d oses st u die d.
R o de nt a n d d o g t o xic o l og y  st u dies ha ve i n dicate d t hat t he pri mar y tar get or ga n of t o xicity is 
t he b o ne marr o w wit h rec o ver y s e e n fol l owi n g wi t hdra wal of Ola pari b.  Ex viv o stu dies ha ve 
c o nfir me d t hat Ola pari b is c yt ot o xic t o h u ma n b o ne marr o w cells.
Ol a pari b was n ot muta ge nic i n t he A mes test b ut was clast o ge nic i n t he C hi nese ha mster 
o var y  ( C H O) c hr o mos o m e a berratio n test i n vitr o.  W he n d ose d orall y, Ola pari b als o i n d uce d 
micr o n uclei i n t he b o ne marr o w of rats.  T his pr ofile is c o nsiste nt wit h t he p ote ntial f or 
ge n ot o xi cit y in ma n. 
Re pr o d ucti ve t o xic o l og y  data i n dicate t hat Ola pari b ca n ha ve a d verse effects o n e m br yof o et al  
s ur vi val a n d de vel o p me nt at d ose le vels t hat d o n ot i n d uce si g nifica nt mater nal t o xicit y. 
F urt her i nf or mat i on ca n be f o u n d i n t he c urre nt versi o n of t he Ola pari b I B.
1. 1. 6
Cli nic al e x perie nce wit h Ol a p ari b
Bel o w i s a n o utli ne of t he m o n ot hera p y Ola pari b st u dies c o n d ucte d i n pa ncreas ca ncer 
pati e nts.
1. 1. 6. 1
Ol a p ari b m o n ot her a p y st u dies i n p a ncre as c a ncer p atie nts
 
 
All patie nts ha d see n a pri or ge mcita bi ne 
re gi me n a n d o ver half a pri or plati n u m c o ntai ni n g re gi me n. T he O R R was 2 2 %, D C R 5 7 %, 
P F S 4. 6 m os. a n d O S 9. 8 m os ( Ka uf ma n B et al 2 0 1 3 ). T his le vel of act i vity c o m pares 
fa v o ura bl y wit h t hat re p orte d f or ot her t hera pies re p orte d i n a d va nce d pre vi o usl y treate d 
pa ncreas ca ncer (Ra h ma et al 2 0 1 3 ). A retr os pecti ve a nal ysis of t he patie nt data fr o m 
 
s u g geste d greatest be nefit fr o m Ola pari b i n t h ose ( 1 5) patie nts w h ose t u m o urs ha d n ot 
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Edition Number 3
Date 30 August 2019
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progressed on a prior platinum treatment (ORR 33%, DCR 66%, PFS 6.4 mos., OS 13.1 
mos.).
1.2
Research hypothesis
Single agent Olaparib tablet 300 mg bid has superior efficacy and acceptable tolerability 
profile as compared with placebo in patients with deleterious or suspected deleterious 
germline mutation in BRCA1 and/or BRCA2 and metastatic pancreas cancer who have 
achieved disease control (absence of objective progression) after receiving a minimum of 16 
weeks of first line platinum based chemotherapy.  The efficacy in this study will be assessed 
by the primary analysis of PFS defined as the time from randomisation until the date of 
objective radiological disease progression according to modified RECIST1.1 criteria, or death 
(by any cause in the absence of disease progression) regardless of whether the patient 
withdraws from randomised therapy or receives another anti-cancer therapy prior to disease 
progression. To reduce bias, primary analysis of PFS will be based on blinded, independent 
central review of RECIST scans. Secondary endpoints include overall survival, DCR at 16 
weeks, ORR (in patients with baseline evaluable disease), PFS2, safety assessments and 
patient-reported symptoms, functioning and health related quality of life.
1.3
Rationale for study design, doses and control group
Mutations in gBRCA1 and gBRCA2 are a very rare but definable molecular subgroup of 
pancreas cancer which may be found in some identifiable populations with a prevalence as 
high as 15%. Cells that lack gBRCA1/2 function, such as cancer cells from patients with 
germline mutations in these genes, are deficient in their ability to repair double-strand DNA 
breaks through homologous recombination (Roy et al 2012). This deficiency is presumed to 
underlie the observation that gBRCA1/2-deficient cells are sensitive to interventions that 
promote double strand DNA breaks or cross-links, such as ionizing radiation and platinum-
based chemotherapeutic agents. Platinum based regimens are increasingly being used early in 
the treatment of advanced gBRCA-mutated breast and pancreas cancer, in addition to their 
established use in ovarian cancer. It is also presumed to underlie the observation that
gBRCA1/2-deficient cells are sensitive to treatment with inhibitors of poly-(ADP-ribose)-
polymerases (PARP inhibitors) (Bryant et al 2005) which are presumed to force repair of 
single-strand breaks towards the homologous repair pathway rather than the pathways that 
usually address single-strand breaks.  Phase I and proof-of-concept phase II studies have 
shown that PARP inhibitors have significant activity with limited toxicity when used as single 
agents in the treatment of gBRCA1/2 mutation-associated breast and ovarian cancer (Tutt A et 
al 2010; Audeh et al 2010) and pancreas cancer (Kaufman B et al 2013). The present trial is an 
important step in defining the role of Olaparib as a PARP inhibitor in patients with deleterious 
germline BRCA1/2 mutations and metastatic pancreas cancer and the strategy of switch 
maintenance to prolong disease control after beneficial effect of a platinum regimen as has 

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 0( 1 3 3)
bee n s u g geste d f or g B R C A -m ut ate d o varia n ca ncer (Ki m et al 2 0 1 4 , Le der ma n n et al 2 0 1 3 ).  
T he st u d y  will assess t he efficac y of Ola pari b relati ve t o place b o as mai nte na nce t hera p y  aft er 
d oc u m e nt atio n of  disease c o ntr ol (a bse nce of pr o gressi on) o n a n i nit ial plati n u m base d 
re gi me n f or metastatic gB R C A pa ncreas ca ncer. T he preli mi nar y a nal ysis o f 
 s u g gests 
selecti n g patie nts wit h t u m o urs w hic h are n ot k n o w n t o be pl at i n u m resista nt w o ul d i ncrease 
t he li keli h o o d of be nefit. 
 
 
 
  I n t he f ut ure it ma y be p ossi ble t o e xte n d 
t he use of P A R Pi t o patie nts wit h t u mo urs ha vi n g n o n -B R C A deficie ncies i n ds D N A 
re pair. Ola pari b has s h o w n act i vity i n A T M ne gat i ve gastric ca ncer (Ba n g et al  2 0 1 3) a n d 
t here is s u g gest i on of  a si milar s u b-p o p ul at i on i n pa ncreas ca ncer (Ki m et al 
2 0 1 4 ). F urt her m ore, i n de pe n de nt gr o u ps ha ve als o i de ntife d ge n o mic si g nat ures i n pa ncreas 
ca ncer pre dicte d t o be ass ociate d wit h se nsitivit y t o P A R P i n hi bit ors ( Ale xa n dr o v et al 2 0 1 3 ; 
C o wle y  et al 2 0 1 3). I n or der t o f urt her u n dersta n d ca n di date met h o ds f or i de ntif yi n g t hese 
pati e nts i n f ut ure cli nical trials we are as ki n g all patie nts t o d o nate a t u m o ur sa m ple at 
scree ni n g. I n or der t o u n dersta n d t he pre vale nce a n d relati ons hi p of t hes e mar kers t o B R C A
stat us it is i m p orta nt t hat we are a ble t o test sa m ples fr o m pat ient s wit h a n d wit ho ut g B R C A
m utati o ns.
If t he trial is s uccessf ul it will gi ve patie nts a relat i vel y n o n-t o xic oral t hera pe utic w hic h will 
d el a y pr o gressio n after st o p pi n g f irst li ne plati n u m base d c he m ot hera p y.
1. 3. 1
R ati o n ale f or usi n g M yri a d Ge netics
T he F D A has i n dicate d t hat t he g B R C A 1 a n d gB R C A 2 m ut atio n assa y  will nee d t o be 
a p pr o ve d as a c o m pa ni o n dia g n ostic i n t he U S.
M y ria d Ge net ics has bee n c h ose n as a part ner i n de vel o pi n g a c o m pa ni o n dia g n ostic f or 
testi n g beca use it has 
.  M yria d kee ps a c o mpre he nsi ve 
 
.  F urt her mor e, M y ria d has a n esta blis he d la b orat or y  
i nfrastr uct ure, w hic h s u p p orts hi g h v ol ume testi n g wit h t ur nar o u n d ti mes t hat ca n meet t he 
nee ds of a cli nical trial.
1. 4
Be nefit/ris k a n d et hic al assess me nt 
As of 2 Oct o ber 2 0 1 3, a n esti mate d 2 1 0 3 patie nts wit h o varia n, brea st, gastric, pa ncreas, a n d a 
variet y of  ot her s oli d t u m o urs are esti mate d t o ha ve recei ve d treat me nt wit h Ola pari b acr oss 
t he d ose ra n ge 1 0 m g q d t o 6 0 0 m g bi d i n Astra Ze neca -s p o ns ore d, i n vesti gat or-s p o ns ore d, a n d 
c olla b orati ve gr o u p st u dies. Ol a pari b has bee n gi ve n as eit her m o n ot hera p y  ( 1 8 st u dies, a n 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 1( 1 3 3)
esti mate d 1 2 1 4 patie nts) or i n c o m bi nat i on wi t h ot her c he m ot hera p y/a ntica ncer a ge nts 
( 2 5 stu dies, a n est i mate d 8 8 9 patie nts). Ma n y o f t hese c o m bi nati ons st u dies are o n g oi n g. T he 
maj orit y of  p atie nts t o date ha ve recei ve d t he ca ps ule f or m ulati on of Ola pari b (a n esti mate d 
1 6 3 5 pati e nts). A p pr o xi matel y 4 6 8 pat ient s ha ve recei ve d t he ta blet f or m ulati on t o 
date.
 
A n a nal ysis o f m o n ot hera p y  data acr oss 1 2 Astra Ze neca s p o ns ore d m o n ot hera p y st u dies i n 
9 7 5 pati e nts w h o ha ve bee n gi ve n Ola pari b ca ps ule esti mate d t hat 1 6. 1 % ( 1 5 7/ 9 7 5) of patie nts 
ha d bee n e x p ose d t o Ola pari b ca ps ule f or ≥1 2 m o nt hs at t he ti me of d ata base clos ure f or t he 
1 2 st u di es.  F urt her more, 4 1/ 9 7 5 pati e nts recei ve d treat me nt f or > 2 4 m o nt hs (l o n gest d urati o n 
was 4 4 m o nt hs).  Fr o m  t he a vaila ble data t o date, t here is n o e vi de nce of a n y u ne x pecte d 
t o xicit y foll o wi n g l o n g- t er m Ola pari b (ca ps ule) m o n ot hera p y  e x p os ure. 
A d dit i onall y  st atistical a nal ysis of t he p o ole d Q T/ Q Tc data fr o m 2 st u dies i n a t otal of 
1 0 9 pati e nts f or t he pri mar y m ult i ple d ose a nal ysis a n d 1 1 9 pati e nts f or t he s u p p orti ve si n gle 
d ose a nal ysis s h o we d t hat f o ll owi n g m ul tiple d osi n g of ol a pari b ( 3 0 0 m g b d), t he u p per 
c o nfi de nce li mit of t he 2-side d 9 0 % c o nfi de nce i nter val ( CI) ar o u n d t he mea n treat me nt effect 
f or Q T Fridericia C orrecti o n F or m ula ( Q Tc F) was < 1 0 ms at all ti me p o i nts. F urt her m ore, t he 
s u p p orti ve a nal ysis s h o we d t hat foll o wi n g a si n gle d ose of ola pari b, of eit her 1 0 0 m g or 3 0 0 m g 
t he u p per c o nfi de nce li mit of t he 2 -side d 9 0 % CI ar o u n d t he mea n treat me nt effect f or Q Tc F 
was als o < 1 0 ms at all t i me p oi nts.
I n c o ncl usi on, t here was n o i n dicat i on of a cli nicall y rele va nt effect of ola pari b o n car diac 
re p olarisat i on (as deter mi ne d b y  pr olo n gati o n of  Q Tc F) f oll owi n g m ul tiple d osi n g 
( 3 0 0 m g b d) or f oll o wi n g si n gle d osi n g.
As a f urt her s u p p orti n g a nal ysis, c o nce ntrati o n- effect mo delli n g o f t he p o ole d Q T/ Q Tc data 
fr om t he sa me patie nts was c o n d ucte d. Pre dict i ons, fr o m t he c o nce ntrati o n-effect relati o ns hi p 
o btai ne d of t he li kel y ma g nit u de of effect of ola pari b o n Δ Q Tc F, s h o we d t hat at t he ra n ge of 
pl as ma c o nce ntrati o ns ac hie ve d f oll o wi n g t he 3 0 0 m g b d ta blet d ose, ola pari b w o ul d n ot be 
e x pecte d t o ca use pr ol o n gat i on of Q Tc i nter val of a ma g nit u de t hat w o ul d be of cli nical 
c o ncer n or w hic h w o ul d cr oss t he t hres h o l d f or re g ulat or y c o ncer n as descri be d i n I C H E 1 4.
Ol a pari b as mo n ot hera p y  at d oses u p t o 4 0 0 m g bi d ca ps ule is ge nerall y well t olerate d, wit h 
m o st c o m mo n  A Es i ncl u di n g na usea, fati g ue, v omit i n g, a nae mia mai nl y mil d-t o-m o derate 
( C T C A E Gra de ≤ 2) i n se verit y.   I n a d ditio n, i n a s mall n u m ber of pat ient s M D S/ A M L or 
p ne u m o nit is ha ve bee n o bser ve d a n d i de nt ifie d as i m p orta nt ris ks. 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 2( 1 3 3)
1. 4. 1
I m p ort a nt p ote nti al ris ks
1. 4. 1. 1
M yel o d ys pl astic s y n dr o me/ ac ute m yel oi d le u k ae mi a
T here ha ve bee n 1 6 re p orts of m yel o d ys plastic s y n dr o me ( M D S) a n d/ or ac ute m yel o i d 
le u kae mia ( A M L) i n patie nts treate d wit h Ola pari b as of 0 2 Oct 2 0 1 3; 1 1 cases i n Ola pari b 
m o n ot hera p y  trials a n d 5 cases i n Ola pari b c o m bi nati o n st u dies wit h car b o plat i n a n d 
paclita xel ( n = 4) or ce dira ni b ( n = 1).  A t otal of 2 1 0 3 patie nts are esti mate d t o ha ve recei ve d 
Ol a pari b, gi vi n g a c u m ulat i ve i nci de nce of 0. 7 6 % f or M D S/ A M L, si milar t o t he cu m ulat i ve 
i nci de nce re p orte d fr o m c o ntr ol ar ms of Ola pari b ra n d omise d st u dies 0. 7 % 
.  
All 1 6 pat ient s ha d pri mar y o varia n or perit o neal ca ncer a n d 1 2 of t he m were gB R C A 1/ 2
p osi tive ( 3 cases g B R C A stat us u n k n o w n; 1 case ne gati ve).  It has bee n h y p ot hesise d t hat a 
deficie nc y i n t he e x pressi o n o f B R C A ge nes ma y lea ve patie nts m ore v ul nera ble t o t he a d verse 
effects of c he m ot hera p y, a n d t heref ore, at a n i ncrease d ris k of M D S/ A M L as a res ult of ca ncer 
treat me nt ( C o le a n d Strair 2 0 1 0).  M ost patie nts ha d bee n treate d wit h e xte nsi ve pre vi o us 
c he m ot hera p y ra n gi n g fr o m 6 t o 9 5 c y cles o ver perio ds of 3. 5 m o nt hs t o 1 5 y ears, i ncl u di n g 
pl at i n u m a ge nts, t o p ois omerase I I i n hi bit ors, al k ylati n g a ge nts a n d ta xa nes.  T he me dia n ti me 
fr om dia g n osis of ca ncer t o o nset of M D S was 5. 3 yrs (ra n ge 2. 9 -1 2. 7).  T he me dia n t i me 
fr om start of Ola pari b treat me nt t o o nset of M D S was 0. 9 years ( 0. 1 t o 4. 8 years).  T he 
re p orte d e ve nts of M D S/ A M L occ urre d p ost disc o nt i n uati on of Ola pari b treat me nt i n 8 of t he 
1 6 pati e nts f o ll owi n g a m e dia n of 0. 1 years p ost treat me nt disc o nt i n uati on (ra n ge: 0. 1 t o 1 
years).  Half o f t he patie nts ( n = 8) ha d recei ve d Ola pari b f or ≤ 1 2 m o nt hs ( 5 patie nts ha d ≤ 6 
m o nt hs e x p os ure) a n d t he ot her 8 cases occ urre d f oll o wi n g l o n ger t ha n 1 2 m o nt h Ola pari b 
e x p os ure ( 3 patie nts f o ll owi n g 1 2 -1 8 m o nt hs e x p os ure a n d 5 patie nts f oll o wi n g > 2 years 
e x p os ure t o Ola pari b). 
Si nce b o ne marr o w is k n o w n t o be a tar get or ga n f or O la pari b t o xicit y, a ris k of M D S/ A M L 
wi t h lo n g- t er m e x p os ure t o Ola pari b ca n n ot be e xcl u de d, b ut t here is i ns ufficie nt data at 
prese nt t o e val uate t he stre n gt h, if a n y, of t his relati o ns hi p. M ore o ver, w hile n o n -cli nical data 
s u g gest b o ne marr o w pr o ge nit or cell p o p ulati o ns are re d uce d te m p oraril y f o ll owi n g Ola pari b 
treat me nt, t here is n o e vi de nce t o date li n ki n g Ola pari b treat me nt t o t he ge nerati o n o f 
a b n or mal bo ne marr o w prec urs ors.  F urt her m ore, all pat ient s w h o de vel o pe d M D S/ A M L ha d 
e xte nsi ve pri or c he m ot hera p y a n d w hile it is n ot p ossi ble t o e xcl u de t he c o ntri b uti on of 
Ol a pari b, it is als o c o nsi dere d t hat t here were ot her p ote ntial c o ntri b uti n g fact ors i n all cases.  
Precli nical data als o s u g gest p ote n tial be nefit wit h P A R P i n hi bit ors i n M D S/ A M L a n d cli nical 
trials are n o w u n der wa y t o assess t his effect (Ga y mes et al 2 0 0 8 ).
T o e ns ure r o b ust safet y m o nit ori n g, pati e nts i n t his cli nical trial will ha ve wee kl y safet y 
assess me nts d uri n g t he first c ycle a n d t he n safet y assess me nts e ver y 4 wee ks d uri n g t he rest of 
t he treat me nt peri o d. Cli nical g ui deli ne of ma na gi n g b o ne marr o w t o xicit y a n d use of G- C S F 
is i m ple me nte d as t he safet y ma na ge me nt pla n.
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 3( 1 3 3)
1. 4. 1. 2
P ne u m o nitis
As of 2 n d of  Oct 2 0 1 3, 1 0 patie nts o ut of a t otal o f 2 1 0 3 pati e nts esti mate d t o ha ve recei ve d 
Ol a pari b ha ve re p orte d p ne u m o nit is, gi vi n g a c u m ulati ve i nci de nce of 0. 5 % f or p ne u m o nitis.  
P ne u m o nit is was als o re p orte d f or 
 ( 0. 7 %) of  
 t hat recei ve d place b o or 
c o mparat or i n t he Ol a pari b trial pr o gra m me ( 1 patie nt o n place b o i n 
 a n d 1 patie nt o n 
paclita xel i n 
).  T he patie nts were treate d wit h Ola pari b f or breast ca ncer ( n = 2), 
o vari a n ca ncer ( n = 2), n o n-s mall cell l u n g ca ncer ( n = 2), s mall cell l u n g ca ncer ( n = 1), pa ncreas 
ca ncer ( n = 1), gastric ca ncer ( n = 1) a n d t h y mic ca ncer ( n = 1).  Fi ve of t he 1 0 patie nts ha d a 
hist or y  of t o bacc o s mo ki n g.  T he m ajori t y of patie nts ha d recei ve d pri or ra di ot hera p y a n d/ or 
c he m ot hera p y.  T he maj orit y of  patient s ha d rele va nt me dical hist ories i ncl u di n g p ne u m o nit is, 
i nterst itial l u n g fi br osis, d ys p n oea, hae m o pt ysis, c hest i nfect i on, aller gic ast h ma, ple ural 
eff usi o n, a n d ple ural metastases.  
I n vesti gati on of a n y  ne w or w orse ni n g p ul m o nar y s ym pt o ms has bee n i m ple me n te d as a 
safety ma na ge me nt pla n (sect i on 6. 7. 2 ).
1. 4. 1. 3
Ne w Pri m ar y M ali g n a ncies 
O verall, t he n u m ber of re p orts of ne w pri mar y  mali g na ncies is lo w, wi t h 2 1 e ve nts (i n 1 9 
pati e nts) bei n g re p orte d i n 0 2 Oct 2 1 0 3 Ola pari b treate d patie nts ( 0. 9 %) a n d o ne e ve nt 
( bla d der ca ncer) re p orte d i n t he place b o ar m of t he d o u ble-bli n d 
.  I n ra n d o mise d 
c o ntr olle d st u dies, 5 e ve nts of ne w pri mar y mali g na ncies ha ve bee n re p orte d i n f our Ola pari b 
treate d patie nts a n d o ne e ve nt i n a place b o treate d patie nt:
I n t he d o u ble bli n d mai nte na nce 
 t w o e ve nts of ne w pri mar y mali g na ncies ha ve bee n 
re p orte d i n Ola pari b treate d patie nts a n d o ne e ve nt i n a place b o treate d patie nt.  I n t he o pe n 
la bel g B R C A o vari a n mo n ot hera p y  d ose-fi n di n g 
, t hree e ve nts were re p orte d i n t w o 
Ol a pari b treate d patie nts. 
Of  t he 2 1 re p orte d e ve nts i n Ola pari b treate d patie nts, i n te n t he e ve nts were n o n-me la n oma 
s ki n ca ncers.  T here was o ne re p ort of mali g na nt mela n oma.  T he ot her 1 0 e ve nts of ne w 
pri mar y  mali g na ncies were breast ca ncer ( n = 2), breast ca ncer i n sit u, gastric ca ncer, lu n g 
ne o pl as m ( pl us e ve nt of rec urre nce of t he l u n g carci n o ma), plas ma cell m yel o ma, c ol o n 
ca ncer, mali g na nt m uscle ne o plas m (lesi o n prese nt pre -Ola pari b treat me nt) a n d o ne fatal 
e ve nt of T -l y m p h o blastic l y m p h o ma/le u kae mia. 
Of  t he 1 9 Olapari b treate d pati e nts s u bse q ue nt l y dia g n ose d wit h a ne w pri mar y mali g na nc y, 
t he maj orit y were re p orte d w hilst recei vi n g Ola pari b treat me nt ( 1 6 patie nts).  I n 3 patie nts t he 
e ve nt was re p orte d after Ola pari b disc o nt i n uati on 
T he d urati o n of Ola pari b treat me nt  for t he 1 9 pati e nts was:
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 4( 1 3 3)

