A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 of 1 5 5
Cli nic al St u d y Pr ot oc ol 
St u d y I nter ve nti o n 
Sa v oliti ni b + Osi merti ni b
St u d y C o de 
D 5 0 8 4 C 0 0 0 0 9
Ve rsi o n
3. 0
Date
0 9 Ma y  2 0 2 2 
A M ulti -ce ntre P h ase II, D o u ble-Bli n d, R a n d o mise d St u d y of 
S a v oliti ni b i n C o m bi n ati o n wit h Osi merti ni b vs S a v oliti ni b i n 
C o m bi n ati o n wit h Pl ace b o i n P atie nts wit h E G F R m + a n d M E T 
A m plifie d L oc all y A d v a nce d or Met ast atic N o n -S m all Cell L u n g 
C a ncer w h o h a ve Pr o gresse d F oll o wi n g T re at me nt wit h 
Osi merti ni b
S p o ns or  N a me: Astr a Ze nec a
Le g al Re gister e d A d dress: 
Astra Ze neca A B, 1 5 1 8 5 S ö dertälje, S we de n
Astra Ze neca K. K., 3 -1, Of u ka -c h o, Kit a-k u, Osa ka 5 3 0 -0 0 1 1, Ja pa n
Re g ul at or y A ge nc y I de ntifier  N u m ber(s)
E u dra C T n u m ber: 2 0 2 0- 0 0 0 8 1 3- 3 3
I N D: 1 3 3 2 4 8
T his Cli nical St u d y  Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
Sta n dar d pr oce d ures. T he Cli nical St u d y Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
di s close d a n d/ or p u blis he d acc or di n g t o t he Astr a Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o mplia nce wi t h pre vaili n g la ws a n d re g ulati ons.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
2 of 1 5 5
P r ot oc ol N u m ber: D 5 0 8 4 C 0 0 0 0 9
A me n d me nt N u m ber: 2
St u d y  I nter ve nti on: Sa v o liti ni b i n c om bi nat i on wi t h osi merti ni b, a n d sa v oliti ni b i n 
c o m bi nat i on wi t h place b o t o osi mert i ni b
St u d y  P hase: P hase II
S h ort Title: Sa v o liti ni b pl us osi merti ni b vers us sa v o liti ni b pl us place b o i n E G F R m +/ M E T 
a mplifie d N S C L C f o ll owi n g pri or osi merti ni b
Me dic al M o nit or  N a me a n d C o nt act I nf or m ati o n will be pro vi de d se p ar atel y
I nter n ati o n al c o-o r di n ati n g i n vesti g at or: 
,  
, De part me nt of 
O nc o l og y, Natio nal Taiwa n U ni versit y H os pi t al, N o. 7, C h u n g-S h a n S o ut h R oa d, Tai p ei, 
Ta i wa n, 1 0 0 0 2.
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt 2
0 9 Ma y
2 0 2 2
A me n d me nt 1
2 8 Ma y  2 0 2 1
Ori gi nal Pr ot oc ol
9 J u ne 2 0 2 0
A me n d me nt 2 ( 0 9 M a y
2 0 2 2)
O ver all R ati o n ale f or t he A me n d me nt:
T he ma i n reas o n f or t his gl o bal a me n d me nt is t o i m ple me nt earl y ter mi nati on of st u d y  
recr uit me nt, e x plai n t he s p o ns or’s decisio n  t o ter mi nate recr uitme nt  earl y a n d t o clarif y t he 
necessar y  c ha n ges t o pla n ne d pr ocesses as a res ult of t his. T he desi g n of t his c o ntri but i on of 
c o mp o ne nt st u d y  is n o lo n ger s u p p orti ve of t he sa v olit i ni b de vel o p me nt pr o gra m me i n t his 
st u d y p o p ulat i on. T he c o ntri b uti o n of c o m p o ne nt of sa v o liti ni b m on ot hera p y  (sa v olitini b pl us 
pl ace b o t o osi merti ni b) vers us sa v o liti ni b i n c o m bi nati on wi t h osi merti ni b will c o nti n ue t o be 
assesse d i n t he o n g o i n g S AV A N N A H st u d y . F urt her c ha n ges i ncl u de a d ditio n al  instr ucti o ns i n 
r elat i on t o t he ma na ge me nt of t o xicities t o ali g n wit h e mer gi n g safet y data, t he a d ditio n of  a n 
I n de pe n de nt He patic Assess me nt C o m mittee u p o n Re g ulat or y  re q uest, u p dates t o te xt t o ali g n 
wi t h t he c urre nt C S P te m plate, mi n or a d mi nistrati ve c ha n ges , a n d t he c orrecti o n of mi n or 
err ors. C ha n ges i n G l obal C S P A me n d me nt 2 are prese nte d i n t he ta ble bel o w .
P P D
P P D

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 of 1 5 5
Secti o n # a n d N a me 
Descri pti o n of C h a n ge
Brief R ati o n ale 
S u bst a nti al/
N o n -s u bst a nti al
1. 1 S y n o psis, 4. 1. 1 
Ra n d o mise d St u d y 
Desi g n, 9. 2 Sa m ple Size 
Deter mi nati o n
Te xt a me n de d a n d a d de d t o 
e x plai n t hat t he pla n ne d n u m ber 
of ra n d o mise d patie nts will n ot 
be met d ue t o earl y ter mi nati o n 
of st u d y recr uit me nt. 
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
1. 1 S y n o psis, 4. 1. 1 
Ra n d o mise d St u d y 
Desi g n, 4. 1. 2 Cr oss -o ver 
St u d y Desi g n, 9. 5 
I nteri m A nal yses, 9. 6. 1 
I n de pe n de nt Data 
M o nit ori n g C o m mittee, 
A p pe n di x A 5 
C o m mittees Str uct ure
Te xt a me n de d a n d a d de d t o 
e x plai n t hat t he pla n ne d i nteri m 
f utilit y a nal ysis will n o l o n ger 
be perf or me d d ue t o ter mi nati o n 
of st u d y recr uit me nt. 
Alter nati vel y, a n earl y re vie w of 
t he data will be perf or me d 
f oll owi n g st u d y recr uit me nt 
ter mi nati o n.
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
1. 1 S y n o psis, 4. 1. 1 
Ra n d o mise d St u d y 
Desi g n, 9. 4. 1. 2 
M ulti plicit y Strate g y f or 
Pri mar y  a n d Ke y 
Sec o n dar y E n d p oi nts, 
9 . 4. 2. 2 A nal ysis of 
Sec o n dar y Efficac y 
E n d p oi nts
  
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
1. 1 S y n o psis, 4. 1. 2 
Cr oss -o ver St u d y 
Desi g n, 9. 5 I nteri m 
A nal y ses, 9. 6.1 
I n de pe n de nt Data 
M o nit ori n g C o m mittee, 
A p pe n di x A 5 
C o m mittees Str uct ure
Te xt a me n de d a n d a d de d t o 
e x plai n t hat t he I D M C, w hic h 
was pla n ne d t o m o nit or 
efficac y, is n o l o n ger re q uire d, 
as a res ult of earl y ter mi nati o n 
of st u d y re cr uit me nt. 
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
1. 3 Sc he d ule of 
Acti vities, Ta ble 1 a n d 
Ta ble 2, 8. 5. 1 
P har mac o ki netics, 
Ta ble 1 0
Re m o val of t he re q uire me nt f or 
P K sa m ple c ollecti o n at 
C y cle 1 1 a n d Treat me nt 
Disc o nti n uati o n Visit d uri n g t he 
ra n d o mise d treat me nt peri o d, 
a n d f or all P K sa m ple c ollecti o n 
d uri n g t he cr oss -o ver treat me nt 
peri o d.
N o l o n ger re q uire d 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 of 1 5 5
Secti o n # a n d N a me 
Descri pti o n of C h a n ge
Brief R ati o n ale 
S u bst a nti al/
N o n -s u bst a nti al
1 . 3 Sc he d ule of 
Acti vities, Ta ble 1 a n d 
Ta ble 2
 
 
 
 
 
T o pr o vi de clarificati o n. 
N o n -s u bsta ntial
1. 3 Sc he d ule of 
Acti vities , Ta ble 1 a n d 
Ta ble 2
A d de d te xt pertai ni n g t o 
acti vities f or t h ose patie nts t hat 
c o nti n ue o n st u d y after t he fi nal 
D C O .
T o pr o vi de clarificati o n. 
N o n -s u bsta ntial
1. 3 Sc he d ule of 
Acti vities , Ta ble 2 , 8. 1. 1 
C T a n d M RI Sca ns 
T u m o ur Assess me nts 
( R E CI S T 1. 1)
A d de d te xt t o clarif y ti mi n gs f or 
t u m ou r assess me nt sc he d ules 
f or patie nts w h o cr oss-o ver t o 
sa v oliti ni b pl us osi merti ni b.
T o pr o vi de clarificati o n. 
N o n -s u bsta ntial
1. 1 S y n o psis, 4. 1. 1 
Ra n d o mise d St u d y 
Desi g n, 4. 1 . 2 Cr oss-o ver 
St u d y Desi g n, 4. 1. 4 
Earl y  St u d y Recr uit me nt 
Ter mi nati o n, 9. 4. 1. 2 
M ulti plicit y Strate g y f or 
Pri mar y  a n d Ke y 
Sec o n dar y E n d p oi nts, 
9. 4. 2. 2 A nal ysis of 
Sec o n dar y Efficac y 
E n d p oi nts
Te xt a me n de d t o descri be t he 
c ha n ges t o t he ori gi nal pla n ne d 
ti mep oi nts f or a nal ysis, a n d t o 
e x plai n t hat t he fi nal a nal ysis 
will occ ur f oll o wi n g a fi nal 
D C O , w hic h will occ ur
9 m o nt h s after t he last patie nt 
has bee n ra n d o mise d.
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
4. 1. 2 Cr oss -o ver St u d y 
Desi g n, 4. 1. 4 Earl y 
St u d y Recr uit me nt 
Ter mi nati o n, 9. 4. 2. 2 
A nal y sis of Sec o n dar y 
Efficac y E n d p oi nt s, 9. 5 
I nteri m A nal yses
Te xt a me n de d t o clarif y t hat 
f oll o wi n g Astra Ze neca’s earl y 
re vie w of data after recr uit me nt 
ter mi nati o n, t he st u d y will be 
u n bli n de d, a n d patie nts 
ra n d o mise d t o t he sa v oliti ni b 
pl us place b o ar m will be gi ve n 
t he o p p ort u nit y t o cr oss-o ver t o 
t he sa v oliti ni b pl us osi merti ni b 
ar m. 
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
4. 1. 2 Cr oss -o ver St u d y 
Desi g n, 4. 1. 4 Earl y 
St u d y Recr uit me nt 
Ter mi nati o n
Te xt a d de d t o e x plai n t hat a n y 
patie nts re mai ni n g o n 
sa v oliti ni b m o n ot hera p y at t he 
ti me of fi nal data base l oc k will 
be offere d t he s witc h t o 
sa v oliti ni b pl us Osi merti ni b.
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 of 1 5 5
Secti o n # a n d N a me 
Descri pti o n of C h a n ge
Brief R ati o n ale 
S u bst a nti al/
N o n -s u bst a nti al
4. 1. 4 Earl y St u d y 
Re cr uit me nt Ter mi nati o n
Ne w secti o n a d de d t o clarif y t he 
decisi o n b y Astra Ze neca t o 
ter mi nate st u d y recr uit me nt a n d 
t he st u d y acti vities t o be 
perf or me d f oll o wi n g 
ter mi nati o n of recr uit me nt.
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
4. 4 E n d of St u d y 
Defi niti o n
E n d of st u d y defi niti o n 
a me n de d fr o m 1 8 m o nt hs after 
t he last patie nt ra n d o mise d, or 
w h e n 7 0 % of patie nts ha ve 
pr o gresse d or die d, t o t he date 
of t he last visit of t he last patie nt 
i n t he st u d y. 
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
6. 2 
Pre parati o n/ Ha n dli n g/
St ora ge/ Acc o u nta bilit y 
of I nter ve nti o ns
Te xt c orrecte d t o i n dicate t hat 
g ui da nce o n fi nal dis p ositi o n of 
u n use d st u d y i nter ve nti ons ca n 
be f o u n d i n t he P har mac y 
Ma n ual a n d n ot t he Ce ntral 
La b orat o r y Ma n ual.
T o c orrect err or.
N o n -s u bsta ntial
6. 3 Meas ures t o 
Mi ni mise Bias: 
Ra n d o misati o n a n d 
Bli n di n g
Te xt a me n de d t o clarif y t hat t he 
st u d y will be u n bli n de d 
f oll o wi n g c o m pleti o n of data 
clea ni n g acti vities o n t he i nitial 
D C O data. 
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
6. 7 I nter ve nti o n after t he 
E n d of t he St u d y
Te xt a d de d t o clarif y t he pr ocess 
relati n g to pr o visi o n of st u d y 
i nter ve nti on b y  Astra Ze neca at 
t he e n d of t he st u d y.
A d de d i n li ne wit h u p date d 
C S P te m plate la n g ua ge.
N o n -s u bsta ntial
6. 7 I nter ve nti o n after t he 
E n d of t he St u d y
Te xt a d de d t o e x plai n h o w 
tra nsiti oni n g t o a r oll -o ver st u d y 
(if a vaila ble) w o ul d occ ur. 
A d de d i n li ne wit h t he 
p ossi bilit y of j oi ni n g a 
r oll-o ver st u d y.
N o n -s u bsta ntial
8 St u d y Assess me nts a n d 
Pr oce d ures
Deleti o n of t he l ast b ullet p oi nt 
relati n g t o t he ma xi m u m 
a m o u nt of bl o o d c ollect e d fr o m 
eac h patie nt d uri n g t he st u d y.
T o ali g n wit h t he c urre nt 
C S P te m plate.
N o n -s u bsta ntial
8. 2. 5 Cli nical Safet y 
La b orat o r y Assess me nts
Te xt c orrecte d t o i n dicate t hat 
cli nical safet y la b orat or y 
assess me nts will be perfor me d 
i n a lice nse d l ocal cli nical 
la b orat or y acc or di n g t o l ocal 
sta n dar d pr oce d ures a n d n ot i n 
acc or da nce wit h t he Ce ntral 
La b orat o r y Ma n ual.
T o c orrect err or.
N o n -s u bsta ntial

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi mert i ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 of 1 5 5
Secti o n # a n d N a me 
Descri pti o n of C h a n ge
Brief R ati o n ale 
S u bst a nti al/
N o n -s u bst a nti al
9. 4 Statistical A nal yses
Te xt a me n de d t o clarif y t hat t he 
S A P will n o l o n ger be fi nalise d 
pri or t o t he f utilit y a nal ysis 
D C O b ut pri or t o t he u n bli n di n g 
of t he st u d y t hat will occ ur 
f oll o wi n g recr uit me nt 
ter mi nati o n.
T o pr o vi de clarificati o n 
f oll o wi n g Astra Ze neca’s 
decisi o n t o ter mi nate st u d y 
recr uit me nt.
S u bsta ntial
9. 4. 4 P har mac o ki netic 
A nal y ses
Re m o ve d t he calc ulati o n of t he 
rati o of Cpr e -d ose C ycle 1 1 
Da y 1/ C pr e -d ose C ycle 2 Da y 1
N o l o n ger a p plica ble si nce 
t he re q uire me nt f or P K 
sa m ple c ollecti o n at 
C y cle 1 1 has bee n 
re m o ve d.
N o n -s u bsta ntial
9. 6 Data M o nit ori n g 
C o m mittee, A p pe n di x 
A 5 C o m mittee s Str uct ure
Secti o n 9. 6 n o w s plit i nt o 2 
s u b-secti o ns ( 9. 6. 1 I n de pe n de nt 
Data M o nit ori n g C o m mittee) 
a n d 9. 6. 2 I n de pe n de nt He patic 
Assess me nt C o m mittee) t o 
i nc or p orate t he a d diti o n of t he 
I n de pe n de nt He patic 
Assess me nt C o m mit tee, w hic h 
will re vie w safet y data relate d t o 
he patic e ve nts as per case 
defi niti o n of dr u g -i n d uce d li ver 
i nj ur y.
Pr o gra m -wi de i ntr o d ucti o n 
base d o n Re g ulat or y 
re q uest.
S u bsta ntial
A p pe n di x I 1 
Ma na ge me nt of St u d y 
Treat me nt -relate d 
T o xicities, Ta ble I 2
A d diti o nal i nstr ucti o n f or 
osi merti ni b disc o nti n uati o n f or 
s ym pt o matic c o n gesti ve heart 
fail ure.
T o ali g n wit h e mer gi n g 
safet y data.
S u bsta ntial
A p pe n di x I 1. 1 
G ui deli nes f or t he 
Ma na ge me nt of 
O verla p pi n g T o xicities 
bet wee n Osi merti ni b a n d 
Sa v oliti ni b, Ta bl e I 3
A d diti o nal i nstr ucti o n f or Q Tc 
pr ol o n gati o n i ncl u de d i n 
relati on t o rec o m me nce me nt of 
osi merti ni b d osi n g w h er e 
ca usalit y ma y be diffic ult t o 
deter mi ne.
T o ali g n wit h e mer gi n g 
safet y data.
S u bsta ntial
A p pe n di x I 2 
Osi merti ni b D ose 
M o dificati o n a n d 
G ui da nce
Te xt a d de d t o clarif y t hat 
wit h dra wal fr o m t he st u d y 
s h o ul d occ ur 3 wee ks fr o m t he 
ti me osi merti ni b was 
wit h hel d/i nterr u pte d, rat her t ha n 
3 wee ks fr o m o nset of t o xicit y.
T o pr o vi de clarificati o n.  
N o n -s u bsta ntial
A p pe n di x I 3. 2. 1 D ose 
M o dificati o n D ue t o 
Dr u g -relate d 
He pat ot o xicit y
A d diti o nal i nstr ucti o n i ncl u de d 
i n relati o n t o disc o nti n ui n g dr u g 
w h e n dr u g is alrea d y bei n g 
wit h hel d.
T o ali g n wit h e mer gi n g 
safet y data.
S u bsta ntial

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 of 1 5 5
Secti o n # a n d N a me 
Descri pti o n of C h a n ge
Brief R ati o n ale 
S u bst a nti al/
N o n -s u bst a nti al
A p pe n di x J 1 Dr u gs 
I n d uci n g C Y P 3 A 4 
Meta b olis m t hat 
Astra Ze neca Str o n gl y 
Rec o m me n d are n ot 
C o m bi ne d wit h 
Osi merti ni b or 
Sa v oliti ni b, Ta ble J 1
Clarificati o n t o hi g hli g ht t hat 
p h e n o bar bital is als o k n o w n as 
p h e n o bar bit o ne a n d c ha n ge i n 
re q uire d wit h dra wal peri o d f or 
p h e n o bar bit o ne pri or t o 
o si merti ni b or sa v oliti ni b start 
fr o m 5 wee ks t o 3 wee ks.
T o pr o vi de clarificati o n.  
N o n -s u bsta ntial
A p pe n di x J 5. 1 Dr u gs 
wit h a K n o w n Ris k of 
T d P, Ta ble J 4
F o ot n ote “ b” a d de d t o clarif y 
t hat t he val ues f or eac h dr u g are 
deter mi ne d fr o m i nter nal re vie w 
of P K half- life of eac h 
c o m p o u n d.
T o pr o vi de clarificati o n. 
N o n -s u bsta ntial
A p pe n di x K 
A b bre viati o ns
Ne w a b bre viati o ns a d de d 
A d mi nistrati ve c ha n ge. 
N o n -s u bsta ntial
A p pe n di x L S u m mar y of 
C ha n ges
Create d t o c o ver s u m mar y of 
c ha n ges t o A me n d me nt 1 
( 2 8 Ma y
2 0 2 1)
A d mi nistrati ve c ha n ge. 
N o n -s u bsta ntial
1 1 Refere nces
A d diti o n of o ne ne w refere nce 
( Ait hal et al 2 0 1 1)
I n li ne wit h u p date d te xt i n 
Secti o n 9. 6. 2.
N o n -s u bsta ntial
C pr e -d ose = plas ma c o nce ntrati o n pre -d ose; C S P = Cli nical St u d y Pr ot oc ol ; C T = c o m p ute d t o m o gra p h y; D C O = 
data c ut -off; I D M C = i n de pe n de nt data m o nit ori n g c o m mittee; M RI
= ma g netic res o na nce i ma gi n g; P K = 
p har mac o ki netic s; Q Tc = c orrecte d Q T i nter val; 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; S A P 
= Statistical A nal ysis Pla n; T d P = T orsa des de P oi ntes.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 of 1 5 5
T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................1
P R O T O C O L  A M E N D M E N T SU M M A R Y O F C H A N G E S T A B L E .....................................2
T A B L E O F C O N T E N T S ......................................................................................................8
1 
P R O T O C O L  S U M M A RY ................................................................................1 3
1. 1 
S y n o psis ...........................................................................................................1 3
1. 2 
Sc he ma .............................................................................................................1 8
1. 3 
Sc he d ule of Ac tivit ies .......................................................................................1 9
2 
I N T R O D U C TI O N ............................................................................................3 0
2. 1 
St u d y  Ratio nale ................................................................................................3 2
2. 2 
Bac k gr o u n d ......................................................................................................3 3
2. 3 
Be nefit/ Ris k Assess me nt ...................................................................................3 3
2. 3. 1 
Ris k Assess me nt ...............................................................................................3 3
2. 3. 2 
Be nefit Assess me nt ...........................................................................................3 7
2. 3. 3 
O verall Be nefit: Ris k C o ncl usi o n ......................................................................3 7
3 
O BJ E C TI V E S A N D E N D P O I N T S ...................................................................3 8
4 
S T U D Y  D E SI G N .............................................................................................4 0
4. 1 
O verall De si g n ..................................................................................................4 0
4. 1. 1 
Ra n d o mise d St u d y  Desi g n................................................................................4 0
4. 1. 2 
Cr oss -o ver St u d y  Desi g n ..................................................................................4 1
4. 1. 3 
E n d of St u d y  Desi g n.........................................................................................4 2
4. 1. 4 
Earl y St u d y  Recr uit me nt Ter mi nat i on ...............................................................4 2
4. 2 
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................4 3
4. 2. 1 
Rati o nale f or St u d y  Desi g n...............................................................................4 3
4. 3 
J ustificati o n f or D ose........................................................................................4 4
4. 3. 1 
Rati o nale f or E n d p oi nts ....................................................................................4 5
4. 4 
E n d of St u d y  Defi niti on ....................................................................................4 5
5 
S T U D Y  P O P U L ATI O N ....................................................................................4 5
5. 1 
I ncl usi on Cri t eria ..............................................................................................4 6
5. 2 
E xcl usi o n Cri t eria .............................................................................................4 8
5. 3 
Lifest yle C o nsi derat i ons ...................................................................................5 1
5. 3. 1 
Meals a n d Dietar y  Restrict i ons .........................................................................5 1
5. 3. 2 
Pre g na nc y a n d C o ntrace pti o n ............................................................................5 1
5. 3. 3 
Ot her Lifest yle Restrict i ons ..............................................................................5 2
5. 4 
Scree n Fail ures ................................................................................................. 5 2
6 
S T U D Y  I N T E RV E N TI O N ...............................................................................5 2
6. 1 
St u d y  I nter ve nti ons A d mi nistere d .....................................................................5 3
6. 1. 1 
I n vesti gati onal Pr o d ucts ....................................................................................5 3

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 of 1 5 5
6. 2 
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y of  I nter ve nti ons ..........................5 5
6. 3 
Meas ures t o Mi ni mise Bias: Ra n d o misat i on a n d Bli n di n g ................................. 5 5
6. 4 
St u d y  I nter ve nti on C o m plia nce .........................................................................5 6
6. 5 
C o nc o mita nt T hera p y ........................................................................................5 7
6. 5. 1 
Ot her C o nc o mita nt Treat me nt ...........................................................................6 0
6. 6 
D ose M o dificat i on ............................................................................................6 0
6. 7 
I nter ve nti o n after t he E n d of t he St u d y..............................................................6 0
7 
DI S C O N TI N U A TI O N 
O F 
S T U D Y  IN T E R V E N TI O N 
A N D 
P ATI E N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................6 1
7. 1 
Di sc o nti n uatio n of  St u d y I nter ve nti on ...............................................................6 1
7. 1. 1 
Rec halle n ge ......................................................................................................6 2
7. 1. 2 
Pr oce d ures f or Disc o nt i n uati on of St u d y  I nter ve nti o n.......................................6 2
7. 2 
Pati e nt With dra wal  fr o m t he St u d y....................................................................6 3
7. 3 
L ost t o F oll o w u p ..............................................................................................6 3
8 
S T U D Y  A S S E S S M E N T S A N D P R O C E D U R E S ..............................................6 4
8. 1 
Ef ficac y Assess me nts........................................................................................6 5
8. 1. 1 
C T a n d M RI Sca ns T u m o ur Assess me nts ( R E CI S T 1. 1) ....................................6 5
8. 1. 2 
S ur vi val F o ll ow- u p ...........................................................................................6 6
8. 2 
S af et y Assess me nts ...........................................................................................6 7
8. 2. 1 
P h ysical E xa mi nat i ons ......................................................................................6 7
8. 2. 2 
Vit al Sig ns........................................................................................................ 6 7
8. 2. 3 
Electr ocar di o gra ms ...........................................................................................6 8
8. 2. 4 
M ul ti-gate d Ac q uisit i on/ Ec h ocar di o gra m ..........................................................6 8
8. 2. 5 
Cli nical Safet y  La b orat or y Assess me nts............................................................6 9
8. 2. 6 
Ser u m  of Uri ne Pre g na nc y Test .........................................................................7 0
8. 3 
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................7 0
8. 3. 1 
Ti me Peri o d a n d Fre q ue nc y f or C ollect i n g A E a n d S A E I nf or mati on ................7 1
8. 3. 2 
F o ll ow- u p of  A Es a n d S A Es .............................................................................7 1
8. 3. 2. 1 
A d verse E ve nt Varia bles ...................................................................................7 1
8. 3. 3 
Ca usalit y C o llecti on ..........................................................................................7 2
8. 3. 4 
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ................................................7 2
8. 3. 5 
A d verse E ve nts Base d o n E xa mi nat i ons a n d T ests ............................................7 2
8. 3. 6 
H y ’s La w ..........................................................................................................7 3
8. 3. 7 
Di sease Pr o gressio n ..........................................................................................7 3
8. 3. 8 
Di sease U n der St u d y.........................................................................................7 3
8. 3. 9 
Ne w Ca ncers .....................................................................................................7 3
8. 3. 1 0 
Re p orti n g of Seri o us A d verse E ve nts ................................................................7 4
8. 3. 1 1 
Pre g na nc y .........................................................................................................7 4
8. 3. 1 1. 1 
Mater nal E x p os ure ............................................................................................7 5
8. 3. 1 1. 2 
Pater nal  E x p os ure.............................................................................................7 5
8. 3. 1 2 
Me dicat i on Err or ...............................................................................................7 6
8. 4 
O ver d ose ..........................................................................................................7 6
8. 5 
H u m a n Biol o gical  Sa m ples...............................................................................7 6

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 of 1 5 5
Ta ble 2 
Sc he d ule of Act i vities f or Patie nts w h o Cr oss-o ver t o Sa v olit i ni b pl us 
Osi mert i ni b fr om Sa v o liti ni b Pl us Place b o...............................................2 6
Ta ble 3 
Ris k Assess me nt ......................................................................................3 4
Ta ble 4 
O bject i ves a n d E n d p oi nts.........................................................................3 8
Ta ble 5 
I n vesti gati onal Pr o d ucts ...........................................................................5 4
Ta ble 6 
Restricte d Me dicat i ons .............................................................................5 8
Ta ble 7 
D ose Re d ucti o n f or Sa v olit i ni b t o Ma na ge A d verse E ve nts......................6 0
Ta ble 8   
D ose Re d ucti o n f or Osi mert i ni b t o Ma na ge A d verse E ve nts ....................6 0
Ta ble 9 
La b orat or y  S afet y Varia bles .....................................................................7 0
Ta ble 1 0 
P har mac o ki net ic Sa m pli n g Sc he d ule .......................................................7 7
Ta ble 1 1 
P o p ul at i ons f or A nal ysis ..........................................................................8 2
Ta ble H 1 
S u m mar y  of I ma gi n g M o dalit ies f or T u mo ur Assess me nt ......................1 2 0
Ta ble H 2 
R E CI S T E val uati o n of Tar get Lesi o ns ...................................................1 2 8
Ta ble H 3 
R E CI S T 1. 1 E val uat i on of N o n -tar get Lesio ns .......................................1 2 9
Ta ble H 4 
R E CI S T 1. 1 O verall Visit Res p o nse ......................................................1 3 0
Ta ble I 1 
St u d y  Treat me nt D ose M o dificati o n I nstr ucti o ns f or T o xicit ies Relate d 
t o Osi merti ni b a n d/ or Sa v oliti ni b (e xcl u di n g t o xicities that re q uire 
s pecific ma na ge me nt g ui deli nes) ...........................................................1 3 2
Ta ble I 2 
T o xicit ies t hat Re q uire Per ma ne nt Disc o nti n uati o n of St u d y Treat me nt .1 3 3
Ta ble I 3 
Ma na ge me nt of Q Tc Pr ol o n gat i on .........................................................1 3 4
Ta ble I 4 
D ose Re d ucti o n f or Osi mert i ni b t o Ma na ge A d verse E ve nts ..................1 3 6
Ta ble I 5 
D ose Re d ucti o n f or Sa v oli tini b A d verse E ve nts .....................................1 3 7
Ta ble J 1 
Dr u gs I n d uci n g C Y P 3 A 4 .......................................................................1 4 1
Ta ble J 2 
Dr u gs I n hi bit i n g C Y P 1 A 2 .....................................................................1 4 1
Ta ble J 3 
E x p os ure, P har mac o l ogical Acti o n a n d T o xicit y m a y  be I ncrease d or 
Decrease d b y  Osi merti ni b......................................................................1 4 2
Ta ble J 4 
Dr u gs wi t h a K n o w n Ris k of T d P ..........................................................1 4 4
Ta ble J 5 
Dr u gs t hat ma y Pr olo n g Q T I nter val ......................................................1 4 5
LI S T O F A P P E N DI C E S
A p pe n di x A 
Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsiderati o ns .........................9 6
A p pe n di x B 
A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or Rec or di n g, E val uati n g, 
F o ll ow- u p, a n d Re p orti n g ......................................................................1 0 1
A p pe n di x C 
Ha n dli n g of H u ma n Bi o l ogical  Sa m ples ................................................1 0 6

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 of 1 5 5
A p pe n di x D
A p pe n di x E 
Act i ons Re q uire d i n Cases of I ncreases i n Li ver Bi oc he mistr y  a n d 
E val uat i on of H y’s La w .........................................................................1 1 1
A p pe n di x F 
Ne w Y or k Heart Ass ociat i on classificat i on of heart disease ...................1 1 7
A p pe n di x G 
Defi nit i on o f W o me n o f C hil d beari n g P ote ntial a n d Acce pta ble 
C o ntrace pti ve Met h o ds ..........................................................................1 1 8
A p pe n di x H 
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 
R E CI S T 1. 1 Criteria ..............................................................................1 2 0
A p pe n di x I 
D ose M o dificat i ons f or t he Ma na ge me nt of A d verse E ve nts ..................1 3 2
A p pe n di x J 
G ui da nce Re gar di n g P ote ntial I nteracti o ns wit h C o nc o mit a nt 
Me dicat i ons ...........................................................................................1 4 1
A p pe n di x K 
A b bre viat i ons ........................................................................................1 4 6
A p pe n di x L 
S u m mar y  of C ha n ges.............................................................................1 5 0
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 6 of 1 5 5
U n der C S P V 3. 0, t he pla n ne d n u m ber of ra n d o mise d patie nts will n ot be met. T his is a res ult 
of  t he decisio n  b y Astra Ze neca t o ter mi nate st u d y recr uitme nt  earl y.
I nter ve nti o n Gr o u ps a n d D ur ati o n:
All patie nts c o nfir me d as eli gi ble will be gi n treat me nt o n Da y 1 wi t h sa v oliti ni b pl us 
osi mert i ni b or sa v oliti ni b pl us place b o. Treat me nt will c o nti n ue   
 i n 2 8-da y  c ycles 
u nt il either o bjecti ve P D b y  R E CI S T 1. 1 i s assesse d, u nacce pta ble t o xicity occ urs, c o nse nt is 
wi t hdra w n, or a n ot her disc o nt i n uati on cri terio n i s met.
Pati e nts ra n d o mise d t o t he sa v o liti ni b pl us place b o ar m ma y cr oss-o ver t o o pe n -label 
sa v oliti ni b pl us osi merti ni b f oll owi n g i n vest i gat or-assesse d o bject i ve P D t o e ns ure t hat all 
pati e nts e nr olle d ma y ha ve t he o p p ort u nit y t o recei ve t he c o m bi nati on o f sa v oliti ni b pl us 
osi mert i ni b.
D at a M o nit ori n g C o m mittee: 
A n I D M C was t o meet f or t he pla n ne d i nteri m f utilit y a nal ysis t o pr o vide a rec o m me n dat i on 
f or t he c o nti n uatio n of  t his st u d y base d o n efficac y o bser ve d. 
U n der C S P V 3. 0, as a res ult of Astra Ze neca ’s decisio n t o ter mi nate st u d y  recr uit me nt earl y, 
t he pla n ne d i nteri m f ut ility a nal ysis will n ot be perf or me d a n d t here will be n o re q uire me nt f or 
data re vie w b y t he I D M C. Alt er nat i vel y, a n earl y re vie w o f t he data will occ ur f oll owi n g t he
earl y ter mi nati on of  st u d y recr uit me nt .
St atistic al met h o ds:
T he pri mar y  o bjecti ve of t his st u d y is t o assess t he O R R of sa v o liti ni b i n c o m bi nati on wi t h 
osi mert i ni b vers us sa v o liti ni b i n c o m bi nati on wi t h place b o i n patie nts wit h E G F R m +, M E T 
a mplifie d l ocall y a d va nce d or metastatic N S C L C w h o ha ve pr o gresse d o n pre vi o us 
osi mert i ni b t hera p y. T he O R R is defi ne d as t he pr o p orti o n of patie nts wit h meas ura ble disease 
w h o ha ve a C R or P R as deter mi ne d b y  t he i n vesti gat or at t he l ocal site per R E CI S T 1. 1.
Sec o n dar y  effica c y varia bles i ncl u de P F S, D o R, perce nta ge c ha n ge i n t u m o ur size b y  
i n vesti gat or assess me nt a n d O S d uri n g ra n d omise d treat me nt a n d O R R, P F S, D o R a n d 
perce nta ge c ha n ge i n t u m o ur size b y  in vesti gat or assess me nt d uri n g t he cr oss -o ver peri o d.
Ef ficac y data will be s u m marise d a n d a nal yse d usi n g t he FA S. T he F A S will  incl u de all  
ra n d omise d pat ient s wit h treat me nt gr o u ps assig ne d i n acc or da nce wit h t he ra n d o misat i on, 
re gar dless of t he treat me nt act uall y recei ve d. Patie nts w h o were ra n d o mise d b ut di d n ot 
s u bse q ue ntl y recei ve treat me nt will be i ncl u de d i n t he FA S. T he a nal ysis o f data usi n g t he 
F A S t heref ore f oll o ws t he pri nci ples of i nte nt i on- t o-treat. Safety data will be s u m marise d 
usi n g t he S A S, a n d P K data will be s u m marise d usi n g t he P K A nal ysis Set.
Pri or t o C S P V 3. 0, a pri mar y a nal ysis was pla n ne d t o occ ur 6 m o nt hs after t he last patie nt was 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 7 of 1 5 5
ra n d omise d. Wit h 5 6 pati e nts ( 2 8 per ar m)
 
 
. 
A n o n- c o m parati ve i nteri m f utilit y a nal ysis f or t he sa v o liti ni b pl us place b o ar m was pla n ne d 
after 2 0 patie nts o verall ( 1 0 pe r ar m) ha d t he o p p ort u nity t o be treate d f or 2 R E CI S T 
p ost -baseli ne sca ns ( 1 2 wee ks). T he o utc o me of t he i nteri m f ut ility a nal ysis was t o be as 
f oll ows:
 
St o p f urt her e nr ol me nt i nt o t he st u d y  if n o res p o nses are o bser ve d.
 
If tr ue rate = 5 %, t here is a 5 9. 9 % pr o ba bilit y of  o bser vi n g n o res p o nses.
 
If tr ue rate = 1 0 %, t here is a 3 4. 9 % pr o ba bility of  o bser vi n g n o res p o nses.
 
If tr ue rate = 4 3 %, t here is a 0. 4 % pr o ba bility of  o bser vi n g n o res p o nses.
Recr ui t me nt was t o c o nti n ue d uri n g t he i nteri m f utilit y a nal ysis. 
U n der C S P V 3. 0, as a res ult of t he decisi o n b y Astra Ze neca t o ter mi nate st u d y recr uit me nt 
earl y, t he pla n ne d i nteri m f utilit y a nal ysis a n d pri mar y  a nal ysis will  not be perf or m e d. 
Alt er nat i vel y, an earl y re vie w of t he data b y Ast ra Ze neca will  occ ur f oll o wi n g t he earl y 
ter mi nati o n of st u d y recr uit me nt. T he fi nal D C O will  occ ur 9 m o nt hs after t he last patie nt has 
bee n ra n d o mise d, after w hic h t he fi nal a nal ysis will be perf or me d . 
 
 
T he O R R will be a nal yse d usi n g a l o gistic re gressi o n m o d el  a dj usti n g f or t he stratificati on 
use d i n t he ra n d o misat i on. T he res ults of t he a nal ysis will be prese nte d i n ter ms of a n o d ds 
r atio (a n o d ds rati o greater t ha n 1 will fa v o ur sa v o liti ni b i n c om bi nat i on wi t h osi merti ni b 
vers us sa v oliti ni b pl us place b o) t o get her wit h its ass ociate d pr ofile li keli h o o d 9 5 % CI a n d 
p- val ue ( base d o n t wice t he c ha n ge i n l o g -li keli h oo d res ul ti n g fr om t he a d ditio n of  a treat me nt 
fact or t o t he m o del). If t here are n ot e n o u g h res p o nses f or a mea ni n gf ul a nal ysis usi n g l o gist ic 
re gressi o n t he n a C M H test will be prese nte d. S u m maries will be pr o d uce d t hat prese nt t he 
n u m ber a n d perce nta ge of patie nts i n eac h treat me nt gr o u p wit h a t u m o ur res p o nse ( C R/ P R).
S af et y data will be s u m marise d descri pt i vel y a n d will n ot be f or m all y a nal yse d. 
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 1 5 5
1. 3 
Sc he d ule of Acti vities
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
I nf or me d c o nse nt 
f or M E T stat us 
testi n g
X
5. 1
Retrie ve or c ollect 
t u m o ur s peci me n 
f or M E T stat us 
testi n g
X c
5. 1 a n d 8. 6
C o nfir m t u m o ur 
har b o urs E G F R m 
X d
5. 1
Ca ncer t hera p y 
rec or d
X   
X
X   
X
4. 1. 1 a n d 
5. 2
I nf or me d c o nse nt 
f or mai n st u d y
X
5. 1
I ncl usi o n a n d 
e xcl usi o n criteria
X
5. 1 a n d 5. 2
Ra n d o misati o n
X
6. 3

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 1 5 5
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
R o uti ne cli nic al pr oce d ures
De m o gra p h y
X
5. 1
P h ysical 
e xa mi nati o n 
X   
X   
X   
X   
X
E ver y  visit
X
8. 2. 1
Hei g ht
X
8. 2. 2
Wei g ht 
e
X   
X
Da y 1 of e ver y 
c ycle
Q 8 W
X
8. 2. 2
Me dical/s ur gical 
hist or y
X   
X
5. 1
E C O G/ W H O 
perf or ma nce sc ore
X   
X   
X   
X   
X
Da y 1 of e ver y c ycle
X
X
5. 1
Vital si g ns
X   
X   
X   
X   
X
Da y 1 of e ver y c ycle
X
X
8. 2. 2
Tri plicate E C G
X   
X   
X   
X   
X 
Da y 1 of e ver y c ycle f
X
X g
8. 2. 3
M U G A/ E C H O
X
Q 1 2 W ( ± 2 wee ks) relati ve t o ra n d o misati o n
X
X g
8. 2. 4
C o nc o mita nt 
me dicati o n a n d 
pr oce d ures
X
At e ver y visit a n d ma y be c o n d ucte d b y p h o ne if n ot tie d t o a 
cli nical visit
X
X
6. 5

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 1 5 5
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
R o uti ne s afet y me as ure me nts
A d verse e ve nts
X
At e ver y visit a n d ma y be c o n d ucte d b y p h o ne if n ot tie d t o a 
cli nical visit
X
X
8. 3
Pre g na nc y test 
(ser u m or uri ne, 
W O C B P o nl y)
X
Da y 1 of e ver y c ycle
X
8. 3. 1 1
Safet y la b orat or y 
assess me nts 
(cli nical c he mistr y, 
hae mat ol o g y a n d 
uri nal ysis)
X   
X   
X   
X   
X
E ver y  visit
X
8. 2. 5
C oa g ulati o n
X
5. 1
Li ver f u ncti o n 
tests h
X
Wee kl y f or t he first 1 0 wee ks relati ve t o ra n d o misati o n, t he n 
Da y 1 of e ver y s u bse q ue nt c ycle a n d at t he ti me of disease 
pr o gressi o n
X
8. 2. 5

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 1 5 5
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
Bi o m ar ker a n al yses
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 1 5 5
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
P K me as ure me nts
Bl o o d sa m ple f or 
P K a nal ysis of 
sa v oliti ni b m, n
X
n
Da y 1 of C ycles 
2, 3, a n d 6 n
8. 5. 1
Bl o o d sa m ple f or 
P K a nal ysis of 
osi merti ni b m, n
X
n
Da y 1 of C ycles 
2, 3, a n d 6 n
8. 5. 1
Effic ac y me as ure me nts
T u m o ur i ma gi n g o
( R E CI S T 1. 1)
X p
Q 6 W ( ± 7 da ys) u p t o 2 4 wee ks relati ve t o ra n d o misati o n, t he n Q 8 W ( ± 7 da ys) u ntil o bjecti ve disease 
pr o gressi o n
8. 1
St u d y i nter ve nti o n a d mi nistr ati o n
D ose wit h 
osi merti ni b or 
place b o 
X ( dail y d osi n g)
6. 1
D ose wit h 
sa v oliti ni b
X ( dail y d osi n g)
6. 1

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 1 5 5
Ta ble 1 
Sc he d ule of Acti vities f or  R a n d o mise d Tre at me nt
Visit
Pre -
scree ni n g Scree ni n g
I nter ve nti o n Peri o d 
F oll o w -u p a
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit b
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
N A
-4 t o 0
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y
-2 8 t o - 1
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
± 1 d a y
± 3 d a ys 
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
S ur vi v al f oll o w -u p
S ur vi val stat us
Q 1 2 W q
8. 1. 2
a
T he f oll o w -u p peri o d is o nl y a p plica ble f or t h ose w h o disc o nti n ue ra n d o mise d treat me nt a n d d o n ot cr oss -o ver t o treat me nt wit h sa v oliti ni b pl us osi merti ni b. Patie nts w h o 
cr oss -o ver are t o carr y o n assess me nts as per t he S o A i n  Ta ble 2.
b
As a mi ni m u m, tele p h o ne c o ntact s h o ul d be ma de wit h t he patie nt 2 8 da ys f oll o wi n g t he disc o nti n uati o n of st u d y i nter ve nti o n t o c ollect ne w A Es a n d f oll o w u p o n a n y 
o n g oi n g A Es a n d c o nc o mita nt me dicati o ns (i ncl u di n g a n y s u bse q ue nt ca ncer t hera p y, if a p pr o priate).
c
At pre -scree nin g, testi n g f or M E T a m plifie d t u m o ur b y ce ntral FI S H testi n g m ust be perf or me d o n a n F F P E t u m o ur s peci me n c ollecte d after pr o gressi o n of pre vi o us 
osi merti ni b treat me nt, w hic h ma y or ma y n ot ha ve bee n t he m ost rece nt treat me nt. Testi n g ma y be perf or me d as i nitial pre -scree ni n g wit h c o nse nt o btai ne d usi n g t he 
Pre -scree ni n g I C F i n a d va nce of o btai ni n g c o nse nt f or t he mai n st u d y. Detaile d sa m ple re q uire me nts will be defi ne d i n st u d y La b or at or y Ma n ual. M E T a m plifie d is defi ne d 
as i ncrease d ge ne c o p y n u m ber. Sa m ples > 2 years ol d will n ot be acce pte d. Ne w t u m o ur s peci me ns s h o ul d o nl y be c ollecte d s pecificall y f or pre-scree ni n g f or t his st u d y 
w here t he e x pecte d ris k of a n A E relate d t o t he pr oce d ure is < 2 %.
d
E G F R m stat us is a n i ncl usi o n criteri o n a n d part of diseas e dia g n osis a n d a criteri o n t o recei ve osi merti ni b; pr os pecti ve ce ntral testi n g is n ot re q uire d.
e
Wei g ht will be assesse d as s h o w n a b o ve a n d m ore fre q ue ntl y if cli nicall y i n dicate d.
f
Tri plicate E C Gs will be re q uire d o n C ycle 3 Da y 1 c ollecte d pre -d ose a n d at 1, 3, 4 a n d 6 h o urs p ost -d ose t o c oi nci de wit h c ollecti o n of bl o o d sa m ples f or assess me nt of P K 
of osi merti ni b a n d sa v oliti ni b at t his visit. 
g
A 2 8 -d a y f oll o w-u p assess me nt will be re q uire d if a n o n -treat me nt assess me nt was a b n or mal at t he ti me of disc o nti n uati o n of st u d y t hera p y t o c o nfir m re versi bilit y of t he 
a b n or malit y.
h
Li ver f u ncti o n tests will be perf or me d wee kl y f or t he first 1 0 wee ks, t he n Da y 1 of e ver y s u bse q ue nt c ycle a n d at pr o gressi o n. W here a li ver f u ncti o n test is t he o nl y 
assess me nt, a cli nic visit is n ot re q uire d as t he test ma y be perf or me d offsite. I n t he case of ele vate d li ver f u ncti o n tests, please refer t o A p pe n di x  I 3. 2 f or e n ha nce d 
m o nit ori n g a n d ma na ge me nt pr oce d ures.  
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 1 5 5
m
Date a n d ti me of last osi merti ni b d ose pri or t o C ycle 1 Da y 1 ( pri or t o P K sa m ple) will be c ollecte d. I n a d diti o n, date a n d ti me of last osi merti ni b/ place b o d ose a n d last 
sa v oliti ni b d ose pri or t o eac h P K sa m ple will be c ollecte d.
n
Plas ma c o nce ntrati o ns of osi merti ni b, sa v oliti ni b a n d t heir meta b olites. C ollecte d o n: C ycle 1, Da y 1: Pre -d ose a n d 1 a n d 3 h o urs p ost -d ose; C ycle 2, Da y 1: Pre -d ose a n d 
1 a n d 3 h o urs p ost -d ose; C ycle 3, Da y 1: Pre -d ose a n d 1, 3, 4, a n d 6 h o urs p ost -d ose; C ycles 6, Da y 1: Pre -d ose o nl y. P K sa m ple c ollecti o n wi n d o ws are: Pre -d ose, u p t o 
2 h o ur s Pre-d ose; 1 h o ur p ost -d ose, ± 5 mi n utes; 3 h o urs p ost -d ose, ± 1 0 mi n utes; 4 h o urs a n d 6 h o urs p ost -d ose, ± 3 0 mi n utes. 
o
Patie nts w h o disc o nti n ue st u d y i nter ve nti o n f or reas o ns ot her t ha n i n vesti gat or -assesse d disease pr o gressi o n will c o nti n ue R E CI S T 1. 1 t u m o ur assess me nts Q 6 W ( ± 7 da ys) 
relati ve t o ra n d o misati o n u p t o 2 4 wee ks, t he n Q 8 W ( ± 7 da ys) relati ve t o ra n d o misati o n u ntil o bjecti ve disease pr o gressi o n . At t he sa me ti me p oi nts, E C O G/ W H O 
perf or ma nce stat us, vital si g ns, E C Gs, a n d plas ma sa m ples f or c t D N A will be c ollecte d. Seri o us a d verse e ve nts c o nsi dere d relate d t o st u d y i nter ve nti o n a n d/ or st u d y 
pr oce d ures will be c ollecte d t hr o u g h o ut pr o gressi o n f oll o w - u p.
p
At scree ni n g t he M RI/ C T sca ns will i ncl u de brai n i ma gi n g f or all patie nts. T h ose deter mi ne d t o ha ve brai n metastases will ha ve t heir brai n resca n ne d at all s u bse q ue nt 
t u m o ur assess me nts.
q
Patie nts will be c o ntacte d f or s ur vi val f oll o w -u p Q 1 2 W. Patie nts s h o ul d be c o ntacte d i n t he wee k after data c ut -off f or eac h st u d y a nal ysis t o esta blis h s ur vi val stat us. Seri o us 
a d verse e ve nts c o nsi dere d relate d t o st u d y i nter ve nti o n will be c ollecte d t hr o u g h o ut s ur vi val f oll o w - u p.
N ote: F or patie nts c o nti n ui n g i n t he st u d y after fi nal D C O, refer t o Secti o n 6. 7 f or re q uire d acti vities.
A E = A d verse e ve nt; C S P = Cli nical St u d y Pr ot oc ol; C T = C o m p ute d t o m o gra p h y; ct D N A = Circ ulati n g t u m o ur D N A; D C O = data c ut -off; E C G = Electr ocar di o gra m; 
E C H O = Ec h ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E G F R = E pi der mal gr o wt h fact or rece pt or; E G F R m = E pi der mal gr o wt h fact or rece pt or m utate d; 
F F P E = F or mali n fi xe d, paraffi n e m be d de d; FI S H = Fl u oresce nce i n sit u h y bri disati o n; 
I C F = I nf or me d C o nse nt F or m; M E T = He pat oc yte 
gr o wt h fact or rece pt or; M RI = Ma g netic res o na nce i ma gi n g; M U G A
= M ulti -gate d ac q uisiti o n; N A = N ot a p plica ble; P K = P har mac o ki netics; Q 6/ 8/ 1 2 W = E ver y 6/ 8/ 1 2 wee ks; 
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; S o As = Sc h e d ule of acti vities;
W H O
= W orl d Healt h Or ga nizati o n; 
W O C B P
= W o me n of c hil d beari n g p ote ntial.
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 6 of 1 5 5
Ta ble 2 
Sc he d ule of Acti vities f or Patie nts w h o C r oss -o ver  to S a v oliti ni b pl us Osi merti ni b fro m S a v olit i ni b Pl us 
Pl ace b o
Cr oss -o ver Visit
Pri or t o 
cr oss -o ver
Cr oss -o ver Peri o d 
F oll o w -u p
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit a
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y of cr oss -o ver
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
N A
± 1 d a y
± 3 d a ys
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
I nf or me d c o nse nt f or 
cr oss -o ver
X
5. 1
Ca ncer t hera p y rec or d
X
X   
X
4. 1. 1 a n d 
5. 2
R o uti ne cli nic al pr oce d ures
P h ysical e xa mi nati o n 
X
E ver y  visit
X
8. 2. 1
Wei g ht 
b
X
Da y 1 of e ver y 
c ycle
Q 8 W
X
8. 2. 2
E C O G/ W H O perf or ma nce 
sc ore
X
Da y 1 of e ver y c ycle
X
X
5. 1
Vital si g ns
X
Da y 1 of e ver y c ycle
X
X
8. 2. 2
Tri plicate E C G
X
Da y 1 of e ver y c ycle c
X
X d
8. 2. 3
M U G A/ E C H O
Q 1 2 W ( ± 2 wee ks) relati ve t o ra n d o misati o n
X
X d
8. 2. 4
C o nc o mita nt me dicati o n a n d 
pr oce d ures
At e ver y visit, ma y be c o n d ucte d b y p h o ne if n ot tie d t o a 
cli nical visit
X
X
6. 5

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 7 of 1 5 5
Ta ble 2 
Sc he d ule of Acti vities f or Patie nts w h o C r oss -o ver  to S a v oliti ni b pl us Osi merti ni b fro m S a v olit i ni b Pl us 
Pl ace b o
Cr oss -o ver Visit
Pri or t o 
cr oss -o ver
Cr oss -o ver Peri o d 
F oll o w -u p
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit a
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y of cr oss -o ver
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
N A
± 1 d a y
± 3 d a ys
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
R o uti ne s afet y me as ure me nts
A d verse e ve nts
At e ver y visit, ma y be c o n d ucte d b y p h o ne if n ot tie d t o a 
cli nical visit
X
X
8. 3
Pre g na nc y test (ser u m or 
uri ne, W O C B P o nl y)
Da y 1 of e ver y c ycle
X
8. 3. 1 1
Safet y la b orat or y 
assess me nts (cli nical 
c he mistr y, hae mat ol o g y a n d 
uri nal ysis)
X
E ver y  visit
X
8. 2. 5
Li ver f u ncti o n tests
e
Wee kl y f or t he first 1 0 wee ks relati ve t o ra n d o misati o n, t he n 
Da y 1 of e ver y s u bse q ue nt c ycle a n d at t he ti me of disease 
pr o gressi o n
X
8. 2. 5
Bi o m ar ker a n al yses
Effic ac y me as ure me nts
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 8 of 1 5 5
Ta ble 2 
Sc he d ule of Acti vities f or Patie nts w h o C r oss -o ver  to S a v oliti ni b pl us Osi merti ni b fro m S a v olit i ni b Pl us 
Pl ace b o
Cr oss -o ver Visit
Pri or t o 
cr oss -o ver
Cr oss -o ver Peri o d 
F oll o w -u p
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1 
( 2 8-d a y c ycle)
C ycles 2 t o 6 
( 2 8-d a y c ycle)
C ycle 7 o n w ar ds 
( 2 8-d a y c ycle)
Tre at me nt 
disc o nti n u ati o n 
visit
2 8- D a y 
f oll o w-u p 
visit a
S ur vi v al 
f oll o w-u p 
visit
Wee k ( D a y 1 of)
1 t o 4
5 t o 2 4 
2 5 o n w ar ds
St u d y d a y of cr oss -o ver
1 t o 2 8
2 9 t o 1 6 8 
1 6 9 o n w ar ds
D a y of c ycle
1  
8  
1 5  
2 2  
1
1
Visit wi n d o w
N A
± 1 d a y
± 3 d a ys
± 3 d a ys
Wit hi n 7 d a ys of 
t he fi n al d ose of 
st u d y i nter ve nti o n
± 7 d a ys
T u m o ur i ma gi n g h
( R E CI S T 1. 1)
Sc he d ule d i ma gi n g is re q uire d f or patie nts w h o cr oss -o ver after st u d y u n bli n di n g a n d w h o ha ve n ot pr o gresse d 
d uri n g t he i nitial ra n d o mise d treat me nt peri o d: Q 6 W ( ± 7 da ys) u p t o 2 4 wee ks relati ve t o i nitial ra n d o misati o n, 
t he n Q 8 W ( ± 7 da ys) u ntil o bjecti ve disease pr o gressi o n
8. 1
St u d y i nter ve nti o n a d mi nistr ati o n
D ose wit h osi merti ni b 
X ( dail y d osi n g)
6. 1
D ose wit h sa v oliti ni b i
X ( dail y d osi n g)
6. 1
S ur vi v al f oll o w -u p
S ur vi val stat us
Q 1 2 W j
8. 1. 2
S u bse q ue nt a nti -ca ncer 
treat me nt
Q 1 2 W j
8. 1. 2
a
As a mi ni m u m, tele p h o ne c o ntact s h o ul d be ma de wit h t he patie nt 2 8 da ys f oll o wi n g t he disc o nti n uati o n of st u d y i nter ve nti o n t o c ollect ne w A Es a n d f oll o w u p o n a n y 
o n g oi n g A Es a n d c o nc o mita nt me dicati o ns (i ncl u di n g a n y s u bse q ue nt ca ncer t hera p y, if a p pr o priate).
b
Wei g ht will be assesse d as s h o w n a b o ve a n d m ore fre q ue ntl y if cli nicall y i n dicate d.
c
Tri plicate E C Gs will be re q uire d o n C ycle 3 Da y 1 c ollecte d pre -d ose a n d at 1, 3, 4 a n d 6 h o urs p ost -d ose t o c oi nci de wit h c ollecti o n of bl o o d sa m ples f or assess me nt of P K 
of osi merti ni b a n d sa v oliti ni b at t his visit.
d
A 2 8 -d a y f oll o w-u p assess me nt will be re q uire d if a n o n -treat me nt assess me nt was a b n or mal at t he ti me of disc o nti n uati o n of st u d y t hera p y t o c o nfir m re versi bilit y of t he 
a b n or malit y.
e
Li ver f u ncti o n tests will be perf or me d wee kl y f or t he first 1 0 wee ks fr o m ra n d o misati o n, t he n Da y 1 of e ver y s u bse q ue nt c ycle a n d at pr o gressi o n. W here a li ver f u ncti o n test 
is t he o nl y assess me nt, a cli nic visit is n ot re q uire d as t he test ma y be perf or me d offsite. I n t he case of ele vate d li ver f u ncti o n tests, please refer t o A p p e n di x I 3. 2 f or 
e n ha nce d m o nit ori n g a n d ma na ge me nt pr oce d ures.  