< 6 m o nt hs f or 3 pati e nts

6 t o 1 2 m o nt hs f or 6 patie nts

1 2 t o 1 8 m o nt hs f or 2 patie nts

1 8 t o 2 4 m o nt hs f or 2 patie nts

> 2 y ears f or 6 patie nts.
T he t y pe of ne w pri mar y  ca ncers re p orte d were ge nerall y in li ne wi t h sec o n dar y ca ncers 
o bser ve d i n o varia n a n d breast ca ncer p o p ulat i ons re p orte d i n t he literat ure (Ber gfel dt et al 
1 9 9 5 , .
Fi t zsi m mo n s D et al 1 9 9 9, F o n g et al 2 0 0 9 , F o w ble et al 2 0 0 1 , Wes o l ows ki  et al 2 0 0 7), or 
were ca ncers s uc h as s ki n ca ncer, k n o w n t o be t he m ost c o m m o n ca ncer i n t he ge neral 
p o p ul at i on a n d ass ociate d wit h hi g h c ure rates .
O varia n ca ncer patie nts ha ve bee n re p orte d t o ha ve a n i ncrease d ris k o f de vel o pi n g sec o n d 
pri mar y  mali g na ncies.  Patie nts wit h g B R C A m ut ati o ns are at ri s k of de vel o pi n g ot her pri mar y 
ca ncers n ota bl y breast ca ncer ( Gi ns b ur g et al 2 0 1 0 ) re p orte d hi g her rates of s ki n ca ncers i n 
pati e nts wit h gB R C A 1 ( 1. 6 %) a n d gB R C A 2 ( 3. 0 %) m utati o ns.
T here were ot her c o ntri b uti n g fact ors/ p ote ntial alter nat i ve e x pla nati ons f or t he de vel o p me nt of 
t he ne w pri mar y mali g na nc y i n all 1 9 Ola pari b treate d patie nts.  All pat ient s ha d pre vi o usl y 
recei ve d vari o us c he m ot hera p y a ge nts i ncl u di n g m ultiple c ycles of D N A da ma gi n g plat i n u m 
c o ntai ni n g c he m ot hera pies, ta xa nes, a nt hrac ycli nes a n d ot her al k ylat i n g a n d D N A da ma gi n g 
a ge nts.  F o ur patie nts were re p orte d t o ha ve ha d pri or ra di ot hera p y . Se ve n of t he 1 9 patie nts 
ha d pre vi o us me dical hist ories o f ca ncer ( o varia n, cer vi x, breast, perit o neal) a n d 3 patie nts 
wi t h s ki n ca ncers ha d eit her ha d pre vi ous basal  cell carci n o ma re p orte d or ha d s ki n lesi ons 
e vi de nt pri or t o st u d y treat me nt) prior t o t he ca ncer u n der i n vest i gati on i n t he Ola pari b 
st u dies.
T here i s i ns ufficie nt e vi de nce f or a n ass ociat i on bet wee n Ola pari b treat me nt a n d t he 
de vel o p me nt of ne w pri mar y  mali g na ncies i n t he cli nical trial pr o gra m me t o date.
1. 4. 2
P ote nti al be nefit
P hase II cli nical st u dies ha ve i n vest i gate d t he effect of Ola pari b either as m o n ot hera p y  or i n 
c o m bi nat i on wi t h ot her c he mot h era p y a ge nts i n ca ncer patie nts.  I n patie nts carr yi n g ger mli ne 
B R C A m ut atio ns, m o n ot hera p y  st u dies i n pat ient s wit h hea vil y pre-treate d breast ca ncer ha ve 
re p orte d a n o bjecti ve res p o nse rate ( O R R) of u p t o 4 1 %.  I n o varia n ca ncer patie nts, t he 
pi v otal  
 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 5( 1 3 3)
 T he pr o gressi o n-free s ur vi val ( P F S) foll o wi n g Ola pari b mai nte na nce t hera p y was 
sig nifica nt l y l on ger c o m pare d wit h t he place b o gr o u p ( H R 0. 3 5; 9 5 % CI: 0. 2 5, 0. 4 9; 
p < 0. 0 0 0 0 1) i n t he o verall p o p ulat i on.  I n t he s u b gr o u p of pat ient s wit h B R C A m ut a nt o varia n 
ca ncer, t he effect was e ve n greater wit h a P F S H R of 0. 1 8 ( 9 5 % CI: 0. 1 1, 0. 3 1; p < 0. 0 0 0 0 1; 
me dia n 1 1. 2 vers us 4. 3 m o nt hs).  A n i nteri m a nal ysis of O S was perf or me d at 5 8 % mat urit y.   
I n t he o verall p o p ulati on, t he a nal ysis de m o nstrate d a n o n -statisticall y si g nifica nt n u meric al 
a d va nta ge f or Ola parib -treate d patie nts ( O S H R 0. 8 8; 9 5 % CI 0. 6 4 -1. 2 1; p = 0. 4 3 8 0 8) a n d 
t here was a gai n a greater effect i n t he g B R C A -m ut ate d s u b gr o u p:  t he O S H R was 0. 7 4 ( 9 5 % 
CI 0. 4 6 t o 1. 1 9; p = 0. 2 0 8 1 3) wit h a n u merical a d va nta ge i n me dia n o verall s ur vi val o bser ve d 
wi t h Ola pari b ( me dia n 3 4. 9 mo nt hs vers us 3 1. 9 m o nt hs wit h place b o).  A m o n g t he 6 2 
pl ace b o -treate d patie nts wit h gB R C A m ut atio ns, 1 4 s wi tc he d t o a P A R P i n hi bit or p ost 
pr o gressi o n. 
 
 
 T here were 1 C R a n d 4 P R’s ( O R R 2 2 %) wit h a 
di sease c o ntr ol rate of 5 7 %, a P F S of 4. 6 m o nt hs a n d a n O S of 9. 8 m os. Patie nts w h o ha d n ot 
pr o gresse d o n a plat i n u m c o ntai ni n g re gi me n were m ost li kel y t o be nefit. T he res ults of 
 
 i n o varia n ca ncer a n d 
 i n pa ncreas ca ncer are t he cli nical basis for t his 
i n vesti gati on.
I n t his ra n d o mise d d o u ble bli n de d st u d y, p atie nts w h o ha ve disease c o ntr ol after a mi ni m u m 
of  1 6 wee ks of plati n u m base d t hera p y  will, o n t he i n vesti gati onal ar m recei ve mo n ot hera p y  
Ol a pari b 3 0 0 m g ta blet bi d ( or c o ntr ol place b o) u nt il disease pr o gressi o n or de vel o p me nt of 
u nacce pta ble t o xicit y. T here i s n o i nte nt t o ca p d urati o n o n Ola pari b f or t hese patie nts.  
Base d o n t he a vaila ble data o n efficac y a n d safet y,  we a ntici pate t hat i n t he metastatic disease 
setti n g, Ola pari b will ha ve a p osit i ve be nefit ris k pr ofile f or t he treat me nt of t he ver y s mall 
well -defi ne d p o p ul at i on of a d va nce d pa ncreas ca ncer patie nts wit h g B R C A m ut atio ns.
1. 5
St u d y Desi g n 
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
36(133)
Figure 1
Study Flow Chart

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 7( 1 3 3)
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 i-ce ntre st u d y t o assess 
t he efficac y of Ola pari b mai nte na nce m o n ot hera p y i n metastatic pa ncreat ic ca ncer patie nts 
wi t h g B R C A m ut atio ns [ d oc u m e nt e d mut ati o n i n g B R C A 1 or g B R C A 2 t hat is pre dicte d t o be 
d el et erio us or s us pecte d deleteri o us ( k n o w n or pre dicte d t o be detri me ntal/lea d t o l oss of 
f u ncti on) a n d w h ose t u m o urs ha ve n ot pr o gresse d o n at least 1 6 wee ks of first li ne plati n u m 
base d c he m ot hera p y .
A p pr o xi matel y  1 4 5 p atie nts will be ra n d o mise d usi n g a n I nteracti ve V oice Res p o nse S yste m / 
I nteracti ve We b Res p o nse S yst e m (I V R/I W R s yste m) i n a 3: 2 rati o ( Ola pari b: place b o) t o t he 
treat me nts as s pecifie d bel o w:

Ol a pari b ta blets p. o. 3 0 0 m g t wice dail y 

Matc hi n g place b o ta blets p. o. t wice dail y 
Eli gi ble pat ient s will be t h ose patie nts wit h pa ncreas ca ncer pre vi o usl y treate d f or metastatic 
di sease g B R C A m ut ate d, w h o ha ve n ot pr o gresse d f o ll owi n g c o m p leti on of at least 1 6 wee ks 
(ca n be m ore) of first li ne plati n u m-base d c he m ot hera p y .  
All patie nts m ust ha ve a k n o w n deleteri o us or s us pecte d deleteri o us ger mli ne B R C A m utati o n 
t o be ra n d omise d; t his ma y ha v e bee n deter mi ne d prior t o e nr ol me nt i nt o t he st u d y  or ma y be 
assesse d as part of t he e nr o l me nt pr oce d ure f or t he st u d y ( via ce ntrall y pr o vi de d M yria d 
I nte grate d B R A CA n alysis test)
P ati e nts must ha ve c o m plete d a mi ni m u m of 1 6 wee ks of first li ne plat i n u m-b ase d t hera p y 
(e g, o xali plati n, car b o plati n or cis plati n) gi ve n c o nti n u o usl y bef ore ra n d o misati on t o t he st u d y  
a n d s h o ul d i n t he o pi ni o n of t he i n vest i gat or ha ve ha d at least disease c o ntr ol. T here m ust be 
a bse nce of pr o gressi o n b y i ma gi n g d o ne wit hi n 4 weeks of ra n d o misat i on. Patie nts w h ose 
pl at i n u m base d t hera p y  was disc o nti n ue d as a res ult of t o xicities s pecificall y relate d t o t heir 
pl at i n u m c o ntai ni n g re gi me n are eli gi ble if t he y recei ve d at least 1 6 wee ks of plati n u m 
t hera p y a n d ha ve c o nti n u o usl y recei ve d t he ot her c he m ot hera p y dr u g(s) i n t heir re gi me n (f or 
e xa m ple F O L FI RI f or F O L FI RI N O X etc.) a n d f ulfil all ot her eli gi bilit y re q uire me nts 
(incl u di n g n o n -pr o gressi o n at t he ti me of e nr ol me nt).  
P ati e nts k n o w n t o ha ve ger mli ne B R C A m ut atio n/s pri or t o ra n d o misat i on ca n e nter t he st u d y  
base d o n t hi s res ult pr o vide d t he y  meet all ot her eli gi bility crit eria.  T he t ype of B R C A 1/ 2
m utati o n m ust be re p orte d i n t he e C R F.  I n a d dit i on t he patie nts m ust c o nse nt t o gi ve 2 bl o o d 
sa m ples, t he pri mar y p ur p ose of t he first sa m ple is f or u n derta ki n g a c o nfir mat or y M yria d 
g B R C A test p ost ra n d o misati on a n d a sec o n d sa m ple is re q uire d f or assess me nt of c urre nt a n d 
f ut ure B R C A m ut atio n assa ys.
 
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Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
3 8( 1 3 3)
P ati e nts wit h u n k n o w n B R C A stat us m ust c o nse nt t o gi ve 2 bl o o d sa m ples f or ger mli ne B R C A
testi n g b y M yria d (a n d all lo c al  et hical pr oce d ures f or s uc h ge netic testi n g).  O ne sa m ple will 
be use d t o test f or B R C A m ut atio ns usi n g t he c urre nt c o m mercial M yria d B R C A a nal ysis test 
pri or t o st u d y  e ntr y ( M yria d I nte grate d B R A C A n alysis ).  T he sec o n d bl o o d sa m ple fr o m all 
teste d patie nts (i ncl u di n g t h ose w h o d o n ot ha ve a B R C A m ut atio n) is re q ui r e d for assess me nt 
of  c urre nt a n d f ut ure B R C A m ut atio n assa ys.  W he n t he res ult fr o m t he M y ria d test i n dicates 
t he patie nt d oes ha ve a deleteri o us or s us pecte d deleteri o us ger mli ne B R C A m ut atio n a n d t he 
pati e nt meets all ot her eli gi bilit y criteria, t he patie nt ca n be ra n d o mise d i nt o t he st u d y. T he 
pati e nts will als o s u b mit t he dia g n ostic pat h olo g y  s peci me ns ( bl oc k or sli des) if a vaila ble. 
 
 
 
T he 2 bl o o d sa m ples f r o m p atie nts wit h bot h  k n o w n a n d u n k n o w n B R C A m ut atio n stat us are 
nee de d i n or der t o e ns ure s ufficie nt i nf or mat i on is c ollecte d i n t he st u d y t o e na ble t he pre-
mar ket a p pr o val of t he M yria d ger mli ne B R C A test as a c o m pa ni o n dia g n ostic f or Ola pari b i n 
t he U S A.  I n a d dit i on resi d ual material ma y  be use d f or t he assess me nt of ot her c urre nt a n d 
f ut ure B R C A m ut atio n dia g n osti c assa ys a n d/ or assa ys t hat pre dict se nsit i vity t o Ola pari b.
P ati e nts will be ra n d o mise d wit hi n 6 wee ks after t heir last d ose of c he m ot hera p y (last d ose is 
t he da y of t h e last i nf usi o n) a n d treat me nt starte d as s o o n as p ossi ble b ut n o less t ha n 4 a n d n o 
m o re t ha n 8 wee ks of t he last c he m ot hera p y d ose. At  t he ti me of starti n g pr ot oc ol treat me nt, 
all pre vi o us c he m ot hera p y tr e at me nt s h o uld be disc o nti n ue d. 
F o ll owi n g ra n d o misat i on, pati e nts will atte n d cli nic visits wee kl y f or t he first 4 wee ks of 
treat me nt ( Da ys 8, 1 5, 2 2 a n d 2 9). Patie nts will t he n atte n d cli nic visits e ver y  4 wee ks w hilst 
o n st u d y  treat me nt. 
P ati e nts s h o uld c o nt i n ue t o recei ve st u d y treat me nt u ntil o bjecti ve ra di ol ogi cal disease 
pr o gressi o n as per R E CI S T as assesse d b y t he i n vesti gat or a n d as l o n g as i n t he i n vest i gat or’s 
o pi ni o n t he y  are be nefiti n g fr om treat me nt a n d t he y d o n ot meet a n y ot her disc o nti n uati on 
criteria as o utli ne d i n Secti on 3. 9 .
O nce a pat ient  has disc o nti n ue d st u d y treat me nt, cli nic visits will be re d uce d t o e ver y 8 wee ks.  
F o ll owi n g di sc o nti n uatio n of  st u d y tr e at me nt, furt her treat me nt will be at t he discret i on of t he 
i n vesti gat or h o we ver it is a ntici pate d ( b ut n ot re q uire d) t hat patie nts will be retreate d wit h 
t heir plat i n u m base d re gi me n.  Details o f a n y f urt her s yste mic a nti-ca ncer treat me nt will be 
c ollecte d u nt il deat h, l oss t o f oll ow- u p or wi t hdra wal  of c o nse nt.  I n a d ditio n t o t hei r re g ular 8 
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Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
39(133)
weekly contact, patients will be contacted in the 7 days following a specified date (data cut off 
date) to capture survival status at that point for each survival analysis.  Assessments will be 
performed as described in Table 1.
Patients will have tumour assessments according to RECIST at baseline and every 8 weeks 
(±1week) up to 40 weeks and then every 12 weeks (±1 week) relative to date of randomisation 
until objective radiological disease progression according to modified RECIST criteria. All 
CT/MRI scans will be sent to an AstraZeneca appointed Clinical Research Organisation 
(CRO) for blinded independent central review. All treatment decisions will be based on site 
assessment of scans. After the final primary progression free survival (PFS) analysis, central 
review of scans will no longer be required and investigators will be advised when to stop 
sending copies of the scans to the CRO conducting the central review.  Ongoing collection of 
site review tumour assessment is required and must be recorded in the electronic case report 
form (eCRF).
RECIST will be modified to assess patients with clinical CR at entry who will be assessed as 
having no evidence of disease (NED) until they have progressed based on the appearance of 
new lesions.
Any patient who discontinues study treatment for reasons other than objective radiological 
progression should continue, to undergo scheduled objective tumour assessments according to 
the study plan (see Table 1) in order to assess objective radiological progression of disease. 
Failure to do so may result in bias to the study results.
Once a patient has progressed the patient will be followed for second progression (PFS2) 
every 8 weeks and then survival until the final analysis.  Patients will be contacted in the week 
following last patient last visit for each analysis of survival. 
The primary analysis of the study will occur when approximately 87 progression events have 
occurred, although an interim analysis for futility will be done when 50% of the planned PFS 
events have occurred (see statistical Section 8).  
The primary analysis will be based on a blinded independent central review (BICR) of disease 
progression by modified RECIST; however, a sensitivity analysis will be performed using the 
investigator-recorded assessment.  All efficacy variables including overall survival will be 
analysed at the time of the primary analysis (providing sufficient events are available to make 
the analyses meaningful).

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
40(133)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:

To determine the efficacy of Olaparib 
maintenance monotherapy compared to 
placebo by progression free survival 
(PFS)

Progression Free Survival (PFS) by BICR 
using modified RECIST 1.1
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :

To determine the efficacy of Olaparib 
maintenance monotherapy compared to 
placebo

Overall Survival (observed and predicted 
using observed PFS and OS data)

Time from randomisation to second 
progression (PFS2)

Time from randomisation to first subsequent 
therapy or death (TFST)

Time from randomisation to second 
subsequent therapy or death (TSST).

Time from randomisation to study treatment 
discontinuation or death (TDT)

Objective Response Rate by BICR using 
modified RECIST 1.1 criteria for evaluable 
patients

Disease Control Rate at 16 weeks by BICR 
using modified RECIST 1.1 criteria

To assess the effect of Olaparib on the 
Health-related Quality of Life 
(HRQoL) as measured by EORTC 
QLQ-C30 global QoL scale.

Adjusted mean change from baseline in 
global QoL score from the EORTC-QLQ-C30 
questionnaire

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
4 1( 1 3 3)
2. 3
S afet y o bjecti ves
S afet y O bjecti ve:
O utc o me Me as ure:

T o assess t he safet y a n d t olera bilit y of 
Ol a pari b mai nte na nce m o n ot hera p y

A d verse e ve nt ( A E), p h y sical e xa mi nati on, 
vit al si g ns i ncl u di n g bl o o d press ure ( B P), 
p ul s e, electr ocar dio gra m  ( E C G) a n d 
la b orat or y fi n di n gs i ncl u di n g cli nical 
c he mistr y a n d hae mat olo g y
2. 4
E x pl or at or y o bjecti ves  
E x pl or at or y O bjecti ve:
O utc o me Me as ure:

 
 
 
 
 
 
 
 

 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
4 2( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he e x pl orat or y  a nal yses ma y n ot be re p orte d i n t he cli nical st u d y re p ort ( C S R).  If n ot, t he y 
will be re p orte d se paratel y .
3.
P A TI E N T S E L E C TI O N, E N R O L M E N T, R A N D O MI S A T I O N, 
R E S T RI C TI O N S, DI S C O N TI N U A TI O N A N D WI T H D R A W A L 
Eac h patie nt s h o ul d meet all o f t he i ncl usi o n cri teria a n d n o ne of t he e xcl usi on cri t eria for t his 
st ud y pri or t o ra n d o misat i on.  U n der n o circ u msta nces ca n t here be e xce pt i ons t o t his r ule.
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
43(133)
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
*Provision of informed consent prior to any study specific procedures 
2.
*Patients must be male or female ≥18 years of age
3.
*Histologically or cytologically confirmed pancreas adenocarcinoma receiving 
initial chemotherapy for metastatic disease and without evidence of disease 
progression on treatment
4.
Patients with measurable disease and/or non-measurable or no evidence of disease 
assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in 
this study. RECIST 1.1 has been modified to allow the assessment of progression 
due to new lesions in patients with no evidence of disease at baseline.
5.
Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or 
suspected deleterious (known or predicted to be detrimental/lead to loss of function) 
(See Section 1.5)
6.
Patients are on treatment with a first line platinum-based (cisplatin, carboplatin or 
oxaliplatin) regimen for metastatic pancreas cancer, have received a minimum of 16 
weeks of continuous platinum treatment and have no evidence of progression based 
on investigator’s opinion.  Patients who have received at least 16 weeks of a 
platinum regimen but had the platinum discontinued for toxicity but continued on 
the remaining drugs of their regimen are also eligible if they have no evidence of 
disease progression within 4 weeks of their last dose of chemotherapy.
7.
Patients who have received platinum as potentially curative treatment for a prior 
cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for pancreas cancer 
are eligible provided at least 12 months have elapsed between the last dose of 
platinum-based treatment and initiation of the platinum-based chemotherapy for 
metastatic pancreas cancer.
8.
Patients must have normal organ and bone marrow function measured within 4 
weeks prior to administration of study treatment as defined below:

Haemoglobin ≥  9.0 g/dL with no blood transfusions (packed red blood cells 
and platelet transfusions) in the past 28 days

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

White blood cells (WBC) >3 x 109/L

No features suggestive of MDS/AML on peripheral blood smear

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
4 4( 1 3 3)

Pl at elet c o u nt ≥ 1 0 0 x 1 0 9/ L

T ot al  bilir u bi n ≤ 1. 5 x i nst ituti o nal  u p per li mit of n or mal 

A S T ( S G O T)/ A L T ( S G P T) ≤ 2. 5 x i nst ituti o nal  u p per li mit of n or mal val ue 
u nless li ver metastases are prese nt i n w hic h case t he y  must be ≤ 5 x U L N

S er u m  creati ni ne ≤ 1. 5 x i nst ituti o nal  u p per li mit of nor m al ( U L N)
9.
1 0.
* P ost m e n o pa usal or e vi de nce of n o n-c hil d beari n g stat us f or w o me n of c hil d beari n g 
p ote nti al: ne gati ve uri ne or ser u m pre g na nc y test. P ost me n o pa usal is defi ne d as:

A me n orr heic f or 1 y ear or mor e f ol l owi n g cessat i on of e x o ge n o us h or m o nal 
treat me nts

L ut ei nizi n g h or m o ne ( L H) a n d F o llicle sti m ulati n g h or m o ne ( F S H) le vels i n 
t he p ost me n o pa usal ra n ge f or w o me n u n der 5 0

Ra diati o n -i n d uce d o o p h orect o m y wit h last me nses > 1 year a g o

C he m ot h era p y-i n d uce d me n o pa use wit h > 1 year i nter val si nce last me nses

S ur gical sterilisati o n ( bilateral o o p h orect o m y  or h ysterect o m y)
1 1.
* Pati e nt is willi n g a n d a ble t o c o m pl y wit h t he pr ot oc ol f or t he d urati o n of t he st u d y  
i ncl u di n g u n der g oi n g treat me nt a n d sc he d ule d visits a n d e xa mi nati ons
1 2.
F or mali n fi xe d, paraffi n e m be d de d ( F F P E) t u m o ur sa m ple fr o m t he pri mar y t u m o ur 
or a m etastatic sit e if a vaila ble or 3 u nstai ne d c yt ol o g y sli des if a vaila ble.
3. 2
E xcl usi o n Criteri a 
P ati e nts s h o uld n ot e nter t he st u d y  if a n y of t he f oll owi n g e xcl usi o n cri t eria are f ulfille d:
1.
*I n v o l ve me nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o Astra Ze neca 
staff a n d/ or staff at t he st u d y sit e).
2.
g B R C A 1 a n d/ or g B R C A 2 m ut atio ns t hat are c o nsi dere d t o be n o n detri me ntal (e g, 
“ Varia nts of u ncertai n cli nical si g nifica nce” or “ Varia nt of u n k n o w n si g nifica nce” 
or “ Varia nt, fa v o ur p ol y m or p his m” or “ be ni g n p ol y m or p his m” etc.).
3.
Pr o gressi o n of t u m o ur bet wee n start of first li ne plati n u m base d c he m ot hera p y f or 
metastati c pa ncreas ca ncer a n d ra n d o misat i on.
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
45(133)
4.
Cytotoxic chemotherapy or non-hormonal targeted therapy within 28 days of Cycle 
1 Day 1 is not permitted. Palliative radiotherapy must have been completed 14 or 
more days before Cycle 1 Day 1. The patient can receive a stable dose of 
bisphosphonates or denosumab for bone metastases, before and during the study as 
long as these were started at least 2 weeks prior to study treatment.
5.
*Previous randomisation in the present study.
6.
Exposure to an investigational product within 30 days or 5 half lives (whichever is 
longer) prior to randomisation
7.
*Any previous treatment with a PARP inhibitor, including Olaparib.
8.
*Patients with second primary cancer, EXCEPTIONS: adequately treated non-
melanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal 
Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid 
tumours including lymphomas (without bone marrow involvement) curatively 
treated with no evidence of disease for ≥ 5 years prior to study entry.
9.
Resting ECG with QTC ≥450 msec detected on 2 or more time points within a 24 
hour period or family history of long QT syndrome. If ECG demonstrates QTC ≥
450 msec, patient will only be eligible if repeat ECG demonstrates QTC ≤450 
msec.
10.
Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, 
itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and 
nelfinavir.  For further detail refer to Appendix H.
11.
Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, 
excluding alopecia and CTCAE grade 3 peripheral neuropathy.
12.
*Patients with myelodysplastic syndrome/acute myeloid leukaemia.
13.
Major surgery within 2 weeks of starting study treatment: patients must have 
recovered from any effects of any major surgery.
14.
*Immunocompromised patients, eg, patients who are known to be serologically 
positive for human immunodeficiency virus (HIV).
15.
*Clinically significant uncontrolled medical conditions are not permitted (eg active 
infection requiring IV antibiotics, symptomatic congestive heart failure, unstable 
angina pectoris, recent (3 months) myocardial infarction, extensive bilateral 
interstitial lung disease, psychiatric illness that would limit ability to comply with 
study procedures, and any other medical condition that, in the opinion of the 
investigator, places the patient at unacceptable risk of toxicity. NB: Diabetes which 
is controlled by medication does not exclude participation in the study