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 9 of 1 5 5
h
F or patie nts w h o cr oss -o ver base d o n c o nfir me d o bjecti ve disease pr o gressi o n d uri n g t he i nitial ra n d o mi se d treat me nt peri o d (i ncl u di n g patie nts w h o ha ve alrea d y cr osse d 
o ver base d o n c o nfir me d P D pri or t o C S P Versi o n 3. 0), sc he d ule d R E CI S T 1. 1 t u m o ur assess me nts are n ot re q uire d, a n d t he s u bse q ue nt assess me nt of disease pr o gressi o n 
will be base d o n sta n dar d -of -care sca n or i n vesti gat or deter mi ne d cli nical pr o gressi o n. Sc he d ule d R E CI S T 1. 1 t u m o ur assess me nts are re q uire d (t he sca n fre q ue nc y is a gai nst 
i nitial ra n d o misati o n) f or patie nts w h o cr oss-o ver after st u d y u n bli n di n g a n d w h o ha ve n ot o bjecti vel y pr o gresse d d uri n g t he i nitial ra n d o mi se d treat me nt peri o d. Patie nts 
w h o cr oss -o ver after st u d y u n bli n di n g, w h o ha ve n o o bjecti ve pr o gressi o n d uri n g i nitial ra n d o misati o n peri o d, a n d w h o disc o nti n ue st u d y i nter ve nti o n after cr oss -o ver f or 
reas o ns ot her t ha n i n vesti gat or-c o nfir me d disease pr o gr essi o n will c o nti n ue sc he d ule d R E CI S T 1. 1 t u m o ur assess me nts u ntil o bjecti ve disease pr o gressi o n per R E CI S T 1. 1 
as assesse d b y i n vesti gat or, u nless t he y wit h dra w c o nse nt t o t he e ntire st u d y. At t he sa me ti me p oi nts , vital si g ns, E C Gs a n d plas ma sa m ples f or ct D N A will be c ollecte d. 
Seri o us a d verse e ve nts c o nsi dere d relate d t o st u d y i nter ve nti o n a n d/ or st u d y pr oce d ures will be c ollecte d t hr o u g h o ut pr o gress i o n f oll o w- u p.
i
Patie nts w h o cr oss -o ver m ust n ot recei ve a n y ot her a nti -ca ncer t hera pies bet wee n t he asses s me nt of P D a n d t he a d diti o n of osi merti ni b. Sa v oliti ni b treat me nt s h o ul d c o nti n ue 
u ni nterr u pte d d uri n g t his peri o d.
j
Patie nts will be c o ntacte d f or s ur vi val f oll o w -u p Q 1 2 W. Patie nts s h o ul d be c o ntacte d i n t he wee k after data c ut -off f or eac h st u d y a nal ysis t o esta blis h s ur vi val stat us. Seri o us 
a d verse e ve nts c o nsi dere d relate d t o st u d y i nter ve nti o n will be c ollecte d t hr o u g h o ut s ur vi val f oll o w - u p.
N ote: F or patie nts c o nti n ui n g i n t he st u d y after fi nal D C O, refer t o Secti o n  6. 7 f or re q uire d acti vities.
A E = A d verse e ve nt; C S P = Cli nical St u d y Pr ot oc ol; ct D N A = Circ ulati n g t u m o ur D N A; E C G = Electr ocar di o gra m; E C H O = Ec h ocar di o gra m; E C O G = Easter n C o o perati ve 
O nc ol o g y Gr o u p; E G F R = E pi der mal gr o wt h fact or rece pt or; M U G A = M ulti -gate d ac q uisiti o n; N A = N ot a p plica ble; P D = Pr o gressi ve disease; P K = P har mac o ki netics; 
Q 6/ 8/ 1 2 W = E ver y 6/ 8/ 1 2 wee ks; 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; W H O = W orl d Healt h Or g a nizati o n; W O C B P = W o me n of c hil d beari n g p ote ntial.
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 0 of 1 5 5
2 
I N T R O D U C TI O N
L u n g ca ncer has bee n t he m ost c o m m o n ca ncer i n t he w orl d f or se veral deca des, a n d b y 2 0 1 8, 
t here were a n esti mate d 2. 1 milli o n ne w cases, re prese nt i n g 1 1. 6 % of all ne w ca ncers. It was 
als o t he m ost c o m m o n ca use of deat h fr o m ca ncer, wit h 1. 7 6 milli o n deat hs ( 1 8. 4 % of t he 
t otal; G L O B O C A N 2 0 1 8 ). N o n-s mall cell lu n g ca ncer re prese nts a p pr o x i matel y 8 0 % t o 
8 5 % of  all l u n g ca ncers. U nf ort u natel y, at t he ti me of dia g n osis a p pr o xi matel y 7 0 % of patie nts 
wi t h N S C L C alrea d y ha ve a d va nce d or metastatic disease n ot a me na ble t o s ur gical resecti on. 
F urt her m ore, a si g nifica nt perce nta ge of patie nts wit h earl y sta ge N S C L C w h o ha ve 
u n der g o ne s ur ger y s u bse q ue nt l y de vel o p dista nt rec urre nce a n d die as a res ult of t heir l u n g 
ca ncer (Pisters a n d Le C he valier 2 0 0 5 ). 
I n c urre nt cli nical pract ice, t hera pe utic decisi ons f or pati e nts wit h a d va nce d N S C L C are 
i nf or me d b y t h e mol ec ular s u bt y pes of t he t u m o ur (Kee d y et al 2 0 1 1 ; Tra vis et al 2 0 1 1 ; 
Lei g hl a n d C uri glia n o 2 0 1 4 ; Rec k et al 2 0 1 4 ; S ori a et al 2 0 1 5 ; Nati o nal C o m pre he nsi ve 
Ca ncer Net w or k [N C C N 2 0 2 0 ]). E pi der mal gr o wt h fact or rece pt or m utati o n a n d a na plastic 
l y m p h oma ki nase rearra n ge me nt are t he m ost well -k n o w n ge netic alterati o ns i n N S C L C. 
E pi d er m al gr o wt h fact or rece pt or-T KIs are t he esta blis he d first -li ne t hera p y i n patie nts wit h 
N S C L C p ossessi n g E G F R m + (Rec k et al 2 0 1 4 ; Masters
et al 2 0 1 5 ; N C C N 2 0 2 0 ). T he 
prese nce of E G F R m i n pat ient s wit h N S C L C t u mo urs c o nfers se nsit i vity t o t he E G F R-T KI 
class of dr u gs i n a hi g h perce nta ge of patie nts, h o we ver, t he res p o nse t o t his class o f a ge nts is 
e ve nt uall y l ost d ue t o de vel o p me nt of a variet y of  resista nce mec ha nis ms, wit h t he E G F R 
T 7 9 0 M m utati o n bei n g a maj or r o ute of de vel o p me nt of resista nce t o t his class of t hera p y . I n 
a d ditio n t o t he de vel o p me nt of T 7 9 0 M m utati o ns, ot her r o utes of ac q uire d resista nce t o 
E G F R -T KI t hera p y  incl u de acti vati o n o f a b y pass si g nalli n g pat h wa y (s uc h as M E T 
a mplificat i on, h u ma n e pi der mal gr o wt h fact or rece pt or 2 u pre g ulat i on or reti c ular acti vat i n g 
s yste m mut ati o ns), hist ol o gi c al tra nsf or mati o n t o s mall c ell lu n g ca ncer a n d e pit helial 
mese nc h y mal tra nsit i on ( O has hi et al 2 0 1 2 ; C h o n g a n d Jä n ne 2 0 1 3 ; Ca mi d ge et al 2 0 1 4 ). 
Treat me nt f o ll owi n g pr o gressi o n o n E G F R -T KI t hera p y  will be g uid e d b y patie nt 
perf or m a nce stat us, s y m pt o ms, m o lec ular a berrat i o n a n d e xte nt of disease. I n patie nts a ble t o 
t olerate d o u blet c he mot h era p y a nd w h o are T 7 9 0 M -ne gat i ve, or if osi merti ni b is u na vaila ble, 
pl at i n u m-base d c he m ot hera p y  w o uld m ost of te n be t he preferre d sec o n d-li ne treat me nt 
( NC C N 2 0 2 0 ). T here is n o gl o bal sta n dar d of care f or later li nes of t hera p y; f oll owi n g 
pr o gressi o n o n a n E G F R -T KI or d o u blet c he m ot hera p y, t he o nl y re mai ni n g o pti o ns are 
rec halle n ge with E G F R -T KI or sal va ge si n gle -a ge nt c he m ot hera p y or cli nical st u dies 
(La n ger et al 2 0 1 3 ). Plat i n u m-base d c he mot h era p y p ost E G F R-T KI f or E G F R m + N S C L C 
ge nerall y pr o vi des res p o nse rates i n t he ra n ge o f 2 0 % t o 3 0 % (Gri delli et al 2 0 1 2 ; 
S oria et al 2 0 1 5 ), a n d t he P F S is relati vel y s h ort ( me dia n P F S a p pr o xi matel y 3 t o 6 m o nt hs). 
T hese data t o get her wit h t he t o xicit y b ur de n ass ociate d wit h d o u blet c he m ot hera p y  (incl u di n g 
na usea, v o mit i n g, b o ne marr o w s u p pressi o n res ulti n g i n ris k of i nfecti on a n d blee di n g, 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 1 of 1 5 5
alo pecia, fat i g ue a n d peri p heral ne ur o pat h y) s u p p orts a n u n met me dical nee d i n t his patie nt 
p o p ul at i on.
Osi mert i ni b ( TA G RI S S O ™, A Z D 9 2 9 1) is a p ote nt a n d s pecifi c irre versi ble d ual i n hi bit or of 
b ot h t he se nsit isi n g E G F R m utati o ns a n d t he T 7 9 0 M resista nce m utati o n with mar gi n a gai nst 
E G F R wil d t y pe (Cr oss et al 2 0 1 4 ; Ballar d et al 2 0 1 6 ). Base d o n rece nt data 
(Bec ker et al 2 0 1 1 ; La n ger et al 2 0 1 3 ; M o k
et al 2 0 1 6 ) a n d F D A a p pr o val, t he N C C N 
rec o m me n ds osi merti ni b as a first-li ne treat me nt i n patie nts wit h metastatic E G F R p ositi ve 
N S C L C wit h E G F R e x o n 1 9 deleti o ns or e x o n 2 1 L 8 5 8 R m utati o ns i n t u m o ur s peci me ns a n d 
as s u bse q ue nt t hera p y for pati e nts wit h metastatic E G F R T 7 9 0 M mut ati o n p osi tive N S C L C 
w h o ha ve pr o gresse d o n E G F R -T KI t hera p y  (N C C N 2 0 2 0 ). E vide nce fr o m t he A U R A  
P hase I/II st u d y ( N C T 0 1 8 0 2 6 3 2) of osi merti ni b i n a d va nce d N S C L C patient s wit h P D 
f oll owi n g pri or E G F R -T KI t hera p y , s u g gests t hat patie nts wit h T 7 9 0 M ne gati ve t u m o ur stat us 
ma y als o deri ve be nefit fr o m osi mert i ni b (Jä n ne et al 2 0 1 5 ). I n t his st u d y, 6 9 pre-treate d 
pati e nts wit h T 7 9 0 M-ne gat i ve stat us b y ce ntral testi n g, recei ve d osi merti ni b with a n O R R of 
2 5 % ( 9 5 % CI: 1 5, 3 7) a n d disease c o ntr ol rate of 6 4 % ( 9 5 % CI: 5 1, 7 5). S u bse q ue ntl y, t he 
P hase III st u d y , F L A U R A ( N C T 0 2 2 9 6 1 2 5), c o n d ucte d i n u ntreate d E G F R m+ a d va nce d 
N S C L C pat ient s, has de m o nstrate d a si g nifica nt l y l on ger P F S wit h osi merti ni b vers us 
sta n dar d E G F R-T KIs ( gefit i ni b or erl oti ni b; 1 8. 9 m ont hs vs 1 0. 2 m o nt hs; H R 0. 4 6; 
9 5 % CI 0. 3 7 t o 0. 5 7; p < 0. 0 0 1;  S oria et al 2 0 1 8 ).
U p t o 2 2 % of patie nts wit h N S C L C w h o pr o gress o n first or sec o n d ge nerat i on E G F R -T K Is 
ha ve M E T a m plificat i on or ot her M E T-base d mec ha nis ms o f resista nce (Bea n et al 2 0 0 7 ; 
E n gel ma n et al 2 0 0 7 ; Se q uist et al 2 0 1 1 ). Usi n g tiss ue bi o ps y, M E T a m plificati on is 
c o m m o nl y  fo u n d af ter ac q uire d resista nce t o osi merti ni b (Pi otr o ws ka et al 2 0 1 7 ). M ore o ver, 
i n a s u b gr o u p of t he A U R A  patient s w h o were treat me nt naï ve a n d pr o vi de d p ost-pr o gressi o n 
pl as ma sa m ples ( n = 3 8), n o e vi de nce of ac q uire d E G F R T 7 9 0 M m utati o n was f o u n d. Ni ne of 
1 9 pati e nts ha d p utati ve resista nce mec ha nis ms, i ncl u di n g a m plificat i on of M E T i n o ne pati e nt 
(Ra m ali n ga m et al 2 0 1 8 ).
T he M E T pat h wa y is o ne of t he m ost f re q ue ntl y d ysre g ulate d pat h wa ys i n h u ma n ca ncer. 
Rece pt or acti vat i on lea ds t o t he recr uitme nt  a n d acti vati on of s pecific d o w nstrea m si g nalli n g 
part ners t hat partici pate i n t he re g ulat i on of di verse pr ocesses s uc h as t u m o ur cell gr o wt h, 
mi grati o n, scatteri n g a n d metastasi s. I n e n d ot helial cells a n d str o ma cells ar o u n d t u m o ur 
tiss ue, H G F/ M E T w or ks as a pr oa n gi o ge nesis fact or t o sti m ulate e n d ot helial cell pr oliferati o n, 
mi grati o n a n d s ur vi val, w hic h ca n ca use a n gi o ge nesis a n d s u p p ort t u m o ur e x pa nsi o n a n d 
pr o gr essi o n. He pat oc yte gr o wt h fact or a n d M E T e x pressi on ha ve bee n o bser ve d i n t u m o ur 
bi o psies of m ost s oli d t u m o urs, a n d M E T si g nalli n g has bee n d oc u me nte d i n a wi de ra n ge of 
h u ma n mali g na ncies, i ncl u di n g bla d der, breast, cer vical, c ol orectal, gastric, hea d a n d nec k, 
li ver, l u n g, o varia n, pa ncreatic, pr ostrate, re nal a n d t h yr oi d ca ncers, as well as i n vari o us 
sarc o mas, hae mat o p oietic mali g na ncies a n d mela n o ma. Acti vati n g m utati o ns i n t he t y r osi ne 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 2 of 1 5 5
ki nase d o mai n of M E T ha ve bee n p osit i vel y i de ntifie d i n patient s wi t h a here ditar y for m  of 
pa pillar y  re nal ca ncer, directl y i m plicati n g M E T i n h u ma n t u m o uri ge nesis (E der et al 2 0 0 9 ). 
I n se veral cli nical st u dies, a berra nt M E T o vere x pressi o n has bee n c orrelate d wit h p o or cli nical 
o utc o m e, wit h r a pid P D a n d s h ort s ur vi val ( Par k et al 2 0 1 2 ). O vere x pressi o n of M E T a n d 
H G F are als o t h o u g ht t o res ult i n resista nce of t u m o ur cells t o c he m ot hera p y  a n d ra diot h era p y, 
c orrelat i n g wit h de vel o p me nt of dista nt metastases a n d s h orter metastasis-free s ur vi val 
(Sc h mi dt et al 1 9 9 7 ).
Sa v o liti ni b (i nter nati onal n o n -pr o pri etar y na me; A Z D 6 0 9 4, H M P L-5 0 4, v olit i ni b [ C hi nese 
acce pte d na me]) is a p ote nt a n d hi g hl y se lecti ve M E T ki nase i n hi bit or (Jia et al 2 0 1 4 ), w hic h 
has de m o nstrate d a nti -t u mo ur acti vi t y in M E T dri ve n pa pillar y re nal cell carci n o ma 
(C h o ueiri et al 2 0 1 7 ). Sa v oliti ni b has als o s h o w n acti vity i n n o n-cli nical st u dies of M E T 
a mplifie d N S C L C ( He nr y et al 2 0 1 6 ).
T he c o m bi nat i on of sa v o liti ni b pl us osi merti ni b i n t he o n g oi n g TA T T O N st u d y  
( N C T 0 2 1 4 3 4 6 6) is e x pl ori n g h o w t o o verc o me M E T-a m p lificati on a gai nst t u m o urs t hat ha ve 
de vel o pe d resista nce t o E G F R -T KI a ge nts i n N S C L C or dela y  t he de velo p m e nt of  s u bse q ue nt 
resista nce via t hese alter nati ve r o utes. I n t he TA T T O N st u d y , sa v oliti ni b pl us osi merti ni b ha d 
a n acce pta ble ris k-be nefit pr ofile a n d de m o nstrate d e vi de nce of a nt i-t u mo ur acti vit y i n 
pati e nts with E G F R m + N S C L C (O x nar d et al 2 0 2 0 ; Se q uist et al 2 0 2 0 ). Recr uit me nt is 
o n g oi n g i n t he f o ll owi n g st u dies:
 
T he P hase II S A V A N N A H st u d y  ( N C T 0 3 7 7 8 2 2 9), w hic h is assessi n g t he efficac y of 
osi mert i ni b i n t he c o m bi nati on wi t h sa v olitini b i n pati e nts wit h E G F R m + a n d M E T 
a mplificat i on/ hi g h -e x pressio n  N S C L C f oll owi n g pri or osi me rtini b.
 
T he P hase II O R C H A R D st u d y ( N C T 0 3 9 4 4 7 7 2), w hic h is assessi n g t he efficac y of 
m ult i ple st u d y int er ve nt i ons i ncl u di n g t he c o m bi nati o n of sa v oliti ni b a n d osi merti ni b i n 
pati e nts wit h E G F R m + a d va nce d N S C L C wit h e vi de nce of ra di ol ogi cal pr o gressio n  
f ollo wi n g first -li ne osi merti ni b t hera p y. 
A s u m mar y of c o m bi natio n data i s pr o vide d i n t he sa v olit i ni b I B.
2. 1 
St u d y R ati o n ale
O ne of t he maj or mec ha nis ms f or resista nce t o E G F R -T KIs i s a m plificatio n of  t he M E T 
rece pt or t yr osi ne ki nase, w hic h acti vates d o w nstrea m i ntracell ular si g nalli n g i n de pe n de nt of 
E G F R. T his st u d y  will e xpl ore t he i n di vi d ual c o ntri b ut i on of sa v o liti ni b t o M E T-me d iate d 
osi mert i ni b resista nce.
T his st u d y  will a nal yse t he i n di vi d ual c o ntri b ut i on of  sa v oliti ni b t o t he c o m bi nati on b y 
i n vestigat i n g t he efficac y of t he c o m bi nati o n vers us sa v olit i ni b plus pl ace b o i n pat ient s wit h 
E G F R m + a n d M E T a m plifie d, l ocall y a d va nce d or metastatic N S C L C w h o ha ve pr o gresse d 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 3 of 1 5 5
f oll owi n g treat m e nt wit h osi merti ni b.  
T he rati o nale f or t he desi g n o f t he st u d y is prese nte d i n Secti o n 4. 2 .
2. 2 
B ac k gr o u n d
Refer t o Secti o n 2.
A detaile d descri pti o n o f t he c he mistr y, p har ma c ol o g y, efficac y, a n d safety of  sa v oliti ni b a n d 
osi mert i ni b is pr o vi de d i n t heir res pecti ve I Bs.
2. 3 
Be nefit/ Ris k Assess me nt
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefi ts a n d p ote ntial ris ks of 
sa v oliti ni b a n d osi merti ni b ma y be f o u n d i n t heir res pecti ve I Bs.
2. 3. 1 
Ris k Assess me nt
I n vesti gat ors f or a st u d y usi n g sa v oliti ni b m on ot hera p y  in pat ient s wit h E G F R m + N S C L C 
will be c o g nisa nt of t he p ote ntial ris k of ra pi d disease pr o gr essi o n via E G F R m t u m o ur dri ver 
reacti vati on. T he N C C N G ui deli nes f or N S C L C (N C C N 2 0 2 0 ) i nclu de a war ni n g a b o ut t he 
ris k of flare p he n ome n o n occ urri n g i n pat ient s w h o disc o nti n ue E G F R-T K I. T u m o ur flare 
after disc o nti n uatio n of  E G F R-T KI has bee n a rec o g nise d p he n o me n o n f or ma n y  years 
(C haft et al 2 0 1 1 ; C he n et al  2 0 1 3) a n d i n dicates t hat t he E G F R m se nsitisi n g m utatio n i s n ot 
eli mi nate d fr o m t he t u mo ur f oll o wi n g treat me nt wit h a n E G F R- T KI i n m ost patie nts. I n s o me 
pati e nts, t his ma y ca use a ra pid cli nical deteri orati o n after disc o nt i n ui n g E G F R-T KI pri or t o 
e nteri n g t he st u d y (see Secti on 4. 2. 1 ). To mi ni mise t his ris k, patie nts will be cl osel y m o nit ore d 
o ver t he f irst mo nt h of parti ci pat i on i n t he st u d y t o lo o k f or e vi de nce of t u m o ur flare. At  
i n vesti gat or-assesse d P D per R E CI S T 1. 1, treat me nt all o cat i on will be u n bli n de d a n d t h ose 
pati e nts ra n d o mise d t o t he sa v o liti ni b pl us place b o ar m will ha ve t he o p p ort u nity t o cr oss-o ver 
t o t he sa v oliti ni b plus osi merti ni b re gi me n. Patie nts will be i nf or me d of t he p ossi bilit y of  
cr oss-o ver t o sa v o liti ni b pl us osi merti ni b d uri n g t he i nf or me d c o nse nt pr ocess a n d at t he ti me 
of  pr o gressio n o n ra n d o mise d treat me nt. F urt her ris ks a n d t he res pecti ve mit i gatio n ste ps are 
prese nte d i n  Ta ble 3.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 4 of 1 5 5
Ta ble 3 
Ris k Assess me nt
P ote nti al ris k of 
cli nic al si g nific a nce
S u m m ar y of d at a/r ati o n al f or ris k
Miti g ati o n str ate g y
St u d y i nter ve nti o n: osi merti ni b a
I nterstitial l u n g disease
I nterstitial l u n g disease or I L D-li ke a d verse reacti o ns were 
re p orte d i n 3. 9 % of patie nts i n t he osi merti ni b pi v otal cli nical 
st u dies dataset, wit h 1. 1 % of t hese bei n g se vere ( C T C A E 
Gra de 3 or 4) a n d 0. 4 % res ulte d i n a fatal o utc o me.
Patie nts wit h past or cli nicall y acti ve I L D will be e xcl u de d. 
S pecific g ui da nce o n d ose m o dificati o n t o ma na ge ne w or 
w orse ni n g p ul m o nar y s y m pt o ms is i ncl u d e d i n t his C S P .
See Secti o n 5. 2 a n d A p pe n di x I 2. 1
Q Tc i nter val 
pr ol o n gati o n
I n t he osi merti ni b cli nical st u dies dataset 0. 9 % of patie nts were 
re p orte d t o ha ve a Q Tc greater t ha n 5 0 0 msec a n d 3. 6 % of 
patie nts ha d a n i ncrease fr o m baseli ne Q Tc greater t ha n 
6 0 msec.
Patie nts wit h car diac diseases a n d restricti o n of dr u gs k n o w n t o 
pr ol o n g Q T i nter val will be e xcl u de d. Re g ular car diac 
m o nit ori n g t hr o u g h E C Gs has als o bee n i ncl u de d i n t he S o As. 
S pecific g ui da nce o n d ose m o dificati o n i n t he e ve nt of Q Tc 
i nter val pr ol o n gati o n has bee n i ncl u de d i n t his C S P .
See  Ta ble 1 , Ta ble 2 , Secti o ns 5. 2 a n d 6. 5 , a n d A p pe n di x I 1. 1
Keratitis
I n t he osi merti ni b cli nical st u dies dataset 0. 7 % of patie nts were 
re p orte d t o ha ve si g ns or s y m pt o ms s u g gesti ve of keratitis. 
P h y sical e xa mi nati o ns, whi c h i ncl u de assess me nts of t he 
patie nt’s e yes will be c o m plete d at e ver y visit. Patie nts 
prese nti n g wit h si g ns or s y m pt o ms s u g gesti ve of keratitis will be 
pr o m ptl y referre d t o a n o p ht hal m ol o gist.
See Secti o n 8. 2. 1 a n d A p pe n di x I 2. 2
Er y t he ma m ultif or me 
a n d Ste ve ns-J o h ns o n 
s yn dr o me 
Case re p orts of E M a n d SJ S ha ve bee n u nc o m m o nl y a n d rarel y 
re p orte d, res pecti vel y, i n ass ociati o n wit h osi merti ni b treat me nt.
Bef ore i nitiati n g treat me nt, patie nts will be a d vise d of t he si g ns 
a n d s ym pt o ms of E M a n d SJ S. P h ysical e xa mi nati o ns, w hic h 
i ncl u de assess me nts of t he patie nt’s s ki n will be c o m plete d at 
e ver y visit. S peci fic g ui da nce o n d ose m o dificati o n i n t he e ve nt 
of t he E M or SJ S has bee n i ncl u de d i n t his C S P .
See Secti o n 8. 2. 1 a n d A p pe n di x I 1. 1
C ha n ges i n car diac 
c o ntractilit y
Left ve ntric ular ejecti o n fracti o n decreases ≥1 0 perce nta ge 
p oi nts a n d a dr o p t o less t ha n 5 0 % occ urre d i n 3. 9 % of patie nts 
w h o ha d baseli ne a n d at least 1 f oll o w-u p L V E F assess me nt 
( N = 9 0 8).
Patie nts wit h car diac diseases will be e xcl u de d. Re g ular car diac 
m o nit ori n g t hr o u g h E C H O/ M U G A sca ns has als o bee n i ncl u de d 
i n t he S o As. S pecific g ui da nce o n d ose m o dificati o n i n t he e ve nt 
of c ha n ges i n car diac c o ntractilit y has bee n i ncl u de d i n t his C S P .
S ee Ta ble 1 , Ta ble 2 , Secti o n 5. 2 a n d A p pe n di x I 2. 3

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 5 of 1 5 5
Ta ble 3 
Ris k Assess me nt
P ote nti al ris k of 
cli nic al si g nific a nce
S u m m ar y of d at a/r ati o n al f or ris k
Miti g ati o n str ate g y
St u d y i nter ve nti o n: s a v oliti ni b b
He pat ot o xicit y
He pat ot o xicit y ( A Es wit hi n sta n dar dise d Me d D R A q uer y of 
Dr u g -i n d uce d he patic dis or ders): was re p orte d i n 3 5. 0 % of 
patie nts, of w hic h 4. 8 % were re p orte d as seri o us.
I n t otal, 1 1. 5 % of patie nts ha d a n A E of he pat ot o xicit y 
C T C A E Gra de ≥3.
Patie nts wit h i ncrease d li ver e nz y mes will be e xcl u de d. 
Restricti o ns o n t he use of c o nc o mita nt me dicati o ns t hat are 
k n o w n t o effect t he li ver, ie, paraceta m ol/aceta mi n o p he n a n d 
stati ns ha ve als o bee n i ncl u de d. Re g ular L F Ts a n d s pecific 
g ui da nce o n d ose m o dificati o n i n t he e ve nt of he pat ot o xicit y 
ha ve bee n i ncl u de d i n t his C S P .
See  Ta ble 1 , Ta ble 2 , Secti o ns 5. 1 , 5. 2 , a n d 6. 5 a n d 
A p pe n di x I 3. 2
SJ S
A c u m ulati ve searc h i n t he Astra Ze neca’s gl o bal Patie nt Safet y 
data base f or sa v oliti ni b usi n g t he preferre d ter ms of SJ S, t o xic 
e pi der mal necr ol ysis a n d E M retrie ve d 1 case of SJ S.
Patie nts w h o s h o w s y m pt o ms or si g ns s u g gesti n g e mer g i n g SJ S 
w h ile o n st u d y treat me nt (e g, pr o gressi ve s ki n ras h ofte n wit h 
blisters o r m uc osal lesi o ns), m ust disc o nti n ue sa v oliti ni b 
i m me diatel y a n d recei ve a p pr o priate treat me nt. If e mer gi n g SJ S 
is s us pecte d, re-c halle n ge wit h sa v oliti ni b m ust be a v oi de d.
Se e Secti o n 8. 2. 1 a n d A p pe n di x I 3. 3
H y perse nsiti vit y
C u m ulati vel y t o date, 2 2 S A Es of dr u g h y perse nsiti vit y ha ve 
bee n recei ve d, i ncl u di n g a na p h yla xis, of w hic h 1 7 occ urre d i n 
St u d y D 5 1 6 0 C 0 0 0 0 6 ( T A T T O N), w hi c h st u die d t he 
c o m bi nati o n of osi merti ni b a n d sa v oliti ni b.
S pecific g ui da nce f or t he ma na ge me nt of h y perse nsiti vit y has 
bee n i ncl u de d i n t he C S P.
 
 
See A p pe n di x I 3. 3
Q Tc pr ol o n gati o n
Electr ocar di o gra m Q T pr ol o n ge d was re p orte d as a n A E i n 
1. 2 % of patie nts i n t he sa v oliti ni b cli nical data base.
See a b o ve f or miti gati o n strate g y.
See  Ta ble 1 , Ta ble 2 , Secti o ns 5. 2 a n d 6. 5 , a n d A p pe n di x I 3. 3
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 1 5 5
Ta ble 3 
Ris k Assess me nt
P ote nti al ris k of 
cli nic al si g nific a nce
S u m m ar y of d at a/r ati o n al f or ris k
Miti g ati o n str ate g y
St u d y pr oce d ures
Bi o psies
Ris ks fr o m bi o psies i ncl u de pai n, blee di n g, i nfecti o n a n d 
acci de ntal i nj ur y t o near b y tiss ues. T here is als o a ris k 
ass ociate d w he n a naest hetic is re q uire d.
Ne w bi o psies s h o ul d o nl y be ta ke n s pecificall y f or Pre -scree ni n g 
f or t his st u d y w here t he e x pecte d ris k of a n A E relate d t o t he 
pr oce d ure is < 2 %. Hi g h -ris k sites s uc h as t he brai n a n d 
pa ncreas s h o ul d be a v oi de d.
See  Ta ble 1 , a n d Secti o n 8. 6
a
I nci de nces of A Es re p orte d f or osi merti ni b are fr o m t he osi merti ni b pi v otal cli nical st u dies dataset, w hic h is c o m prise d of 11 4 2 patie nts w h o recei ve d 
osi merti ni b m o n ot hera p y f or N S C L C i n A U R A ( St u d y D 5 1 6 0 C 0 0 0 0 1) a n d F L A U R A ( St u d y D 5 1 6 0 C 0 0 0 0 7) a n d i ncl u des data u p t o t he D C O of 
1 2 N o ve m ber 2 0 1 9.
b
I nci de nces of A Es re p orte d f or sa v oliti ni b are fr o m t he cli nical data base, w hic h i ncl u des 6 4 3 patie nts fr o m St u dies D 5 0 8 1 C 0 0 0 0 1, D 5 0 8 1 C 0 0 0 0 2, 
D 5 0 8 2 C 0 0 0 0 2, D 5 0 8 1 C 0 0 0 0 3, D 5 1 6 0 C 0 0 0 0 6, D 5 0 8 1 C 0 0 0 0 4, D 5 0 8 0 C 0 0 0 0 1, D 5 0 8 4 C 0 0 0 0 1 a n d D 5 0 8 1 C 0 0 0 1 3 a n d i ncl u des data u p t o t he D C O of 
2 6 Fe br uar y 2 0 1 9.
A E = A d verse e ve nts; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; C S P = Cli nical st u d y pr ot oc ol; D C O = Data c ut -off; 
E C G = Electr ocar di o gra m; E C H O = Ec h ocar di o gra m; E M = Er y t he ma m ultif or me;
I L D = I nterstitial l u n g disease; L F T = Li ver 
f u ncti o n test; L V E F = Left ve ntric ular ejecti o n fracti o n; Me d D R A = Me dical Dicti o nar y f or Re g ulat or y Acti vities; M U G A
= M ulti -gate d ac q uisit i o n; 
N S C L C = N o n -s mall cell l u n g ca ncer; Q Tc = c orrecte d Q T i nter val; S A E = Seri o us a d verse e ve nts; S o A s = Sc he d ule of acti vities; SJ S = Ste ve ns -J o h ns on 
s yn dr o me.
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
3 7 of 1 5 5
2. 3. 2
Be nefit Assess me nt
Sa v o liti ni b has t he p ote ntial t o be acti ve a gai nst a wi de ra n ge of t u m o ur t y pes a n d is c urre ntl y 
bei n g assesse d i n P hase I, II a n d III of cli nical de vel o p me nt f or s oli d t u m o urs (i ncl u di n g 
N S C L C) as m o n ot hera p y  or i n c o m bi nati on t hera p y  wit h osi merti ni b.
Osi mert i ni b has a n esta blis he d efficac y pr o file with pr o ve n effect i ve ness i n a d ult patie nts wit h 
l ocall y a d va nce d or metastatic E G F R T 7 9 0 M m utati o n- p osi tive N S C L C w h ose disease has 
pr o gresse d o n or after E G F R -T KI t hera p y  a n d as a first-li ne treat me nt of patient s wit h locall y  
a d va nce d or metastatic N S C L C w h ose t u m o u rs ha ve E G F R e x o n 1 9 deleti ons or e x o n 2 1 
( L 8 5 8 R) s u bstit uti o n m utati o n. I n a d diti on, osi merti ni b has a well -esta blis he d safet y pr ofile 
t hat is si milar i n b ot h p o p ulat i ons.
Astra Ze neca belie ves t he i n vest i gati on of sa v o liti ni b a n d osi merti ni b i n patien ts wit h 
a d va nce d N S C L C a p pears acce pta ble base d u p o n: t he n o n -cli nical safet y pr ofile, t he e m er gi n g 
cli nical safet y pr ofile, t he ris k mi ni misat i on a n d A E ma na ge me nt pr o p osals, earl y e vi de nce of 
acti vit y i n patient s wit h a d va nce d ca ncer, t he li mite d life e xpecta nc y  d ue t o mali g na nt disease, 
t he lac k of effect i ve alter nati ve treat me nts, a n d t he stre n gt h of t he scie ntific h y p ot hesis u n der 
e val uat i on.  
I n a d diti on t o t he p ote ntial be nefits fr o m st u d y int er ve nt i on, pati e nts will als o be nefit fr o m 
access t o me dical c ar e wit h re g ular disease assess me nts.
2. 3. 3
O ver all Be nefit: Ris k C o ncl usi o n
O verall t he be nefit/ris k assess me nt s u p p orts t he f urt her i n vest i gati on of sa v o liti ni b a n d 
osi mert i ni b i n patient s wit h locall y a d va nce d or metastatic N S C L C base d u p o n: t he 
n o n- cli nical s af et y pr ofile, t he e mer gi n g cli nical safety pr ofile, t he ris k mi ni misati o n, 
i ncl u di n g cl ose m o nit ori n g f or t u m o ur flare o ver t he first m o nt h o n st u d y, A E m a na ge me nt 
pr o p osals, t he st u d y  desi g n, t he li mite d life e x pecta nc y d ue t o mali g na nt disease, t he lac k of 
effecti ve alter nati ve treat me nts, t he stre n gt h of t he scie ntific h y p ot hesis u n der e val uati on, a n d 
t he safet y a n d efficac y data fr o m T A T T O N.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 0 of 1 5 5
4 
S T U D Y D E SI G N
4. 1 
O ver all Desi g n
T his is a m ult i-ce ntre, P hase II, d o u ble -bli n d, ra n d o mise d st u d y  desi g ne d t o deter mi ne t he 
efficac y of sa v oliti ni b a d mi nistere d orall y in c o m bi nat i on wi t h osi merti ni b vers us sa v o liti ni b 
i n c o m bi nat i on wi t h place b o i n patie nts wit h E G F R m +, M E T a m plifie d , locall y a d va nce d or 
metastati c N S C L C w h o ha ve pr o gresse d o n pre vi o us osi mert i ni b treat me nt.
F or a n o ver vie w of t he st u d y  desi g n see Fi g ure 1 a n d Secti o n 1. 3 . F or details o n treat me nts 
gi ve n d uri n g t he st u d y, see Secti on  6. 1 .  
F or details o n w hat is i ncl u de d i n t he efficac y a n d safet y e n d p o i nts, see Secti o n 3 . 
4. 1. 1 
R a n d o mise d St u d y Desi g n
Pri or t o C S P  V 3. 0, a p pr o xi matel y 5 6 pat ient s were pla n ne d t o be ra n d o mise d i n a rati o of 1: 1 
t o recei ve treat me nt wit h  
 sa v oliti ni b  
 pl us  
 osi merti ni b   
 or 
 sa v olitini b   
 pl us place b o. At  least half of t he patie nts ra n d o mise d i nt o t he 
st u d y will be sec o n d -li ne patient s w h o were treate d wit h osi mert i ni b as first-li ne t hera p y. 
Ra n d o misat i on will be stratifie d acc or di n g t o t he n u m ber of pri or li nes o f t hera p y (ie, 
osi mert i ni b m o n ot hera p y  as first li ne or ≥sec o n d li ne [ w hic h i ncl u des pat ient s w h o recei ve d 
osi mert i ni b m o n ot hera p y  b efore or after c he m ot h era p y]).
Pr os pecti ve testi n g of t u m o ur s peci me ns t o deter mi ne M E T a m plificat i on b y ce ntral FI S H 
usi n g t u m o ur s peci me ns c o llecte d after pr o gressi o n o n pri or treat me nt wit h osi merti ni b s h o ul d 
be perf or m e d at Pre-scree ni n g i n a d va nce of Scree ni n g f or t he mai n st u d y . Patie nts deter mi ne d 
t o be M E T a m plifie d
i n Pre-scree ni n g will u n der g o scree ni n g d uri n g t he 2 8 da ys pri or t o 
ra n d omisat i on t o c o nfir m eli gi bilit y ( Secti o ns  5. 1 a n d 5. 2 ).
Pr o visi o n of a F F P E t u m o ur s peci me n is ma n dat or y (refer t o t he La b orat or y Ma n ual f or 
detaile d s peci me n re q uire me nts). T his will be use d f or pr os pecti ve a nal ysis of M E T 
a mplificat i on b y FI S H.
Pati e nts will c o nti n ue t o recei ve st u d y me dicati on   
 i n 2 8 -da y  c ycles u ntil o bjecti ve 
P D b y  R E CI S T 1. 1 i s assesse d, u nacce pta ble t o xicity occ urs, c o nse nt i s wit hdra w n or a n ot her 
di sc o nti n uati on cri t eria is met ( Sectio n 7 ). At  t he ti me of i n vesti gat or assess me nt per 
R E CI S T 1. 1 of P D, t he ra n d o misati o n bli n d ca n be br o ke n a n d patie nts w h o were i nit iall y 
ra n d omise d t o t he sa v o liti ni b pl us place b o ar m will be give n t he o p p ort u nit y  t o cr oss-o ver (see 
Secti o ns  4. 1. 2 a n d 6. 3 ). Patie nts ori gi nall y ra n d o mise d t o sa v o liti ni b pl us osi merti ni b ma y 
c o nti n ue t o recei ve treat me nt wit h sa v o liti ni b pl us osi merti ni b or osi merti ni b m o n ot hera p y (if 
sa v oliti ni b was st o p pe d earlier) be y on d R E CI S T 1. 1 defi ne d P D as l o n g as t he y c o nti n ue t o 
recei ve cli nical be nefit, i n t he o pi nio n  of t he i n vesti gat or, a n d d o n ot meet a n y of t he 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 1 of 1 5 5
di sc o nti n uati on cri t eria. N o ot her a nti-ca ncer a ge nt is per mitte d i n c o m bi nat i on wi t h 
osi mert i ni b withi n t his st u d y. P atie nts ca n c o nt i n ue o n sa v oliti ni b m o n ot hera p y (if ra n d omise d
t o t he sa v oliti ni b plus pl ace b o ar m or if osi merti ni b was st o p pe d earlier) u ntil o bjecti ve P D b y 
R E CI S T 1. 1 is assesse d. Sa v o liti ni b m on ot hera p y  p ost-pr o gressi o n is n ot per mitte d. 
Pri or t o C S P  V 3. 0, a n o n-c o mparati ve i nteri m f utilit y a nal ysis f or t he sa vol iti ni b pl us place b o 
ar m was pla n ne d t o occ ur after 2 0 patie nts o verall ( 1 0 per ar m) ha d t he o p p ort u nity of  bei n g 
treate d f or 2 R E CI S T p ost -baseli ne sca ns ( 1 2 wee ks; Sect i on 9. 5 ). Recr uit me nt was t o 
c o nti n ue d uri n g t his i nteri m f ut ility a nal ysis. T he pri mar y a nal ysis was pla n ne d t o occ ur 
6 m o nt hs after t he last patie nt ha d bee n ra n d o mise d. T he fi nal a nal ysis was pla n ne d t o be 
perf or m e d after t he earlier of 1 8 m o nt hs after t he last patie nt was ra n d o mise d or w he n 7 0 % of 
t he patie nts ha d pr o gresse d or die d d ue t o a n y ca use. 
U n der C S P V 3. 0, as a res ult of Astra Ze neca ’s decisio n t o ter mi nate st u d y  recr uit me nt earl y, 
t he pla n ne d n u m ber of ra n d o mise d patie nts will n ot be me t, a n d t he pla n ne d i nteri m f utilit y 
a nal ysis a n d pri mar y  a nal ysis will n ot be perf or me d. Alt er nat i vel y, a n earl y re vie w of  t he data 
b y Astra Ze neca will  occ ur f oll o wi n g t he earl y ter mi nati on of st u d y  recr uit me nt. T he fi nal
a nal ysis will be perf or m e d f oll owi n g t he fi nal D C O , w hic h will  ta ke place 9 m o nt hs after t he 
last patient  has bee n ra n d omi se d.
4. 1. 2 
Cr oss -o ver St u d y Desi g n
Pati e nts ra n d o mise d t o t he sa v o liti ni b pl us place b o ar m ma y cr oss-o ver t o o pe n -label 
sa v oliti ni b pl us osi merti ni b f oll o wi n g i n vest i gat or-assess me nt of P D per R E CI S T 1. 1 t o 
e ns ure t hat all pat ient s e nr olle d ma y ha ve t he o p p ort u nity t o recei ve t he c o m bi nati o n of 
sa v oliti ni b pl us osi merti ni b. Patie nts will be i nf or me d of t he p ossi bility of  cr oss-o ver t o 
sa v oliti ni b pl us osi merti ni b d uri n g t he i nf or me d c o nse nt pr ocess a n d at t he ti me of pr o gressi o n 
o n ra n d o mise d treat me nt. A se parate I C F f or cr oss-o ver patie nts m ust be si g ne d pri or t o 
starti n g cr oss-o ver treat me nt. 
Pati e nts w h o cr oss-o ver m ust n ot recei ve a n y ot her a nti- ca ncer t hera pies bet wee n t he 
assess me nt of P D a n d t he a d diti o n of osi mert i ni b. Sa v oliti ni b treat me nt s h o ul d c o nti n ue 
u ni nterr u pte d d uri n g t his peri o d. Patie nts s h o ul d be cr osse d o ver as s o o n as p ossi ble after t he 
assess me nt of P D a n d wit hi n 2 8 da ys of t heir pr o gressi o n sca n.
Pati e nts w h o cr oss-o ver will recei ve st u d y  me dicati o n   
 i n 2 8 -da y  c ycles u nt il 
occ urre nce of i n vest i gat or-assesse d o bj ecti ve P D, u nacce pta ble t o xicit y occ urs, c o nse nt is 
wi t hdra w n or a n ot her disc o nt i n uati on crit eria is met. As i n t he ra n d omise d part of t he st u d y , 
pati e nts ma y c o nt i n ue t o recei ve treat me nt wit h osi merti ni b pl us sa v oliti ni b or osi merti ni b 
m o n ot hera p y  (if sa v oliti ni b is st o p pe d d uri n g cr oss-o ver beca use of sa v o liti ni b-r elate d 
t o xicit y) b e yo n d R E CI S T 1. 1 defi ne d P D as l o n g as t he y  c o nti n ue t o recei ve cli nical be nefit, 
i n t he o pi ni on of t he i n vest i gat or, a n d d o n ot meet a n y of t he disc o nti n uati on cri teria. N o ot her 
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 2 of 1 5 5
a nt i-ca ncer a ge nt is per mitte d i n c o m bi nati o n wit h osi mert i ni b withi n t his st u d y.
Pr i or t o C S P V 3. 0, if after t he pla n ne d i nteri m f utility a nal ysis (see Sect i on  9. 5 ) t he st u d y was 
decl are d f ut ile a n d a rec o m me n dati on t o st o p t he st u d y was ma de b y t he I D M C, t here was t o 
be a data base l oc k, f o ll owe d b y t he us ual e n d of st u d y  re p orti n g acti vities. 
U n der C S P V 3. 0, as a res ult of Astra Ze neca ’s decisio n t o ter mi nate st u d y  recr uit me nt earl y, 
t he pla n ne d i nteri m f ut ility a nal ysis will n ot be perf or m e d a n d t here will be n o re q uire me nt f or 
data re vie w b y t he I D M C. Alt er nat i vel y, a n i nit ial D C O will occ ur f oll owi n g t he earl y 
ter mi nati o n of st u d y recr uit me nt t o all o w a n earl y re vie w of t he data b y Ast ra Ze neca. T he 
st u d y will be u n bli n de d after c o m p leti on of data clea ni n g act i vities o n t he i nit ial D C O data,
a n d pat ient s o n sa v oliti ni b m on ot hera p y  (sa v olitini b pl us pl ace b o) will be gi ve n t he 
o p p ort u nit y t o cr oss-o ver t o t he sa v o liti ni b pl us osi merti ni b ar m. If it is deci de d t hat a patie nt 
will s witc h t o sa v olitini b pl us osi mert i ni b bef ore fi nal data base l oc k, t he n t he y  will fol l ow t he 
sc he d ule d pr oce d ures descri be d i n Ta ble 2 . Patie nts ma y ot her wise c h o ose t o re mai n o n 
sa v oliti ni b m o n ot hera p y (as l on g as, i n t he o pi ni o n of t he i n vest i gat or, t he y are still recei vi n g 
cli nical be nefit a n d ha ve n ot re p orte d P D). All pat ie nts will be f oll owe d u nt il t he fi nal 
a nal ysis. All decisi o ns re gar di n g t he e val ua bilit y of  t he data fr o m eac h i n di vi d ual patie nt will 
be ma de a n d d oc u me nte d, bef ore t he st u d y  is u n bli n de d. A n y patient s re mai ni n g o n sa v o liti ni b 
pl us place b o ar m at t he ti me of fi nal data base l oc k, will be c o ntacte d a n d o ffere d t he s witc h t o 
t he sa v o liti ni b pl us osi merti ni b ar m. 
4. 1. 3 
E n d of St u d y Desi g n
F or pati e nts w h o c o ntin ue t o recei ve treat me nt be y o n d t he ti me of t he D C O f or t he fi nal 
a nal ysis, i n vesti gat ors will c o nt i n ue t o re p ort all S A Es t o Astra Ze neca Patie nt Safet y u nt il t he 
e n d of t he f o ll ow -u p peri o d, p ost -treat me nt disc o nti n uati on, i n acc or da nce wit h Sect i on 8. 3. 1 0
( Re p orti n g of S A Es). If a n i n vesti gat or lear ns of a n y S A Es, i ncl u di n g deat h, at a n y ti me after 
a patie nt has c o m plete d t he st u d y, a n d he/s he c o nsi ders t here is a reas o na ble p ossi bility t hat 
t he e ve nt is ca usall y relate d t o t he o ne or m ore of t he pr o d ucts use d i n t his st u d y, t he 
i n vesti gat or s h o ul d n otif y Astra Ze neca, Patie nt Safet y. A d dit i onall y  as state d in Sect i on 8. 3. 2
( F oll o w-u p of  A Es a n d S A Es), a n y S A E or n o n-seri o us A E t hat is o n g oi n g at t he ti me of t he 
fi nal D C O, mu st be f oll owe d u p b y  t he i n vesti gat or f or as l o n g as me dicall y i n dicate d.
4. 1. 4 
E arl y St u d y Recr uit me nt Ter mi n ati o n
O n 2 2 Fe br uar y 2 0 2 2, Astra Ze neca ma de t he decisi o n t o ter mi nate st u d y  recr uit me nt. T his 
was base d o n pr o gra m me de vel o p me nt strate g y  c o nsi deratio ns , beca use t he desi g n of t he 
c o ntri b uti o n o f c o mp o ne nt st u d y  is n o lo n ger s u p p orti ve of t he sa v o liti ni b de vel o p me nt 
pr o gra m me i n t his st u d y  p o p ulat i on. T he c o ntri b uti o n of c o m p o ne nt of sa v o liti ni b 
m o n ot hera p y  (sa v oliti ni b pl us place b o t o osi merti ni b) vers us sa v oliti ni b i n c om bi nat i on wi t h 
osi mert i ni b will c o nti n ue t o be assesse d i n t he o n g oi n g S AV A N N A H st u d y . F oll o wi n g earl y 
ter mi nati o n of st u d y recr uit me nt, a n i nitial D C O will occ ur t o all o w a n earl y re vie w of t he 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 3 of 1 5 5
data b y Ast ra Ze neca. T he st u d y  will be u n bli n de d after c o mplet i on of data clea ni n g acti vit ies 
o n t he i nit ial D C O data, a n d patie nts o n sa v o liti ni b mo n ot hera p y  (sa v olitini b pl us place b o) 
will be gi ve n t he o p p ort u nit y t o cr oss-o ver t o t he sa v o liti ni b pl us osi merti ni b ar m. Patient s 
ma y ot her wise c h o ose t o re mai n o n sa v olit i ni b m on ot hera p y  (as lo n g as, i n t he o pi ni o n of t he 
i nvesti g at or , t he y are still recei vi n g cli nical be nefit a n d ha ve n ot re p orte d P D). All pat ient s 
will be f o ll owe d u nt il t he fi nal a nal ysis. Patie nts alrea d y in pre -scree ni n g/scree ni n g ( w h o ha ve 
sig ne d t he pre -scree ni n g/ mai n I C F) at t he ti me of st u d y recr uit me nt  ter mi nati on will ha ve t he 
o pti o n t o be ra n d o mise d if eli gi ble. T he fi nal D C O will occ ur 9 m o nt h s after t he last patie nt 
has bee n ra n d omise d . F ollo wi n g t he fi nal  data base loc k, a n y  patient s w h o are still o n t he 
sa v oliti ni b pl us place b o ar m will be gi ve n t he o p p ort u nit y t o cr oss-o ver t o t he sa v o liti ni b pl us 
osi merti ni b ar m. Ra n d o mise d patie nts ma y c o nt i n ue t o recei ve t heir assi g ne d treat me nt f or as 
l on g as t he y  are deri vi n g cli nical be nefit, or u ntil t he y meet an y disc o nti n uat i on crit eria, a n d 
will be m o ni t ore d acc or di n g t o r o utine cli nical practice as defi ne d b y t he i n vest i gat or. F or t he 
defi nit i on o f t he e n d of t he st u d y please see Sect i on  4. 4 . F or access t o st u d y i nter ve nt i on after 
t he e n d of t he st u d y please see Secti o n 6. 7 .
4. 2 
Scie ntific R ati o n ale f or St u d y Desi g n
4. 2. 1 
R ati o n ale f or St u d y Desi g n
T he e x pa nsi o n c o h or t Part B of t he TA T T O N st u d y de m o nstrate d a nti- t u mo ur acti vit y of  
osi mert i ni b i n c om bi nat i on wi t h sa v oliti ni b ( O R R 3 0 %, 9 5 % CI: 2 0, 4 3) i n M E T a m plifie d
N S C L C pat ient s (c o nfir me d ce ntrall y b y FI S H; M E T ge ne c o p y ≥5 or M E T/ C E P 7 rati o ≥2) 
w h o were treate d wit h pri or 3r d ge nerati o n T 7 9 0 M -di recte d E G F R-T KI (Se q uist et al 2 0 2 0 ).
T his P hase II st u d y  has bee n desi g ne d t o a nal yse t he i n di vi d ual c o ntri b uti o n of sa v oliti ni b t o 
t he efficac y see n wit h t he c o m bi nati on b y assess me nt of O R R i n patie nts wit h E G F R m + a n d 
M E T a m plifie d , locall y  a d va nce d or metastatic N S C L C w h o ha ve pr o gresse d fol l owi n g 
treat me nt wit h osi merti ni b. T his st u d y will e nr ol patie nts w h o ha ve recei ve d u p t o 3 li nes of 
pri or t hera p y, w hic h m ust i ncl u de osi merti ni b b ut c o ul d als o i ncl u de ot her E G F R-T KIs, 
c he m ot hera p y or c he m ot hera p y in c o m bi nat i on wi t h a n i m m u n o-o nc o l ogi c a ge nt.
Ar o u n d 5 % t o 2 2 % of patie nts w h o recei ve a 3r d ge nerat i on E G F R -T K I de vel o p M E T 
a mplificat i on (Bea n et al 2 0 0 7 ; E n gel ma n et al 2 0 0 7 ; Se q uist et al 2 0 1 1 ; 
Ra mali n ga m et al 2 0 1 8 ). He pat oc yte gr o wt h fact or rece pt or a m plificati o n pr o vi des a b y-pass 
mec ha nis m o f resista nce t o E G F R-T KIs acti vat i n g t he p h os p h oi n ositi de 3-ki nase pat h wa y. 
H o we ver, si m pl y tar geti n g t he e mer ge nt M E T a m plificati o n with o ut m ai ntai ni n g c o ntr ol of 
t he E G F R se nsit isi n g m utati o n has bee n de m onstrate d t o be i na de q uate t o s u p press t u m o ur 
gr o wt h i n hi bit i on i n n o n-cli nical mo dels (E n gel ma n et al 2 0 0 7 ). I n or der t o o verc o me 
resista nce t o E G F R-T KI, t he E G F R m ust still be i n hi bite d, a n d E G F R i n hi bit i on is re q uire d t o 
mai ntai n re missi o n. F urt her m ore, literat ure data de m o nstrate t hat f or ca ncers t hat start t o 
pr o gress o n E G F R -T KIs, disc o nt i n uati on of t he E G F R -T K I ca n lea d t o a n accelerati on of P D 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 4 of 1 5 5
(C haft et al 2 0 1 1 ; C he n et al  2 0 1 3). T his f urt her s u p p orts e vi de nce t hat t he E G F R m utati o n is 
n ot eli mi nate d fr o m t he t u m o ur f o ll owi n g treat m e nt wit h a n E G F R-T K I a n d is ca pa ble i n 
s o me patie nts to ca use a ra pi d cli nical deteri orati o n o nce t he E G F R bl oc ka de is re m o ve d. T he 
N C C N G ui deli nes f or N S C L C, V 3. 2 0 2 0 i ncl u de a war ni n g a b o ut t he ris k o f flare p he n ome n o n 
occ urri n g i n patie nts w h o disc o nti n ue E G F R -T KI (N C C N 2 0 2 0 ). T h us, c o nti n ui n g E G F R-T K I 
is be neficial i n ma n y patie nts e ve n after ca ncer re gr o wt h o n E G F R -T KI. H o we ver, t he 
I M P R E S S st u d y d e mo n strate d t here was n o cli nical be nefit i n c o nti n uati on of  first ge nerati on 
E G F R t y r osi ne ki nases be yo n d ra di ol o gi c P D w he n c he m ot hera p y is i nitiate d 
(M o k
et al 2 0 1 7 ). A si milar st u d y has n ot bee n perf or me d i n t he p ost -3r d ge nerati o n E G F R 
T KI pati e nt p o p ulat i on.
I n or der t o de m o nstrate t he i n di vi d ual c o ntri b uti o n of sa v oliti ni b i n t he treat me nt of patient s 
wi t h M E T-dri ve n resista nce t o osi mert i ni b, a sa v oliti ni b pl us place b o ar m has bee n i ncl u de d i n 
t he st u d y desi g n. Patie nt s will be ra n d o mise d o n a 1: 1 basis t o recei ve eit her sa v oliti ni b pl us 
osi mert i ni b or sa v oliti ni b pl us place b o. To a d dress cli nical c o ncer n a b o ut t he p ote ntial f or 
t u mo ur flare wi t h t he wit hdra wal  of E G F R-T K I c o ver i n a n E G F R m dri ve n i n dicati on, all 
pati e nts will be clos el y  mo ni t ore d o ver t he first mo nt h o n st u d y  t o lo o k f or e vi de nce of t u m o ur 
flare. To o verc o me t he c o ncer ns t hat arise fr o m t he n o n-cli nical a n d cli nical e vi de nce 
prese nte d a b o ve, t his st u d y  incl u des t he o pti o n f or pati e nts ra n d o mise d t o t he sa v oliti ni b pl us 
pl ace b o ar m t o cr oss-o ver t o recei ve sa v o liti ni b i n c o m bi nati on wi t h osi merti ni b f oll owi n g 
o bj ect i ve P D b y R E CI S T 1. 1 assess me nt. T his will e ns ure t hat all patie nts e nr olle d ma y ha ve 
t he o p p ort u nit y t o recei ve t he c o m bi nati on of sa v o liti nib pl us osi mert i ni b.
4. 3 
J u stific ati o n f or D ose
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 5 of 1 5 5
4. 3. 1 
R ati o n ale f or E n d p oi nts
O bject i ve res p o nse rate, P F S, D o R a n d perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size 
assessed b y  R E CI S T 1. 1 usi n g i n vesti gat or assess me nt a n d O S are sta n dar d meas ures of 
cli nical act i vity a n d are use d t o assess efficac y i n s oli d t u m o ur cli nical st u dies.
T he T A T T O N data i n dicate e nc o ura gi n g a nti -t u mo ur acti vit y i n patient s wit h ce ntrall y 
c o nfir me d M E T a m plifie d t u m o ur stat us. T his st u d y  is desi g ne d t o all o w f urt her assess me nt of 
res p o nse i n patient s c o nfir me d as M E T a m plifie d b y FI S H f or t he pri mar y  e nd p oi nt. 
I n 2 P hase III st u dies ( A U R A 3 a n d F L A U R A), a c orrelati o n was o bser ve d bet wee n cleara nce 
o f pl as ma E G F R m after 3/ 6 wee ks of osi merti ni b m o n ot hera p y  a n d a n u meric al i m pr o ve me nt 
i n P F S (S he p her d et al 2 0 1 8 ; Z h o u et al 2 0 1 9 ). As s uc h, pre vale nce of plas ma ct D N A 
cleara nce after 6 wee ks of t hera p y is a sec o n dar y o bjecti ve of t his st u d y.
Sta n dar d safet y para m eters ( disc o nt i n uati on rate d ue t o A Es/ S A Es, vital si g ns, cli nical 
c he mistr y/ hae mat olo g y  para meters a n d E C Gs) will be use d t o assess t he safety a n d 
t olera bilit y of sa v o liti ni b i n c om bi nat i on wi t h osi merti ni b. To e val uate t he safet y a n d 
t olera bilit y of sa v o liti ni b i n c om bi nat i on wi t h osi merti ni b, t he pr o p orti o n of pat ient s 
di sc o nti n ui n g d ue t o a n y A E a n d t he pr o p orti o n of patie nts disc o nti n ui n g d ue t o A E of 
h y perse nsit i vity/a na p h yla xis ma y  be assesse d.
Sta n dar d P K para meters will be use d t o e val uate t he P K of osi merti ni b a n d sa v o liti ni b w he n 
gi ve n i n c o m bi nat i on a n d sa v o liti ni b al one w he n a d mi nistere d i n c o m bi nat i on wi t h place b o i n 
t his p o p ulat i on. 
 