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
46(133)
16.
*Patients with a history of treated CNS metastases are eligible, provided they meet 
all of the following criteria: Disease outside the CNS is present. No evidence of 
interim progression between the completion of CNS-directed therapy and the 
screening radiographic study. No history of intracranial haemorrhage or spinal cord 
haemorrhage. Minimum of 2 weeks between completion of radiotherapy and cycle 
1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with no ongoing 
requirement for ≥ 10mg of prednisone per day or an equivalent dose of other 
corticosteroid.
17.
*Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.
18.
*Pregnant or breast feeding women.
19.
*Previous allogeneic bone marrow transplant.
20.
*Patients with a known hypersensitivity to Olaparib or any of the excipients of the 
product.
21.
*Whole blood transfusions in the last 120 days prior to enrolment to the study 
which may interfere with gBRCA testing (packed red blood cells and platelet 
transfusions are acceptable, for timing refer to inclusion criteria no.8)
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Principal Investigator will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
2.
Assign potential patients a unique enrolment number, beginning with ‘E#’.  (This 
number will be obtained through Interactive Voice/Web Response System 
[IVRS/IWRS]).
3.
Determine patient eligibility. See Sections 3.1 and 3.2
4.
Obtain the randomisation code (patient number) through IVRS/IWRS.
As patients are screened for the study, they must be allocated an enrolment code (E-code). The 
E-code is a 7-digit number made up of the centre number and the patient number within that 
particular centre (eg, the first patient screened at centre number 0001 would be assigned the E-

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
47(133)
code E0001001, the second patient screened would be E0001002 and so on). This number is 
the patient unique identifier and is used to identify the patient on the eCRFs. If a patient 
withdraws from participation in the study, then his/her enrolment/randomisation code cannot 
be reused.
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be randomised or receive study medication.  There can be no exceptions to this 
rule.
Where patients that do not meet the selection criteria are randomised in error or incorrectly 
started on treatment, or where patients subsequently fail to meet the study criteria post 
initiation, a discussion should occur between the AstraZeneca Study Team Physician and the 
investigator regarding whether to continue or discontinue the patient from treatment. Once a 
decision is made, Investigators need to ensure they comply with all applicable requirements 
for human patient protection and ethical review.
The AstraZeneca Study Team Physician is to ensure all such decisions are appropriately 
documented. In situations where an agreement cannot be reached, the patient should have their 
study treatment stopped and be withdrawn from the study
3.5
Methods for assigning treatment groups
Patient eligibility will be established before treatment randomisation. Once the eligibility of a 
patient has been confirmed, the Investigator (or nominated assistant) should contact the 
IVRS/IWRS Centralised Randomisation Centre for allocation of randomised study treatment.
The actual treatment given to individual patients will be determined by a randomisation
scheme that has been loaded into the (IVRS/IWRS) database. The randomisation scheme will 
be produced by a computer software program called GRand (AZ Global Randomisation
system) that incorporates a standard procedure for generating random numbers.
A blocked randomisation will be generated and all centres will use the same list in order to 
minimise any imbalance in the number of patients assigned to each treatment group. 
Patients will be identified to the Centralised Randomisation Centre using patient Ecode and 
month/ year of birth.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
48(133)
Eligible patients will be randomised in a 3:2 ratio (Olaparib:placebo) as specified below:

Olaparib tablets p.o. 300 mg twice daily

Placebo tablets p.o. twice daily 
It is recommended that patients commence study treatment as soon as possible after 
randomisation, and ideally within 3 days.
The IVRS/IWRS Centralised Randomisation Centre will inform the Investigator of the Kit ID 
number to be allocated to the patient at the randomisation visit. The Investigator will call/log 
in to the IVRS/IWRS for each subsequent dispensing visit for assignment of a new Kit ID 
number (s).
The Kit ID number dispensed at each visit will correspond to the treatment to which the 
patient was originally randomised.
3.6
Methods for ensuring blinding
Olaparib and placebo treatment will be blinded.
The study medication will be labelled using a unique Kit ID number, which is linked to the 
randomisation scheme. The active and placebo tablets will be identical and presented in the 
same packaging to ensure blinding of the study medication.
3.7
Methods for unblinding 
3.7.1
Methods for ensuring blinding
Olaparib and placebo treatment will be blinded.
The study medication will be labelled using a unique Kit ID number, which is linked to the 
randomisation scheme. The active and placebo tablets will be identical and presented in the 
same packaging to ensure blinding of the study medication.
If a patient is continuing to derive benefit from olaparib at the end of the study (at DCO3), 
then they may continue to receive treatment as open labelled drug via manual supply outside 
of the study setting once the IVRS/IWRS has been closed. 
3.7.2
Methods for unblinding the study
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) from the IVRS/IWRS. Routines for this will be 
described in the IVRS/IWRS user manual that will be provided to each centre.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
49(133)
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment
given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.
Except for medical reasons, patients, investigators and study monitors in the field will have no 
access to the individual treatment code until final analysis.
3.8
Restrictions
3.8.1
Contraception
Patients of child bearing potential and their partners, who are sexually active, must agree to 
the use of two highly effective forms of contraception, while they are receiving study 
treatment and for 3 months after last dose of study drug.  For details please refer to Appendix 
E Acceptable Birth Control Method.
3.8.2
Olaparib and CYP3A4/5
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods 
known to modulate CYP3A4/5 enzyme activity (see Section 7.7.2) starting 5 days before they 
are randomised until 30 days after the last dose of study medication.
3.9
Discontinuation of investigational product
Patients may discontinue study treatment in the following situations:

Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Objective radiological disease progression

Adverse Event

Severe non-compliance to study protocol 

Death

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
50(133)
3.9.1
Procedures for discontinuation of a patient from investigational product 
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any adverse events.  If possible, they will be seen and assessed by an 
investigator(s).  Adverse events will be followed up (See Sections 6.3 and 6.4); questionnaires
and all study drugs should be returned by the patient.
If a patient is withdrawn from study, see Section 3.10.
Any patient discontinuing study treatment should be seen at 30 days post discontinuation for 
the evaluations outlined in the study schedule.  The patient’s tumour status should be assessed 
clinically and, if appropriate, disease progression should be confirmed by radiological 
assessment.  After discontinuation of study treatment, the principal investigator/sub-
investigator will perform the best possible observation(s), test(s) and evaluation(s) as well as 
give appropriate medication and all possible measures for the safety of the patient.  In 
addition, they will record on the eCRF the date of discontinuation, the reasons, manifestation 
and treatment at the time of discontinuation.  Patients will be required to attend the treatment 
discontinuation visit.  The patient should return all study medication.
After discontinuation of the study treatment at any point in the study, all ongoing AEs or 
SAEs must be followed until resolution unless, in the investigator’s opinion the condition is 
unlikely to resolve due to the patients underlying disease, or the patient is lost to follow up 
(see Sections 6.3 and 6.4).  All new AEs and SAEs occurring during the 30 calendar days after 
the last dose of study medication must be reported (if SAEs, they must be reported to 
AstraZeneca within 24 hours as described in Section 6.4) and followed to resolution as above.  
Patients should be seen at least 30 days after discontinuing study treatment to collect and / or 
complete AE information.  Any untoward event occurring subsequent to the 30-day follow-up 
AE reporting period that the investigator assesses as possibly related to the study treatment 
should also be reported as an AE.
Patients who discontinue treatment prior to disease progression should continue to have 
RECIST assessments as per the study schedule. All patients must be followed for objective 
progression (as per RECIST 1.1) and survival, up to the final analysis.
3.10
Criteria for withdrawal 
Patients are at any time free to withdraw from study (study treatment and assessments), 
without prejudice to further treatment (withdrawal of consent).  Such patients will always be 
asked about the reason(s) and the presence of any adverse events.  If possible, they will be 
seen and assessed by an investigator.  Adverse events will be followed up (See Sections 6.3
and 6.4); questionnaires (eg, for patient reported outcomes) and all study drugs should be 
returned by the patient.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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Withdrawn patients will not be replaced. 
Reasons for withdrawal from the study:

Voluntary withdrawal by the patient who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment*

Incorrectly enrolled patients ie, the patient does not meet the required 
inclusion/exclusion criteria for the study

Patient lost to follow-up

Death
*If a patient decides at any point in the trial that they do not wish to continue with the full 
study schedule of assessments but are still willing to provide important study information (eg 
disease recurrence information and/or survival status information) then the patient should 
continue in the study and information should continue to be collected on the clinical database.  
However if a patient does not wish to have any further data collected, only then should they be 
considered as withdrawing consent from the study.  To minimise the number of cases of early 
withdrawal the investigator should discuss the options with the patient in case they would still 
be willing to undergo reduced assessments and/or reduced data collection, in which case they 
would remain in the study.
*If a patient withdraws consent, they will be specifically asked if they are withdrawing 
consent to:

to further participation in the study including any further follow up (eg, 
survival calls)

withdrawal of consent to the use of their study generated data

withdrawal to the use of any samples (see Section 5.6.5)
Data obtained prior to withdrawal of consent will be maintained in the clinical database and 
used in the study reporting.
The status of ongoing, withdrawn (from the study) and ‘lost to follow up’ patients at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
patients notes, hospital records, contacting the patients general practitioner and checking 
publicly available death registries.  In the event that the patient has actively withdrawn 
consent to collection of further data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study 
withdrawal recorded as ‘Incorrect Enrolment’ (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(not randomised patients).
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study. 
The patient will return electronic PRO (ePRO) devices.  
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn patients will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:

meet individual stopping criteria or are otherwise considered significant 

are assessed as causally related to study drug, 

are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests
4.
STUDY PLAN AND TIMING OF PROCEDURES 
A study initiation visit must be conducted at the centre prior to the commencement of any 
study activities requiring informed consent. A schedule for the tests and evaluations to be 
conducted in this study is contained in this section and in Table 1.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
53(133)
Table 1
Study Schedule – Screening, On Study Treatment, Discontinuation and Follow-up
Screen 
PART 1 
(Patients 
with 
unknown 
BRCA
status only)
Screen 
PART 2 
(All 
patients)
Treatment Duration 
Study 
treatment 
discontinued
30-Day 
follow-
up
Survival Follow-
up v
Cycle/ Visit 
1 (28 days)
2
3+ (every 
28 days)
Until 
DCO2
Between 
DCO2 & 
DCO3
Day
-28 to 0
1
8
15
22
29
57+
Every 
8 
weeks
Every 12 
Weeks
Visit window
±3d
±3d
±3d
±3d
±3d
±7d
±7d
±7d
±7d
Informed consent 
X
X
Randomisation f
X f
Demographics
X
X
Medical and 
surgical history, 
including blood 
transfusions a
X
Prior cancer 
therapies including 
radiotherapy
X
Inclusion/exclusion 
criteria
X (all * 
criteria) b
X

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5 4( 1 3 3)
Scree n 
P A R T 1 
( P atie nts 
wit h 
u n k n o w n 
B R C A
st at us o nl y)
Scree n 
P A R T 2 
( All 
p atie nts)
Tre at me nt D ur ati o n 
St u d y 
tre at me nt 
disc o nti n ue d
3 0- D a y 
f oll o w-
u p
S ur vi v al F oll o w -
u p v
C ycle/ Visit 
1 ( 2 8 d a ys)
2
3 + (e ver y 
2 8 d a ys)
U n til 
D C O 2
Bet wee n 
D C O 2 & 
D C O 3
D a y
-2 8 t o 0
1 
8 
1 5 
2 2 
2 9 
5 7 +
E ver y 
8 
wee ks
E ver y 1 2 
Wee ks
Visit wi n d o w
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d
Bl o o d sa m ples f or 
g B R C A stat us c
X 
X d
Arc hi val paraffi n 
e m be d de d t u m o ur 
tiss ue or c yt ol o g y 
sa mple e
X  
X
C o nc o mita nt 
me dicati o ns 
X  
X  
X  
X  
X  
X  
X  
X
X
 
 
Vital si g ns 
X g
X   g
X  
X  
X
X
P h ysical 
e xa mi nati o n h
X
X  
X  
X
X
E C G i
X
As cli nicall y i n dicate d
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
55(133)
Screen 
PART 1 
(Patients 
with 
unknown 
BRCA
status only)
Screen 
PART 2 
(All 
patients)
Treatment Duration 
Study 
treatment 
discontinued
30-Day 
follow-
up
Survival Follow-
up v
Cycle/ Visit 
1 (28 days)
2
3+ (every 
28 days)
Until 
DCO2
Between 
DCO2 & 
DCO3
Day
-28 to 0
1
8
15
22
29
57+
Every 
8 
weeks
Every 12 
Weeks
Visit window
±3d
±3d
±3d
±3d
±3d
±7d
±7d
±7d
±7d
Tumour assessment 
(modified RECIST 
1.1) j
X (no 
more 
than 28 
days 
before 
start of 
treatment
) j
Every 8 weeks (± 1 week) until week 40 then 
every 12 weeks (±1 week), relative to the 
date of randomisation j
If patient does 
not have 
disease 
progression at 
the time of 
treatment 
discontinuatio
n tumour 
assessments 
should be 
continued per 
the CSP 
schedule k
Haematology/clinic
al chemistry 
X
X l
X
X
X
X
X
X 
X
Coagulation m
X
As clinically indicated
Urinalysis n
X
As clinically indicated
Pregnancy test  o
X
X
X

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5 6( 1 3 3)
Scree n 
P A R T 1 
( P atie nts 
wit h 
u n k n o w n 
B R C A
st at us o nl y)
Scree n 
P A R T 2 
( All 
p atie nts)
Tre at me nt D ur ati o n 
St u d y 
tre at me nt 
disc o nti n ue d
3 0- D a y 
f oll o w-
u p
S ur vi v al F oll o w -
u p v
C ycle/ Visit 
1 ( 2 8 d a ys)
2
3 + (e ver y 
2 8 d a ys)
U n til 
D C O 2
Bet wee n 
D C O 2 & 
D C O 3
D a y
-2 8 t o 0
1 
8 
1 5 
2 2 
2 9 
5 7 +
E ver y 
8 
wee ks
E ver y 1 2 
Wee ks
Visit wi n d o w
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d
Bi o mar ker bl o o d 
sa mple p
X
X ( o nl y at 
pr o gressi o n)
E O R T C Q L Q -C 3 0 
q
X
X  
X  
X
X
 
 
 
A d verse e ve nt r
S A Es 
relate d t o 
st u d y 
pr oce d ures 
o nl y
X  
X  
X  
X  
X  
X  
X  
X
X
St u d y dr u g 
dis pe nsi n g s
X
X
X 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5 7( 1 3 3)
Scree n 
P A R T 1 
( P atie nts 
wit h 
u n k n o w n 
B R C A
st at us o nl y)
Scree n 
P A R T 2 
( All 
p atie nts)
Tre at me nt D ur ati o n 
St u d y 
tre at me nt 
disc o nti n ue d
3 0- D a y 
f oll o w-
u p
S ur vi v al F oll o w -
u p v
C ycle/ Visit 
1 ( 2 8 d a ys)
2
3 + (e ver y 
2 8 d a ys)
U n til 
D C O 2
Bet wee n 
D C O 2 & 
D C O 3
D a y
-2 8 t o 0
1 
8 
1 5 
2 2 
2 9 
5 7 +
E ver y 
8 
wee ks
E ver y 1 2 
Wee ks
Visit wi n d o w
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d
St u d y dr u g ret ur n 
X  
X  
X
X
S u bse q ue nt ca ncer 
treat me nt t
X 
X  
X
Sec o n d pr o gressi o n 
assess me nt u
X
u
S ur vi val stat us v
X
v
X
v
a
I ncl u de hist or y of bl o o d tra nsf usi o n wit hi n pre vi o us 1 2 0 da ys fr o m start of st u d y treat me nt a n d t he reas o ns e g blee di n g or m yel os u p pressi o n.
b
T hese scree ni n g assess me nts d o n ot nee d ca pt uri n g o n t he e C R F, b ut t he y m ust be rec or de d i n t he patie nt’s n otes.
c
Patie nts m ust ha ve a k n o w n deleteri o us or s us pecte d deleteri o us B R C A m uta ti o n t o be ra n d o mise d t o t he st u d y; t his ca n be eit her a l ocal la b res ult or a 
M y ria d test res ult. Patie nts f or w h o m t heir g B R C A stat us is alrea d y k n o w n, s h o ul d be c o nse nte d t o t he st u d y wit hi n 2 8 da ys pri or t o da y 1 of st u d y 
treat me nt.  A n y patie nt w h o c onse nts t o st u d y  relate d M yria d 
, m ust als o ha ve a bl o o d sa m ple ta ke n at t he sa me ti me f or t he 
p ur p ose of de vel o pi n g a n d vali dati n g a 
.
d
Sa m ples t o be ta ke n o n Da y 1 o nl y f or patie nts wit h k n o w n  g B R C A m utati o n w h o ha ve n ot c o m plete d P A R T 1 Scree ni n g. T he scree ni n g g B R C A test 
a n d met h o d perf or me d at site m ust be rec or de d i n t he e C R F.
e
C ollecti o n of a n arc hi val t u m o ur sa m ple is re q ueste d, if a vaila ble, f or all patie nts. T hese sa m ples will be c o llecte d fr o m t he site pat h ol o gist d uri n g t he 
scree ni n g Part 1 f or patie nts wit h u n k n o w n g B R C A stat us a n d scree ni n g Part 2 f or patie nts wit h k n o w n l ocal g B R C A test.
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5 8( 1 3 3)
f
Patie nts will be ra n d o mise d wit hi n 6 wee ks after t heir last d ose of c he m ot hera p y (last d ose is t he da y of t he last i nf usi o n) a n d treat me nt starte d as s o o n 
as p ossi ble b ut n o less t ha n 4 a n d n o m ore t ha n 8 wee ks of t he last c he m ot hera p y d ose. At t he ti me of starti n g pr ot oc ol treat me nt, all pre vi o us 
c he m ot hera p y treat me nt s h o ul d be disc o nti n ue d.
g
Vital si g ns perf or me d o n da y 1 bef ore e ver y c ycle. If vital si g ns assesse d wit hi n 7 da ys bef ore starti n g st u d y treat me nt, it d oes n ot nee d t o be re peate d o n 
Da y  1 of st u d y treat me nt u nless i n vesti gat or belie ves t hat it is li kel y t o ha ve c ha n ge d si g nifica ntl y. 
h
P h y sical e xa mi nati o n s h o ul d be perf or me d acc or di n g t o t he sc he d ule. After t he baseli ne assess me nt it is n ot necessar y t o rec or d t h e details o n t he e C R F, 
a n y cli nicall y si g nifica nt c ha n ges n ot u ne q ui v ocall y relate d t o disease pr o gressi o n, s h o ul d be re p orte d as a d verse e ve nts.
i
E C G assess me nts t o be c o m plete d wit hi n 1 4 da ys bef ore starti n g treat me nt if patie nt is eli gi ble f oll o wi n g c o m pleti o n of all ot her P A R T 2 assess me nts. 
After scree ni n g, E C Gs will o nl y be re q uire d if cli nicall y i n dicate d.
j
B aseli ne R E CI S T assess me nts will be perf or me d usi n g C T sca ns of t he c hest, a b d o me n a n d pel vis ( or M RI w here C T is c o ntrai n dica te d) a n d s h o ul d be 
perf or me d n o m ore t ha n 2 8 da ys bef ore start of st u d y treat me nt a n d as cl ose as p ossi ble t o ra n d o misati o n. A ra n d o misati o n m ust be wit hi n 6 wee ks of 
last c he m ot hera p y. Treat me nt s h o ul d be starte d as s o o n as p ossi ble b ut n o less t ha n 4 wee ks a n d n o m ore t ha n 8 wee ks after t heir last d ose of 
c he m ot hera p y. R E CI S T f oll o w-u p assess me nts will be perf or me d e ver y 8 wee ks ( ± 1 wee k) f or t he first 4 0 wee ks, t he n e ver y 1 2 wee ks ( ± 1 wee k) 
irres pecti ve of treat me nt decisi o ns. F oll o w-u p assess me nt will i ncl u de C T assess me nts of c hest, a b d o me n a n d pel vis ( or M RI w here C T is 
c o ntrai n dicate d) f or all patie nts. A n y ot her sites at w hic h n e w disease is s us pecte d s h o ul d als o be a p pr o priatel y i ma ge d. Patie nts m ust be f oll o we d u ntil 
disease pr o gressi o n assesse d usi n g m o difie d R E CI S T 1. 1 criteria.  If a n u nsc he d ule d assess me nt was perf or me d a n d t he patie nt has n ot pr o gresse d, e ver y 
atte m pt s h oul d be ma de t o perf or m t he s u bse q ue nt assess me nts at t heir sc he d ule d visits. Pri or t o pri mar y a nal ysis f or P F S, all sca ns wil l be s u b mitte d f or 
i n de pe n de nt re vie w. If pr o gressi o n is n ot c o nfir me d at ce ntral re vie w a n a d diti o nal R E CI S T assess me nt will be req ueste d at t he ne xt sc he d ule d visit.
k
F or patie nts w h o disc o nti n ue st u d y treat me nt pri or t o disease pr o gressi o n, R E CI S T assess me nts will c o nti n ue u ntil o bjecti ve d isease pr o gressi o n (e very 
8 wee ks ( ± 1 wee k) f or t he first 4 0 wee ks, t he n e ver y 1 2 wee ks ( ± 1 wee k) relati ve t o date of ra n d o misati o n, u ntil o bjecti ve disease pr o gressi o n as defi ne d 
b y m o difie d R E CI S T 1. 1.).
l
Hae mat ol o g y a n d cli nical c he mistr y s h o ul d be perf or me d at scree ni n g , c ycle 1 da y 1, 8, 1 5, 2 2 a n d da y 1 of e ver y c ycle.  Safet y bl o o d sa m ples d o n ot 
nee d t o be re peate d o n Da y 1 of st u d y treat me nt if assesse d at least 3 wee ks after t he last d ose of c he m ot hera p y b ut wit hi n 7 da y s bef ore starti n g st u d y 
treat me nt, u nless t he i n vesti gat or belie ves t hat it is li kel y t o ha ve c ha n ge d si g nifica ntl y.  
m 
C oa g ulati o n test s ho ul d be perf or me d at scree ni n g a n d if cli nicall y i n dicate d. 
n
Ur i nal ysis s h o ul d be perf or me d at scree ni n g. After scree ni n g, uri nal ysis will o nl y be re q uire d if cli nicall y i n dicate d. 
o
I n t he e ve nt of s us pecte d pre g na nc y d uri n g t he st u d y, t he test s h o ul d be re peate d a n d, if p ositi ve, t he patie nt disc o nti n ue d fr o m st u d y treat me nt 
i m me diatel y.
p
Ma n dat or y bl o o d sa m ples f or bi o mar ker a nal ysis t o be ta ke n pri or t o d osi n g o n C ycle 1 Da y 1 a n d at disease pr o gressi o n.
q
 
r
A d verse e ve nts m ust be ca pt ure d fr o m ti me of c o nse nt. O n l y S A E’s relate d t o bl o o d sa m pli n g f or t he M yria d g B R C A test will be c ollecte d at t his visit.
s
C o nti n u o us Ola pari b 3 0 0 m g/ place b o t wice dail y d osi n g. S ufficie nt st u d y tre at me nt s h o ul d be dis pe nse d f or at least eac h treat me nt peri o d pl us o vera ge, 
h o we ver a d diti o nal treat me nt ca n be dis pe nse d t o patie nts t o last l o n ger i n acc or da nce wit h l ocal practice. 
t
All a nti -ca ncer treat me nts (i ncl u di n g, b ut n ot li mite d t o, c he m ot hera p y a n d tar gete d a ge nts), a n d t he I n vesti gat or’s o pi ni o n of res p o nse t o t he m nee d t o 
be rec or de d u ntil e n d of st u d y peri o d ( D C O 3), pl us t he date of pr o gressi o n p ost disc o nti n uati o n of st u d y treat me nt, nee d t o be rec or de d. 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
5 9( 1 3 3)
u
Sec o n d disease pr o gressi o n ( P F S 2 ) assess me nt will be perf or me d b y t he I n vesti gat or a n d defi ne d acc or di n g t o l ocal sta n dar d cli nical practice a n d ma y 
i n v ol ve a n y of; o bjecti ve ra di ol o gical or s y m pt o matic pr o gressi o n or deat h.  S u bse q ue nt t hera p y will be c ollecte d f or t hese patie nts fr o m the ti me of 
treat me nt disc o nti n uati o n u ntil e n d of st u d y peri o d ( D C O 3).
v
T he stat us of o n g oi n g, wit h dra w n (fr o m t he st u d y) a n d ‘l ost t o f oll o w -u p’ patie nts at t he ti me of a n O S a nal ysis s h o ul d be o btai ne d b y t he site pers o n nel 
b y c hec ki n g t he patie nts n ote s, h os pital rec or ds, c o ntacti n g t he patie nt’s ge neral practiti o ner a n d c hec ki n g p u blicl y a vaila ble deat h re gistries.  I n t he 
e ve nt t hat t he patie nt has acti vel y wit h dra w n c o nse nt t o t he pr ocessi n g of t heir pers o nal data t he vital stat us of t he patie n t ca n be o btai ne d b y site 
pers o n nel fr o m p u blicl y a vaila ble res o urces w here it is p ossi ble t o d o s o u n der a p plica ble l ocal la ws (see Secti o n 3. 1 0 ). I n a d diti o n t o t heir re g ular 8 
wee kl y c o ntact, patie nts will be c o ntacte d i n t he 7 da ys f oll o wi n g a s pecifie d date ( data c ut off date) f or eac h s ur vi val a na l ysis u ntil fi nal f or mal a nal ysis 
of O S ( D C O 1 & D C O 2) . P ost D C O 2 peri o d, patie nts will be c o ntacte d e ver y 1 2 wee ks f or s u r vi val stat us a n d i n t he 7 da ys f oll o wi n g t he s pecifie d date 
of D C O 3 f or 
.
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
6 0( 1 3 3)
4. 1
E nr ol me nt/scree ni n g peri o d
Pr oce d ures will be perf or me d acc or di n g t o t he St u d y  Pla n. 
At  scree ni n g, c o nse nti n g patie nts are assesse d t o e ns ure t hat t he y meet eligi bili t y crit eria. 
P ati e nts w h o d o n ot meet t hese criteria m ust n ot be e nr olle d i n t he st u d y .
T he f o ll owi n g assess me nts a n d pr oce d ures s h o ul d be perf or me d d uri n g scree ni n g Part 1 a n d 
Part 2 as per Ta ble 1 .
F or details o f t he sc he d ule a n d nat ure of assess me nts see bel o w:

M o nt h/ y ear of birt h, se x, race a n d et h nicit y 

Me dical a n d s ur gical hist or y  incl u di n g pre vi o us ca ncer a n d ra di ot hera p y  a n d hist or y 
of  blo o d tra nsf usi o n s i n pre vi o us 1 2 0 da ys 

Pre vi o us c he m ot hera p y

If patient  recei ve d a pri or plati n u m dr u g, i n w hat setti n g (a dj u va nt or a d va nce d) 
a n d reas o n f or disc o nt i n uati on ( pr o gressi o n o n t hera p y , disc o nti n uatio n of  
t hera p y for reas o n ot her t ha n pr o gressi o n, c o m plet i o n of pla n ne d pr o gra m 
wi t ho ut pr o gressi o n,)

C urre nt a n d c o nc o mita nt me dicat i ons i ncl u di n g pre vi o us ca ncer t hera pies 


Vi t al si g ns ( bl o o d press ure a n d p ulse; b o d y t e mperat ure), b o d y  w eig ht, hei g ht

Hae m at olo g y  / Cli nical c he mistr y/ Uri nal ysis 

C oa g ulati o n test

acti vate d partial t hr o m b o blast i n ti me { A P T T } will be perf or me d at baseli ne a n d 
if cli nicall y i n dicate d

i nter nat i onal n or m alise d ratio {I N R } will be perf or me d at baseli ne a n d if 
cli nicall y i n dicate d u nless t he patie nt is recei vi n g warfari n. Patie nts ta ki n g 
warfari n ma y  p artici pate i n t his st u d y; h o we ver, it is rec om me n de d t hat 
pr ot hr o m bi n t i me (I N Ra n d A P T T) be m o nit ore d caref ull y at least o nce per 
wee k f or t he first m o nt h, t he n m o nt hl y if t he I N R is stable

P h ysical e xa mi nat i on
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
6 1( 1 3 3)

C T ( or M RI if C T is c o ntrai n dicate d) of c hest, a b d o me n a n d pel vis

E C G ( wi t hi n 1 4 da ys pri or t o t he start of t he st u d y  tr e at me nt)

Me n o pa usal stat us; ser u m or uri ne pre g na nc y test f or w o me n of c hil d beari n g 
p ote nti al.  T he pre g na nc y test s h o uld be pri or t o perf or mi n g t he g B R C A bl o o d test 
d uri n g scree ni n g part 1, wit hi n 2 8 da ys pri or t o t he start of st u d y  treat me nt a n d 
c o nfir me d o n da y 1 prior t o d osi n g

F or pati e nts wit h u n k n o w n g B R C A stat us: g B R C A 1/ 2 m ut atio n stat us. 2 bl o o d 
sa m ples: One bl o o d sa m ple t o test f or g B R C A m ut atio ns usi n g t he c urre nt 
c o m mercial M yria d B R A C A n alysis test, a n d t he sec o n d bl o o d sa m ple f or a bri d gi n g 
st u d y t o vali date t he c o mpa ni o n  dia g n ostic test f or Ola pari b a n d/ or assess me nt of 
c urre nt or f ut ure B R C A m ut at i on assa ys

P ati e nt Re p orte d Q ualit y of life q uest i on naire: E O R T C Q L Q -C 3 0 a n d 
 
s h o uld b e c o m plete d pri or t o ra n d o misati o n o nce eli gi bilit y is c o nfir me d

A d verse e ve nts m ust be ca pt ure d fr o m t i me of c o nse nt.  O nl y S A E’s rel ate d t o 
bl o o d s a m pli n g f or t he M yri a d g B R C A test will be c ollecte d at t his visit. I n 
Scree ni n g P art 2 all A Es/ S A Es will be c ollecte d

Arc hi val paraffi n e m be d de d t u m o ur tiss ue sa m ple or c yt ol o g y  sa m ple re q ueste d, if 
a vaila ble
T he Pri nci pal I n vest i gat or/ S u b-I n vesti gat or s h o ul d a d here t o t he st u d y pla n, pr oce d ures a n d 
perf or m  tests/ o bser vati ons i n acc or da nce wit h t he pr ot oc ol.
4. 2
Tre at me nt peri o d
T he visit sc he d ule is base d o n 2 8 -d a y  c ycles. 
P ati e nts will atte n d t he cli nic wee kl y o n da ys 1 ( 1st da y of treat me nt), 8, 1 5, 2 2, 2 9 f oll o wi n g 
t he c o m me nce me nt of st u d y treat me nt a n d t he n e ver y 4 wee ks ( da y 1 of e ver y c ycle) u ntil 
di sc o nti n uati on of treat m e nt. T he f oll o wi n g assess me nts will be perf or me d at ti me p oi nts 
s pecifie d i n t he st u d y sc he d ule (see Ta ble 1 ):

Vi t al si g ns: Da y 1 of e ver y c ycle. B o d y wei g ht is o nl y re q uire d at da y 1 of 1st da y 
of  st u d y tr e at me nt, if it has n ot bee n assesse d wit hi n 7 da ys of ra n d o misati o n.  A n y 
ot her ti me as cli nicall y  in dicate d

 
 
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
6 2( 1 3 3)

Hae mat ol o g y  a n d cli nical c he mistr y: c ycle 1 da y 1, 8, 1 5, 2 2 a n d da y 1 of e ver y
c ycle. Safet y bl o o d sa m ples d o n ot nee d t o be re peate d o n Da y  1 of st u d y treat me nt 
if t here ha ve bee n se parate assess me nts wit hi n 7 da ys bef ore starti n g st u d y 
treat me nt a n d w hic h m ust ha ve bee n 3 wee ks after last d ose of c he m ot hera p y  base d 
t hera p y, u nless t he i n vest i gat or belie ves t hat it is li kel y t o ha ve c ha n ge d 
sig nifica nt l y.

P h ysical e xa mi nat i on: Da y  1 before e ver y  c ycle b ut assess me nts p ost Da y 1 are n ot 
re q uire d t o be ca pt ure d o n a n e C R F, h o we ver a n y si g nifica nt c ha n ges fr o m baseli ne 
m ust be re p orte d as a n A E.

C T of c hest, a b d o me n a n d pel vis ( or M RI if C T is c o ntrai n dicate d) perf or me d u nt il 
o bj ect i ve disease pr o gressi o n. R E CI S T assess me nts t o be sc he d ule d e ver y 8 wee ks 
( ± 1 wee k) fr o m ra n d omisat i on f or t he first 4 0 wee ks a n d t he n e ver y 1 2 wee ks ( ± 1 
wee k). If pr o gressi o n is n ot c o nfir me d b y  BI C R a n a d ditio n al  sca n will be re q ueste d 
at t he ne xt sc he d ule d visit. C T/ M RI of c hest, a b d o me n a n d pel vis t o be perf or me d 
u nt il o bjecti ve disease pr o gressi o n. 

E C G at baseli ne a n d a n y ti me if cli nicall y i n dicate d 

Ur i nal ysis at baseli ne a n d a n y ti me if cli nicall y i n dicate d

S er u m  or uri ne pre g na nc y t est for w o m e n of c hil d beari n g p ote ntial ( pri or t o 
treat me nt o n da y 1 of 1st da y of st u d y treat me nt).  If t he test is p osit i ve t he n a 
c o nfir mat or y test s h o uld be perf or m e d

F or pati e nts wit h k n o w n g B R C A stat us: g B R C A 1/ 2 m ut atio n stat us. 2 bl o o d 
sa m ples: O ne bl o o d sa m ple t o test f or gB R C A m ut atio ns usi n g t he c urre nt 
c o m mercial M yria d B R A C A n alysis test, a n d t he sec o n d bl o o d sa m ple f or a bri d gi n g 
st u d y t o vali date t he c o mpa ni o n  di a g n ostic test f or Ola pari b a n d/ or assess me nt of 
c urre nt or f ut ure B R C A m ut at i on assa ys

A E a n d c o nc o mit a nt me dicat i ons (i ncl u di n g a n y bl o o d tra nsf usi o ns) at e ver y  visit

P ati e nt Re p orte d Q ualit y of life q uest i on naire: E O R T C Q L Q -C 3 0 at baseli ne ( pri or 
t o ran d o misati o n o nce eli gi bilit y is c o nfir me d), e ver y 4 wee ks u ntil o bjecti ve 
r a diol o gical  disease pr o gressio n, at di sc o nti n uati on of st u d y  treat me nt visit a n d t he n 
3 0 da y s p ost last d ose.  

 
 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
6 3( 1 3 3)

 
 
 
 
 
 
 
O nce pat ient s ha ve disc o nti n ue d st u d y treat me nt, ot her treat me nt o pti o ns will be at t he 
di scretio n of  t he i n vesti gat or.
4. 3
F oll o w -u p peri o d
4. 3. 1
Tre at m e nt disc o nti n u ati o n visit d ue t o o bjecti ve r a di ol o gic al dise ase 
pr o gressi o n
P ati e nts s h o uld be disc o nt i n ue d fr o m st u d y treat me nt if t he y ha ve o bjecti ve ra di ol ogi c al 
di sease pr o gressio n acc or di n g t o m o difie d R E CI S T 1. 1 criteria (see A p pe n di x F ). 
F o ll owi n g ra di ol o gi cal disease pr o gressi o n pat ient s will be f oll ow e d f or P F S 2 a n d O S.
4. 3. 2
Tre at m e nt disc o nti n u ati o n visit d ue t o a n y ot her disc o nti n u ati o n criteri a

P ati e nts s h o uld be disc o nt i n ue d fr o m st u d y treat me nt if a n y disc o nti n uati on cri teria 
are f ulfille d (see Secti o n 3. 9 ).  T he assess me nts t o be carrie d o ut at t he visit are 
detaile d i n t he st u d y  sc he d ule (Ta ble 1 ).
P ati e nts w h o ha ve disc o nt i n ue d fr o m treat me nt b ut d o n ot ha ve ra di ol ogi cal disease 
pr o gressi o n will c o nt i n ue t o be f oll owe d f or P F S b y  mo difie d R E CI S T 1. 1 assess me nts e ver y  
8 wee ks ( +/ -1 wee k) fr o m date of ra n d o misat i on d uri n g t he first 4 0 wee ks a n d t he n e ver y 1 2 
wee ks ( +/ -1 wee k) t hereafter. 
4. 3. 3
P atie nts w h o h a ve o bjecti ve r a di ol o gic al dise ase pr o gressi o n b ut 
c o nti n ue o n st u d y tre at me nt
P ati e nts s h o uld be disc o nt i n ue d fr o m st u d y treat me nt if t he y ha ve o bjecti ve ra di ol ogi c al 
di sease pr o gressio n acc or di n g t o R E CI S T (see A p pe n di x F), h o we ver, patie nts ma y be 
all o we d t o c o nti n ue st u d y treat me nt if t he i n vest i gat or belie ves, a n d A Z St u d y P h ysicia n 
c o nc urs, t hat t he patie nt c o ul d c o nt i n ue t o recei ve be nefit, t he patie nt is n ot e x perie nci n g 
serio us t o xicit y,  a n d t here is n o a vaila ble better alter nati ve treat me nt t hat c o ul d be nefit t he 
patie nt. T hese patie nts will c o nt i n ue st u d y pr oce d ures as per Ta ble 1 a n d will be f oll owe d f or 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
6 4( 1 3 3)
O S. Safet y assess me nt ca n occ ur wit h t he sa me fre q ue nc y as t he visits u nless m ore fre q ue nt 
testi n g is cli nicall y in dicate d.
4. 3. 4
F oll o w- u p 3 0 d a y after l ast d ose of st u d y tre at m e nt (f oll o w-u p visit)
A f oll ow- u p visit s h o ul d be c o n d ucte d 3 0 da y s after t he last d ose of st u d y tr e at me nt.  A n y 
serio us a n d/ or n o n -serio us A Es o n g oi n g at t he ti me of t he Disc o nt i n uati on Visit or w hic h ha ve 
occ urre d d uri n g t he defi ne d 3 0 -d a y  fol l ow- u p peri o d m ust be f oll o we d -u p (i n acc or da nce wit h 
Secti o n 6. 3 ).  A p pr o priate safet y e val uati ons s h o ul d be re peate d a n d/ or a d dit i onal tests 
perf or m e d at a n y time w he n cli nicall y i n dicate d, or at t he discreti o n o f t he i n vesti gat or, u ntil 
res olut i on, u nless, i n t he i n vest i gat or’s o pi ni on, t he c o n diti o n is u nli kel y  t o res ol ve d ue t o t he 
pati e nt’s u n derl yi n g disease.  If t he patie nt is l ost t o f o ll ow- u p, t he n t hi s s h o uld be n ote d i n t he 
e C R F.  T he assess me nts t o be carrie d o ut at t he 3 0 da y  fol l ow u p visit are detaile d i n t he st u d y  
sc he d ule (Ta ble 1 ).
4. 3. 5
S ur vi v al
S ur vi val data s h o ul d be c ollecte d, e ver y  8 wee ks u ntil fi nal f or mal s ur vi val a nal ysis ( D C O 2) 
a n d e ver y 1 2 wee ks u ntil t he 
( D C O 3), fol l owi n g 
o bj ect i ve ra di ol ogi c al disease pr o gressio n.  S ur vi val  inf or mat i on ma y be o btai ne d via 
t ele p h o ne c o ntact wit h t he patie nt, patie nt’s fa mil y or b y c o ntact wit h t he patie nt’s c u rre nt 
p h ysicia n. I n a d dit i on, pati e nts s h o uld be c o ntacte d i n t he wee k f oll o wi n g t he data c ut -off f or 
t he pri mar y P F S ( D C O 1), fi nal for m al s ur vi val a nal yses ( D C O 2, at 1 0 6 O S e ve nts) a n d at t he 
 
t o pr o vid e c o m plete s ur vi val data.
P ati e nts will be fol l owe d u p as per Ta ble 1 t o t he p oi nt of
 
  At t his p oi nt i n vesti gat ors will 
be n otifie d t hat n o f urt her data c ollect i on f or t he st u d y is re q uire d.  M o nit ori n g a n d rec or di n g 
of  S A Es will c o nti n ue as per Secti o n 6. 4 .
T he stat us of patie nts at t he ti me of a n o verall s ur vi val a nal ysis s h o ul d be o btai ne d b y t he site 
pers o n nel b y  c hec ki n g t he patie nt’s n otes, h os pital rec or ds, c o ntacti n g t he patie nts ge neral 
pra ctitio ner a n d c hec ki n g p u blicl y a vaila ble deat h re gistries. I n t he e ve nt t hat t he patie nt has 
acti vel y wit h dra w n c o nse nt t o t he pr ocessi n g of t heir pers o nal data t he vital stat us of t he 
pati e nt ca n be o btai ne d b y site pers o n nel fr o m p u blicl y a vaila ble res o urces w here it is p ossi ble 
t o d o s o u n der a p plica ble l ocal la ws (see Secti on 3. 1 0 ).
4. 3. 6
Sec o n d Pr o gressi o n
F o ll owi n g o bj ect i ve pr o gressi o n, c o pies of t he patie nt’s r a diol o gi c al sca ns are n o lo n ger 
re q uire d t o be se nt f or bli n de d i n de pe n de nt ce ntral re vie w. Patie nts will be assesse d e ver y 8 
wee ks f or a sec o n d pr o gressi o n ( usi n g t he patie nts’ stat us at first pr o gressi o n as t he refere nce 
C CI
C CI
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
65(133)
for assessment of second progression). A patient’s progression status is defined according to 
local standard clinical practice and may involve any of; objective radiological or symptomatic 
progression or death. RECIST measurements will not be collected for assessment of PFS2. 
The date of PFS2 assessment and investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in the eCRF.
4.3.7
Subsequent Treatment
Following objective progression on study as per modified RECIST 1.1, copies of the patient’s 
radiological scans are no longer required to be sent for blinded independent central review, 
provided that the central read confirms progression. If progression is not confirmed, one 
additional scan will be required at the next scheduled visit. Following objective progression 
patients will be assessed every 8 weeks for survival (see Section 4.3.5) but also for nature of 
subsequent treatment, response to subsequent treatment and investigator assessment of time to 
progression on the subsequent treatment. While other than the PFS2, response and time to 
progression on later therapies is not a specific endpoint of the trial, the information garnered 
will help determine if there is an optimal sequencing of treatments for gBRCA-associated 
pancreas cancer and for planning of future clinical studies.
The data cut-off date for the final statistical analysis for the primary objective of the study will 
be established when approximately 87 confirmed progression events are expected to have 
occurred.
Patients on study treatment at the time of the data cut-off will continue to receive study 
treatment until they meet any discontinuation criteria as per Section 3.9. 
Patients on study treatment will be followed for core safety assessments (haematology, 
clinical chemistry, AEs/SAEs, concomitant medications and study treatment dosing details)
Once the primary PFS analysis has been performed the collection of RECIST data for 
independent central review will cease. Patients who have not had an objective disease 
progression at the time of the data cut off for the primary analysis should continue to have 
RECIST assessments until first objective disease progression is determined by the 
investigator. RECIST assessments should be performed every 12 weeks (± 1week) from the 
last assessment prior to the data cut off date.  Patients will also be followed for information on 
vital status to obtain the data needed for the OS analysis and information on subsequent 
treatment.  
4.4
Patient management post final analysis
The data cut-off date (DCO3) for the final statistical analysis of the study will be established 
12 months after the time when ~106 confirmed OS events (~75 % maturity for OS analysis) 
are expected to have occurred.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
66(133)
At this time point, the clinical study database will close to new data.  Patients who are 
receiving treatment can either choose to discontinue from the study or where the investigator 
believes patients are gaining clinical benefit; patients may continue to receive study treatment.  
All patients will receive follow up care in accordance with standard local clinical practice.
AstraZeneca will continue to supply Olaparib after completion of this study until either 
Olaparib is licensed in that country, or it is determined that the benefit to risk profile does not 
support continued development of Olaparib, or the national health authority has deemed the 
drug not approvable.  In all these scenarios, AstraZeneca will work with investigators on the 
proper transition of patients to alternative therapies if possible.
SAEs will continue to be reported to AstraZeneca Patient Safety Department, for any patients 
who continue on Olaparib until 30 days after study treatment is discontinued, in accordance 
with Section 6.4.  Additionally as stated any SAE or non-serious adverse event, that is 
ongoing at the end of the study, must be followed up to resolution unless the event is 
considered by the investigator to be unlikely to resolve, or the patient is lost to follow-up.  If 
an investigator learns of any SAEs, including death, at any time after a patient has completed 
the study, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety.
Drug accountability should continue to be performed until the patient stops study treatment 
completely
5.
STUDY ASSESSMENTS  
The Rave Web Based Data Capture (WBDC) system will be used for data collection and
query handling. The investigator will ensure that data are recorded on the electronic Case
Report Forms as specified in the study protocol and in accordance with the instructions
provided.
The investigator ensures the accuracy, completeness and timeliness of the data recorded and
of the provision of answers to data queries according to the Clinical Study Agreement. The
investigator will sign the completed electronic Case Report Forms. A copy of the completed
electronic Case Report Forms will be archived at the study site.
5.1
Efficacy assessments
5.1.1
CT and MRI scans Tumour assessments (Modified RECIST 1.1)
Following the baseline assessment, subsequent tumour assessments according to modified 
RECIST 1.1 should be performed every 8 weeks (±1 week) for the first 40 weeks and then 
every 12 weeks (± 1 week) thereafter, relative to the date of randomisation, up to objective 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
67(133)
disease progression by RECIST. Patients who are determined to have progressed according to 
modified RECIST 1.1 criteria by the Investigator will have scans centrally reviewed for 
confirmation of objective disease progression. If disease progression is not confirmed at 
central review an additional RECIST assessment will be requested preferably at the next 
scheduled RECIST visit (8 weeks from last scan).  
For those patients with no evidence of disease at baseline, following a clinical complete 
response to chemotherapy, progression is defined by the detection of new lesions on follow up 
radiological assessments (modified RECIST 1.1).
The imaging modalities used for RECIST assessment will be CT (MRI where CT is 
contraindicated) scans of the chest, abdomen and pelvis with other regions as clinically 
indicated for the assessment of disease.  Any other sites at which new disease is suspected 
should also be appropriately imaged.  The methods of assessment of tumour burden used at 
baseline must be used at each subsequent follow-up assessment.
Radiological examinations performed in the conduct of this study should be retained at site as 
source data.
Any missed copies of the scans are to be sent to an AstraZeneca appointed CRO for blinded 
independent central review.
All treatment decisions will be based on site assessment of scans.  After the primary PFS 
analysis, central review of scans will no longer be required and investigators will be advised 
when to stop sending copies of the scans to the CRO conducting the central review.  
It is important to follow the assessment schedule as closely as possible. If scans are performed 
outside of scheduled visit ± 1 week window interval and the patient has not progressed, every 
attempt should be made to perform the subsequent scans at their scheduled time points.  
Patients will be evaluated until objective radiological disease progression by modified 
RECIST 1.1 as per the study schedule (see Table 1), and then followed for second progression 
and survival, regardless of whether study treatment is discontinued or delayed and/or protocol 
violations, unless they withdraw consent.
5.1.2
Tumour Evaluation
Modified RECIST 1.1 criteria will be used to assess patient response to treatment by 
determining progression free survival (PFS) times.  (The modified RECIST 1.1 guidelines for 
measurable, non-measurable, target and non-target lesions and the objective tumour response 
criteria (complete response, partial response, stable disease, no evidence of disease or 
progression of disease) are presented in Appendix F.) 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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The methods of assessment of tumour burden used at baseline - CT or MRI scans of chest, 
abdomen and pelvis, with other regions as clinically indicated for the assessment of disease 
must be used at each subsequent follow-up assessment, see Section 4.3. 
Following the baseline assessment, efficacy for all patients will be assessed by objective 
tumour assessments every 8 weeks (±1 week) up to 40 weeks then every 12 weeks (±1 week) 
relative to date of randomisation, according to the planned study schedule Table 1 until 
objective radiological disease progression as defined by modified RECIST. If a patient 
discontinues treatment (and/or receives a subsequent cancer therapy) prior to progression then 
the patient should still continue to be followed until objective radiological disease progression 
as defined by modified RECIST 1.1.
Categorization of objective tumour response assessment will be based on the modified 
RECIST criteria of response: complete response (CR), partial response (PR), stable disease 
(SD), progression of disease (PD), no evidence of disease (NED) and not evaluable (NE).  
Target lesion (TL) progression will be calculated in comparison to when the tumour burden 
was at a minimum (ie, smallest sum of diameters previously recorded on study).  In the 
absence of a best response of progression, tumour response (CR, PR, SD) will be calculated in 
comparison to the baseline tumour measurements obtained before randomisation.
For patients with non-measurable disease only at baseline, categorization of objective tumour 
response assessment will be based on the RECIST criteria of response: CR (complete 
response), PD (progression of disease) and Non CR/Non PD. Patients with no disease at 
baseline will be assessed according to modified RECIST 1.1 criteria for new lesions with 
responses of No Evidence of Disease (NED) or progression of disease.
If the investigator is in doubt as to whether disease progression has occurred on study therapy, 
particularly with response to NTL (non-target lesion) or the appearance of a new lesion, it is 
advisable to continue treatment until the next scheduled assessment or sooner if clinically 
indicated and reassess the patient’s status.  If repeat scans confirm disease progression, then 
the date of the initial scan should be declared as the date of disease progression. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.
Following progression, patients should continue to be followed up for survival every 8 weeks 
as outlined in the study plan. It is important to follow the assessment schedule as closely as 
possible. Please refer to the study plan in Section 1.5 and CT/MRI scans in section 5.1.1