 
4. 4 
E n d of St u d y Defi niti o n
A pat ient  is c o nsi dere d t o ha ve c om p lete d t he st u d y if he/s he has c o m p lete d all p hases of t he 
st u d y incl u di n g t he l ast sc he d ule d pr oce d ure s h o w n i n t he S o As (Ta ble 1 a n d Ta ble 2 ).
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t he last patie nt i n t he st u d y. 
5 
S T U D Y P O P U L A TI O N
Pr os pecti ve a p pr o val o f C S P de viat i ons t o recr uit me nt a n d e nr o l me nt criteria, als o k n o w n as 
C S P wai vers or e xe m pt i ons, is n ot per mitte d.
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 u d y in or der t o be e nr olle d o n t he st u d y. U n der n o circ u msta nces ca n t here be e xce pti o ns t o 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 6 of 1 5 5
t his r ule. Patie nts w h o d o n ot meet t he e ntr y re q uire me nts are scree n fail ures, refer t o 
Secti o n 5. 4 .
F or pr oce d ures f or wit h dra wal o f i nc orrectl y e nr olle d patie nts see Sectio n  7. 2 .
5. 1 
I ncl usi o n Criteri a
Pati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:
I nf or me d C o nse nt
1 
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n  A p pe n di x A , w hic h i ncl u des 
c o mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he I C F a n d i n t his C S P.
2 
Pr o visi o n of si g ne d a n d date d writte n I C F pri or t o a n y ma n dat or y st u d y s pecific 
pr oce d ures, sa m pli n g a n d a nal yses.
A ge
3 
Pati e nts must be ≥1 8 years of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt ( ≥2 0 years 
of  a ge i n Ja pa n). All gen ders are per mitte d.
T y pe of P atie nt a n d Dise ase C h ar acteristics
4 
Hi st olo gi call y or c yt olo gi call y c o nfir me d locall y a d va nce d or metastatic E G F R m + 
N S C L C har b o uri n g a n E G F R m utati o n k n o w n t o be ass ociate d wit h E G F R -T KI 
se nsiti vity a n d t hat is per mitte d i n t he osi mert i ni b nat i onal la bel (s uc h as e x o n 1 9 deleti o n 
a n d/ or L 8 5 8 R), w hic h is n ot a me na ble t o c urati ve t hera p y. 
5 
D oc u m e nte d ra diol o gic P D f o ll owi n g treat m e nt wit h osi merti ni b ( osi merti ni b d oes n ot 
nee d t o be t he m ost rece nt t hera p y ).
6 
Ha ve M E T a m plificat i on as deter mi ne d b y ce ntral M E T FI S H testi n g o n t u m o ur 
s peci me n c ollecte d f oll owi n g pr o gressi o n o n pri or osi mert i ni b treat me nt.
7 
A vaila ble F F P E t u m o ur s peci me n f or ce ntral M E T FI S H a nal ysis or willi n g ness t o c ollect 
a n a d dit i onal s peci me n f or ce ntral testi n g, w hic h f ulfils t he f oll owi n g re q ui re me nts:
 
O btai ne d f o ll owi n g pr o gressi o n o n pre vi o us osi merti ni b t hera p y .
 
O btai ne d wit hi n 2 years of s u b missi o n f or M E T a nal ysis.
 
S ufficie nt s peci me n t o meet t he mi ni m u m s peci me n re q uire me nt defi ne d i n t he 
c urre nt La b orat o r y Ma n ual.
8 
At  least o ne lesi on, n ot pre vi o usl y irra diate d, n ot bi o psie d d uri n g t he scree ni n g peri o d, 
t hat ca n be acc uratel y meas ure d at baseli ne as ≥1 0 m m i n t he l o n gest di a meter (e xce pt 
l y m p h n o des w hic h m ust ha ve s h ort a xis ≥1 5 m m) wit h C T or M RI, w hic h is s uita b le f or 
acc urate re peate d meas ure me nts. If o nl y o ne meas ura ble lesi o n e xists, it is acce pta ble t o 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 7 of 1 5 5
be use d as l o n g as baseli ne t u m o ur assess me nt sca ns are d o ne at least 1 4 da y s after t he 
scree ni n g t u m o ur s peci me n c ollecti o n is perf or me d. 
9 
Pati e nts must ha ve recei ve d at least o ne b ut n o m ore t ha n 3 pri or li nes o f t hera p y 
(incl u di n g i n vesti gat i onal t hera p y ) i n t he locall y  a d va nce d/ metastatic setti n g.
 
N o m ore t ha n o ne pri or li ne of c he m ot hera p y  re gi me n is acce pta ble.
 
A c he m ot hera p y  re gi me n i ncl u di n g a pr o gra m me d cell deat h-1 or a pr o gra m me d cell 
deat h li ga n d -1 a ge nt i s acce pta ble, pr o vi de d it was n ot t he m ost rece nt li ne of 
t hera p y.
 
N o m ore t ha n 2 pri or li nes of t hera p y  c o ntai ni n g E G F R-T K I are acce pta ble.
1 0
A de q uate hae mat ol o gical f u nct i on defi ne d as:
 
A bs ol ute ne ut r o p hil c o u nt ≥1 5 0 0/ μ L
 
Hae m o gl o bi n ≥9 g/ d L ( n o tra nsf usi o n i n t he past 2 wee ks) 
 
Pl at elets ≥1 0 0 0 0 0/ μ L ( n o tra nsf usi o n i n t he past 1 0 da ys)
1 1
A de q uate li ver f u nct i on defi ne d as:
 
A L T a n d A S T ≤ 2. 5 × t he U L N wit h T B L ≤ U L N
O R
 
T B L > U L N t o ≤1. 5 × U L N wit h A L T a n d A S T ≤ U L N
1 2
A de q uate re nal f u nct i on defi ne d as a creati ni ne < 1. 5 ti mes t he i nstit uti o nal U L N O R a 
gl o m er ular filtrat i on rate ≥5 0 m L/ mi n, as assesse d usi n g t he sta n dar d met h o d ol o g y at t he 
i n vesti gati n g ce ntre (e g, C oc kcr oft-Ga ult, M o dificati o n of Diet i n Re nal Disease or 
C hr o nic Ki d ne y  Disease E pide mi ol o g y  C olla b orati o n f or mulae, 
et h yle ne dia mi netetraacetic aci d cleara nce or 2 4 -h o ur uri ne c ollecti o n). C o nfir mati o n o f 
creati ni ne cleara nce is o nl y re q uire d w he n creat i ni ne is > 1. 5 ti mes U L N. 
1 3
A de q uate c oa g ulat i on para meters, defi ne d as I N R < 1. 5 × U L N a n d acti vate d partial 
t hr o mb o pl asti n ti me < 1. 5 × U L N u nless pat ient s are recei vi n g t hera pe utic 
a nt i-c oa g ulat i on w hic h affects t hese para meters. Use of warfari n is n ot per mitte d i n t his 
st u d y, b ut L M W H is all owe d (A p pe n di x J).
1 4
Pati e nts wit h k n o w n t u mo ur t hr o m b us or dee p vei n t hr o m b osis are eli gi ble if cli nicall y 
sta ble o n L M W H f or ≥ 2 wee ks.
1 5
Easter n C o o perati ve O nc ol o g y  Gro u p/ W H O perf or m a nce stat us of 0 or 1 wit h n o 
deteri or ati o n o ver t he pre vi o us 2 wee ks a n d a mi ni m u m life e x pecta nc y of 1 2 wee ks.
1 6
A bilit y t o s wallo w a n d retai n oral  me dicat i ons.
1 7
Willi n g ness a n d a bilit y t o co m pl y  wit h st u d y a n d f ollo w -u p pr oce d ures.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 8 of 1 5 5
Re pr o d uc ti o n
1 8
Fe males of c hil d beari n g p ote ntial s h o ul d be willi n g t o use a de q uate c o ntrace pti ve 
meas ures, s h o ul d n ot be breast fee di n g, a n d m ust ha ve a ne gati ve pre g na nc y test if of 
c hil d beari n g p ote ntial, or m ust ha ve e vi de nce of n o n -c hil d beari n g p ote ntial b y f ulfilli n g 
o ne of t he f o ll owi n g cri t eria at scree ni n g:
 
P os t-me n o pa usal is defi ne d as a ge d m ore t ha n 5 0 years a n d a me n orr h oeic f or at least 
1 2 m o nt hs f ol l owi n g cessati o n of all e x o ge n o us h or m o nal treat me nts.
 
W o me n u n der t he a ge of 5 0 y ears w o uld be c o nsi dere d p o stme n o pa usal if t he y ha ve 
bee n a me n orr h oeic f or 1 2 m o nt hs or m ore f o ll owi n g cessat i on of e x o ge n o us 
h or m o nal  tr e at me nts a n d wit h lutei nizi n g h or m o ne a n d f o llicle sti m ulati n g h or m o ne 
le vels i n t he p ost-me n o pa usal ra n ge f or t he i nstit uti o n.
 
W o me n wi t h d oc u me nt atio n of  irre versi ble s ur gical sterilisati on b y h ysterect o m y, 
bilateral  o o p h orect o m y or bilateral sal pi n gect o m y but n ot t u bal  li gati on.
F urt her i nf or mat i on is a vaila ble i n A p pe n di x G ( Defi niti on o f W O C B P a n d Acce pta ble 
C o ntrace pti ve Met h o ds). 
1 9 
Male patie nts wit h a fe male part ner of c hil d beari n g p ote ntial s h o ul d be willi n g t o use 
barrier c o ntrace pti o n d uri n g t he st u d y  a n d f or 6 m o nt hs f oll owi n g disc o nt i n uati on of 
st u d y int er ve ntio n. Pati e nts s h o uld ref rai n fr om d o nat i n g s per m fr om t he start of d osi n g 
u nt il 6 m o nt hs after disc o nt i n ui n g st u d y i nter ve nti o n.
5. 2 
E xcl usi o n Criteri a 
Pati e nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1 
U nres o l ve d t o xicities fr om a n y prior t hera p y  greater t ha n C T C A E Gra de 1 at t he ti me of 
starti n g st u d y int er ve nt i on wi t h t he e xce pti on of al o pecia, hae m o gl o bi n ≥9 g/ d L a n d 
Gra de 2, pri or plat i n u m-t hera p y relate d ne ur o pat h y.
2 
As j u d ge d b y  t he i n vesti gat or, acti ve gastr oi ntesti nal disease or ot her c o n diti on t hat will 
i nterfere si g nifica nt l y with t he a bs or pti o n, distri b uti o n, m eta b o lis m, or e xcreti o n of oral 
t hera p y (e g, ulcerat i ve disease, u nc o ntr olle d na usea, v o miti n g, diarr h oea Gra de ≥ 2, 
mala bs or pti o n s y n dr o me or pre vi o us si g nifica nt b o wel resect i on).
3 
A n y of t he f o ll owi n g car di ac diseases c urre nt l y or wit hi n t he last 6 m o nt hs:
 
U nsta ble a n gi na pect oris
 
C o n gest i ve heart fail ure ( N Y H A Gra de ≥ 2) 
 
Ac ute m y ocar dial  infarct i on
 
Str o ke or tra nsie nt isc he mic attac k 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
4 9 of 1 5 5
 
U nc o ntr olle d h y perte nsi o n ( B P ≥ 1 5 0/ 9 5 m m H g des pite me dical t hera p y).
 
Mea n resti n g c orrecte d Q T i nter val ( Q Tc F) > 4 7 0 msec f or w o me n a n d > 4 5 0 msec 
f or me n at Scree ni n g, o btai ne d fr o m 3 E C Gs usi n g t he scree ni n g cli nic E C G mac hi ne 
deri ve d Q Tc F val ue.
 
A n y fact ors t hat ma y  increase t he ris k of Q Tc F pr ol o n gat i on or ri s k of arr h yt h mic 
e ve nts s uc h as heart fail ure, c o n ge nital or fa milial l o n g Q T s y n dr o me, fa mil y hist or y 
of  u ne x plai ne d s u d de n deat h u n der 4 0 years of age i n first -de gree relati ves, a n y 
c o nc o mita nt me dicat i on k n o w n t o pr ol o n g t he Q T i nter val a n d ca use T orsa de de 
P oi ntes, c hr o nic h y p o kalae mia n ot c orrecta ble wit h s u p ple me nts, or electr ol yte 
a b n or malities i ncl u di n g:
o 
Ser u m / plas ma p otassiu m < L L N
o 
Ser u m / plas ma ma g nesi u m < L L N
o 
Ser u m / plas ma calci u m < L L N
 
A n y cli nicall y  i m p orta nt a b n or malities i n r h yt h m, c o n d uctio n or m or p h ol o g y  of 
resti n g E C Gs, e g, c o m plete left b u n dle bra nc h bl oc k, t hir d de gree heart bl oc k, sec o n d 
de gree heart bl oc k, P -R i nter val > 2 5 0 msec.
 
Ac u te c or o nar y s y n dr ome
4 
Wi de fiel d ra di ot hera p y (i ncl u di n g t hera pe ut ic ra di ois ot o pes s uc h as str o nti u m 8 9) 
a d mi nistere d ≤ 2 8 da ys or li mite d fiel d ra diati o n f or palliat i on ≤ 7 da ys pri or t o starti n g 
st u d y int er ve ntio n or has n ot rec o vere d fr o m si de effects of s uc h t hera p y.
5 
Maj or s ur gi cal pr oce d ures ≤ 2 8 da y s of be gi n ni n g st u d y int er ve ntio n or mi n or s ur gi cal 
pr oce d ures ≤ 7 da ys. N o waiti n g is re q uire d f o ll owi n g p ort -a-cat h place me nt.
6 
As j u d ge d b y  t he I n vesti gat or, a n y e vi de nce of se vere or u nc o ntr olle d s yste mic diseases, 
i ncl u di n g re nal tra ns pla nt or acti ve blee di n g diat heses, w hic h i n t he i n vesti gat or's o pi ni o n 
ma kes i t u n desira ble f or t he patie nt t o e nter t he st u d y or w hic h w o uld je o par di se 
c o mplia nce wi t h t he C S P . 
7 
Act i ve H B V ( p ositi ve H Bs A g res ult) or H C V. Viral testi n g is n ot re q uire d f or assess me nt 
of  eli gi bility f or t he st u d y. P atie nts wit h a past or res ol ve d H B V or H C V i nfecti on are 
eli gi ble if:
 
Ne gati ve f or H Bs A g a n d p osit i ve f or he patitis B c ore a nti b o d y or 

P osi tive f or H Bs A g, b ut f or > 6 m o nt hs ha ve ha d n or m al tra nsa mi nases a n d H B V 
D N A le vels bet wee n 0 a n d 2 0 0 0 I U/ m L (i nact i ve carrier state) a n d willi n g t o start 
a n d mai ntai n a nt i viral treat me nt f or at least t he d urati o n of t he st u d y.
 