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
69(133)
5.1.3
Central reading of scans
An independent review of all scans used in the assessment of tumours according to modified 
RECIST will be conducted for data collected up to the data cut off for the primary analysis of 
PFS.  All imaging assessments including unscheduled visit scans will be collected on an 
ongoing basis and sent to an AstraZeneca appointed Contract Research Organisation (CRO) 
for central analysis. Results of this independent review will not be communicated to 
investigators (with the exception of confirmation of progression assessments), and the 
management of patients will be based solely upon the results of the RECIST assessment 
conducted by the investigator.
The primary analysis for this study will be based on the blinded independent central review 
(BICR) of the radiological scans.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the Study Schedule (see Table 1).
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.
The following laboratory variables will be measured:
Table 2
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin 
S-Sodium
B-Red blood cells [RBC]
S-Potassium
B-Platelets
S-Magnesium (baseline only and if clinically 
indicated)
B-Mean cell volume [MCV]
S-Calcium 
B-Mean cell haemoglobin concentration [MCHC] 
S-Creatinine
B-Mean cell haemoglobin [MCH]
S-Total bilirubin
B-White blood cells [WBC] 
S-Gamma glutamyltransferase [GGT] 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
70(133)
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Absolute differential white cell count

(neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) and absolute 
neutrophil count or segmented neutrophil 
count and Band forms should be 
performed at each visit and when clinically
indicated. If absolute differentials not 
available please provide % differentials.
S-Aalkaline phosphatase [ALP]
S-Aspartate transaminase [AST]
S- alanine transaminase [ALT]
S-Urea or blood urea nitrogen [BUN]
S-Total protein
S-Albumin
S-Lactate dehydrogenase (LDH)
Urine Tests
Urinalysis (Dipstick, baseline only and if clinically 
indicated)
U-Hb/Erythrocytes/Blood
U-Protein/Albumin
U-Glucose
Urinalysis (Microscopic analysis, baseline only 
and if clinically indicated)
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 5.2.
NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
For blood volume see Section 5.6.1.
5.2.2
Physical examination
For timing of individual measurement refer to study schedule (Table 1).
A physical examination will be performed and include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities) and neurological systems.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 1( 1 3 3)
 
 
 
 
 
 
5. 2. 4
E C G
5. 2. 4. 1
Resti n g 1 2 -le a d E C G
E C Gs are re q uire d d uri n g scree ni n g wit hi n 1 4 da ys pri or t o starti n g st u d y  treat me nt a n d w he n 
cli nicall y i n dicate d after war d s. 
T wel ve -lea d E C Gs will be o btai ne d after t he patie nt has bee n reste d i n a s u pi ne p ositi o n f or at 
least 5 mi n utes i n eac h case.  T he i n vesti gat or or desi g nate d p h ysicia n will re vie w t he pa per 
c o pies of eac h of t he ti me d 1 2-lea d E C Gs o n eac h of t he st u d y da ys w he n t he y  are c ollecte d. 
E C Gs will be rec or de d at 2 5 m m/sec.  All E C Gs s h o ul d be assesse d b y t he i n vesti gat or as t o 
w het her t he y  are cli nicall y sig nifica nt l y a b n or mal / n ot cli nicall y si g nifica ntl y a b n or mal.  If 
t here is a cli nicall y si g nifica nt a b n or mal fi n di n g, t he i n vest i gat or will rec or d it as a n A E o n t he 
e C R F.  T he ori gi nal E C G traces m ust be st ore d i n t he pat ient  me dical rec or d as s o urce data.
5. 2. 5
Vit al si g ns
H ei g ht will be assesse d at scree ni n g o nl y .
Wei g ht will be assesse d at scree ni n g a n d as
cli nicall y in dicate d at a n y  ot her ti me. 
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
72(133)
5.2.5.1
Pulse and blood pressure
Blood pressure and pulse rate will be measured preferably using a semi automatic BP 
recording device with an appropriate cuff size.
5.2.5.2
Body temperature
Body temperature will be measured in degrees Celsius using an automated thermometer.
5.2.6
Other safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the Study Schedule (see Table 1).
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.
5.2.6.1
Serum or urine pregnancy test
Pregnancy tests on blood or urine samples will be performed for women of childbearing 
potential within 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, at the time points shown in Table 1 during study treatment. Tests will 
be performed by the hospital’s local laboratory. If results are positive the patient is 
ineligible/must be discontinued from study treatment immediately.  Details of the pregnancy 
tests must be recorded in the patient’s medical records.
Any changes in vital signs should be recorded as an AE, if applicable.
5.2.7
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected as clinically indicated for 
patients with prolonged haematological toxicities as defined in Section 0
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the investigator for documentation on the Patient Safety database.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 3( 1 3 3)
5. 3
Ot her assess me nt s
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 4( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 5( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 6( 1 3 3)
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 7( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 8( 1 3 3)
P ati e nts will be re q uire d t o pr o vide:

 
 
 
 
 
 
 
5. 6
Bi ol o gic al s a m pli n g pr oce d ures 
5. 6. 1
V ol u me of bl o o d
T he v o l ume of bl o o d t hat will be dra w n fr o m eac h patie nt will var y , de pe n de nt u p o n t he
le n gt h of ti me t hat t he patie nt re mai ns i n t he trial.  T he t otal v ol u me of bl o o d t o be dra w n 
fr om eac h pat ient  i n t he st u d y, ass u mi n g t he y c o m plete scree ni n g, 6 c ycles of treat me nt, a 
treat me nt disc o nt i n uati on visit a n d t he 3 0 -d a y  fol l o w-u p visit, is 2 5 5 m L.
S af et y lab orat or y  assess me nts will be perf or me d l ocall y at eac h ce ntre’s la b orat or y b y mea ns 
of  t h eir esta blis he d met h o ds.  T he n u m ber of sa m ples/ bl o o d v ol u mes is t heref ore patie nt t o 
sit e-s pecific c ha n ge.  E xtr a blo o d sa m ples ma y  als o be c ollecte d if, f or e xa m ple, a d diti onal 
sa m ples are re q uire d f or re peat safet y assess me nts.
T he t otal v ol u me o f bl o o d t hat will be dra w n fr o m eac h patie nt i n t his st u d y is as f oll ows:
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
7 9( 1 3 3)
T a ble 5
V ol u me of bl o o d t o be dr a w n fr o m e ac h p atie nt
Assess m e nt
S a m ple v ol u me 
( mL)
N o. of 
s a m ples
T ot al v ol u me 
( mL)
Safet y
Cli nical c he mistr y
5
2 1
1 0 5
Hae mat ol o g y
5
2 1
1 0 5
C oa g ulati o n
3
1
3
W h ole bl o o d sa m ple f or M yria d B R C A
test (retr os pecti ve/ pr os pecti ve)
W h ole bl o o d sa m ple f or assess me nt of 
c urre nt a n d f ut ure B R C A m utati o n 
assa y(s)
9
9
1
1
9
9
Ser u m Pre g na nc y test (site ma y use uri ne 
i nstea d)
Site de pe n de nt
Site ma y use 
uri ne i nstea d
 
 
 
 
 
T otal
2 5 5
5. 6. 2
H a n dli n g, st or a ge a n d destr ucti o n of bi ol o gic al s a m ples
T he sa m ples will be use d u p or dis p ose d of after a nal yses or retai ne d f or f urt her use as 
descri be d here.
Bi ol o gi cal sa m ples f or f ut ure researc h will be retai ne d at Astra Ze neca or a C R O, o n be half of 
A stra Ze neca f or a ma xi m u m of 1 5 year s f oll owi n g t he Last Pati e nt’s Last Visit in t he st u d y .  
T he res ults fr o m f ut ure a nal ysis will n ot be re p orte d i n t he Cli nical St u d y  Re p ort b ut 
se paratel y in a Sci e nt ific Re p ort.
5. 6. 3
L a belli n g a n d s hi p me nt of bi o h az ar d s a m ples
T he Pri nci pal I n vest i gat or e ns ures t hat sa m ples are la belle d a n d s hi p pe d i n acc or da nce wit h 
t he La b orat or y Ma n ual a n d t he Bi ol ogi cal S u bsta nce, Cate g or y B Re g ulatio ns ( m at erials 
c o ntai ni n g or s us pecte d t o c o ntai n i nfect i ous s u bsta nces t hat d o n ot m eet Cate g or y A crit eria), 
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
80(133)
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.6.4
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site, 
according to local regulations or at the end of the retention period, whichever is the sooner.
5.6.5
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
gBRCA sample: As collection of the biological samples is an integral part of the study, then 
the patient is withdrawn from further study participation.
Archival tumour sample: If consent to use the sample is withdrawn this will not impact 
eligibility to study. The patient may continue in the study if the patient is already randomised.
Blood samples for biomarker analysis: Although mandatory, the patient may continue in the 
study if the patient is already randomised.
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
81(133)

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory (ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory (ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (e.g.  an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
82(133)

Results in persistent or significant disability/incapacity or substantial disruption 
of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfill the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy.
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (i.e., it is not the tumour for which entry into the study is a criterion and that 
is being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumour under study). Malignant tumours that – as part of normal, if 
rare, progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumour.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of signature of informed consent throughout the 
treatment period up to and including the 30-day follow-up period.  All ongoing and any new 
AEs/SAEs identified during the 30 calendar days follow up period, after the last dose of study 
medication must be followed to resolution. After any interim analysis, any ongoing AEs/SAEs 
need to be unlocked and followed for resolution.
SAEs will be recorded from the time of informed consent.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
83(133)
6.3.1.1
Adverse events after the 30 day follow up period 
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify AstraZeneca, Patient Safety.
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post study completion (after DCO3) then all SAEs must continue to be collected 
and reported to Patient Safety within the usual timeframe. After study completion (after 
DCO3) SAE reporting to be followed using paper reporting process.
Otherwise, after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow up period (30 
days).
6.3.2
Follow-up of unresolved adverse events
Any SAEs or non-serious adverse event that is ongoing at the time of the 30-day 
follow up, must be followed up to resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow up. 
AstraZeneca retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

The date when the AE started and stopped

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or 
no)Action taken with regard to investigational product

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
84(133)

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment in relation to Other medication

Description of AE.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
Severity of AE
For each episode on an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTC grade should be reported.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE.
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades the recommendation is that the CTCAE criteria that convert mild, moderate 
and severe events into CTCAE grades should be used.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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A copy of the CTCAE version can be downloaded from the NCI website.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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 to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The reporting of laboratory/vital signs/ECG abnormality as AE should be avoided unless one 
of the following is met:

Any criterion for an SAE is fulfilled

Causes study treatment discontinuation

Causes study treatment interruption

Causes study treatment dose reduction

The investigator believes that the abnormality should be reported as an AE
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). 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
86(133)
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
NB. Cases where a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may 
need to be reported as SAEs, please refer to Appendix D ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions.
6.3.7
Hy’s Law
Cases where a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need 
to be reported as SAEs. Please refer to Appendix D for further instruction in cases of 
combined increase of aminotransferase and total bilirubin.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  The development of local 
regional recurrence or distant metastasis to the primary cancer under study should be 
considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study.
New cancers
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE and will generally meet at least one of the serious criteria (see Section 6.2).  New primary 
cancers are those that are not the primary reason for the administration of the study treatment 
and have developed after the inclusion of the patient into the study.  They do not include 
metastases of the original cancer.  Symptoms of metastasis or the metastasis itself should not 
be reported as an AE/SAE, as they are considered to be disease progression.
Lack of efficacy
When there is deterioration in the cancer, for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the 
Sponsor or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
87(133)
Deaths
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:

Death clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the DEATH 
eCRF but should not be reported as an SAE

Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours (see Section 6.4 for further details).  The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  This information can be 
captured in the ‘death eCRF’.
Deaths with an unknown cause should always be reported as a SAE.  A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes.
Olaparib adverse events of special interest
Adverse events of special interest [AESI] are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. Adverse Events of Special Interest for 
olaparib are the Important Potential Risks of MDS/AML, new primary malignancy (other than 
MDS/AML) and pneumonitis.  
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
88(133)
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one
calendar day of initial receipt for fatal and life threatening events and within five calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed
6.4.1
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.          
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.

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Edition Number 3
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6.5
Overdose
There is currently no specific treatment in the event of overdose of Olaparib and possible 
symptoms of overdose are not established.  
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. The Maximum Tolerated Dose is 300 mg twice daily 
(tablet).
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
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 drug occurs in the course of the study, then 
Investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with SAE, standard reporting timelines apply (see Section 6.4).  For 
other overdoses, reporting should be done within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
Women of childbearing potential are not allowed to be included in this study.  Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to AstraZeneca
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 

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Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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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) 
occurring from the date of the first dose of study medication until 1 month after the last dose 
of study medication should be followed up and documented even if the patient was 
discontinued from the study.
If any pregnancy occurs, then the Investigator or other site personnel informs the appropriate 
AstraZeneca representatives within 1day ie, immediately but no later than 24 hours of when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.6.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose.  Pregnancy of the patient’s partners is not considered to be 
an adverse event.  However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if possible be 
followed up and documented.
The outcome of any conception occurring from the date of the first dose until 3 months after 
the last dose should be followed up and documented.
To capture information about a pregnancy from the partner of a male patient, the male 
patient’s partner consent must be obtained to collect information related to the pregnancy and 
outcome; the male patient should not be asked to provide this information. A consent form 
specific to this situation must be used.
6.7
Management of toxicity of Olaparib
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions (Table 8) Repeat dose interruptions are allowed as 
required, for a maximum of 4 weeks on each occasion. If the interruption is any longer, the 
study team must be informed. Study treatment can be dose reduced to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step. If the reduced dose of 200 mg twice 
daily is not tolerable, no further dose reduction is allowed and study treatment should be 
discontinued. Once dose is reduced, escalation is not permitted 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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6.7.1 Management of haematological toxicity Olaparib
6.7.1.1
Management of anaemia
Patients can enter the study with a haemoglobin value of > 9g/dl, this should be taken into 
account when considering the management of anaemia. Anaemia should be managed as 
described in Table 6.
Table 6
Management of anaemia
Haemoglobin
Action to be taken
Hb ≥8 g/dl (CTCAE 
Grade 1 or 2)a
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue study treatment with supportive 
treatment (eg transfusion) or interrupt dose for a maximum of 4 weeks. 
Study treatment can be restarted if Hb has recovered to > 9g/dl.
Subsequent occurrences:
If  Hb< 10 but ≥ 9 g/dl investigator judgement to continue study treatment  
Consideration could be given to supportive treatment (eg transfusion) or
dose interrupt (for max of 4 weeks) and upon recovery dose reduction (to 
250 mg twice daily as a first step and to 200 mg twice daily as a second 
step). 
If  Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
Hb < 8 g/dl
(CTCAE Grade 3)a
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality. 
Interrupt study treatment for a maximum of 4 weeks until improved to Hb 
≥9 g/dl.
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease.
a
CTCAE Version 4.
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases 
management of anaemia may require blood transfusions. If a patient has been treated for 
anaemia with multiple blood transfusions without study treatment interruptions and becomes 
blood transfusion dependant as judged by investigator, study treatment should be interrupted 
for up to a maximum of 4 weeks to allow for bone marrow recovery.  Study treatment should 
be restarted at a reduced dose if bone marrow recovers.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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For cases where patients develop prolonged haematological toxicity (≥2 week 
interruption/delay in study treatment due to CTC grade 3 or worse anaemia and/or 
development of blood transfusion dependence), refer to guidance later in this section for the 
management of this. 
6.7.1.2
Management of neutropenia, leukopenia and thrombocytopenia
Adverse event of neutropenia, leukopenia and thrombocytopenia should be managed as 
described in Table 7.  
Table 7
Management of neutropenia, leukopenia and thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE Grade 1-2
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation
CTCAE Grade 3-4
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce <<select 
olaparib or study treatment>> to 250 mg twice daily as a first step and 
200 mg twice daily as a second step
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs.
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 h (7 days for 
pegylated G-CSF) of the last dose of study treatment unless absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
For cases where patients develop prolonged haematological toxicity (≥2 week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to guidance later in 
this section for the management of this. 
Management of prolonged haematological toxicities while on study treatment
If a patient develops prolonged haematological toxicity such as:

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
and/or development of blood transfusion dependence

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L)

≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets 
< 50 x 109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to haematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
haematological practice. Study treatment should be discontinued if blood counts do not 
recover to CTC gr 1 or better within 4 weeks of dose interruption.
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as an SAE and full reports must be provided by the investigator to AstraZeneca 
Patient Safety. Olaparib treatment should be discontinued if patient’s diagnosis of MDS 
and/or AML is confirmed.
6.7.2
Management of non-haematological toxicity Olaparib
6.7.2.1
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality occurs, 
an interruption in study treatment dosing is recommended and a diagnostic workup (including 
a high resolution CT scan) should be performed, to exclude pneumonitis.  Following 
investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator.  If 
significant pulmonary abnormalities are identified, these need to be discussed with the 
AstraZeneca Study Physician. 
6.7.2.2
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with Olaparib treatment. In Study 
D0810C00019 nausea was reported in 71% of the Olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the Olaparib treated patients and 
14% in the placebo treated patients. They are generally mild to moderate (CTCAE Grade 1 or 
2) severity, intermittent and manageable on continued treatment. The first onset generally 
occurs in the first month of treatment for nausea and within the first 6 months of treatment for 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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vomiting. For nausea, the incidence generally plateaus at around 9 months, and for vomiting at 
around 6 to 7 months.
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines. 
As per international guidance on antiemetic use in cancer patients (ESMO, NCCN), generally 
a single agent antiemetic should be considered eg dopamine receptor antagonist, 
antihistamines, dexamethasone.
6.7.2.3
Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AZ study physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery 
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any biopsy procedure.
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.
Because the AEs related to Olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
Table 8
Dose reductions for study treatment
Initial Dose
Following re-challenge post 
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
6.7.3
Management of toxicity on placebo
Adverse events on placebo will be handled in the same manner as those arising on Olaparib 
(see sections 6.7)

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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6.7.4
Renal impairment
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls 
below the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24 hour urine test 
of between 31 and 50 ml/min) for any reason during the course of the study: the dose of 
olaparib should be reduced to 200 mg twice daily.
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤ 
30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease is it recommended that olaparib be discontinued.
6.8
Study governance and oversight
6.8.1
Data Monitoring Committee
This study will use an external independent data monitoring committee (IDMC) to perform 
interim reviews of accumulating study safety data and the interim analyses for futility based 
on PFS.  
This committee will be composed of therapeutic area experts and statisticians, who are not 
employed by AZ, and do not have any major conflict of interest.  Following the review the 
IDMC will recommend whether the study should continue unchanged, be terminated, or be 
modified in any way.  Once the IDMC has reached a recommendation, a report will be 
provided to AstraZeneca.  The report will only include the recommendation and any potential 
protocol amendments and will not contain any unblinding information.
A separate IDMC charter will be developed which will contain details of the IDMC members 
and clearly define the responsibilities of the IDMC.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply Olaparib and 
matching placebo to the Investigator as film-coated tablets as shown below.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
96(133)
Investigational product
Dosage form and strength
Olapariba
Tablet –100mg and 150 mg 
Placebo to match Olaparib
Tablet to match each strength of Olaparib
a
Descriptive information for Olaparib can be found in the Investigator’s Brochure
7.2
Dose and treatment regimens
Study treatment is available as a green film-coated tablet containing 150 mg or 100 mg of 
Olaparib or matching placebo.
For all centres, Olaparib and matching placebo will be packed in high-density polyethylene 
(HDPE) bottles with child-resistant closures.  The randomised study treatment will be 
dispensed to patients.  Each dosing container will contain sufficient medication for at least 
each treatment period plus overage.  The planned dose of 300 mg bid will be made up of two 
(2) x 150 mg tablets bid with 100 mg tablets used to manage dose reductions.  Tablets should 
be taken at the same times each morning and evening of each day, approximately 12 hours 
apart with approximately 240 mL of water.  The Olaparib tablets should be swallowed whole 
and not chewed, crushed, dissolved or divided.  Olaparib tablets can be taken with a light 
meal/snack (eg, two pieces of toast or a couple of biscuits). Multiple bottles of Olaparib or 
matching placebo maybe required for dispensing in order to make up the desired dose. 
No cross over to Olaparib will be provided in this study. 
If vomiting occurs shortly after the Olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (eg, as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time.
Once patients have been discontinued from study treatment, other treatment options will be at 
the discretion of the investigator. If a patient is continuing to derive benefit from olaparib at 
the end of the study (at DCO3), then they may continue to receive treatment as open labelled 
drug via manual supply outside of the study setting once the IVRS/IWRS has been closed. 
7.3
Labelling
Labels for Olaparib will be prepared in accordance with Good Manufacturing Practice (GMP) 
and local regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for 
labelling.  Label text will be translated into local language. 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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Specific dosing instructions will not be included on the label; the site must complete the 
“Patient Dispensing Card” with the details of the dosing instructions at the time of dispensing.  
The patient emergency contact details will not be on the label, unless it is a country-specific 
regulatory requirement, but can be found in the informed consent and the ‘Patient Dispensing 
Card’.  For emergency purposes the patient must be in possession of the emergency contact 
details at all times.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions and may 
only dispensed by investigator or pharmacist qualified designee. The investigational product 
label on the Olaparib bottle and the IB specifies the appropriate storage conditions. 
7.5
Compliance
The administration of all study drugs (including Olaparib and placebo) should be recorded in 
the appropriate sections of the eCRF.
Patients should be given clear instructions on how and when to take their Olaparib.  Patients 
will self-administer Olaparib.  Study site staff will make tablet counts at regular intervals 
during treatment.  Compliance will be assessed by the tablet count and the information will be 
recorded in the appropriate section of the eCRF.  After the tablet count has been performed, 
the remaining tablets will not be returned to the patient, but will be retained by the 
investigative site until reconciliation is completed by the study monitor.  All patients must 
return their bottle(s) of Olaparib at the appropriate scheduled visit, when a new bottle will be 
dispensed.  Patients will be instructed to notify study site personnel of missed doses.  Dates of 
missed or held doses will be recorded by the site staff on the eCRF.
Patients must return all containers and any remaining tablets at the end of the study.
7.6
Accountability
The study treatment provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Study site personnel, will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery, destruction and return should be 
signed.  Any discrepancies must be accounted for on the appropriate forms.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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7.7
Concomitant and other treatments 
Any medications (with the detailed exceptions) which are considered necessary for the 
patient's welfare, and which it is believed will not interfere with the study medication, may be 
given at the discretion of the investigator, providing the medications, the doses, dates and 
reasons for administration are recorded.
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded.  This includes any blood transfusions.
The reasons for the use, doses and dates of treatment should be recorded in the patient’s 
medical records and appropriate sections of the eCRF.
All medications (prescriptions or over the counter medications) continued at the start of study 
or started during the study or until 30 days from the end of the last protocol treatment and 
different from the study medication must be documented.
7.7.1
Medications that may NOT be administered
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel 
agent) is to be permitted while the patient is receiving study medication.
Live virus and bacterial vaccines should not be administered whilst the patient is receiving 
study medication and during the 30 days follow up period.  An increased risk of infection by 
the administration of live virus and bacterial vaccines has been observed with conventional 
chemotherapy drugs and the effects with Olaparib are unknown.
7.7.2
CYP3A4/5 restrictions 
The use of any natural/herbal products or other “folk remedies” should be discouraged but use 
of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded.
Olaparib is an investigational drug for which no data on in vivo interactions are currently 
available.  Based on in vitro data and clinical exposure data, Olaparib is considered unlikely to 
cause clinically significant drug interactions through inhibition or induction of cytochrome 
P450 enzyme activity.  In vitro data have, however, also shown that the principal enzyme 
responsible for the formation of the 3 main metabolites of Olaparib is CYP3A4/5 and 
consequently, to ensure patient safety, the following potent inhibitors of CYP3A4/5 must not 
be used during this study for any patient receiving Olaparib.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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While this is not an exhaustive list, it covers the known potent inhibitors, which have most 
often previously been reported to be associated with clinically significant drug interactions:

ketoconazole, itraconazole, ritonavir, idnavir, saquinavir, telithromycin, 
clarithromycin and nelfinavir 
For patients taking any of the above, the required wash-out periods prior to starting Olaparib 
is one week.
In addition, to avoid potential reductions in exposure due to drug interactions, the following 
CYP inducers should be avoided:

Phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, phenobarbitone, 
nevirapine, modafinil and St John’s Wort (Hypericum perforatum) 
For patients taking any of the above, the required wash-out periods prior to starting Olaparib 
are phenobarbitone 5 weeks, and for any of the others, 3 weeks.
After randomisation if the use of any potent CYP inducers or inhibitors of CYP3A4/5 are 
considered necessary for the patient’s safety and welfare, the investigator must contact the 
AstraZeneca Study Physician.  A decision to allow the patient to continue in the study will be 
made on a case-by-case basis.
7.7.3
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.
7.7.4
Anti-emetics/ Anti-diarrhoeals
Should a patient develop nausea, vomiting and/or diarrhoea, then these symptoms should be 
reported as AEs (see section 6.3) and appropriate treatment of the event given.
7.7.5
Anticoagulant Therapy
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
prothrombin time (INR and APTT) be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable.  Subcutaneous heparin is permitted.
7.7.6
Administration of other anti-cancer agents
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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Treatment with bisphosphonates or RANKL inhibitor for the prevention of skeletal related 
events in patients with bone metastasis is permitted and must be started at least 5 days prior to 
randomisation.
7.7.7
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer after discontinuation of treatment, will be 
collected.  Response to subsequent therapies and PFS on those therapies will also be collected.
The choice of subsequent systemic anticancer treatment will be entirely at the discretion of the 
investigator although it is expected that many/most patients upon progression on study will be 
treated with a platinum based regimen
8.
STATISTICAL ANALYSIS AND SAMPLE SIZE 
DETERMINATION BY PAREXEL
8.1
Statistical considerations

All personnel involved with the analysis of the study will remain blinded until 
database lock and protocol violators identified. Please refer to Section 3.7.

Analyses will be performed by AstraZeneca or its representatives. 

A comprehensive statistical analysis plan (SAP) will be prepared and finalised 
before first patient in (FPI).
8.2
Definitions of analysis sets
Table 9 gives a summary of outcome variables and analysis populations
8.2.1
Full analysis set
Intention to treat (ITT): The primary statistical analysis of the efficacy of Olaparib will 
include all randomised patients and will compare the treatment groups on the basis of 
randomised treatment, regardless of the treatment actually received.  Patients who were 
randomised but did not subsequently go on to receive study treatment are included in the Full 
Analysis Set (FAS). Therefore, all efficacy and health-related QoL data will be summarised 
and analysed using the FAS on an intention-to-treat (ITT) basis. 
In addition, key sensitivity analyses of efficacy endpoints will be performed in the subgroup 
of patients in the FAS that have a gBRCA mutation confirmed by the Myriad test.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0 1( 1 3 3)
8. 2. 2
S afet y a n al ysis set
All patie nts w h o recei ve d at least o ne d ose of ra n d o mise d i n vest i gati onal pr o d uct, Ola pari b or 
pl ace b o, will be i ncl u de d i n t he safet y a nal ysis set.  T hr o u g h o ut t he safet y res ults sect i ons, 
err o ne o usl y treate d Ola pari b patie nts (t h ose ra n d o mise d t o Ola pari b b ut act uall y gi ve n 
pl ace b o at a n y ti me) will be acc o u nte d f or i n t he Ola pari b treat me nt gr o u p.  Err o ne o usl y 
treate d place b o patie nts (t h ose ra n d o mise d t o placeb o b ut act uall y recei ve d at least o ne d ose 
of  Ola pari b) will be acc o u nte d f or i n t he Ola pari b treat me nt gr o u p.
 
T a ble 9
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 ble
P o p ul ati o ns
Effic ac y D at a
- Pri mar y: P F S
F A S  (I T T), M yria d c o nfir me d B R C A m s u b gr o u p 
- Sec o n dar y e n d p oi nts t o be a nal yse d:
O S, P F S 2, ti me t o first s u bse q ue nt t hera p y 
( T F S T), ti me t o sec o n d s u bse q ue nt t hera p y 
( T S S T), ti me t o treat me nt disc o nti n uati o n ( T D T)
F A S  (I T T), M yria d c o nfir me d B R C A m s u b gr o u p
 
 
 
-Sec o n dar y e n d p oi nts t o be s u m marise d:
-O bjecti ve res p o nse rate
F A S  (I T T) ( patie nts wit h meas ura ble disease at 
baseli ne o nl y) , M yria d c o nfir me d B R C A m
s u b gr o u p
-Disease c o ntr ol rate
F A S  (I T T), M yria d c o nfir me d B R C A m s u b gr o u p
De m o gra p h y
F A S (I T T)
Safet y Data
- E x p os ure
Safet y
- A d verse E ve nts
Safet y
- La b meas ure me nts
Safet y
- Vital Si g ns
Safet y
C CI
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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8.3
Calculation or derivation of efficacy variable(s)
At each visit patients will be assigned a RECIST visit response of CR, PR, SD, PD, NE, NED 
depending on the status of their disease compared to baseline and previous assessments, based 
on the BICR review. This will be repeated using the Investigator assessed RECIST data.
8.3.1
Primary endpoint (PFS)
PFS is defined as the time from randomisation until the date of objective radiological disease 
progression according to modified RECIST 1.1 or death (by any cause in the absence of 
disease progression) regardless of whether the patient withdraws from randomised therapy or 
receives another anticancer therapy prior to disease progression.  Patients who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable RECIST assessment.  However, if the patient progresses 
or dies after two or more missed visits, the patient will be censored at the time of the latest 
evaluable RECIST assessment. If the patient has no evaluable visits or does not have a 
baseline assessment they will be censored at day 1 unless they die within two tumour 
assessment visits of randomisation (17 weeks allowing for visit window).
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:
a) Date of progression will be determined based on the earliest of the RECIST 
assessment/scan dates of the component that triggered the progression
b) When censoring a patient for PFS the patient will be censored at the latest of the 
RECIST assessment/scan dates contributing to a particular overall visit assessment
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS.
Objective progression is defined as at least a 20% increase in the sum of the diameters of the 
target lesions (compared to previous minimum sum) and an absolute increase of > 5 mm, or an 
overall non-target lesion assessment of progression or a new lesion. 
The primary analysis will be based on the blinded independent central review (BICR) of the 
radiological scans. A charter for the BICR will be developed in advance of the start of the 
study. A sensitivity analysis based on the programmatically derived PFS based on 
Investigator-recorded assessments will be carried out.

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
103(133)
8.3.2
Secondary endpoints 
8.3.2.1
Overall Survival
Overall survival is defined as the time from the date of randomisation until death due to any 
cause.  Any patient not known to have died at the time of analysis will be censored based on 
the last recorded date on which the patient was known to be alive.
Note: Survival calls will be made in the week following the date of Data Cut Off (DCO) date 
for the analysis, and if patients are confirmed to be alive or if the death date is post the DCO 
date these patients will be censored at the date of DCO.
8.3.2.2
Best overall RECIST response (BoR)
Best overall RECIST response (BoR) is calculated based on the overall visit responses from 
each RECIST assessment, described in Appendix F. It is the best response a patient has had 
after randomisation but prior to starting any subsequent cancer and prior to RECIST 
progression or the last evaluable assessment in the absence of RECIST progression. 
Categorisation of best overall response will be based on the RECIST criteria (Appendix F) 
using the following response categories: complete response (CR), partial response (PR), stable 
disease (SD), No Evidence of Disease (NED; applies only to those patients entering the study 
with no disease at baseline), progressive disease (PD) and not evaluable (NE).
Best overall response will be determined programmatically based on the RECIST criteria 
using BICR data.  In addition, this will also be reported using investigator-recorded 
assessment.
For patients whose progression event is death, BoR will be calculated based on data up until 
the last evaluable RECIST assessment prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurred ≤ 17 weeks 
(ie 16 weeks ±1 week) after randomisation then BoR will be assigned to the progression (PD) 
category. For patients who die with no evaluable RECIST assessments, if the death occurred 
17 weeks (ie 16 weeks ±1week) after randomisation then BoR will be assigned to the 
nonevaluable (NE) category.
Progression events that have been censored due to them being more than two missed visits 
after the last evaluable assessment will not contribute to the BoR derivation.
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied 
at any time up to and including the defined analysis cut-off point. For each treatment group, 
the objective response rate (ORR) is the number of CR and PR divided by the number of

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
104(133)
patients in the group in the FAS with measurable disease at baseline. Only patients with PR 
and measurable disease at enrolment can achieve an objective response of CR or PR, other 
permissible categories of BoR are NE, PD.
The disease control rate (DCR) is defined as the percentage of patients who have at least one 
confirmed visit response of CR or PR or have demonstrated SD or NED for at least 15 weeks 
(ie 16 weeks ±1 week) prior to any evidence of progression. In the case of SD and NED, 
follow up assessments must have met the SD or NED criteria for a minimum interval of 15 
weeks following randomisation.
8.3.2.3
Time from randomisation to second progression (PFS2)
Time from randomisation to second progression (PFS2) is defined as the time from the date of 
randomisation to the earliest of the progression event subsequent to that used for the primary 
variable PFS or death. 
The date of second progression will be recorded by the Investigator and defined according to 
local standard clinical practice and may involve any of; objective radiological or symptomatic 
progression or death. RECIST measurements will not be collected for assessment of PFS2. 
The date of the PFS2 assessment and investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in the eCRF. Second progression status 
will be reviewed every 8 weeks following the progression event used for the primary variable 
PFS (the first progression) and status recorded. Patients alive and for whom a second disease 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression, ie censored at the last progression assessment date if the 
patient has not had a second progression or death).
8.3.2.4
Time to first subsequent therapy or death (TFST)
Time to start of first subsequent therapy or death (TFST) will be assessed. TFST is defined as 
the time from randomisation to the earlier of first subsequent therapy start date following 
study treatment discontinuation, or death. Any patient not known to have died at the time of 
the analysis and not known to have had a further intervention of this type will be censored at 
the last known time to have not received subsequent therapy, ie the last follow-up visit where 
this was confirmed.
8.3.2.5
Time to second subsequent therapy or death (TSST)
Time to start of second subsequent therapy or death (TSST) will be assessed. TSST is defined 
as the time from randomisation to the earlier of the second subsequent therapy start date 
following study treatment discontinuation, or death. Any patient not known to have died at the 
time of the analysis and not known to have had a further intervention of this type will be 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
105(133)
censored at the last known time to have not received second subsequent therapy, ie the last 
follow-up visit where this was confirmed.
8.3.2.6
Time to study treatment discontinuation or death (TDT)
Time to study treatment discontinuation or death (TDT) will be assessed. TDT is defined as 
the time from randomisation to the earlier of the date of study treatment discontinuation or 
death. Any patient not known to have died at the time of analysis and not known to have 
discontinued study treatment will be censored based on the last recorded date on which the 
patient was known to be alive. 
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if patients are confirmed to be alive or if the death date is post the DCO date these patients 
will be censored at the date of DCO.
8.3.2.7
Disease Control Rate (DCR)
The disease control rate (DCR) is defined as the percentage of patients who have at least one 
confirmed visit response of CR or PR or have demonstrated SD for at least 16 weeks (ie 17 
weeks ±1 week) prior to any evidence of progression. In the case of SD, follow up 
assessments must have met the SD criteria for a minimum interval of 16 weeks following 
randomisation.
8.4
Calculation or derivation of safety variable(s)
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
and ECG.  These will be collected for all patients.  Appropriate summaries of these data will 
be presented.
8.4.1
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0 6 (1 3 3 )
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0 7( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0 8( 1 3 3)
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola par i b  
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 0 9 (1 3 3 )
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 0( 1 3 3)
 
 
8. 8
Met h o ds f or st atistic al a n al yses
A si n gle i nteri m P F S a nal ysis f or f ut ility will be perf or m e d w he n 5 0 % of t he n u m ber of 
pr o gressi o n e ve nts re q uire d f or t he pri m ar y P F S a n al ysis has bee n reac he d (a p pr o xi matel y  
4 4 P F S e ve nts).  T he i nteri m a nal ysis will be perf or me d b y a n I n de pe n de nt Data M o nit ori n g 
C o m mittee (I D M C) a n d f ull details will be pr o vi de d i n t he I D M C c harter. A fi nal P F S 
a nal ysis will be perf or me d w he n a p pr o xi matel y 8 7 pr o gressi o n e ve nts ha ve occ urre d ( 6 0 %
mat urit y) .  N o f urt her a nal yses of P F S are pla n ne d be yo n d t his p oi nt u nless re q ueste d b y  
healt h a ut h orit ies
Ti mi n g of t he statist ical a nal yses are gi ve n i n Ta ble 1 2
T a ble 1 2
Ti mi n g of st atistic al a n al yses
Ti mi n g of a n al yses
O utc o me V ari a ble
Efficac y Data
I nteri m P F S a nal yses ( ~ 4 4 P F S e ve nts)
- P F S 
Fi nal P F S ( ~ 8 7 P F S e ve nts, D C O 1)
- P F S, P F S 2, T D T, T F S T, T S S T, O S, a dj uste d mea n 
c ha n ge fr o m baseli ne i n gl o bal Q o L sc ore
Fi nal f or mal O S a nal yses ( ~ 1 0 6 O S e ve nts, 
D C O 2)
- O S, P F S 2, T F S T, T S S T, a dj uste d mea n c ha n ge fr o m 
baseli ne i n gl o bal Q o L sc ore
 
T he treat me nt c o m paris o n is Ola pari b 3 0 0 m g bi d vs. place b o t o Ola pari b 3 0 0 m g bi d.
Res ults of all statist ical a nal ysis will be prese nte d usi n g a 9 5 % c o nfi de nce i nter val a n d 2-side d 
p- val ue. 
T he f o ll owi n g ta bl e details w hic h e n d p oint s are t o be s u bject t o f or mal statistical a nal ysis, 
t o get her wit h pre-pl a n ne d se nsit i vity a nal yses ma ki n g clear w hic h a nal ysis is re gar de d as 
pri mar y  for t hat e n d p oi nt
C CI
C CI

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
111(133)
Table 13
Formal Statistical Analyses to be Conducted and Pre-Planned 
Sensitivity Analyses
Endpoints Analysed
Notes
PFS (Time from randomisation to first 
progression or death)
Primary analysis: log-rank test using BICR data
Key sensitivity analysisa: log rank test using 
BICR data in randomised patients confirmed as 
gBRCA mutation positive by central Myriad test 
(if subset of FAS) 
Additional sensitivity analyses:
1) Evaluation time bias analysis; log-rank test
using BICR data
2) Attrition bias analysis (using alternative 
censoring rules); log-rank test using BICR data
3) Ascertainment bias analysis; log-rank test 
using investigator data
4) Deviation bias analysis (if meaningful to do); 
log-rank test using BICR data
Overall Survival (Time from randomisation to 
death due to any cause)
Primary analysis: log-rank test 
Key sensitivity analysis: log rank test using in 
randomised patients confirmed as gBRCA
mutation positive by central Myriad test (if subset 
of FAS)
Supportive analysis: KM plot of time to censoring 
for OS
Second Progression Free Survival (PFS2)
Primary analysis: log-rank test 
Key sensitivity analysis: log rank test using in 
randomised patients confirmed as gBRCA
mutation positive by central Myriad test (if subset 
of FAS)
Time to treatment discontinuation (TDT)
Primary analysis: log rank test of time from 
randomisation to treatment discontinuation 
Key sensitivity analysis: log rank test using in 
randomised patients confirmed as gBRCA
mutation positive by central Myriad test (if subset 
of FAS)
Time to first subsequent therapy (TFST)
Primary analysis: log rank test of time from 
randomisation to first subsequent therapy or death 

Revised Clinical Study Protocol_Global
Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
112(133)
Endpoints Analysed
Notes
Key sensitivity analysis: log rank test using in 
randomised patients confirmed as gBRCA
mutation positive by central Myriad test (if subset 
of FAS)
Time to second subsequent therapy (TSST)
Primary analysis: log rank test of time from 
randomisation to second subsequent therapy or 
death 
Primary analysis: log rank test of time from 
randomisation to treatment discontinuation 
Adjusted mean change from baseline in global 
QoL score from the EORTC QLQ-C30 
questionnaire
Primary analysis: mixed model for repeated 
measures (MMRM) analysis of all of the post-
baseline scores for each visit
Supportive analysis: logistic regression on global 
QoL score improvement rate.
a
See Section 8.8.3 for further details
8.8.1
Multiplicity strategy for primary and key secondary endpoints
In order to describe the nature of the benefits of Olaparib maintenance treatment, PFS, PFS2 
and OS will be tested at a 1-sided significance level of 2.5%.
However, in order to strongly control the type I error at 2.5% 1-sided, a multiple testing 
procedure will also be employed across the primary endpoint and secondary endpoints 
intended for key label claims (ie OS). 
A hierarchical testing strategy will be employed where PFS is tested first using the full test 
mass (full test mass = alpha 5% 2 sided) and the key secondary endpoint of OS will then be 
tested using a multiple testing procedure with a recycling strategy (ie, the MTP will recycle 
the test mass to the endpoint not yet rejected in the hierarchy outlined in Figure 2).
Figure 2
Multiple Testing Procedures
OS will only be tested if the null hypothesis (of no difference) is rejected for PFS. One interim 
analysis for OS will be performed at the time of the final PFS analysis (approximately 87 PFS 
events) (DCO1).  A final formal analysis of OS will be performed when approximately 106 

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 3( 1 3 3)
deat h e ve nts ha ve occ urre d ( D C O 2). H o we ver, t he m ult i ple testi n g strate g y will not a p pl y  t o 
t he 
 a n d o nl y descri pti ve a nal ysis will be d o ne f or t his 
a nal ysis ( D C O 3). T he La n a n d De Met s a p pr oac h t hat a p pr o xi mates t he O’ Brie n & Fle mi n g 
s pe n di n g f u ncti on will be e m pl o ye d t o preser ve t he o verall 1 -si de d ty pe I err or rate of 2. 5 % 
(La n a n d De Mets 1 9 8 3 ).  If t he i nteri m a nal ysis f or O S ( D C O 1) occ urs at e xactl y 5 7 % of t he 
1 0 6 O S e ve nts, statist ical si g nifica nce f or O S will be declare d if t he n ull h y p ot hesis f or P F S is 
r ejecte d a n d t he o bser ve d p-val ue f or O S is p < 0. 0 0 3, w hic h e q uates t o a H R ≤ 0. 4 9.  T he 
sig nifica nce l e vel at t he fi nal f or mal O S a nal ysis ( D C O 2) will be deter mi ne d base d o n t he 
e xact n u m ber of e ve nts at t he ti me of t he i nteri m O S a nal yses ( D C O 1) a n d fi nal f or mal O S 
a nal yses ( D CO 2).  If t he i nteri m a nal ysis f or O S occ urs at e xactl y  5 7 % of e ve nts a n d t he 
n u m ber of O S e ve nts at t he fi nal f or mal O S a nal ysis is a p pr o xi matel y 1 0 6 t he n t he 1 -si de d 
sig nifica nce l e vel t o be a p plie d f or t he fi nal f or mal O S a nal ysis will be 2. 4 %.  Statist ical 
sig nifica nce f or O S will be declare d if t he o bser ve d p -val ue f or O S is p < 0. 0 2 4, w hic h e q uates 
t o a H R ≤ 0. 6 8.
All pla n ne d a nal yses will be perf or me d, re gar dless of t he o utc o me of t he M T P. 
8. 8. 2
A n al ysis of t he pri m ar y v ari a ble (s)
T he pri m ar y P F S a nal ysis w ill be perf or me d w he n a p pr o xi matel y 8 7 pr o gressi o n e ve nts ha ve 
occ urre d ( 6 0 % mat urit y)  base d o n t he BI C R.  N o f urt her a nal yses of P F S are pla n ne d be yo n d 
t his p oi nt u nless re q ueste d b y Healt h Aut h ori ties
P F S will be a nal yse d usi n g a l o g ra n k test.  T he haza r d ratio ( H R) a n d c o nfi de nce i nter val will 
be est i mate d fr om t he U a n d V statistics o btai ne d direct l y fr om t he LI F E T E S T mo d el  (a n d 
usi n g t he Bresl o w a p pr oac h f or ha n dli n g ties).
T he H R a n d its c o nfi de nce i nter val will be est i mate d fr om t he lo g -ra n k as f ollo ws ( Berr y  et al 
1 9 9 9 a n d Sell ke et al 1 9 8 3 )
T he H R ( Ol a pari b vs. place b o) t o get her wit h its c orres p o n di n g 9 5 % c o nfi de nce i nter val ( CI) 
a n d p-v al ue will  b e prese nte d (a H R less t ha n 1 will fa v o ur Ola pari b).  
C CI
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 4( 1 3 3)
A Ka pla n -Meier ( K M) pl ot of  P F S will be prese nte d b y tr e at me nt gr o u p. S u m maries of t he 
n u m ber a n d perce nta ge of patie nts e x perie nci n g a P F S e ve nt, a n d t he t y pe o f e ve nt ( R E CI S T 
or deat h) will be pr o vi de d alo n g wi t h me dia n P F S f or eac h treat me nt ar m.
T he ass u m pt i on of pr o p orti o nalit y will  be assesse d. N ote t hat i n t he prese nce of n o n -
pr o p orti o nali t y, t he H R will be i nter prete d as a n a vera ge H R o ver t he o bser ve d e xte nt of 
f oll ow -u p.  Pr o p orti o nalit y will  be teste d firstl y b y pr o d uci n g plots of  c o mple me n t ar y lo g -l og 
(e ve nt ti mes) vers us l o g (ti me) a n d, if t hese raise c o ncer ns, a ti me de pe n de nt c o variate w o ul d 
be fitte d t o assess t he e xte nt t o w hic h t his re prese nts ra n d o m variati on. 
T he pri mar y  a nal ysis will be base d o n t he pr o gra m maticall y deri ve d P F S base d o n BI C R 
o verall visit assess me nts (ie I n di vi d ual t u m o ur meas ure me nts will n ot be use d) a n d usi n g all 
sca ns re gar dless of w het her t he y  were sc he d ule d or n ot. 
T he est i mate d P F S rates at 6 m o nt hs a n d 1 2 m o nt hs will be s u m marise d ( usi n g t he K M c ur ve) 
a n d prese nte d b y  tr e at me nt gr o u p.
T he n u m ber of pat ient s pre mat urel y ce ns ore d will be s u m marise d b y treat me nt ar m t o get her 
wi t h baseli ne pr o g n ostic fact ors of t he pre mat urel y ce ns ore d patie nts.  A patie nt is defi ne d as 
pr e m at urel y ce ns ore d if t he y ha d n ot pr o gresse d a n d t he latest sca n pri or t o D C O was m ore 
t ha n o ne sc he d ule d t u m o ur assess me nt i nter val ( + 2 wee ks) pri or t o t he D C O date.
S u b gr o u p a nal yses will be c o n d ucte d c o m pari n g P F S bet wee n treat me nts. T he p ur p ose of t he 
s u b gr o u p a nal yses is t o assess t he c onsiste nc y of treat me nt effect acr oss p ote ntial or e x pecte d 
pr o g n osti c fact ors.  If t here are t o o fe w e ve nts a vaila ble f or a mea ni n gf ul a nal ysis of a 
parti c ular s u b gr o u p (it is n ot c o nsi dere d a p pr o priate t o prese nt a nal yses w here t here are less 
t ha n 2 0 e ve nts i n a s u b gr o u p), t he relati o ns hi p bet wee n t hat s u b gr o u p a n d P F S will n ot be 
f or mall y a nal yse d.  I n t his case, o nl y descri pti ve s u m maries will be pr o vi de d
C CI

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 5( 1 3 3)

 
 
Ot her baseli ne varia bles ma y  als o be assesse d if t here is cli nical j ustificati on. 
F or eac h s u b gr o u p, t he H Rs ( Ola pari b: place b o) a n d ass ociate d CIs will be calc ulate d fr o m a 
C o x pr o p orti o nal hazar ds m o del (t ies = Efr o n) t hat c o ntai ns t he treat me nt ter m, fact or a n d 
treat me nt -b y- fact or i nteracti o n ter m.  T he treat me nt effect H Rs f or eac h treat me nt c o m paris o n 
alo n g wi t h t heir c o nfi de nce i nter vals will be o btai ne d f or eac h le vel of t he s u b gr o u p fr o m t his 
si n gle m o del.  T he H Rs a n d 9 5 % CIs will be prese nte d o n a f orest pl ot i ncl u di n g t he H R a n d 
9 5 % CI fr o m t he o verall p o p ulat i on ( usi n g t he pri mar y  a nal ysis).  
 