H B V D N A le vels > 2 0 0 0 I U/ m L b ut o n pr o p h ylactic a nt i viral treat me nt f or t he past 
3 m o nt hs a n d will mai ntai n t he a nt i viral treat me nt d uri n g t he st u d y
 
Pati e nts wit h p ositi ve H C V a nti b o d y are eli gi ble o nl y if t he p ol y merase c hai n 
reactio n is ne gati ve f or H C V ri b o n ucleic aci d.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 0 of 1 5 5
8 
K n o w n seri o us act i ve i nfecti o n i ncl u di n g, b ut n ot li mite d t o, t u berc ul osis, or HI V 
( p ositive HI V 1/ 2 a nti b o dies). Testi n g is n ot re q uire d f or assess me nt of eli gi bilit y f or t he 
st u d y.
9 
Prese nce of ot her acti ve ca ncers, or hist or y  of treat me nt f or i n vasi ve cancer, wi t hi n t he 
last 5 years. Pati e nts wit h Sta ge I ca ncer w h o ha ve recei ve d defi niti ve l ocal treat me nt at 
least 3 years pre vi o usl y, a n d are c o nsidere d u nli kel y  t o rec ur are eli gible. All pat ient s 
wi t h pre vio usl y treate d i n sit u carci n o ma (i e, n o n-i n vasi ve) are eli gi ble, as are patie nts 
wi t h hist or y of no n -mela n o ma s ki n ca ncer.
1 0
S pi nal c or d c o m pressi o n or brai n metastases u nless as y m pt o mat ic, sta ble a n d n ot 
re q uirin g ster oi ds f or at l east 2 wee ks prior t o start of st u d y  int er ve nt i on.
1 1
Past m e dical hist or y of I L D, dr u g-i n d uce d I L D, ra diati on p ne u m o nit is, w hic h re q uire d 
ster oid treat m e nt, or a n y e vi de nce of cli nicall y acti ve I L D.
Pri or/ C o nc o mit a nt T her a p y
1 2
Pri or or c urre nt treat me nt wit h a 3r d ge nerati o n E G F R- T K I ot her t ha n osi merti ni b.
1 3
Pri or or c urre nt treat me nt wit h sa v olit i ni b or a n ot her M E T i n hi bit or (f or e xa m ple, 
f oreti ni b, criz oti ni b, ca b oza nt i ni b, o nart uz u ma b, ca p mati ni b).
1 4
Pati e nts w h o ha ve recei ve d ≥ 4 li nes of s yste mic t hera p y  for N S C L C are n ot eli gi ble. 
1 5
A n y c y t ot o xic c he mot h era p y, i n vest i gati onal a ge nts or ot her a nti -ca ncer dr u gs f or t he 
treat me nt of a d va nce d N S C L C fr o m a pre vi o us treat me nt re gi me n or cli nical st u d y  wit hi n 
1 4 da y s prior t o t he first d ose of st u d y  int er ve nt i on wi t h t he e xce pti on of m o n ot hera p y  
osi mert i ni b w hic h ma y c o nti n ue u ni nterr u pte d d uri n g scree ni n g.
1 6
Pati e nts c urre ntl y recei vi n g ( or u na ble t o st o p use pri or t o recei vi n g t he first d ose of st u d y  
i nter ve nt i on) m e dicat i ons or her bal s u p ple me nts k n o w n t o be str o n g i n d ucers o f C Y P 3 A 4 
or str o n g i n hi bit ors of C Y P 1 A 2, or C Y P 3 A 4 s u bstrates w hic h ha ve a narr o w t hera pe utic 
ra n ge wit hi n 2 wee ks of  t he first d ose of st u d y int er ve nt i on ( 3 wee ks f or St J o h n's W ort) 
will be e xcl u de d. All pat ient s must tr y  t o a v oid c o nc o mi ta nt use of a n y me dicatio ns, 
her bal s u p ple me nts a n d/ or i n gesti o n of f o o ds wit h k n o w n i n d ucer effects o n C Y P 3 A 4 
d uri n g t he st u d y  a nd f or 3 m o nt hs l ater t he last d ose i nta ke.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 7
Parti cip ati o n i n a n ot her cli nical st u d y  wit h a c yt ot o xic, i n vestig ati o n al  pr o d uct, or ot her 
a nt i-ca ncer dr u g f or t he treat me nt of a d va nce d N S C L C if recei ve d st u d y int er ve nt i on 
fr om t hat st u d y wit hi n 1 4 da ys of t he first d ose of st u d y int er ve nt i on.  
1 8
K n o w n h y perse nsit i vity t o t he acti ve or i nact i ve e xci pie nts of osi merti ni b or sa v oliti ni b or 
dr u gs wi t h a si milar c he mical str uct ure or class.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 1 of 1 5 5
Ot her E xcl usi o ns
1 9
I n v ol 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 b ot h Astra Ze neca 
staff a n d/ or staff at t he st u d y site).
2 0
J u d g me nt b y t he i n vesti gat or t hat t he patie nt s h o ul d n ot partici pate i n t he st u d y if t he 
pati e nt is u nli kel y t o c o m pl y wit h st u d y pr oce d ures, restrict i ons a n d re q uire me nts.
2 1
Pre vi o us e nr ol me nt i n t he prese nt st u d y . 
2 2
F or w o m e n o nl y - c urre nt l y pre g na nt (c o nfir me d with p osi ti ve pre g na nc y test) or 
breast -fee di n g.
2 3
Pati e nts u na ble t o pr o vi de t he re q uire d n u m ber of sa m ples f or M E T a nal ysis.
5. 3 
Lifest yle C o nsi der ati o ns
5. 3. 1 
Me als a n d Diet ar y Restricti o ns
Sa v o liti ni b s h o uld be ta ke n wi t hi n 1 5 mi n utes after t he start of a meal. Osi merti ni b ca n be 
ta ke n wit h water, wit h or wit h o ut f o o d. Osi merti ni b a n d sa v oliti ni b ca n be ta ke n t o get her.
O n P K da ys, patie nts s h o ul d c o me t o t he cli nic faste d (t he patie nt s h o ul d n ot eat b ut
ma y dri n k 
bef ore ha n d) w here t he y  will be gi ve n a mo derate brea kfast bef ore d osi n g (t he sa me brea kfast 
s h o uld be gi ve n o n all P K da ys). 
5. 3. 2 
Pre g n a nc y a n d C o ntr ace pti o n
W o me n of c hil d be ari n g p ote nti al
Fe males of c hil d beari n g p ote ntial s h o ul d use relia ble met h o ds of c o ntrace pti o n fr o m t he ti me 
of  scree ni n g u ntil 6 wee ks after disc o nti n ui n g st u d y i nter ve nti on. Acce pta ble met h o ds of 
c o ntrace pti o n i ncl u de f ull a bst i ne nce, t u bal li gati o n, c o m bi ne d oral, tra ns der mal or i ntra 
va gi nal h or m o nal c o ntrace pti ves, me dr o x y pr o gester o ne i njecti o ns (e g, De p o -pr o vera), 
c o p per-ba n de d i ntra -uteri ne de vices, h or m o ne i m pre g nate d i ntra -uteri ne s yste m s a n d 
vasect o mise d part ners. All met h o ds of c o ntrace pti o n ( wit h t he e xce pti o n of t otal a bst i ne nce) 
s h o uld be use d i n c o m bi nat i on wi th t he use of a c o n d o m b y t heir male se x ual part ner f or 
i nterc o urse. 
M ales
Male patie nts m ust use a c o n d o m d uri n g se x ual i nterc o urse wit h a fe male part ner of 
c hil d beari n g p ote ntial d uri n g t he st u d y a n d f or 2 4 wee ks after disc o nti n ui n g st u d y 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 2 of 1 5 5
i nter ve nt i on. 
Male patie nts s h o ul d refrai n fr o m d o nati n g s per m fr o m t he start of d osi n g u nt il 2 4 wee ks after 
di sc o nti n ui n g st u d y int er ve nt i on.
5. 3. 3 
Ot her Lifest yle Restricti o ns
F or sa v olit i ni b, d uri n g t he st u d y t hera p y a n d for 4 wee ks after t he last d ose of st u d y  
i nter ve nt i on patie nts s h o ul d be a d vise d t o a v oi d pr ol o n ge d e x p os ure t o t he s u n, wear 
pr otecti ve cl ot hi n g, a hat a n d see k s ha de fr o m t he s u n as far as p ossi ble; i n a d dit i on s u n 
pr otecti o n f act or 3 0 + s u nscree n s h o ul d be use d. E x p os ure t o ot her s o urces of ultra vi o let lig ht 
i ncl u di n g s u n be ds a n d ta n ni n g b o ot hs, etc, s h o ul d be a v oi de d.
Pati e nts s h o ul d n ot d o nate bl o o d or blo o d pr o d ucts d uri n g t he st u d y.  
5. 4 
Scree n F ail ures
Scree n fail ures are defi ne d as pat ient s w h o c o nse nt t o partici pate i n t he cli nical st u d y but are 
n ot s u bse q ue ntl y ra n d o ml y assi g ne d t o st u d y i nter ve nt i on. A mi ni mal set of scree n fail ure 
i nf or mat i on is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure patient s t o meet t he 
C o ns o li date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries 
fr om re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, 
M E T stat us i nf or mat i on, eli gi bilit y crit eria, a n d a n y S A Es.
I n di vi d uals w h o d o n ot i nitiall y meet t he criteria f or partici pati on i n t his st u d y (for e xa m ple, 
d ue t o l o gi stical c o nstrai nts or sl o w rec o ver y of si de effects fr om pre vi o us treat me nt; ie, 
scree n fail ures) ma y be rescree ne d. Rescree ne d patie nts retai n t he sa me patie nt n u m ber as f or 
t he i nit ial scree ni n g. H o we ver, rescree ni n g assess me nts s ho ul d be d oc u me nte d s o t hat its 
effect o n st u d y res ults, if a n y, ca n be assesse d.
T hese pat ient s s h o ul d ha ve faile d i ncl usi o n/e xcl usi o n criteria a n d t he reas o n f or st u d y  
wi t hdra wal  rec or de d i n t he e C R F.
Pre -scree n fail ures are defi ne d as patient s w h o sig ne d t he pre-scree ni n g I C F b ut are n ot 
c o nfir me d as M E T a m plifie d
b y ce ntral  la b orat or y testi n g If t he patie nt is s u bse q ue ntl y 
pre -scree ne d a gai n t he sa me patie nt n u m ber as f or t he i nit ial pre-scree ni n g will be retai ne d.
6 
S T U D Y I N T E R V E N TI O N
St u d y  int er ve nt i on is defi ne d as a n y in vest i gati onal i nter ve nt i on(s), m ar kete d pr o d uct(s), 
pl ace b o, or me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  patient  acc or di n g t o t he 
C S P .

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 3 of 1 5 5
6. 1 
St u d y I nter ve nti o ns A d mi nistere d
6. 1. 1 
I n vesti g ati o n al Pr o d ucts
Refer t o  Ta ble 5 f or i nf or mati on re gar di n g t he st u d y  int er ve nt i ons.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 5 of 1 5 5
6. 2 
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y of I nter ve nti o ns
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nt i on recei ve d a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.
O nl y patie nts e nr olle d i n t he st u d y  ma y recei ve st u d y int er ve nt i on a n d o nl y a ut h orise d site 
staff ma y s u p pl y or a d mi nister st u d y  int er ve nt i on. All st u d y int er ve nt i on m u st be st ore d i n a 
sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wi t h t h e la belle d st ora ge c o n diti o ns wit h access li mite d t o t he i n vest i gat or a n d a ut h orise d site 
staff.
T he i n vest i gat or, i nstituti o n, or t he hea d of t he me dical i nst ituti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y int er ve ntio n acc o u nta bilit y,  rec o nciliati on, a n d rec or d mai nte na nce (ie, 
receipt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds).
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal  dis p ositio n of  u n use d st u d y int er ve ntio ns are 
pr o vi de d i n t he P har mac y Ma n ual.
6. 3 
Me as ures t o Mi ni mise Bi as: R a n d o mis ati o n a n d Bli n di n g
Pati e nt eli gi bilit y will be esta blis he d bef ore treat me nt ra n d o misat i on. O nce t he eli gi bilit y of  a 
pati e nt has bee n c o nfir me d, t he i n vest i gat or ( or n o mi nate d assista nt) s h o ul d c o ntact t he 
I V R S/I W R S Ce ntralise d Ra n d omisat i on Ce ntre f or all ocat i on of ra n d o mise d t hera p y .
All patie nts will be ce ntrall y assi g ne d t o ra n d o mise d st u d y  int er ve nt i on usi n g a n I V R S/I W R S. 
Bef or e t he st u d y is i nitiate d, t he tele p h o ne n u m ber a n d call- i n dir e ctio ns f or t he I V R S a n d/ or 
t he lo g i n i nf or mati o n a n d di recti ons f or t he I W R S will be pr o vi de d t o eac h site. Patie nts will 
be ra n d o mise d i n a 1: 1 rati o wit h stratificat i on acc or di n g t o t he n u m b er of prior li nes o f 
t hera p y (ie, osi mert i ni b m o n ot hera p y  as first li ne or ≥sec o n d li ne [ w hic h i ncl u des patie nts 
w h o recei ve d osi merti ni b m o n ot hera p y  as first li ne t hera p y fol l owe d b y c he m ot h era p y or 
osi mert i ni b m o n ot hera p y  after c he mot h era p y]). If a p atie nt wit hdra ws fr o m t he st u d y, t he n 
his/ her e nr ol me nt/ra n d o misat i on c o de ca n n ot be re -use d. W ith dra w n pat ient s will n ot be 
r e place d.
It is rec o m me n de d t hat patie nts c o m me nce st u d y i nter ve nti on as s o o n as p ossi ble after 
ra n d omisat i on, a n d i deall y  wit hi n 3 days. Patie nts will c o m p lete treat me nts as s pecifie d a b o ve 
or u ntil disease pr o gressi o n is c o nfir me d, u nacce pta ble t o xicit y occ urs, wi t hdra wal of c o nse nt, 
or a n ot her disc o nt i n uati on cri t erio n i s met.  
T he I V R S/I W R S will pr o vi de t o t he i n vest i gat or(s) or p har macists t he kit ide nt ificati on 
n u m ber t o be all ocate d t o t he patie nt at t he dis pe nsi n g visit. R o uti nes f or t his will be descri be d 
i n t he I V R S/I W R S user ma n ual t hat will be pr o vi de d t o eac h ce ntre.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 6 of 1 5 5
T he ra n d o misat i on c o de ca n be br o ke n after i n vesti gat or -assesse d P D per R E CI S T 1. 1. 
Pati e nts i nitiall y ra n d o mise d t o t he sa v o liti ni b pl us place b o ar m ma y t he n be offere d t he 
o p p ort u nit y t o cr oss-o ver t o recei ve sa v o liti ni b i n c o m bi nati on wi t h osi merti ni b. O nce t he 
i n vesti gat or has d oc u me nte d pr o gressi o n i n t he e CR F , a n d o btai ne d a p pr o val f or u n bli n di n g 
fr om t he st u d y p h ysicia n, t he treat me nt c o de f or a patie nt ma y be o btai ne d fr o m t he I W R S via 
a de dicate d o ptio n t he y  ma y select i n t his sit uati on. I n all ot her circ u msta nces t he 
ra n d omisat i on c o de s h o ul d n ot be br o k e n e xce pt i n me dical e mer ge ncies w he n t he a p pr o priate 
ma na ge me nt of t he patie nt re q uires k n o wle d ge of t he treat me nt ra n d o misat i on. T he 
i n vesti gat or d oc u me nts a n d re p orts t he acti o n t o Astra Ze neca, wit h o ut re veali n g t he treat me nt 
gi ve n t o t he patie nt t o t he Astra Ze neca staff.
Astra Ze neca retai ns t he ri g ht t o brea k t he c o de f or S A Es t hat are u ne x pecte d a n d are 
s us pecte d t o be ca usall y relate d t o a n i n vesti gati onal  pr o d uct a n d t hat p ote ntiall y re q uire 
e x pe dite d re p orti n g t o re g ulat or y a ut h orities. Ra n d o misat i on c o des will n ot be br o ke n f or t he 
pl a n ne d a nal yses of data u ntil all decisi o ns o n t he e val ua bilit y of  t he data fr o m eac h i n di vi d ual 
pati e nt ha ve bee n ma de a n d d oc u me nte d.
T he I V R S/I W R S will be pr o gra m me d wit h bli n d -brea ki n g i nstr ucti o ns. I n case of a n 
e mer ge nc y, i n w hic h t he k n o wle d ge of t he s pecific bli n de d st u d y int er ve ntio n will  affect t he 
i m me diate ma na ge me nt of t he patie nt’s c o n ditio n  (e g, a ntid ote a vaila ble), t he i n vest i gat or has 
t he s ole res p o nsi bilit y f or deter mi ni n g if u n bli n di n g of a patie nts’ i nter ve nti on assi g n me nt is 
warra nte d. Patie nt safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a 
deter mi nat i on. If a patie nt ’s i nter ve ntio n assi g n me nt is u n bli n de d, t he s p o ns or m ust be 
n otifie d wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he i n vesti gat or d oc u me nts a n d re p orts t he 
actio n t o Astra Ze neca, wit h o ut re veali n g t he treat me nt gi ve n t o t he patie nt t o t he Astra Ze neca 
staff. A d diti onall y, p atie nts wit h in vesti gat or -assesse d o bject i ve P D ma y be u n bli n de d.
Pri or t o C S P  V 3. 0, t he Astra Ze neca st u d y  t e a m was t o be u n bli n de d at t he ti me of t he pri mar y 
a nal ysis. U n der C S P V 3. 0, f oll o wi n g t he earl y ter mi nat i on of st u d y  recr uit me nt, a n i nitial 
D C O will occ ur t o all o w a n earl y re vie w of  t he data. T he st u d y will be u n bli n de d after data 
clea ni n g act i vities o n t his i nitial D C O data ha ve bee n c o m p lete d. 
T he pers o n nel a nal ysi n g t he P K sa m ples will be u n bli n de d t o t he i n vest i gati onal treat me nt f or 
eac h patie nt. 
Ret ur ne d st u d y  int er ve nt i on s h o ul d n ot be re -dis pe nse d t o t he patie nts.
6. 4 
St u d y I nter ve nti o n C o m pli a nce
W he n pat ient s self-a d mi nister st u d y int er ve nt i ons at h o me, c o mplia nce wi t h st u d y 
i nter ve nt i on will be assesse d at eac h visit. C o m plia nce will be assesse d b y c o u nt i n g of 
ret ur ne d ta blets d uri n g t he site visits a n d d oc u me nte d i n t he s o urce d oc u me nts a n d e C R F. 
Pati e nts s h o uld ret ur n all  u n use d me dicat i on a n d e m pt y c o ntai ners t o t he i n vesti gat or. 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
5 7 of 1 5 5
De viat i on(s) fr o m t he prescri be d d osa ge re gi me n s h o ul d be rec or de d i n t he e C R F.
A rec or d of t he n u m ber of sa v oliti ni b a n d osi merti ni b/ place b o ta blets dis pe nse d t o a n d ta ke n 
b y eac h pat ient  must be mai ntai ne d a n d rec o ncile d wit h st u d y  int er ve nt i on a n d c o m p lia nce 
rec or ds. I nter ve nti o n start a n d st o p dates, i ncl u di n g dates f or i nter ve nti on dela ys a n d/ or d ose 
re d uctio ns will  als o be rec or de d i n t he e C R F.
6. 5 
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he- c o u nter or prescri pt i on me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts or ot her s pecific cate g ories of i nterest) t hat t he patie nt is recei vi n g 
at t he ti me of e nr ol me nt  or recei ves d uri n g t he st u d y must be rec or de d al o n g wit h:
 
Reas o n f or use
 
Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates
 
D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y
T he Me dical M o nit or s h o ul d be c o ntacte d if t here are a n y  q u estio ns re gar di n g c o nc o mit a nt or 
pri or t hera p y.
F or pati e nts c o nti n ui n g treat me nt wit h osi mert i ni b d uri n g Scree ni n g, t he date a n d ti me of 
a d mi nistrati o n of t he last d ose of osi merti ni b pri or t o C y cle 1 Da y 1 ( prior t o P K sa m pli n g) 
s h o uld be rec or de d.
Me dicat i on ot her t ha n t hat descri be d i n  A p pe n di x J, w hic h is c o nsi dere d necessar y for t he 
pati e nt ’s safety a n d well bei n g, ma y be gi ve n at t he discret i on of t he i n vest i gat or a n d rec or de d 
i n t he a p pr o priate sectio ns of t he e C R F.
G ui da nce o n me dici nes t o a v oi d, me dicat i ons t hat re q ui re clos e m o ni t ori n g, a n d was h o ut 
p eri o ds i s pr o vide d i n  A p pe n di x J a n d a list of me dici nes t o a v oi d is ke pt u p t o date at t he 
f oll owi n g: htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n -ta ble.
T he use of me dicat i ons liste d i n Ta ble 6 is restricte d, t hese me dicati o ns are per mitte d wit h 
ca utio n a n d caref ul m o nit ori n g of patie nts.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 8 of 1 5 5
Ta ble 6 
Restricte d Me dic ati o ns
Me dic ati o n/cl ass of dr u g 
Us a ge (i ncl u di n g li mits f or d ur ati o n per mitte d a n d s peci al sit u ati o ns i n w hic h it’s all o we d)
Stati ns
Disc o nti n uati o n of stati ns is a d vise d u nless c o nsi dere d esse ntial, i n w hic h case, t he patie nts s h o ul d be prescri be d t he l o wes t d ose 
a vaila ble a n d m o nit ore d f or t he effects of i ncrease d stati n e x p os ure.
Paraceta m ol
T he a d mi nistrati o n of aceta mi n o p he n ( paraceta m ol) t o a patie nt is restricte d t o 3 g per da y or t he ma xi m u m d ose a p pr o ve d 
l ocall y (if less t ha n 3 g/ da y) d uri n g t he st u d y.
Se nsiti ve C Y P 2 C 8 
s u bstrates
T h ose dr u gs defi ne d as se nsiti ve C Y P 2 C 8 s u bstrates (al m ost e xcl usi vel y meta b olise d b y C Y P 2 C 8, s uc h as re pa gli ni de a n d 
r osi glitaz o ne) s h o ul d be use d wit h ca uti o n.
Dr u gs affecte d b y 
P- gl yc o pr otei n
Dr u gs t hat are k n o w n t o be affecte d b y P -gl y c o pr otei n s uc h as di g o xi n, q ui ni di ne, l o pera mi de, rit o na vir a n d sa q ui na vir s h o ul d 
be use d wit h ca uti o n.
Metf or mi n
Use wit h ca uti o n, m o nit or patie nts f or t he effect of i ncrease d metf or mi n e x p os ure.
A def o vir, la mi v u di ne, a n d 
te n of o vir
Use wit h ca uti o n, m o nit or patie nts f or t he effect of i ncrease d e x p os ure.
Dr u gs w h ose dis p ositi o n is 
de pe n de nt u p o n t he B C R P
Patie nts ta ki n g c o nc o mita nt me dicati o ns w h ose dis p ositi o n is de pe n de nt u p o n t he B C R P a n d wit h a narr o w t hera pe utic i n de x 
s h o ul d be cl osel y m o nit ore d f or si g ns of c ha nge d t olera bilit y as a res ult of i ncrease d e x p os ure of t he c o nc o mita nt me dicati o n 
w h ilst recei vi n g osi merti ni b.
Patie nts ta ki n g r os u vastati n s h o ul d ha ve creati ne p h os p h o ki nase le vels m o nit ore d ( d ue t o B C R P -me diate d i ncrease i n e x p os ure). 
If t he patie nt e x perie nces a n y p ote ntiall y rele va nt A Es s u g gesti ve of m uscle t o xicit y i ncl u di n g u ne x plai ne d m uscle pai n, 
te n der ness, or wea k ness, partic ularl y if acc o m pa nie d b y malaise or fe ver, r os u vastati n m ust be st o p pe d a n d a n y a p pr o priate 
f urt her ma na ge me nt s h o ul d be take n.
Dr u gs pr ol o n gi n g Q T 
i nter val
T he c o nc o mita nt a d mi nistrati o n of dr u gs k n o w n t o pr ol o n g Q T i nter val is restricte d u nless c o nsi dere d esse ntial d ue t o patie nt
ma na ge me nt, i n w hic h case, patie nts s h o ul d be cl osel y m o nit ore d wit h m ore fre q ue nt E C Gs. A d diti o nal g ui da nce o n dr u gs 
k n o w n t o pr o l o n g Q T i nter val is pr o vi de d i n A p pe n di x J.
T he f oll o wi n g dr u gs are k n o w n t o pr ol o n g Q T i nter val or i n d uce T orsa des de P oi ntes a n d s h o ul d n ot be c o m bi ne d wit h 
osi mer ti ni b:
Clarit hr o m yci n, dr o peri d ol, er yt hr o m yci n, pr ocai na mi de, cisa pri de, dis o p yra mi de, d ofetili de, d o m peri d o ne, i b utili de, q ui ni di n e, 
s otal ol, s parfl o xaci n, t hi ori dazi ne, be pri dil, c hl or pr o mazi ne, hal ofa ntri ne, hal o peri d ol, mes ori dazi ne, le v o met ha d yl, metha d o ne, 
pi m ozi de, arse nic tri o xi de, pe nta mi di ne, a mi o dar o ne, c hl or o q ui ne (A p pe n di x J). 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 9 of 1 5 5
Ta ble 6 
Restricte d Me dic ati o ns
Me dic ati o n/cl ass of dr u g 
Us a ge (i ncl u di n g li mits f or d ur ati o n per mitte d a n d s peci al sit u ati o ns i n w hic h it’s all o we d)
Dr u gs t hat ma y p ossi bl y 
pr ol o n g Q T i nter val
T he use of t he f oll o wi n g dr u gs i s per mitte d ( n ot wit hsta n di n g ot her e xcl usi o ns a n d restricti o ns) pr o vi de d t he patie nt has bee n 
sta ble o n t hera p y f or t he peri o ds i n dicate d:
Alf uz osi n, c hl oral h y drate, ci pr ofl o xaci n, d olasetr o n, f oscar net, gala nta mi ne, ge mifl o xaci n, isri di pi ne, ket oc o naz ole , 
le v ofl o xaci n, me xileti ne, nicar di pi ne, octre oti de, ofl o xaci n, o n da nsetr o n, q uetia pi ne, ra n olazi ne, telit hr o m yci n, tiza ni di ne,
var de nafil, ve nlafa xi ne, zi prasi d o ne.
A ma nta di ne, a mitri pt yli ne, a m o xa pi ne, cl oza pi ne, d o xe pi n, fel ba mate, flecai ni de, fl uc o naz o le, f os p he n yt oi n, gatifl o xaci n, 
gra nisetr o n, i mi pra mi ne, i n da pa mi de, lit hi u m, m oe xi pril/ H C T Z, m o xifl o xaci n, ris peri d o ne, r o xit hr o m yci n, sertrali ne, 
tri met h o pri m-s ulfa, tri mi pra mi ne, v oric o naz ole.
Azit hr o m y ci n, cital o pra m, cl o mi pra mi ne, itrac o naz ole, n ortri pt y li ne, par o xeti ne, s olife naci n, tacr oli m us
Fl u o xeti ne, pr otri pt yli ne, ta m o xife n (A p pe n di x J).
A E = A d verse e ve nt; B C R P = Br east ca ncer resista nce pr otei n; C Y P = C yt oc hr o me P 4 5 0; E C G = Electr ocar di o gra m.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 0 of 1 5 5
6. 5. 1
Ot her C o nc o mit a nt Tre at me nt
Ot her me dicati o n ot her t ha n t hat descri be d a b o ve, i ncl u di n g de n os u ma b, c ortic oster oi ds 
a n d/ or bis p h os p h o nates f or t he treat me nt of b o ne metastases, w hic h is c o nsi dere d ne cessar y 
f or t he patie nt’s safety a n d well bei n g, ma y be gi ve n at t he discreti on of t he i n vesti gat or a n d 
rec or de d i n t he a p pr o priate secti o ns of t he e C R F.
Pati e nts w h o ha ve recei ve d pri or treat me nt wit h I O t hera pies s h o ul d be cl osel y  mo ni t or e d for 
a n a p pr o pr iate perio d of  ti me after t he last d ose of t he I O treat me nt, i n acc or da nce wit h t he 
res pecti ve I O la bel, as i m m u ne-me d iate d a d verse reacti o ns wit h t he I O t hera p y ma y occ ur at 
a n y ti me d uri n g or after disc o nt i n uati on of t hera p y. T he st o p date of t he pri or IO dr u g t hera p y  
s h o uld be ca pt ure d i n t he e C R Fs.
6. 6 
D ose M o dific ati o n
D ose m o dificat i ons of o ne or b ot h a ge nts are deci de d b y t he i n vest i gat or (f oll o wi n g disc ussi on 
wi t h Astra Ze neca w he n nee de d) base d o n t he t yp e of  A Es a n d t he k n o w n a d verse dr u g 
reactio ns f or eac h dr u g. I n case a d ose re d ucti o n is necessar y, t he st u d y int er ve nt i ons will be 
a d mi nistere d as f o ll ows:
Ta ble 7 
D ose Re d ucti o n f or  S a v oliti ni b t o M a n a ge A d verse E ve nts
St arti n g s a v oliti ni b d ose
Re d uce d d ose - 1
Re d uce d d ose - 2
N ote: O nl y 2 d ose re d ucti o ns of sa v oliti ni b are per mitte d.
Ta ble 8 
D ose Re d ucti o n f or  Osi merti ni b t o M a n a ge A d verse E ve nts
St arti n g osi merti ni b d ose
Re d uce d d ose - 1
F or g ui da nce o n d ose m o dificat i ons f or ma na ge me nt of A Es f or sa v o liti ni b a n d osi merti ni b, 
see A p pe n di x I.
6. 7 
I nter ve nti o n after t he E n d of t he St u d y
Pati e nts recei vi n g st u d y int er ve nt i on at t he ti me of t he fi nal D C O will be a ble t o c o nti n ue t o 
recei ve st u d y int er ve nt i on (i e, sa v olitini b pl us osi mert i ni b, sa v oliti ni b m on ot hera p y, or 
osi mert i ni b m o n ot hera p y  [if sa v olitini b was st o p pe d earlier]) as l o n g as, i n t he o pi ni o n o f t he 
i n vesti gat or, t he y are still recei vi n g cli nical be nefit. F oll o wi n g t he fi nal D C O (9 m o nt hs after 
t he last patie nt has bee n ra n d omise d ), t he cli nical st u d y data base will be cl ose d t o ne w data.
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 1 of 1 5 5
Pati e nts w h o re mai n o n st u d y int er ve nt i on after t he fi nal a nal ysis will be m o nit ore d acc or di n g 
t o r o uti ne cli nical practice as defi ne d b y t he i n vesti gat or. Astra Ze neca will c o nti n ue t o s u p pl y 
st u d y int er ve ntio n after c o m plet i on of t his st u d y  w hile, i n t he o pi ni on of t he in vest i gat or, t he 
pati e nt is be nefit i n g. I n t he e ve nt t hat pr o d uct de vel o p me nt reac hes a p oi nt w here alter nat i ve 
pr o d uct s u p pl y  o ptio ns bec o me a vaila ble, t he n t hese alter nati ve pr o d uct s u p pl y o pti o ns will be 
di sc usse d b y Astra Ze neca with t he in vest i gat or. Astra Ze neca will w or k wit h t he in vest i gat or t o 
tra nsitio n t he pati e nts t o alter nati ve s u p pl y, w here p ossi ble.
St u d y  int er ve nt i on o n g oi n g at t he ti me of fi nal a nal ysis will be s u p plie d t o sites as per o n g oi n g 
pr ocess. Pl ace b o ta blets will n ot be s u p plie d after t he fi nal a nal ysis b ut patie nts ca n c o n tin ue 
o n sa v o liti ni b m on ot hera p y  as lo n g as, i n t he o pi ni o n of t he i n vest i gat or, t he y are still 
recei vi n g cli nical be nefit a n d ha ve n ot re p orte d P D. Dr u g dis pe nsati on a n d rec o nciliat i on will 
be ha n dle d b y site o n eac h patie nt ’s visit. Pa per f or m pr ocess will be use d f or S A E re p orti n g, 
all S A Es, o ver d oses a n d pre g na ncies will be re p orte d u ntil 3 0 da ys after t he last d ose. T he 
st u d y will re mai n o pe n u ntil t he last patie nt is treate d. Last patie nt last visit will be defi ne d as 
t he last patie nt ’s treat me nt disco nt i n uati on. 
I n t he e ve nt t hat a r oll-o ver st u d y  is a vaila ble at t he ti me of t he fi nal D C O a n d data base 
clos ure, patie nts c urre ntl y  recei vi n g st u d y treat me nt ma y be tra nsitio ne d t o s uc h a st u d y, a n d 
t he c urre nt st u d y parti ci pat i on w o ul d reac h its e n d. T he r oll -o ver st u d y  w o uld e ns ure 
treat me nt c o nti n uat i on wi t h visits assess me nt per its pr ot oc ol. A n y patie nt t hat w o ul d be 
pr o p ose d t o m o ve t o s uc h st u d y  w o uld be gi ve n a ne w I C F.
7 
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A TI E N T DI S C O N TI N U A TI O N/ WI T H D R A W A L
7. 1 
Disc o nti n u ati o n of St u d y I nter ve nti o n
It ma y be necessar y for a p ati e nt t o per ma ne ntl y disc o nti n ue ( defi nit i ve disc o nti n uati on) st u d y  
i nter ve nt i on. If st u d y  int er ve nt i on is per ma ne ntl y disc o nti n ue d, t he patie nt will re mai n i n t he 
st u dy t o be e val uate d f or s ur vi val. 
Pati e nts ma y b e disc o nti n ue d fr o m st u d y int er ve nt i o n i n t he f oll owi n g si t u atio ns. N ote t hat 
di sc o nti n uati on fr om st u d y int er ve nt i on is N O T t he sa me t hi n g as a wit h dra wal fr om t he 
st u d y.
 