 
A f urt her a nal ysis of P F S ( usi n g I n vesti gat or assesse d R E CI S T) ma y be perf or me d at t he ti me 
of  t he O S a nal yses, if re q ueste d b y H e alt h a ut h orities.
8. 8. 3
Se nsiti vit y a n al ysis f or t he pri m ar y e n d p oi nt
As a se nsit i vit y a nal ysis t o t he pri mar y e n d p oi nt of P F S, t he pri mar y a nal ysis will be re peate d 
e xcl u di n g a n y patient s w h o did n ot ha ve a g B R C A m utati o n stat us c o nfir me d b y  t he M yria d 
test.  T he sa me met h o d ol o g y a n d mo d el  will be use d as f or t he pri mar y a nal ysis of P F S a n d 
t he H R a n d ass ociate d 9 5 % CI will be re p orte d.
Se nsit i vity a nal yses will be perf or me d t o assess t he p ossi ble prese nce of ti me -assess me nt bias 
(ie, differe nt ial assess me nt ti mes bet wee n treat me nt gr o u ps).
S u m mar y  statistics f or t he n u m ber of wee ks bet wee n t he ti me of pr o gressi o n a n d t he last 
e val ua ble R E CI S T assess me nt pri or t o pr o gressi o n will be prese nte d f or eac h treat me nt gr o u p.
8. 8. 3. 1
E v al u ati o n -Ti me bi as
Se nsit i vity a nal yses will be perf or me d t o assess p ossi ble e val uat i on- ti me bias t hat ma y be 
i ntr o d uce d if sca ns are n ot perf or me d at t he pr ot oc ol-sc he d ule d ti me p oi nts. T he mi d p oi nt 
bet wee n t he ti me o f pr o gressi o n a n d t he pre vi o us e val ua ble R E CI S T assess me nt will be 
a nal yse d usi n g a stratifie d l o g ra n k test, as descri be d f or t he pri mar y  a nal ysis of P F S.  T h is 
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approach has been shown to be robust to even highly asymmetric assessment schedules (Sun 
and Chen 2010). This approach will use the BICR RECIST assessments.
8.8.3.2
Attrition bias
Attrition bias will be assessed by repeating the primary PFS analysis except that the actual 
PFS event times, rather than the censored times, of subjects who progressed or died in the 
absence of progression immediately following two, or more, non-evaluable tumour 
assessments will be included. In addition, subjects who take subsequent therapy prior to their 
last evaluable RECIST assessment or progression or death will be censored at their last 
evaluable assessment prior to taking the subsequent therapy.
Additionally a Kaplan-Meier plot of the time to censoring where the censoring indicator of the 
primary PFS analysis is reversed will be presented.
8.8.3.3
Ascertainment bias
A log-rank test will be repeated using the programmatically derived RECIST using 
Investigator assessed PFS.  The HR and 95% Confidence Interval will be presented.  
If there is an important discrepancy between the primary analysis using BICR assessments and 
this sensitivity analysis using Investigator assessments, then the proportion of patients with 
site but no central confirmation of progression will be summarised.  The approach of imputing 
an event at the next visit in the central review analysis may help inform the most likely HR 
value, but only if an important discrepancy exists.  
Disagreements between investigator and central reviews of RECIST progression will be 
presented for each treatment group.  The summary will include the early discrepancy rate 
which is the frequency of central review declared progressions before the Investigator review 
as a proportion of all central review progressions and the late discrepancy rate which is the 
frequency of central review declared progressions after the Investigator review as a proportion 
of all discrepancies.
8.8.3.4
Deviation bias (if meaningful to do)
As a sensitivity analysis to the primary endpoint of PFS, an analysis excluding patients with 
deviations that may affect the efficacy of the trial therapy will be performed if > 10% of 
patients:

did not have the intended disease or indication or

did not receive any randomised therapy

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 7 (1 3 3 )
A l og- ra n k test will be re peate d usi n g t he BI C R R E CI S T data, usi n g t he sa me ties as 
descri be d f or t he pri mar y a nal ysis of P F S. T he H R a n d 9 5 % CI will be prese nte d.
8. 8. 4
A n al ysis of t he sec o n d ar y v ari a ble(s)
8. 8. 4. 1
A n al ysis of O S e n d p oi nt
I nteri m O S data will be a nal yse d at t he ti me of t he fi nal a nal ysis of P F S ( D C O 1) a n d will use 
t he sa me met h o d olo g y  a n d mo d el  ( pr o vide d t here are s ufficie nt e ve nts a vaila ble f or a 
mea ni n gf ul a nal ysis [ > 2 0 deat hs], if n ot descri pti ve s u m maries will be pr o vi de d).  A fi nal 
f or mal a nal ysis o f O S will  be perf or me d w he n a p pr o xi matel y 1 0 6 deat hs ha ve occ urre d 
( D C O 2). 
 t o ta ke place 1 2 m o nt hs after t he a nal ysis base d o n 
1 0 6 deat hs, will be a descri pt i ve o nl y a nal ysis ( D C O 3) a nd will  use t he sa me met h o d olo g y  as 
t he fi nal f or mal O S a nal ysis.
T he se nsit i vity a nal ysis o utli ne d i n Secti o n 8. 8. 3 will n ot be re peate d f or O S wit h t he 
e xce pti o n of a Ka pla n-Meier pl ot of  t he ti me t o ce ns ori n g w here t he ce ns ori n g i n dicat or of t he 
pri mar y  O S is re verse d.
8. 8. 4. 2
A n al ysis of P F S 2 e n d p oi nt
T he a nal yses of P F S 2 will use t he sa me met h o d ol o g y  a n d mo d el  as t he pri mar y a nal ysis of 
P F S.  N o m ul tiplici t y a dj ust me nt will be a p plie d as t his is vie we d as a s u p p orti ve e n d p o i nt.
T he date of sec o n d pr o gressi o n will be rec or de d b y t he I n vest i gat or a n d defi ne d acc or di n g t o 
l ocal sta n dar d cli nical pract ice a n d ma y i n v ol ve a n y of; o bjecti ve ra di ol ogi cal or s y m pt o mat ic 
pr o gressi o n or deat h. R E CI S T meas ure me nts will n ot be c ollecte d f or assess me nt of P F S 2. 
T he date of t he P F S 2 assess me nt a n d i n vest i gat or o pi ni on of pr o gressi o n stat us ( pr o gresse d or 
n o n -pr o gresse d) at eac h assess me nt  will be rec or de d i n t he e C R F. Sec o n d pr o gressi o n stat us 
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will be reviewed every 8 weeks following the progression event used for the primary variable 
PFS (the first progression) and status recorded. Patients alive and for whom a second disease 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression, ie censored at the last progression assessment date if the 
patient has not had a second progression or death) 
As a key sensitivity, the analysis of PFS2 will be repeated in those patients whose gBRCAm
status is confirmed by the Myriad test. A KM plot of PFS2 in this subset of patients will be 
presented by treatment group.
A KM plot of the time to censoring where the censoring indicator of the primary PFS2 is 
reversed will be produced.
Time from second progression to previous assessment will be summarised by treatment arm.
8.8.4.3
Analysis of TDT endpoint
Time to study treatment discontinuation or death (TDT) will be analysed using the same 
methodology and model as the primary analysis of PFS. The HR for the treatment effect 
together with 95% CIs will be presented.  A KM plot will be presented by treatment arm.  No 
multiplicity adjustment will be applied as this is viewed as a supportive endpoint.
As a key sensitivity, the analyses of TDT will be repeated in those patients whose gBRCAm
status is confirmed by the Myriad test. A KM plot of TDT in this subset of patients will be 
presented by treatment group.
8.8.4.4
Analysis of TFST endpoint
Time to first subsequent therapy or death (TFST) will be analysed using the same 
methodology and model as the primary analysis of PFS. The HR for the treatment effect 
together with 95% CIs will be presented.  A KM plot will be presented by treatment arm.  In 
addition, the time between progression and starting subsequent therapy will be assessed.  
As a key sensitivity, the analyses of TFST will be repeated in those patients whose gBRCAm
status is confirmed by the Myriad test. A KM plot of TFST in this subset of patients will be 
presented by treatment group.
8.8.4.5
Analysis of TSST endpoint
Time to first second subsequent therapy or death (TSST) will be analysed analysed using the 
same methodology and model as the primary analysis of PFS.  The HR for the treatment effect 
together with 95% CIs will be presented.  A KM plot will be presented by treatment arm.  

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 1 9( 1 3 3)
S u m mar y  ta bles of first a n d sec o n d s u bse q ue nt t hera pies b y tr e at me nt ar m will be pr o vide d, as 
well as res p o nse t o first s u bse q ue nt t hera p y  b y tr e at me nt ar m.
As a ke y se nsitivit y,  t he a nal yses of T S S T will be re peate d i n t h ose patie nts w h ose g B R C A m
stat us is c o nfir me d b y t he M yria d test. A K M pl ot of T S S T i n t his s u bset of pat ient s will be 
prese nte d b y treat me nt gr o u p.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 2 0( 1 3 3)
 
 
 
8. 8. 4. 7
S u m m ar y of Best o ver all R E CI S T Res p o nse ( B o R) a n d O R R
F or eac h treat me nt ar m, best o verall res p o nse ( B o R) will be s u m marise d b y  n ( %) for eac h 
cate g or y ( C R, P R, S D, N E D, P D, N E).  N o f or mal statistical a nal yses are pla n ne d.  
T he o bj ect i ve res p o nse rate ( O R R) will be s u m marise d (ie, n u m ber of patie nts ( %)) b y 
treat me nt gr o u p i n pat ient s i n t he F A S (I T T p o p ulati o n) wit h meas ura ble disease at baseli ne.  
A n y pat ient s w h o e x perie nce d C R or P R w hic h was first o bser ve d w hilst recei vi n g s u bse q ue nt 
t hera p y after disc o nti n uati on of Ola pari b/ place b o will be i de nt ifie d. T he de n o mi nat or f or t he 
res p o nse rate will be meas ura ble disease as defi ne d b y  t he BI C R data
O R R a n d B O R will be prese nte d base d o n t he BI C R data a n d als o s u m marise d i n a si milar 
w a y  usi n g t he i n vesti gat or rec or de d data.
8. 8. 4. 8
S u m m ar y of D C R   
T he disease c o nt r ol rate ( D C R) will be s u m marise d (ie, n u m ber of patient s ( %)) b y treat me nt 
gr o u p i n patie nts i n t he F A S (I T T p o p ulati o n).
D C R will be prese nte d base d o n t he BI C R data a n d als o t he i n vesti gat or rec or de d data.
8. 8. 5
E x pl or at or y a n al ysis  
 
 
 
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E diti o n N u m ber 3
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1 2 1( 1 3 3)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
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Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 2 2( 1 3 3)
 
 
 
 
 
 
8. 9
S a m ple Size Deter mi n ati o n
T he pri mar y  e n d p oi nt of t he st u d y is P F S.   A p pr o xi matel y 1 4 5 pat ient s will be ra n d omise d 
( 3: 2 ratio of  Ola pari b: place b o) a n d t he pri mar y P F S a nal ysis will occ ur o nce a p pr o xi matel y 8 7 
P F S e ve nts (c o nfir me d via a ce ntral re vie w) ha ve occ urre d.  A si n gle i nteri m P F S a nal ysis f or 
f utility will be per f or me d w he n 5 0 % of t he fi nal n u m ber of pr o gressi o n e ve nts re q uire d f or t he 
pri mar y  P F S a nal ysis has bee n reac he d (a p pr o xi matel y 4 4 P F S e ve nts) base d o n BI C R.
T he st u d y  is size d ass u mi n g a tr ue treat me nt effect is a P F S Hazar d Rati o ( H R) of 0. 5 4, 
ass u mi n g 8 0 % p o wer a n d 2. 5 % alp ha ( 1 -side d), wi t h 3: 2 ra n d o misati on ( Ol a pari b: place b o). 
Ass u mi n g P F S is e x p o ne nt iall y distri b ute d, a P F S H R of 0. 5 4 e q uates t o a 3. 4 m o nt h 
i m pr o ve me nt i n me dia n P F S o ver a n ass u me d 4 m o nt h me dia n O S f or place b o. 8 7 P F S e ve nts 
will be re q uire d at t he P F S fi nal a nal yses.  
P ati e nts are t o be f o ll owe d f or t he 
 
  Wit h 1 0 6 O S e ve nts t he st u d y has 8 0 % 
p o wer t o s h o w a statist icall y si g nifica nt differe nce i n O S at t he 1-side d 2. 5 % l e vel if t he 
ass u me d tr ue treat me nt effect is a H R 0. 5 7; t his tra nslates t o a n a p pr o xi mate 6 m o nt h 
i m pr o ve me nt i n me dia n O S o ver a n ass u me d 8 m o nt h me dia n O S o n place b o, ass u mi n g O S is 
e x p o ne nt iall y distri b ute d.
Ass u mi n g t hat t he st u d y  accr ual p erio d will  be a p pr o xi matel y 1 5 mo nt hs, 8 7 pr o gressi o n 
e ve nts are a nt ici pate d t o be o bser ve d a p pr o xi matel y 1 8-1 9 m o n t hs after t he first patie nt is 
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randomised in the study. It is estimated that 44 PFS events will occur approximately 13 to 14 
months after first patient in.  It is estimated that 106 death events will occur approximately 31 
months after first patient in.
8.9.1
Interim analysis
A single interim PFS analysis for futility will be performed when 50% of the final number of 
progression events required for the primary PFS analysis has been reached (approximately 44
PFS events) based on BICR.  The interim analysis will be performed by an Independent Data 
Management Committee (IDMC) and full details will be provided in the IDMC charter.  
Safety data including death rates will also be reviewed at this time.
The futility assessment will be based on the probability of eventually showing statistical 
significance for the primary endpoint when the number of PFS events (n=87) is reached 
(Lachin 2005).  The determination of this probability will be conditional on the observed data 
at the time of the interim analysis and on the assumed hazard ratio for the alternative 
hypothesis (PFS HR=0.54).  If the probability is less than 20%, the IDMC will consider the 
option of declaring futility.
The exact figure used for the futility boundary will be calculated by AZ and sent to the IDMC 
at the time of the interim analysis, based on the number of events which have occurred at that 
time.  As an example, if exactly 50% of the PFS events required for the primary PFS analysis 
have occurred at the time of the interim analysis (44 events), then the HR that corresponds to 
20% conditional power for the interim analysis will be 1.02.  Therefore, if the observed HR 
for PFS at the interim is more than 1.02, the IDMC will consider the option of declaring 
futility.
An interim analysis of OS will be performed at the time of the primary analysis of PFS 
(approximately 87 events) with the final formal OS analysis when approximately 106 OS 
events have occurred.
The futility analyses on PFS will be used to guide decisions on stopping the study for futility 
or continuing the study.  Details will be documented in the IDMC charter.
9.
STUDY AND DATA MANAGEMENT BY PAREXEL
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system(s) utilised.

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Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are 
being accurately and timely recorded in the CRFs, that biological samples are 
handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed

Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant 
to the study) including verification of informed consent of participating 
patients. This will require direct access to all original records for each patient 
(eg, clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the 
patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data. 
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 

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Drug Substance Olaparib  
Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q2 2014 and to end by Q2 2017
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with Olaparib.
9.4
Data management by PAREXEL
Data management will be performed by PAREXEL.
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at the AstraZeneca Data Management Centre.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.
When all data have been coded, validated, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.

Re vise d Cli nic al St u d y Pr ot oc ol _ Gl o b al
Dr u g S u bsta nce Ola pari b   
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 3
Date 3 0 A u g ust 2 0 1 9
1 2 6( 1 3 3)
Data ass ociate d wit h bi o l ogical sa m ples will be tra nsferre d fr o m la b orat ories i nter nal or 
e xter nal t o Astra Ze neca.  Data fr o m e xter nal pr o vi ders (e g ce ntral la b orat orie s) will be 
vali date d as a p pr o priate t o e ns ure it is c o nsiste nt wit h t he cli nical data a n d i ncl u de d i n t he 
fi nal data base.  
 
 
 
 
 
 
 
Si te staff will e nter P R O b o o klet data i nt o Me di data Ra ve e xact l y as re p orte d b y t he patie nt.
1 0.
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S
1 0. 1
Et hic al c o n d uct of t he st u d y
T he st u d y  will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he 
Declarati o n of Helsi n ki a n d are c o nsiste nt wit h I C H/ G o o d Cli nical Pract ice, a p plica ble 
re g ulat or y r e q uire me nts a n d t he Astra Ze neca p olic y o n Bioet hics a n d H u m a n Biol o gical  
S a m ples.
1 0. 2
P atie nt d at a pr otecti o n
T he I nf or me d C o nse nt F or m will i nc or p orate ( or, i n s o me cases, be acc o m pa nie d b y a 
se parate d oc u me nt i nc or p orati n g) w or di n g t hat c o m plies wit h rel e va nt data pr otecti o n a n d 
pri vac y  le gislat i on.
Astra Ze neca will n ot pr o vi de i n di vi d ual ge n ot y pe res ul ts t o patie nts, a n y ins ura nce c o m pa n y, 
a n y e m pl o yer, t heir fa mil y me m bers, ge neral p h ysicia n or a n y  ot her t hir d part y, u nless 
re q uire d t o d o s o b y la w.
T he e xce pt i on t o t he a b o ve is t he res ult of t he M y ria d B R C A test. T his will be ma de a vaila ble 
t o t he I n vesti gat or a n d patie nt.
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Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Institutional Review Board (IRB)/Ethics Committee should approve the final study 
protocol, including the final version of the Informed Consent Form and any other written 
information and/or materials to be provided to the patients.  The investigator will ensure the 
distribution of these documents to the applicable Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.

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10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, National Co-ordinating Investigator, and the Principal Investigator 
and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 

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If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
Alexandrov et al 2013 
Alexandrov et al. Signatures of mutational processes in human cancer Nature 
2013;500;7463;415-21
American Cancer Society 2013
American Cancer Society. Cancer Facts and Figures 2013. Atlanta, Georgia: American Cancer 
Society, 2013. http://www.cancer.org
Audeh et al 2010
Audeh, M.W., Carmichael, J, Penson R.T. et al., Oral poly(ADP-ribose) polymerase inhibitor 
Olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-
of-concept trial. Lancet, 2010. 376(9737): p. 245-51.PMID: 20609468
Bang et al 2013 
Bang et al. Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A 
randomized, double-blind phase II study. J Clin Oncol 31, 2013 (suppl; abstr 4013)
Bergfeldt et al 1995
Bergfeldt K, Einhorn S, Rosendahl I & Hall P. Increased risk of second primary malignancies 
in patients with gynecological cancer. A Swedish record-linkage study. Acta Oncol. 
1995;34(6):771-7.
Berry et al 1999
Berry G, Kitchin RM & Mock PA.  A comparison of two simple hazard ratio estimators based 
on the logrank test.  Statistics in Medicine 1991; 10:749-755

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Date 30 August 2019
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Bryant et al 2005
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of 
BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 2005. 
434(7035): p. 913-7. PMID: 15829966 
Chen and Sun 2011
Quantification of PFS Effect for Accelerated Approval of Oncology Drugs. Statistics in 
Biopharmaceutical Research 2011, Vol. 3, No. 3DOI: 10.1198/sbr.2011.09046
Cole and Strair 2010
Cole M, & Strair R.  Acute myelogenous leukemia and myelodysplasia secondary to breast 
cancer treatment: case studies and literature review. Am J Med Sci 2010;339(1):36-40.
Conroy et al 2011 
Conroy T. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, 2011 NEngl J 
Med 364; 1817-25
Cowley et al 2013
Cowley et al Understanding pancreas cancer genomes. J Hepatobiliary Pancreat Sci (2013) 
20:549–556
Fayers et al 1999
Fayers P, Aaronson N, Bjordal K & Sullivan M (1999). EORTC QLQC30, Scoring Manual. 
Belgium: EORTC Data Center.
Fayers et al 2001
Fayers et al. EORTC QLQ-C30 Scoring Manual (Third Edition). Belgium: EORTC Quality of 
Life Group, 2001.
Ferrone CR et al 2009
Ferrone CR. et al.BRCA Germline Mutations in Jewish Patients With Pancreatic 
Adenocarcinoma. Journal of Clinical Oncology, Vol 27, No 3 (January 20), 2009: pp. 433-
438.
Fitzsimmons D et al 1999
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality of life 
(QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the 
QLQ-C30 in patients with pancreatic cancer. Eur. J. Cancer 35: 939-941, 1999.
Fong et al 2009
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of 
poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 
2009;361(2):123-34.