Pati e nt decisio n . T he patie nt is at an y t i me free t o disc o nti n ue treat me nt, wit h o ut 
pr ej u dice t o f urt her treat me nt.
 
A d verse e ve nts.
 
Se vere n o n -c o mplia nce wi t h t he C S P .
 
Di sease pr o gressio n as per R E CI S T 1. 1; u nless t he patie nt is ra n d o mise d t o sa v o liti ni b 
pl us place b o, w he n cr oss -o ver t o sa v o liti ni b pl us osi merti ni b ma y be per mitte d.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 2 of 1 5 5
 
Pati e nts i nc orrectl y i nit iate d o n st u d y me dicat i on.
 
Pre g na nc y.
 
S pecific st o p pi n g criteria, ie, I L D, ac ute a na p h yla xis or Q Tc F i nter val pr o l on gat i on wi t h 
sig ns/s y m pt o m s of serio us arr h y t h mia.
See t he S o As (Ta ble 1 a n d Ta ble 2 ) for data t o be c ollecte d at t he ti me of i nter ve nt i on 
di sc o nti n uati on a n d f o ll ow -u p a n d f or a n y  furt her e val uat i ons t hat nee d t o be c o m plete d.
C o nti n ui n g o n M o n ot her a p y
If a patie nt disc o nti n ues osi merti ni b d ue t o t o xicity t he patie nt ma y c o nt i n ue with sa v o liti ni b 
u nt il pr o gressi o n.
If a patie nt disc o nti n ues sa v oliti ni b d ue t o t o xicity t he y ma y c o nti n ue with osi mert i ni b 
m o n ot hera p y  u ntil t he Pri nci pal I n vesti gat or belie ves t here is n o f urt her be nefit (t his ma y be 
be y o n d P D i n t he a bse nce of cli nical s y m pt o ms or si g ns i n dicat i n g cli nicall y si g nifica nt P D; 
n o de cli ne i n perf or ma nce stat us; a bse nce of ra pi d P D or t hreat t o vital or ga ns or crit ical 
a nat o mical sites [e g, ce ntral ner v o us s yste m metastasis, res pirat or y  fail ure d ue t o t u m o ur 
c o mpressi o n , s pi nal c or d c o m pressi on] re q uiri n g ur ge nt alter nat i ve me dical i nt er ve nt i on; or n o 
sig nifica nt, u nacce pta ble or irre versi ble t o xicit ies relate d t o st u d y int er ve nt i on), acc or di n g t o 
t he S o As (Ta ble 1 a n d Ta ble 2 ).
F o ll owi n g P D, pati e nts ma y c o nti n ue o n osi merti ni b m o n ot hera p y a n d c o nti n ue wit h all safety 
assess me nts as per t he S o As (Ta ble 1 a n d Ta ble 2 ). Sa v oliti ni b m on ot hera p y  ( eit her if 
ori gi nall y ra n d o mise d t o sa v o liti ni b pl us place b o or after disc o nti n uati o n of osi mert i ni b if 
ori gi nall y ra n d o mise d t o sa v o liti ni b pl us osi merti ni b) p ost pro gressi o n is n ot per mitte d. 
7. 1. 1 
Rec h alle n ge
See g ui da nce i n  A p pe n di x I f or circ u msta nces u n der w hic h a patie nt w h ose st u d y int er ve nt i on 
was te m p oraril y i nterr u pte d d ue t o a n A E ca n restart treat me nt, a n d s pecificall y a d dit i onal 
preca uti o ns t o be ta ke n u p o n restarti n g sa v o liti ni b.
7. 1. 2 
Pr oce d ures f or Disc o nti n u ati o n of St u d y I nter ve nti o n
T he i n vest i gat or s h o ul d i nstr uct t he patie nt t o c o ntact t he site bef ore or at t he ti me if an y st u d y  
i nter ve nt i on is st o p pe d. A pati e nt t hat decides t o disc o nti n ue st u d y  int er ve ntio n(s) will  al wa ys 
be as ke d a b o ut t he reas o n(s) a n d t he prese nce of a n y A Es. T he date of last i nta ke of st u d y 
i nter ve nt i on(s) s h o ul d be d oc u me nte d i n t he e C R F. All st u d y i nter ve nt i on(s) s h o ul d be 
ret ur ne d b y t he patie nt at t heir ne xt o n-site st u d y visit or u nsc he d ule d visit. Patie nts 
p er m a ne nt l y disc o nti n ui n g st u d y i nter ve nti o n s h o ul d be gi ve n l ocall y a vaila ble sta n dar d of 
care t hera p y, at t he discret i on of t he i n vest i gator.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 3 of 1 5 5
Di sc o nti n uatio n of  st u d y int er ve ntio n(s), f or a n y  reas o n, d oes n ot i m pact o n t he patie nt´s 
i n v ol ve me nt i n t he st u d y. T he patient  s h o uld c o nti n ue atte n di n g s u bse q ue nt st u d y  visits a n d 
data c ollect i on s h o ul d c o nti n ue acc or di n g t o t he C S P . If t he patie nt d oes n ot a gree t o c o nti n ue 
i n-pers o n st u d y  visits, a mo difie d f oll o w -u p m ust be arra n ge d t o e ns ure t he c ollect i on of 
e n d p o i nts a n d safety i nf or mati o n. T his c o ul d be a tele p h o ne c o ntact wit h t he patie nt, a c o ntact 
wi t h a r elat i ve or treati n g p h ysicia n, or inf or mat i on fr om me d ical rec or ds. T he a p pr oac h ta ke n 
s h o uld be rec or de d i n t he m e dical rec or ds. A pati e nt t hat a grees t o m o difie d f o ll ow- u p i s n ot 
c o nsi dere d t o ha ve wit h dra w n c o nse nt or t o ha ve wit h dra w n fr o m t he st u d y.
As a mi ni m u m, tele p h o ne c o ntact s h o u l d be ma d e wit h t he patie nt 2 8 da ys f oll o wi n g t he 
di sc o nti n uati on of b ot h st u d y  int er ve nt i ons t o c ollect ne w A Es a n d f o ll ow u p o n a n y o n g oi n g 
A Es a n d c o nc o mit a nt me dicat i ons (i ncl u di n g a n y s u bse q ue nt ca ncer t hera p y, if a p pr o priate). 
Refer t o Secti o n  8. 3. 2 f or full details o n A E rec or di n gs d uri n g f o ll ow- u p. 
7. 2 
P atie nt Wit h dr a w al fr o m t he St u d y
 
A pat ient  ma y wit hdra w fr o m  t he st u d y at a n y ti me at his/ her o w n re q uest, or ma y be 
wi t hdra w n at a n y  ti me at t he discretio n of  t he i n vestigat or f or safet y,  be ha vi o ural, 
c o mplia nce or a d mi nistrati ve reas o ns. T his is e x pecte d t o be u nc o m m o n.
 
A pat ient  w h o c o nsi ders wit h dra wi n g fr o m t he st u d y must be i nf or m e d b y t he i n vesti gat or 
a b o ut mo difie d f o ll ow- u p o pti o ns (e g, tel e p h o ne c o ntact, a c o ntact wit h a relati ve or 
treati n g p h ysicia n or i nf or mati o n fr om me dical rec or ds).
 
At  t he ti me of wit h dra wal fr om t he st u d y, if p ossi ble, a n Earl y St u d y I nter ve nti on 
Di sc o nti n uatio n visi t s h o uld be c o n d ucte d, as s h o w n i n t he S o As (Ta ble 1 a n d Ta ble 2 ). 
See t he S o As f or data t o be c ollecte d at t he ti me of st u d y wit hdra wal a n d f oll o w -u p a n d 
f or a n y furt her e val uat i ons t hat nee d t o be c o m plete d.
 
T he patie nt will disc o nti n ue t he st u d y  int er ve nt i on a n d be wit h dra w n fr o m t he st u d y 
at t hat ti me.
 
If t he patie nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati on, t he s p o ns or ma y  
retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.
 
If a patie nt wit h dra ws fr om t he st u d y, it s h o uld be c o nfir me d if he/s he still a grees f or 
e xist i n g sa m ples t o be use d i n li ne wit h t he origi nal  c o nse nt. If he/s he re q uests wit h dra wal 
of  c o nse nt f or use of sa m ples, destr ucti o n of a n y sa m ples ta ke n a n d n ot teste d s h o ul d be 
carrie d i n li ne wit h w hat was state d i n t he i nf or me d c o nse nt a n d l ocal re g ulat i on. T he 
i n vesti gat or m ust d oc u me nt t he decisio n  o n use of e xisti n g sa m ples i n t he site st u d y 
rec or ds a n d i nf or m t he Gl o bal St u d y Tea m.
7. 3 
L ost t o F oll o w u p
A pat ient will be c o nsi dere d l ost t o f o ll ow- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 4 of 1 5 5
T he f o ll owi n g acti o ns m ust be ta ke n if a patie nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y  
visit:
 
T he site m ust atte m pt t o c o ntact t he patie nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he pat ient  o n t he im p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he patie nt wis hes t o a n d/ or s h o ul d c o nti n ue i n t he 
st u d y.
 
Bef ore a patie nt is dee me d l ost t o f oll o w u p, t he i n vesti gat or or desi g nee m ust ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he patie nt ( w here p ossi ble, 3 tele p h o ne calls a n d, if 
necessar y , a certifie d letter t o t he patie nt’s last k n o w n maili n g a d dress or l ocal e q ui vale nt 
met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he patie nt’s me dical rec or d.
 
S h o ul d t he pat ient  c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wi t hdra w n fr o m  t he st u d y. 
 
Si te pers o n nel, or a n i n de pe n de nt t hir d part y, will att e mpt t o c ollect t he vital stat us of t he 
pati e nt wit hi n le gal a n d et hical b o u n daries f or all patie nts ra n d omise d, i ncl u di n g t h ose 
w h o di d n ot get st u d y  int er ve ntio n. P u blic s o urces ma y be searc he d f or vital stat us 
i nf or mat i on. If vital stat us is deter mi ne d as decease d, t his will be d oc u me nte d a n d t he 
pati e nt will n ot be c o nsi dere d l ost t o f oll o w -u p. S p o ns o r pers o n nel will n ot be i n v ol ve d i n 
a n y atte mpts t o c ollect vital stat us i nf or mati o n.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of A p pe n di x A.
8 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
 
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he S o As (Ta ble 1 a n d Ta ble 2 ). 
Pr ot oc ol wai vers or e xe m pt i ons are n ot all o we d.
 
I mme diate safet y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o deter mi ne if t he patie nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nt i on.
 
A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o As
(Ta ble 1 a n d Ta ble 2) , is esse ntial a n d re q uire d f or st u d y c o n d uct.
 
All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote ntial 
pati e nts meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all pat ient s scree ne d a n d t o c o nfir m eli gi bility or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble.
 
Pr oce d ures c o n d ucte d as part of t he patie nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d 
c o u nt) a n d o btaine d bef ore si g ni n g of t he I C F ma y be utilise d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures met t he C S P -s pecifie d criteria a n d were perf or me d 
wi t hi n t he ti me fra me defi ne d i n t he S o As (Ta ble 1 a n d Ta ble 2) .

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 5 of 1 5 5
8. 1 
Effic ac y Assess me nts
8. 1. 1 
C T a n d M RI Sc a ns T u m o ur Assess me nts ( R E CI S T 1. 1)
T he R E CI S T 1. 1 g ui deli nes f or meas ura ble, n o n -meas ura ble, T Ls a n d N T Ls a n d t he o bject i ve 
t u mo ur res p o nse criteria are p rese nte d i n A p pe n di x H of  t his C S P .
Baseli ne t u m o ur assess me nts s h o ul d i ncl u de C T/ M RI of c hest a n d a b d o me n (i ncl u di n g li ver 
a n d a dre nal gla n ds) a n d s h o ul d be perf or me d wit hi n 2 8 da ys of ra n d omisati o n, a n d i deall y as 
close as p ossi ble t o t he start of st u d y int er ve nt i on . At  scree ni n g t he M RI/ C T sca ns will i ncl u de 
brai n i ma gi n g f or all pat ient s. T h ose deter mi ne d t o ha ve brai n metastases will ha ve t heir brai n 
resca n ne d at all s u bse q ue nt t u m o ur assess me nts. A n y ot her re gi o ns s us pecte d, or wit h k n o w n 
metastasis at baseli ne, will be assesse d b y i ma gi n g a n d rec or de d at baseli ne. T he sa me 
i ma gi n g m o dality use d f or baseli ne t u m o ur assess me nt s h o ul d be use d f or eac h s u bse q ue nt 
f oll ow- u p assess me nt t hr o u g h o ut t he st u d y  if p ossi ble. F urt her details of t he C T a n d M RI 
ac q uisit i on para meters will be d oc u me nte d i n a se parate i ma ge ac q uisit i on g ui deli nes 
d oc u m e nt.
F o ll ow- u p assess me nts s h o ul d be perf or me d Q 6 W  ( ± 7 da ys) after ra n d o misat io n u nt il 
C ycle 7 ( u p t o 2 4 wee ks), a n d t he n Q 8 W  ( ± 7 da y s) u ntil o bjecti ve P D as defi ne d b y 
R E CI S T 1. 1 e ve n if a patie nt disc o nt i n ues treat me nt pri or t o pr o gressi o n ( u nless t he y 
wi t hdra w c o nse nt). F o r patie nts w h o cr oss-o ver base d o n c o nfir me d o bject i ve disease 
pr o gressi o n d uri n g t he i nit ial ra n d omi se d treat me nt perio d (i ncl u di n g pat ient s w h o ha ve 
alrea d y cr osse d o ver base d o n c o nfir me d P D pri or t o C S P Versio n 3. 0), sc he d ule d R E CI S T 1. 1 
t u mo ur assess me nts are n ot re q uire d, a n d t he s u bse q ue nt assess me nt of d isease pr o gressi o n 
will be base d o n sta n dar d -of -care sca n or i n vest i gat or deter mi ne d cli nical pr o gressi o n. 
Sc he d ule d R E CI S T 1. 1 t u m o ur assess me nts are re q uire d (t he sca n fre q ue nc y is a gai nst i nit ial 
ra n d omisat i on ) for pati e nts w h o cr oss-o ver aft er st u d y u nbli n di n g a n d w h o ha ve n ot 
o bj ect i vel y pr o gresse d d uri n g t he i nitial ra n d omise d treat me nt peri o d. Patie nts w h o cr oss -o ver 
aft er stu d y u n bli n di n g, w h o ha ve n o o bject i ve pr o gressi on d uri n g i nit ial ra n d omi satio n peri o d, 
a n d w h o disc o nt i n ue st u d y i nter ve nt i on a fter cr oss-o ver f or reas o ns ot her t ha n 
i n vesti gat or-c o nfir me d disease pr o gressi o n will c o nt i n ue sc he d ule d R E CI S T 1. 1 t u m o ur 
assess me nts u nt il o bjecti ve disease pr o gressi o n per R E CI S T 1. 1 as assesse d b y i n vesti gat or, 
u nless t he y  wit hdra w c o nse nt t o t he e nti re st u d y.
It is i m p orta nt t o f oll o w t he assess me nt sc he d ule as cl osel y as p ossi ble. If sca ns are perf or me d 
o utsi d e of  t he sc he d ule d visit ± 1 wee k wi n d o w i nter val a n d t he patie nt has n ot pr o gresse d, 
e ver y atte mpt s h o ul d be ma de t o perf or m  t he s u bse q ue nt sca ns at t heir sc he d ule d ti me p oi nts. 
P ati e nts will be e val uate d u nt il o bjecti ve ra di ol ogical  P D b y R E CI S T 1. 1 as per t he S o As
(Ta ble 1 a n d Ta ble 2 ).
Cate g orisat i on of o bject i ve t u m o ur res p o nse at eac h visit will be base d o n t he R E CI S T 1. 1 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 6 of 1 5 5
g ui deli nes f or res p o nse: C R, P R, S D, N E a n d P D. 
Ta r get lesi on pr o gressi o n will be calc ulate d i n c o m pari s o n t o w he n t he t u m o ur b ur de n was at a 
mi ni m u m (ie, s mallest s u m of dia meters pre vi o usl y rec or de d o n st u d y ). I n t he a bse nce of 
pr o gressi o n, t u m o ur res p o nse ( C R, P R, S D, N E) will be calc ulate d i n c o m paris o n t o t he 
baseli ne t u m o ur meas ure me nts o btai ne d bef ore starti n g treat m e nt.
If t he i n vesti gat or is i n d o u bt as t o w het her pr o gressi o n has occ urre d, partic ularl y with 
res p o nse t o N T Ls or t he a p peara nce of a ne w lesi o n, i t is a d visa ble t o c o nti n ue treat me nt a n d 
reassess t he patie nt’s stat us at t he ne xt sche d ule d assess me nt or s o o ner if cli nicall y i n dicate d.
To  ac hie ve ‘u ne q ui v ocal  pr o gressio n ’ o n t he basis of n o n -tar get disease, t here m ust be a n 
o verall le vel o f s u bsta ntial w orse ni n g i n n o n -tar get disease s uc h t hat, e ve n i n prese nce of S D 
or P R i n tar get d isease, t he o verall t u m o ur b ur de n has i ncrease d s ufficie ntl y t o merit 
u ne q ui v ocal pr o gressi o n b y  N T Ls. A m o dest ‘i ncrease’ i n t he size of o ne or m ore N T Ls is 
us uall y n ot s ufficie nt t o q ualif y f or u ne q ui v ocal P D stat us.
If re peate d sca ns c o nfir m pr o gressi o n, t he n t he date of t he i nitial sca n s h o ul d be declare d as 
t he date of pr o gressi o n.
All C T/ M RI sca ns a n d all i ma gi n g assess me nts perf or me d f or R E CI S T 1. 1 t u m o ur assess me nt 
will be re vie we d at site. All i ma ges, i ncl u di n g u nsc he d ule d visit sca ns, will be c ollecte d o n a n 
o n g oi n g basis a n d se nt t o a n Astra Ze neca -a p p o i nte d C R O t o e na ble BI C R u p t o t he p oi nt of 
t he fi nal a nal ysis (t he earlier of 1 8 m o nt hs after t he last patie nt is ra n d o mise d or w he n 7 0 % of 
pati e nts ha ve pr o gresse d or die d). G ui deli nes f or i ma ge ac q uisi tio n , de-i de ntificati on, st ora ge 
at t he i n vesti gati ve site as s o urce data, a n d tra nsfer t o t he i ma gi n g C R O will be pr o vi de d i n a 
se parate d oc u me nt. F urt her details o f t he BI C R will be d oc u me nte d i n t he I n de pe n de nt 
Re vie w C harter (als o referre d t o as “ I ma gi n g C harter ”). Res ults of t he i n de pe n de nt re vie ws 
will n ot be c o m m u nicate d t o i n vest i gat ors, a n d res ults of i n vesti gat or R E CI S T 1. 1 
assess me nts will n ot be s hare d wit h t he ce ntral re vie wers. T he ma na ge me nt of patie nts will be 
base d w h o ll y u p o n t he res ults of t he R E CI S T 1. 1 assess me nt c o n d ucte d b y t he i n vest i gat or. 
F o ll owi n g i n vesti gat or -assesse d P D, i n pat ient s w h o cr oss-o ver fr o m sa v olit i ni b pl us place b o 
t o recei ve t he c o m bi nati on of sa v o liti ni b a n d osi merti ni b, sec o n dar y O R R, P F S, D o R a n d 
c ha n ge i n t u m o ur size assess me nts will be perf or me d b y t he i n vest i gat or usi n g i ma gi n g 
assess me nts per R E CI S T 1. 1 (see Secti o n  9. 4. 2. 3 ). T hese l ocal-pract ice sca ns s h o ul d n ot be
se nt t o t he a p p oi nte d C R O f or BI C R.
8. 1. 2 
S ur vi v al F oll o w -u p
Pati e nts w h o ha ve disc o nt i n ue d st u d y int er ve nt i on will be f o ll owe d u p f or s ur vi val stat us 
Q 1 2 W  u ntil deat h, wit hdra wal of c o nse nt or t he e n d of t he st u d y, ie, at t he ti me of fi nal 
a nal ysis. S ur vi val inf or mat i on ma y be o btai ne d via tele p h o ne c o ntact wit h t he patie nt, 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 7 of 1 5 5
pati e nt ’s fa mil y or b y c o ntact wit h t he patie nt ’s c urre nt p h ysicia n. I n a d diti on t o t he s ur vi val 
stat us, t he assess me nt of a nti-ca ncer a n d s ur gical treat me nts are als o re q uire d.
Pati e nts s ho ul d be c o ntacte d i n t he wee k f oll o wi n g t he D C Os f or t he fi nal a nal ysis t o pr o vi de 
c o mplete s ur vi val data.
F or pati e nts w h o ha ve n ot acti vel y wit h dra w n c o nse nt, t he stat us of t h ose o n g oi n g, wit h dra w n 
(fr om t he st u d y), a n d “l ost t o f oll o w- u p” at t he ti me of t he first 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 otes, h os pital rec or ds, c o ntacti n g t he patie nts 
ge neral practit i oner 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 
pati e nt has act i vel y wi t hdra 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 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.
8. 2 
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safet y assess me nts are pr o vi de d i n t he S o As ( Ta ble 1 a n d Ta ble 2 ).
8. 2. 1 
P h ysic al E x a mi n ati o ns
A c o m p lete p h ysical e xa mi nati on will be perf or me d a n d i ncl u de assess me nts of t he f o ll owi n g; 
ge neral a p peara nce, res pirat or y, car dio vasc ular, a b d o me n, s ki n, hea d a n d nec k (i ncl u di n g ears, 
e yes, n ose a n d t hr oat), l y m p h n o des, t h yr oid, m us c ul ar-skeletal  (i ncl u di n g s pi ne a n d 
e xtre mit ies) a n d ne ur ol ogi cal s yste ms. 
P h ysical e xa mi nat i on will be perf or me d at ti meli nes as s pecifie d i n t he S o As (Ta ble 1 a n d 
Ta ble 2 ), i n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses, ne w or w orse ni n g a b n or malities ma y q ualif y as A Es, see Sect i on  8. 3. 4 f or details. 
8. 2. 2 
Vit al Si g ns
Vit al si g ns ( heart rate, B P, te m perat ure, a n d res pirati o n rate) will be perf or me d as s pecifie d i n 
t he S o As (Ta ble 1 a n d Ta ble 2 ) a n d as cli nicall y in di cate d. Heig ht will be assesse d at t he 
scree ni n g visit o nl y. Wei g ht will be assesse d at t he scree ni n g visit, Da y  1 of eac h c ycle f or t he 
first 6 c ycles, Q 8 W fr o m C ycle 7 o n war ds, a n d m ore fre q ue ntl y if cli nicall y i n dicate d. If a 
pati e nt cr osses o ver t o sa v olit i ni b pl us osi merti ni b t he y will c o nti n ue t o ha ve f oll ow - u p 
assess me nts i n li ne wit h t hese ti mi n gs relat i ve t o ra n d omisati o n, alt h o u g h t he y will be 
re p orte d wit h a ne w baseli ne of t he pr o gressi o n sca n o n ra n d omise d treat me nt (see 
Secti o n 8. 1. 1 ).
 