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Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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Fowble et al 2001 
Fowble B, Hanlon A, Freedman G, Nocolaou N, Anderson P. Second cancers after 
conservative surgery and radiation for stages I-II breast cancer : identifying a subset of women 
at increased risk. Int J Radiat Oncol, Biol, Phys. 2001; 51 (3);679-690.
Gaymes et al 2008
Gaymes TJ, Shall S, MacPherson LJ, Twine NA, Lea NC, Farzaneh F, and Mufti GJ. 
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic 
cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. 
Haematologica 2009; 94:638-646. doi:10.3324/haematol.2008.00193
Ginsburg et al 2010
Ginsburg et al BRCA1 and BRCA2 families and the risk of skin cancer Springer 
Science+Business Media B.V. 2010
Goggins M. et al 1996
Germline M et al BRCA2 gene mutations in patients with apparently sporadic pancreatic 
carcinomas. Cancer Res. 1996 Dec 1;56(23):5360-4
Hay et al 2009
Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) 
polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary 
tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 
2009;69(9):3850-5.
Hahn et al 2003
Hahn et al BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 
2003 Feb 5;95(3):214-21.
Helleday 2011
Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing 
up the misunderstandings. Molecular Oncology 2011; 5: 387-393.
Jemal A et al 2011
Jemal A et al. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
Kaufman B et al 2013
Kaufman B, Shapira-Frommer R Schmutzler RK, Audeh MW, et al. Olaparib monotherapy in 
patients with advanced cancer and a germline BRCA1/2 mutation: An open label phase II 
study. J Clin Oncol 31, 2013 (suppl; abstr 11024)

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Edition Number 3
Date 30 August 2019
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Kim et al 2014
Kim et al. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein 
expression is associated with a poor prognosis. Clin Cancer Res Published Online First 
January 31, 2014
Lachin 2005
Lachin, J. M. A review of methods for futility stopping based on conditional power. Statist. 
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Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 
659-63.
Ledermann et al 2013
Ledermann, J Clin Oncol 31, 2013. Olaparib maintenance therapy in patients with platinum 
sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm)
Lowery M et al 2011
Lowery M et al.An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known 
BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions The 
Oncologist 2011, 16:1397-1402.
Murai et al 2012
Murai J, Huang SN, Das BB, Renaud A, Zhnag, Y, Doroshow, JH, et al. Trapping of PARP1 
and PARP2 by Clinical PARP Inhibitors. AACR; 72(21); 5588–99.
Murphy KM et al 2002
Evaluation of Candidate Genes MAP2K4, MADH4, ACVR1B, and Mutations in 17% 
BRCA2 in Familial Pancreatic Cancer: Deleterious BRCA2. Cancer Res 2002;62:3789-3793.
Osoba D et al 1998
Osoba D, Rodrigues G, Myles J, Zee B and Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. JCO January 1998 vol. 16 no. 1 139-144
Ozcelik et al 1997
Ozcelik et al Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer 
patients Nature Genetics  16, 17 - 18 (1997) 
Rahma et al 2013
Rahma et al Second-line treatment in advanced pancreatic cancer: a comprehensive analysis 
of published clinical trials. Annals of Oncology 2013 Aug;24(8):1972-9.

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Edition Number 3
Date 30 August 2019
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Robins et al 1991
Robins JM, Tsiatis AA. Correcting for noncompliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics - Theory and Methods 
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Robins 1993
Robins J. Information recovery and bias adjustment in proportional hazards regression 
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Section, American Statistical Association 1993; 24-33.
Rottenberg et al 2008
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High 
sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and 
in combination with platinum drugs. Proc Natl Acad Sci. 2008;105(44):17079-84.
Roy et al 2012
Roy, R., J. Chun, and S.N. Powell, BRCA1 and BRCA2: different roles in a common pathway 
of genome protection. Nat Rev Cancer, 2012. 12(1): p. 68-78. PMID: 22193408
Sadler ZK. 2012
Sadler ZK. 2012. BRCA and Pancreatic Cancer: Selection of Chemotherapy Journal of the 
Pancreas JOP. J Pancreas (Online) 2012 Mar 10; 13(2):180-181
Sellke et al 1983
Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 70: 315-326, 1983
Stone 2010
Stone, A. The application of bespoke spending functions in group sequential designs and the 
effect of delayed treatment crossover in survival trials. Pharm. Statistics 5 (2010) 151-161
Sun and Chen 2010
Sun X, Chen C: Comparison of Finkelstein’s Method With the Conventional Approach for 
Interval-Censored Data Analysis.  Stat Biopharm Research 2:97-108, 2010 
The Breast Cancer Linkage Consortium 1999
The Breast Cancer Linkage Consortium: 1999 J Natl Cancer 91:1310-16
Tutt A et al 2010
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel J et al,. Oral poly(ADP-
ribose) polymerase inhibitor Olaparib in patients with BRCA1 or BRCA2 mutations and 
advanced breast cancer: a proof-of-concept trial.  Lancet 2010; 376: 235–44

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Study Code D081FC00001
Edition Number 3
Date 30 August 2019
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Von Hoff et al 2013 
Daniel D. Von Hoff, M.D. et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel 
plus Gemcitabine N Engl J Med 2013; 369:1691-1703
Wesolowski et al 2007
Wesolowski R, Choueiri TK, Rybicki L, Shealy AG, Casey G, Weng D, et al. BRCA mutation 
status and risk of secondary malignancy following chemotherapy for breast cancer. J Clin 
Oncol, 2007;ASCO Annual Meeting Proceedings Part I. Vol (25);No. 18S (June 20 
Supplement):11017.

Clinical Study Protocol Appendix B
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
1
Date
31 March 2014
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse.

Clinical Study Protocol Appendix B
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?

Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.

Clinical Study Protocol Appendix C
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
1
Date
31 March 2014
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document

Cli nical St u d y Pr ot oc ol A p pe n di x C
Dr u g S u bsta nce Ol a p ari b
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 1
Date 3 1 M ar c h 2 0 1 4
2( 2)
L A B E L LI N G A N D S HI P M E N T O F BI O H A Z A R D S A M P L E S
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on (I A T A) classifies bi o hazar d o us a ge nts i nt o 3 
cate g ories ( htt p:// w w w.i at a. or g/ w h at we d o/c ar g o/ d gr/ P a ges/i nfecti o us _s u bst a nces. as p x). 
F or tra ns p ort p ur p oses t he classificat i on of i nfecti ous s u bsta nces acc or di n g t o ris k gr o u ps was 
r e mo ve d fr o m  t he Da n ger o us G o o ds Re g ulati ons ( D G R) i n t he 4 6t h e dit i on ( 2 0 0 5).  I nfect i ous 
s u bsta nces are n o w classifie d either as Cate g or y  A, Cate g or y B or E xe mpt.  T here i s n o direct 
r elat i ons hi p bet wee n Ris k Gr o u ps a n d cate g ories A a n d B.
C ate g or y A I nfecti o us S u bst a nces are i nfect i ous s u bsta nces i n a f or m t hat, w he n e x p os ure t o 
it occ urs, is ca pa ble of ca usi n g per ma ne nt disa bilit y,  life-t hreate ni n g or fatal disease i n 
ot her wi se health y h u ma ns or a ni mal s.  Cate g or y A pat h o ge ns are e g, E b ol a, Lassa fe ver vir us:

are t o be pac ke d a n d s hi p pe d i n acc or da nce wit h I A T A I nstr ucti o n 6 0 2.
C ate g or y B I nfecti o us S u bst a nces are i nfect i ous S u bsta nces t hat d o n ot meet t he criteria f or 
i ncl usi on i n Cate g or y  A.  Cate g or y B pat h o ge ns are e g, He patit is A, B, C, D, a n d E vir uses, 
H u m a n i m m u n o deficie nc y vir us ( HI V) t ypes 1 a n d 2.  T he y  are assi g ne d t he f oll o wi n g U N 
n u m ber a n d pr o per s hi p pi n g na me:

E xe m pt - all ot her materials wit h mi ni mal ris k of c o ntai ni n g pat h o ge ns

Cli nical trial sa m ples will fall i nt o Cate g or y  B or e xe m pt u n der I A T A re g ulati o ns

Cli nical trial sa m ples will r o uti nel y be pac ke d a n d tra ns p orte d at a m bie nt 
t e mperat ure i n I A T A 6 5 0 c o m plia nt pac ka gi n g 
( htt p:// w w w.i at a. or g/ w h at we d o/c ar g o/ d gr/ P a ges/i nfecti o us _s u bst a nces. as p x)

Bi ol o gic al s a m ples tr a ns p orte d i n dr y ice re q uire a d diti o n al d a n ger o us g o o ds 
s pecific ati o n f or t he dr y-ice c o nte nt

I A T A c om p lia nt c o urier a n d pac ka gi n g materials s h o uld be use d f or pac ki n g a n d 
tra ns p ortati o n a n d pac ki n g s h o ul d be d o ne b y a n I A T A certifie d pers o n, as 
a p plica ble

S a m ples r o uti nel y tra ns p orte d b y  r oa d or rail are s u bject t o l ocal re g ulati o ns w hic h 
re q uire t hat t he y are als o pac ke d a n d tra ns p orte d i n a safe a n d a p pr o priate wa y t o 
c o ntai n a n y ris k of i nfecti on or c o nta mi nat i on b y usi n g a p pr o ve d c o uriers a n d 
pac ka gi n g / c o ntai n me nt materials at all ti mes.  T he I A T A 6 5 0 bi o l ogical  sa m ple 
c o ntai n me nt sta n dar ds are e nc o ura ge d w here ver p ossi ble w he n r oa d or rail tra ns p ort 
is use d.
C CI

Clinical Study Protocol Appendix D
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
2
Date
30 Aug 2019
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
2(8)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.....................................................................................2
1.
INTRODUCTION ...............................................................................................3
2.
DEFINITIONS ....................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES.................................4
4.
FOLLOW-UP ......................................................................................................4
4.1
Potential Hy’s Law Criteria not met .....................................................................4
4.2
Potential Hy’s Law Criteria met...........................................................................4
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES..............5
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT ...........7
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL 
HY’S LAW..........................................................................................................7
8.
REFERENCES ....................................................................................................8

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
3(8)
1.
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication, irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
4(8)
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative 

Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF.
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section 6)

Notify the AstraZeneca representative who will then inform the central Study Team.

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
5(8)

Within 1 day of PHL criteria being met, the Investigator will report the case as an 
SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the subject’s 
condition

The Study Physician contacts the Investigator, to provide guidance, discuss and 
agree an approach for the study patient’s follow-up (including any further 
laboratory testing) and the continuous review of data.  

Subsequent to this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long as 
medically indicated. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete the 3 Liver CRF Modules as information becomes available
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this section should be followed for all cases where PHL criteria were met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
                                               
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a significant change will 
be at the discretion of the Investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
6(8)
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE: update the previously submitted 
Potential Hy’s Law SAE and AE CRFs accordingly with the new information 
(reassessing event term; causality and seriousness criteria) following the AZ 
standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP 
and seriousness criteria is medically important, according to CSP process for SAE 
reporting.

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met.  Update the previously submitted PHL
SAE report following CSP process for SAE reporting, according to the outcome of 
the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
7(8)
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW 
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met (including the 30-day 
follow-up period) the Investigator will determine if there has been a significant change in the 
patients’ condition# compared with the last visit where PHL criteria were met

If there is no significant change no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described is 
Section 4.2 of this Appendix.
# A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms such as 
fatigue, vomiting, rash, right upper quadrant pain, jaundice, eosinophilia.  The determination 
of whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW
This section is applicable when a patient meets PHL criteria on study treatment (including the 
30-day follow-up period) and has already met PHL criteria at a previous on study treatment 
visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
                                               
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a significant change will 
be at the discretion of the Investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.

Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 2
Date 30 Aug 2019
8(8)

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study e.g. chronic or progressing malignant disease or 
did the patient meet PHL criteria prior to starting study treatment and at their first 
on study treatment visit as described in Section 6?
If No: follow the process described in Section 4.2 of this Appendix
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met:

If there is no significant change no action is required

If there is a significant change follow the process described in Section 4.2 of this 
Appendix for reporting PHL as an SAE.
8.
REFERENCES
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
                                               
# A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a 
clinically relevant change in associated symptoms, such as fatigue, vomiting, rash, right upper quadrant pain, 
jaundice, eosinophilia.  The determination of whether there has been a significant change will be at the discretion 
of the Investigator; this may be in consultation with the Study Physician if there is any uncertainty.

Clinical Study Protocol Appendix E
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
1
Date
31 March 2014
Appendix E
Acceptable Birth Control Methods

Clinical Study Protocol Appendix E
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
2(2)
1.
ACCEPTABLE BIRTH CONTROL METHODS
Olaparib is regarded as a compound with medium/high foetal risk.
Patients of childbearing potential and their partners, who are sexually active, must agree to the 
use of two highly effective forms of contraception in combination while they are receiving 
study treatment and for 3 months after last dose of study drug.
Acceptable Non-hormonal birth control methods include

Total/True abstinence: when the subject refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; this must 
continue for the total duration of the study treatment and for 3 months after the last 
dose of study drug.  [Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), and withdrawal are not acceptable methods of 
contraception]

Vasectomised sexual partner plus male condom. With participant assurance that 
partner received post-vasectomy confirmation of azoospermia

Tubal occlusion plus male condom

IUD plus male condom. Provided coils are copper-banded
Acceptable hormonal methods  

Etonogestrel implants (eg, Implanon, Norplan) + male condom

Normal and low dose combined oral pills + male condom

Norelgestromin / EE transdermal system + male condom

Intravaginal device + male condom (eg, EE and etonogestrel)

Cerazette (desogestrel) + male condom. Cerazette is currently the only highly 
efficacious progesterone based pill

Clinical Study Protocol Appendix F
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
1
Date
31 March 2014
Appendix F
Guidelines for Evaluation of Objective Tumour Response Using Modified 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours)

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
2 (10)
1.
INTRODUCTION
This appendix details the implementation of modified RECIST (Response Evaluation Criteria 
in Solid Tumours) 1.1 guidelines (Eisenhauer et al 2009) for the study D081FC00001 with 
regards to investigator assessment of tumour burden including protocol-specific requirements 
for this study.
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, 
TARGET AND NON-TARGET LESIONS
Patients with measurable disease and/or non measurable  disease or no evidence of disease 
assessed at baseline by CT (or MRI where CT is contraindicated) will be entered in this study. 
RECIST 1.1 has been modified to allow the assessment of progression due to new lesions in 
patients with no evidence of disease at base-line.
Measurable lesions 
A lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in 
the longest diameter (except lymph nodes which must have a short axis ≥15 mm with CT or 
MRI and which is suitable for accurate repeated measurements.
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 mm to < 15 mm short axis at baseline.  Nodes with < 10 mm 
short axis are considered non-pathological and should not be recorded as non-target 
lesions (NTLs)

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that are not measurable by CT or 
MRI

Previously irradiated lesions. Localised post-radiation changes which affect lesion 
size, may occur.  Therefore, lesions that have been previously irradiated will not be 
considered measurable and must be selected as NTLs at baseline and followed up as 
part of the NTL assessment

Skin lesions assessed by clinical examination 

Brain metastasis

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
3 (10)
Special cases

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient; these non-cystic lesions should be selected as target lesions 
(TLs).
Target lesions
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.
Non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.
3.
METHODS OF MEASUREMENT
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up.
The methods to be used for RECIST assessment are summarised in Table 1 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided.
Table 1
Summary of Methods of Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
X-ray, Chest x-ray
Clinical examination 
CT (preferred)
MRI
X-ray, Chest x-ray, Clinical 
examination
Ultrasound
Bone scan
FDG-PET
3.1
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions.

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
4 (10)
In study D081FC00001 it is recommended that CT examinations of the chest, abdomen and 
pelvis will be used to assess tumour burden at baseline and follow-up visits.  CT examination 
with intravenous contrast media administration is the preferred method.  MRI should be used 
where CT is not feasible or it is medically contra-indicated.  For assessment of brain lesions 
MRI is the preferred method.
3.2
Clinical examination 
In study D081FC00001 clinical examination will not be used for assessment of TL. Clinically 
detected lesions can be selected as target lesions if they are assessed by CT or MRI scans. 
Clinical examination can be used to assess NTL and to identify the presence of new lesions.
3.3
X-rays
3.3.1
Chest X-ray
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions.
3.3.2
Plain X-ray 
In study D081FC00001 plain X-rays may be used as a method of assessment for bone NTLs 
and to identify the presence of new bone lesions. 
3.4
Ultrasound 
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination.
3.5
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements.
3.6
Tumour markers 
Tumour markers will not be used for tumour response assessments per RECIST 1.1.
3.7
Cytology and histology 
Histology will not be used as part of the tumour response assessment per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
5 (10)
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or the appearance of a 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs or disease progression due to new lesions.
3.8
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTLs and followed by the same method as per baseline 
assessment.  
In the D081FC00001 study isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study.  The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion.  Confirmation by CT, MRI and X-
ray is recommended where bone scan findings are equivocal.
3.9
FDG-PET scan 
In the D081FC00001 study FDG-PET (fluorodeoxyglucose positron emission tomography) 
scans may be used as a method for identifying new lesions, according with the following 
algorithm: New lesions will be recorded where there is positive FDG uptake (defined as when 
an uptake greater than twice that of the surrounding tissue is observed) not present on baseline 
FDG-PET scan or in a location corresponding to a new lesion on CT/MRI at the same follow-
up visit.  If there is no baseline FDG-PET scan available, and no evidence of new lesions on 
CT/MRI scans then follow-up CT/MRI assessments should be continued, scheduled as per 
protocol or clinical indicated, in order to confirm new lesions.
4.
TUMOUR RESPONSE EVALUATION 
4.1
Schedule of evaluation
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients and should be performed no more than 28 
days before the start of study treatment.  Follow-up assessments should be performed every 8 
weeks (±1 week) for 40 weeks and then every 12 weeks ± 1 week relative to date of 
randomisation, until objective disease progression as defined by modified RECIST 1.1.  See 
Table 1: Study Schedule from Study Protocol for further information. Any other sites at which 
new disease is suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
6 (10)
is to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
All patients will continue to be assessed for radiological tumour assessments according to the 
study schedule, until objective radiological disease progression, irrespective of reasons for 
discontinuation of treatment.
4.2
Target lesions 
4.2.1
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion, 
which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 

If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 
mm.

If a TL splits into two or more parts, then record the sum of the diameters of those 
parts.

If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s).

If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm.

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
7 (10)

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion.

When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc, 
during the study, the size of the TL should still be provided where possible.
4.2.2
Evaluation of target lesions
Table 2 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs.
Table 2
Overall Visit Response for Target Lesions
Complete Response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to < 10 
mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not evaluable 
or had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable (NE) as a TL 
response
4.3
Non-Target lesions 
4.3.1
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTLs at the investigational site at each visit.
Table 3
Overall Visit Response for Non-Target Lesions 
Complete Response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (< 10 mm short axis).
Non-CR/Non PD
Persistence of one or more NTLs.

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
8 (10)
Progressive Disease (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST 
clinically significant for the physician to consider changing or 
stopping therapy
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and in the investigator’s opinion they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
4.4
New Lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
4.5
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
4.6
Evaluation of Overall Visit Response and Best Overall Response 
The overall visit response will be derived using the algorithm shown in Table 4

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
9 (10)
Table 4
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/non PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
NA
NA
No
NED
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease
IR = incomplete response, NE = not evaluable, NED = no evidence of disease, NA = not applicable (relevant 
when no TLs/NTLs at baseline)
5.
CENTRAL REVIEW 
All CT/MRI scans will be sent to an AstraZeneca appointed Clinical Research Organisation 
(CRO) for blinded independent central review. After the final Progression Free Survival (PFS) 
analysis, central review of scans will no longer be required.  Patients should continue to 
receive study treatment until objective radiological disease progression as per modified 
RECIST 1.1 as assessed by the investigator, and as long as in the investigator’s opinion they 
are benefiting from treatment and they do not meet any other discontinuation criteria.  The 
CRO appointed by AstraZeneca to perform the independent central review for this study will 
provide specification for radiological imaging protocols in standard acquisition guidelines 
documentation.
6.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  

Clinical Study Protocol Appendix F
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
10 (10)
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  
European Journal of Cancer.  45 (2009) 228-247.

Cli nic al St u d y Pr ot oc ol A p pe n di x G
Dr u g S u bsta nce
Ol a pari b
St u d y C o de
D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber
1
Date
3 1 Marc h 2 0 1 4
A p pe n di x G
C CI

Cli nical St u d y Pr ot oc ol A p pe n di x G
Dr u g S u bsta nce Ol a p ari b
St u d y C o de D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber 1
Date 3 1 M ar c h 2 0 1 4
2 ( 2)
 
 
 
 
 
 
C
CI

Clinical Study Protocol Appendix H
Drug Substance
Olaparib
Study Code
D081FC00001
Edition Number
1
Date
31 March 2014
Appendix H
CYP3A4/5 Restrictions

Clinical Study Protocol Appendix H
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
2(4)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.....................................................................................2
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS.....................................................................3
1.
POTENT INHIBITORS OF CYP3A4/5...............................................................3
2.
INDUCERS OF CYP...........................................................................................3
3.
NATURAL / HERBAL PRODUCTS...................................................................4
4.
INTERACTIONS WITH P450.............................................................................4
LIST OF TABLES
Table 1
Competitive inhibitors of CYP3A4/5.......................................................3
Table 2
Time dependent inhibitors of CYP3A4/5.................................................3
Table 3
Inducers of CYP......................................................................................3

Clinical Study Protocol Appendix H
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
3(4)
GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH 
CONCOMITANT MEDICATIONS
NB. While this is not an exhaustive list, it covers the known potent inhibitors and inducers, 
which have most often previously been reported to be associated with clinically significant 
drug interactions.  Please contact the Medical Monitor or AstraZeneca physician if further 
clarification is required.
1.
POTENT INHIBITORS OF CYP3A4/5
In vitro data has shown that the principal enzyme responsible for the formation of the 3 main 
metabolites of olaparib is CYP3A4/5 and consequently, to ensure patient safety, the following 
inhibitors of CYP3A4/5 must not be used during this study.
Table 1
Competitive inhibitors of CYP3A4/5
Drug
Minimum washout period prior to starting olaparib
Ketoconazole
1 Week
Itraconazole
Indinavir
Saquinavir
Telithromycin
Nelfinavir
Table 2
Time dependent inhibitors of CYP3A4/5
Drug
Minimum washout period prior to starting olaparib
Clarithromycin
1 Week
Ritonavir
2.
INDUCERS OF CYP
In addition, to avoid potential reductions in exposure due to drug interactions, the following 
CYP3 inducers should be avoided:
Table 3
Inducers of CYP
Drug
Minimum washout period prior to starting olaparib
Carbamazepine
3 Weeks

Clinical Study Protocol Appendix H
Drug Substance Olaparib
Study Code D081FC00001
Edition Number 1
Date 31 March 2014
4(4)
Table 3
Inducers of CYP
Drug
Minimum washout period prior to starting olaparib
Modafinil
Nevirapine
Phenytoin
Rifabutin
Rifampicin
Rifapentin
St John’s Wort (Hypericum perforatum)
Phenobarbitone
5 Weeks
After randomisation if the use of any potent CYP inducers or inhibitors of CYP3A4/5 are 
considered necessary for the patient’s safety and welfare, the investigator must contact the 
AstraZeneca Study Physician. A decision to allow the patient to continue in the study will be 
made on a case-by-case basis.
3.
NATURAL / HERBAL PRODUCTS
The use of any natural/herbal products or other “folk remedies” should be discouraged but use 
of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded in the appropriate eCRF.
4.
INTERACTIONS WITH P450
Olaparib is an investigational drug for which no data on in vivo interactions is currently
available.  Based on in vitro data and clinical exposure data, olaparib is considered unlikely to 
cause clinically significant drug interactions through inhibition or induction of cytochrome 
P450 enzyme activity.

Cli nic al St u d y Pr ot oc ol A p pe n di x I
Dr u g S u bsta nce
Ol a pari b
St u d y C o de
D 0 8 1 F C 0 0 0 0 1
E diti o n N u m ber
1
Date
3 1 Marc h 2 0 1 4
A p pe n di x I
C CI

C CI

C CI

C CI

C CI

C CI

C CI

C CI