T e m perat ure, p ulse rate a n d B P will be assesse d.
 
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n t he se mi -s u pi ne p ositio n wi t h 
a c o mpletel y  a ut o mate d de vice. Ma n ual tec h ni q ues will o nl y be use d if a n a ut o mate d 
de vice is n ot a vaila ble.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 8 of 1 5 5
 
Vi t al si g n meas ure me nts s h o uld be prece de d b y at least 1 0 mi n utes of rest f or t he patie nt 
i n a q uiet setti n g wit ho ut di stractio ns (e g, tele visi o n, cell p h o nes).
 
Meas ure me nts will be ta ke n i n a se mi -s u pi ne p ositio n  after 1 0 mi n utes rest a n d will 
i ncl u de te mperat ure, s y st olic a n d diast olic B P a n d p ulse.
A n y c ha n ges i n vital si g ns s h o ul d be rec or de d as a n A E, if a p plica ble.
8. 2. 3 
Electr oc ar di o gr a ms
T he Q T C F e val uat i ons will be d o ne base d o n tri plicate 1 2 -lea d E C Gs as i n dicate d i n t he S o As 
(Ta ble 1 a n d Ta ble 2 ). Twel ve -lea d E C Gs (tri plicate) will be o btai ne d after t he patie nt has 
bee n reste d i n a s u pi ne p osit i on f or at least 5 mi n utes. T he i n vest i gat or or desi g nate d 
p h ysicia n will re vie w t he 1 2 -lea d E C Gs. Electr ocar di o gra ms 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 si g nifica ntl y 
a b n or mal/ n ot cli nicall y si g nifica ntl y a b n or mal. 
Tri p licate E C Gs will be re q uire d o n C ycle 3 Da y 1 c ollecte d pre-d ose, a n d at 1, 3, 4, a n d 
6 h o urs p ost -d ose, o n ra n d o mise d treat me nt a n d a gai n o n cr oss -o ver treat m e nt ( C ycle 3 Da y 1 
o n cr oss -o ver bei n g relati ve t o first d ose of osi merti ni b), t o c oi nci de wit h c ollect i on of bl o o d 
sa m ples f or assess me nt of P K of osi merti ni b a n d sa v oliti ni b at t his visit. 
If t here is a cli nicall y si g nifica nt a b n or mal E C G fi n di n g, t he i n vesti gat or will rec or d it as a n 
A E o n t he e C R F . T he origi nal  E C G traces must be st ore d i n t he patie nt ’s me dical rec or d as 
s o urce data. A 2 8- d a y  fol l ow -u p assess me nt will be re q uire d if a n o n -treat me nt assess me nt 
was a b n or mal at t he ti me of disc o nti n uati o n o f st u d y t hera p y, t o c o nfir m re versi bilit y of t he 
a b n or malit y.
8. 2. 4 
M ulti -g ate d Ac q uisiti o n/ Ec h oc ar di o gr a m 
A n E C H O or M U G A  sca n t o assess left ve ntricle eject i on fracti on will be c o n d ucte d d uri n g 
t he mai n st u d y scree ni n g peri o d, Q 1 2 W ( ± 2 wee ks) relati ve t o ra n d o misati o n, a n d at t he e n d 
of  treat me nt as i n dicate d i n t he S o As (Ta ble 1 a n d Ta ble 2 ). If a patie nt cr osses o ver t o 
sa v oliti ni b pl us osi merti ni b t he y will c o nti n ue t o ha ve f oll ow -u p assess me nts i n li ne wit h 
t hese ti mi n gs relati ve t o ra n d o misati o n, alt h o u g h t he y will be re p orte d wit h a ne w baseli ne of 
t he pr o gressi o n sca n o n ra n d o mise d treat me nt (see Secti o n 8. 1. 1 ). T he m o dalit y of t he car diac 
f u ncti on assess me nts m ust be c o nsiste nt wit hi n a patie nt, ie, if E C H O is use d f or t he scree ni n g 
assess me nt t he n E C H Os s h o ul d als o be d o ne f or s u bse q ue nt testi n g. T he patie nts s h o ul d als o 
be e xa mi ne d usi n g t he sa me mac hi ne a n d o perat or w he ne ver p ossi ble, a n d q ua ntitati ve 
meas ure me nts s h o ul d be ta ke n. A  2 8-da y  fol l ow- u p assess me nt will be re q uire d if a n 
o n -treat me nt assess me nt was a b n or mal at t he ti me of disc o nti n uatio n of  st u d y t hera p y, t o 
c o nfir m re versi bilit y of t he a b n or malit y.   

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
6 9 of 1 5 5
8. 2. 5 
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples f or deter mi nat i on of cli nical c he mistr y, hae mat olo g y, c oa g ulat i on 
a n d uri nal ysis will be ta ke n at t he visits i n dicate d i n t he S o As (Ta ble 1 a n d Ta ble 2 ). All 
C S P -re q uire d safety la b orat or y assess me nts, as defi ne d i n Ta ble 9 , will be perf or me d i n a 
lice nse d l ocal cli nical la b orat or y acc or di n g t o l ocal sta n dar d pr oce d ures. 
T he i n vest i gat or s h o ul d ma ke a n assess me nt of t he a vaila ble res ults wit h re gar d t o cli nically 
r ele va nt a b n or malities. T he la b orat or y res ults s h o ul d be sig ne d a n d date d a n d retai ne d at t he 
ce ntre as s o urce data f or la b orat or y varia bles.  
F or i nf or mat i on o n h o w A Es base d o n la b orat or y  tests s h o uld be rec or de d a n d re p orte d, see 
Secti o n  8. 3. 5 .
A d dit i onal safety sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t he discreti on of t he 
i n vesti gat or. T he date, ti me of c ollecti o n a n d res ults ( val ues, u nits a n d refere nce ra n ges) will 
be rec or de d o n t he a p pr o priate e C R F.
T he cli nical c he mistr y  (i ncl u di n g L F Ts), hae mat ol o g y a n d uri nal ysis will be perf or me d at a 
l ocal la b orat or y at or near t o t he i n vesti gat or site. Sa m ple t u bes a n d sa m ple sizes ma y var y 
de pe n di n g o n t he lab orat or y  met h o d use d a n d r o uti ne practice at t he site.
T he f o ll owi n g la b orat or y  varia bles will be meas ure d. 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 0 of 1 5 5
Ta ble 9 
L a b or at or y S afet y V a r i a bles
Cli nic al c he mistr y
H ae m at ol o g y
Uri n al ysis ( Di pstic k) a
S/ P – Al b u mi n
B – Hae mat ocrit
U – Bl o o d
S/ P – A L P b
B – Hae m o gl o bi n
U – Gl uc ose
S/ P – A L T b
B – Le uc oc yte cell c o u nt
U – Ket o nes
S/ P – A m ylase
B – Platelet c o u nt
U – Le u k oc yte esterase
S/ P – A S T b
B – Re d bl o o d cell c o u nt
U – Pr otei n
S/ P – Bilir u bi n, t otal b
B - Retic ul oc ytes
S/ P – Calci u m, t otal
B – A bs ol ute le uc oc yte differe ntial 
c o u nt:
B – Ne utr o p hil c o u nt
B – L y m p h oc y te c o u nt
B – E osi n o p hil c o u nt
S/ P – Cr eati ni ne
S/ P – Gl uc ose
S/ P – Ma g nesi u m
S/ P – S o di u m 
S/ P – P otassi u m
S/ P – T otal pr otei n
S/ P – Bl o o d urea nitr o ge n or urea
S/ P – Lactate de h y dr o ge nase
a
If 3 + or greater pr otei n uria is i de ntifie d b y di pstic k assess me nt, a 2 4 -h o urs uri ne c ollecti o n f or f or mal 
q ua ntificati o n of t he le vel of pr otei n e xcreti o n s h o ul d be perf or me d
b
Desi g nates tests t hat are c o nsi dere d L F Ts a n d are t o be d o ne wee kl y f or t he first 1 0 wee ks relati ve t o 
ra n d o misati o n, t he n Da y 1 of e ver y s u bse q ue nt c ycle a n d at pr o gressi o n.
A L P = Al kali ne p h os p hatase; A L T = Ala ni ne a mi n otra nsferase; A S T = As partate a mi n o tra nsferase; B = Bl o o d; 
L F T = Li ver f u ncti o n test; P = Plas ma; S = Ser u m; U = Uri ne.
N ote: I n case a patie nt s h o ws a n A S T o r A L T ≥3 × U L N t o get her wit h T B L  ≥2 × U L N 
pl ease refer t o  A p pe n di x E “Act i ons Re q uire 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”, f or furt her i nstr ucti o ns. 
8. 2. 6 
Ser u m of Uri ne Pre g n a nc y Test
A pre g na nc y test o n uri ne or bl o o d sa m ple wi ll be perf or m e d for pr e -me n o pa usal W O C B P, at 
t he st u d y scree ni n g visit, a n d pri or t o t he first d ose of st u d y int er ve nt i on o n C ycle 1 Da y  1, 
Da y 1 of  e ver y c ycle, a n d at treat me nt disc o nti n uati on. Tests will be perf or me d b y t he 
i nstituti o nal  la b orat or y. If res ults are p ositive t he patie nt is i neli gi ble/ m ust be disc o nt i n ue d 
fr om t he st u d y. I n t he e ve nt of a 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 uld be 
re peate d a n d if p ositi ve, t he patie nt will be disc o nti n ue d fr om st u d y int er ve nt i on i m me diatel y.
8. 3 
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he Pri nci pal In vest i gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar with t he c o nte nt of t his sect i on.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 1 of 1 5 5
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n  A p pe n di x B.
A d verse e ve nts will be re p orte d b y  t he patie nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, 
or t he pati e nt's le gall y a ut h orise d re prese ntati ve). 
T he i n vest i gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g a n d rec or di n g 
e ve nts t hat meet t he defi nit i on of a n A E.
8. 3. 1 
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
A d verse E ve nts a n d S A Es will be c o llecte d fr o m ti me of si g nat ure of t he mai n st u d y I C F 
t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w-u p peri o d. T he f o ll ow -u p peri o d i s 
defi ne d as 2 8 ± 7 d a y s after st u d y int er ve nt i on is disc o nti n ue d.
Pr oce d ure -relate d A Es a n d S A Es f or t h ose patie nts w h o p r o vide a ne w t u m o ur bi o ps y  
occ urri n g u p t o a n d i ncl u di n g 2 1 da ys after t he ne w t u m o ur bi o ps y pr oce d ure will be ca pt ure d. 
T his pr oce d ure ma y  be perf or me d prior t o si g ni n g t he mai n st u d y  I C F.
If t he i n vesti gat or bec o mes a ware of a S A E wit h a s us pecte d ca usal relati ons hi p t o t he 
i n vesti gati onal me dici nal pr o d uct t hat occ urs after t he e n d of t he cli nical st u d y  in a patie nt 
treate d b y hi m or her, t he i n vesti gat or s hall, with o ut u n d ue dela y, re p ort t he S A E t o t he 
s p o ns or.
8. 3. 2 
F oll o w- u p of A Es a n d S A Es
A n y A Es t hat ar e u nres o l ve d at t he patie nt’s last A E assess me nt i n t he st u d y are f o ll owe d u p 
b y t he i n vesti gat or f or as l o n g as me dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he 
e C R F. Astra Ze neca retai ns t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or a n y  p atie nt wi t h 
o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if ju d ge d necessar y.
8. 3. 2. 1 
A d verse E ve nt V ari a bles
T he f o ll owi n g varia bles will be c ollecte d f or eac h A E:
 
A E ( ver bat i m)
 
T he date a n d ti me w he n t he A E starte d a n d st o p pe d
 
T he m a xi m u m o n-tr e at me nt C T C A E gra de (acc o r di n g t o C T C A E Versi o n 5. 0)
 
W het her t he A E is seri o us or n ot
 
I n vesti gat or ca usality rati n g a gai nst t he st u d y int er ve nt i ons ( yes or n o)
 
Act i on ta ke n wit h re gar d t o st u d y  int er ve nt i ons
 
O utc o m e.
I n a d diti on, t he f o ll owi n g vari a bles will be c ollecte d f or S A Es:

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 2 of 1 5 5
 
Date A E m et crit eria for S A E
 
Date i n vest i gat or beca me a ware of S A E
 
A E i s serio us d ue t o
 
Date of h os pitalisat i on
 
Date of disc har ge
 
Pr o ba ble ca use of deat h
 
Date of deat h
 
A ut o ps y  p erfor m e d
 
Ca usalit y assess me nt i n relat i on t o st u d y  pr oce d ure(s)
 
Ca usalit y assess me nt t o ot her me dicat i on
8. 3. 3
C a us alit y C ollecti o n
T he i n vest i gat or s h o ul d assess ca usal relati o ns hi p bet wee n st u d y int er ve ntio n a n d eac h A E, 
a n d a ns wer ‘yes ’ or ‘n o ’ t o t he q uesti o n ‘D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y 
t hat t he e ve nt ma y ha ve bee n ca use d b y  t he st u d y int er ve nt i on ?’
F or S A Es, ca usal relat i ons hi p s h o ul d als o be assesse d f or ot her me dicat i on a n d st u d y  
pr oce d ures. N ote t hat f or S A Es t hat c o ul d be ass ociate d wit h a n y st u d y  pr oce d ure t he ca usal 
r elat i ons hi p is i m plie d as ‘ye s’.
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n  A p pe n di x B t o t he C S P .
8. 3. 4
A d verse E ve nts B ase d o n Si g ns a n d S y m pt o ms
All A Es s p o nta ne o usl y re p orte d b y t he patie nt or care pr o vider or re p orte d i n res p o nse t o t he 
o pe n q uesti o n fr o m t he st u d y sit e st aff: “Ha ve y o u ha d a n y  h e alt h pr o ble ms si nce t he pre vi o us 
visit/ y o u were last as ke d? ” or re veal e d b y o bser vatio n  will be c ollecte d a n d rec or de d i n t he 
e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) t o 
rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d t here are ot her 
sig ns or s y m pt o m s t hat are n ot ge nerall y p art of t he dia g n os is, t he dia g n osis a n d eac h si g n or 
s y m pt o m will be rec or de d se paratel y.
8. 3. 5
A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests
T he res ults fr o m t he C S P -ma n date d la b orat or y  tests, E C Gs, a n d vital si g ns will be 
s u m marise d i n t he C S R. 
Deteri or ati o n as c o m pare d wi t h baseli ne i n C S P -ma n date d la b orat or y val ues, E C Gs a n d vital 
sig ns s h o ul d t heref ore o nl y  be re p orte d as A Es if t he y f ulfil a n y of t he S A E criteria, are t he 
reas o n f or disc o nti n uati on of treat me nt wit h t he st u d y  int er ve nt i on, or are c o nsi dere d t o be 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 3 of 1 5 5
cli nically rel e va nt as ju d ge d b y  t he i n vesti gat or ( w hic h ma y i ncl u de b ut n ot li mite d t o 
c o nsi derati o n as t o w het her treat me nt or n o n -pl a n ne d visits were re q uire d or ot her acti o n was 
ta ke n wit h t he st u d y int er ve nt i on, e g, d ose a dj ust me nt or dr u g i nterr u pti o n).
If det eriorati o n i n a la b orat or y  val ue/ E C G/ vital si g n is ass ociate d wit h cli nical si g ns a n d 
s y m pt o ms, t he si g n or s y m pt o m will be re p orte d as a n A E a n d t he ass ociate d la b orat or y 
res ult/ E C G/ vit al si g n will be c o nsidere d as a d di tio nal i nf or mat i on. W here ver p ossi b le t he 
re p orti n g i n vesti gat or uses t he cli nical, rat her t ha n t he la b orat or y ter m (e g, a nae mia vers us l o w 
hae m o gl o bi n val ue). I n t he a bse nce of cli nical si g ns or s y m pt o ms, cli nicall y  rele va nt 
deteri or ati o ns i n n o n -ma n date d para meters s h o ul d be re p orte d as A E(s).
Deteri or ati o n of  a la b orat or y val ue, w hic h is u ne q ui v ocall y d ue t o P D, s h o ul d n ot be re p orte d 
as a n A E/ S A E.
A n y ne w or a g gra vate d cli nicall y rele va nt a b n or mal me dical fi n di n g at a p h ysical e xa mi nat i on 
as c o mpare d wi t h t he baseli ne assess me nt will be re p orte d as a n A E u nless u ne q ui v ocall y 
r elate d t o t he disease u n der st u d y.
8. 3. 6
H y’s L a w
Cases w here a patie nt s h o ws ele vat i ons i n li ver bi oc he mistr y ma y re q uire f urt her e val uati on 
a n d occ urre nces o f A S T or A L T ≥ 3 × U L N t o get her wit h T B L  ≥ 2 × U L N m a y nee d t o be 
re p orte d as S A Es. Please refer t o A p pe n di x E f or f urt her i nstr ucti o n o n cases of i ncreases i n 
li ver bi oc he mistr y a n d e val uati on of H L.
8. 3. 7
Dise ase Pr o gressi o n
Di sease pr o gressio n ca n be c o nsi dere d as a w orse ni n g of a patie nt ’s c o n ditio n  attri b uta ble t o 
t he disease f or w hic h t he st u d y int er ve nt i on is bei n g st u die d. It ma y be a n i ncrease i n t he 
se verity of  t he disease u n der st u d y a n d/ or i ncreases i n t he s y m pt o ms of t he disease. T he 
de vel o p me nt of ne w, or pr o gressi o n of e xisti n g metastasis t o t he pri mar y ca ncer u n der st u d y  
s h o uld be c o nsi dere d as P D a n d n ot a n A E. E ve nts, w hic h are u ne q ui v ocall y d ue t o P D, 
s h o uld n ot be re p orte d as a n A E d uri n g t he st u d y .
8. 3. 8
Dise ase U n der St u d y
S y m pt o m s of disease u n der st u d y are t h ose t hat mi g ht be e x pecte d t o occ ur as a direct res ult 
of  locall y a d va nce d or metastatic N S C L C. E ve nts w hic h are u ne q ui v ocall y d ue t o disease 
u n der st u d y  s h o uld n ot be re p orte d as a n A E d uri n g t he st u d y u nless t he y meet S A E crit eria or 
lea d t o disc o nti n uati o n of t he st u d y int er ve nt i on.
8. 3. 9 
Ne w C a ncers
T he de vel o p me nt of a ne w ca ncer s h o ul d be re gar de d as a n A E a n d will ge nerall y meet at least 
o ne of t he seri o us criteria. Ne w ca ncers are t h ose t hat are n ot t he pri mar y reas o n f or t he 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 4 of 1 5 5
a d mi nistrati o n of t he st u d y int er ve ntio n a n d ha ve bee n i de nt ifie d after t he patie nt’s i ncl usi on 
i n t his st u d y. T he y d o n ot i ncl u de metastases of t he ori gi nal ca ncer.
8. 3. 1 0 
Re p orti n g of Seri o us A d verse E ve nts
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he st u d y  
i nter ve nt i on, or t o t he st u d y  pr oce d ure(s). All S A Es will be rec or de d i n t he e C R F .
If a n y S A E occ urs i n t he c o urse of t he st u d y, t he n i n vestigat ors or ot her si te pers o n nel i nf or m 
t he a p pr o priat e Astra Ze neca re prese ntati ves wit hi n o ne da y , ie, i m me diatel y b ut n o l ater  t h a n 
2 4 h o urs of  w he n he or s he bec omes a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all t he 
necessar y  inf or mat i on is pr o vi de d to t he Astra Ze neca Patie nt Safet y data e ntr y  sit e wit hi n 
1 c ale n d ar d a y of  init ial recei pt f or fatal a n d life-t hreate ni n g e ve nts a n d wit hi n 
5 c ale n d ar d a ys of  init ial recei pt f or all ot her S A Es.
F or fatal  or life-t hreate ni n g A Es w here i m p orta nt or rele va nt i nf or mati on is missi n g, acti ve 
f oll ow- u p i s u n derta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel i nf or m Astra Ze neca 
re prese ntati ves of a n y foll o w -u p i nf or m at i on o n a pre vi o usl y re p orte d S A E wit hi n o ne 
cale n dar da y, ie, i m me diatel y but n o l ater  t h an 2 4 h o urs of  w he n he or s he bec o mes a ware of 
it.
O nce t he i n vest i gat ors or ot her site pers o n nel i n dicate a n A E i s serio us i n t he E D C s yste m , a n 
a ut o mate d e mail alert is se nt t o t he desi g nate d Astra Ze neca re prese ntati ve.
If t he E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y sit e st aff re p orts a n 
S A E t o t he a p pr o priate Astra Ze neca re prese ntati ve b y  t ele p h o ne.
T he Astra Ze neca re prese ntati ve will a d vise t he i n vesti gat or/st u d y site staff h o w t o pr ocee d.
F or f urt her g ui da nce o n t he defi nit i on of  a S A E, see A p pe n di x B of  t he C S P . Sectio n 5. 4 of t he 
osi mert i ni b a n d sa v oliti ni b I Bs pr o vi des i nf or mati o n relate d t o t he e mer gi n g safety pr ofile o f 
b ot h st u d y  int er ve nt i ons.  
8. 3. 1 1 
Pre g n a nc y
All pre g na ncies a n d o utc o mes of pre g na nc y s h o ul d be re p orte d t o Astra Ze neca e xce pt f or:
 
If t he pre g na nc y is disc o vere d bef ore t he st u d y patie nt has recei ve d a n y st u d y int er ve ntio n
If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na nc y.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 5 of 1 5 5
A b n or m al pre g na nc y o utc o mes (e g, s p o nta ne o us a b orti o n, f oeta l deat h, still birt h, c o n ge nital 
a n o ma lies, ect o pic pre g na nc y) are c o nsi dere d S A Es.
8. 3. 1 1. 1 
M ater n al E x p os ure
If a patie nt bec o mes pre g na nt d uri n g t he c o urse of t he st u d y, st u d y int er ve nt i on s h o ul d be 
di sc o nti n ue d i m me diatel y.
Pre g na nc y itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t he st u d y  int er ve nt i on 
u n der st u d y  ma y ha ve i nterfere d wit h t he effect i ve ness of a c o ntrace pti ve me dicati o n. 
C o n ge nital a b n or malit ies/ birt h defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d 
ha n dle d as S A Es. El ecti ve a b ortio ns wi t ho ut c o m plicat i ons s h o ul d n ot be ha n dle d as A Es. T he 
o utc o m e of all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati on, ect o pic pre g na nc y, 
n or m al birt h or c o n ge nit al a b n or malit y) s h o uld be f o ll owe d u p a n d d oc u me nte d e ve n if t he 
pati e nt was disc o nti n ue d fr om t he st u d y.
If a n y pre g na nc y occ urs i n t he c o urse of t he st u d y or wit hi n 6 wee ks of t he l ast d ose of st u d y 
i nter ve nt i on, t he n t he i n vest i gat or or ot her site pers o n nel i nf or ms t he a p pr o priate Astra Ze neca 
re prese ntati ves wit hi n one d a y  ie, i m me diatel y but n o l ater  t h a n 2 4 h o urs of  w he n he or s he 
bec o me s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n 
o ne or 5 cale n dar da ys f or S A Es (see Secti o n  8. 3. 1 ) a n d wit hi n 3 0 da ys f or all ot her 
pre g na ncies.
T he sa me ti meli nes a p pl y w he n o utc o me i nf or mat i o n is a vaila ble.
T he P R E G R E P m o d ule i n t he e C R F is use d t o re p ort t he pre g na nc y a n d t he P R E G O U T is 
use d t o re p ort t he o utc o me of t he pre g na nc y.
8. 3. 1 1. 2 
P ater n al E x p os ure 
Male patie nts s h o ul d refrai n fr o m fatheri n g a c hil d or d o nati n g s per m d uri n g t he st u d y  a n d 
6 m o nt hs f oll owi n g t he l ast d ose.
Pre g na nc y of t he patie nt ’s part ner is n ot c o nsi dere d t o be a n A E. H o we ver, t he o utc o me of all 
pre g na ncies (s p o nta ne o us miscarria ge, elect i ve ter mi nati on, ect o pic pre g na nc y, n or mal birt h 
or c o n ge nital a b n or malit y) , occ urri n g fr o m the date of t he first d ose u ntil 6 m o nt hs after t he 
last d ose a n d as i n dicate d b y pre vio us st u di es ( pre-cli nical a n d cli nical) s h o ul d, if p ossi ble, be 
f oll owe d u p a n d d oc u me nte d i n t he Pre g na nc y Re p ort F or m. 
To  ca pt ure i nf or mati on a b o ut a pre g na nc y fr o m t he part ner of a male pat ient , t he male 
pati e nt ’s part ner’s c o nse nt must be o btai ne d t o c ollect i nf or mat i on rel ate d t o t he pre g na nc y 
a n d o utc o me; t he male patie nt s h o ul d n ot be as ke d t o pr o vi de t his i nf or mati o n. A c o nse nt f or m 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 6 of 1 5 5
s pecific t o t his sit uati o n m ust be use d. T he o utc o me of a n y c o nce pt i on occ urri n g fr o m t he date 
of  t he first d ose u ntil 4 m o nt hs after d osi n g e n ds s h o ul d be f oll o we d u p a n d d oc u me nte d. 
8. 3. 1 2 
Me dic ati o n Err or
If a me dicati on err or occ urs i n t he c o urse of t he st u d y, t he n t he i n vesti gat or or ot her site 
pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne da y, ie, i m me diatel y 
b ut n o l ater t ha n 2 4 h o urs of w he n he or s he bec o mes a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all
r ele va nt i nf or mat i on is c om p lete d wit hi n o ne (I nitial Fatal/ Life-T hreate ni n g or f o ll ow u p 
Fatal / Life-T hreate ni n g) or 5 ( ot her seri o us i nit ial a n d f oll ow u p) cal e n dar da ys if t here is a n 
S A E ass ociate d wit h t he me dicat i on err or (see Secti o n  8. 3. 1 ) a n d wit hi n 3 0 da ys f or all ot her 
me dicat i on err ors.
T he defi nit i on of a Me dicat i on Err or ca n be f o u n d i n  A p pe n di x B . 
8. 4 
O ver d ose
A ma xi m u m t olerate d d ose has n ot bee n esta blis he d f or osi merti ni b or sa v olit i ni b, t heref ore a n 
o ver d ose is a n y d ose w hic h e xcee ds t he dail y  d ose t hat is defi ne d i n t his C S P .
 
A n o ve r d ose wit h ass ociate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
r ele va nt A E mo d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule.
 
A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y  re p orte d o n t he O ver d ose e C R F 
m o d ule
If a n o ver d ose o n a n Astra Ze neca st u d y int er ve ntio n occ urs i n t he c o urse of t he st u d y, t he 
i n vesti gat or or ot her site pers o n nel i nf or m a p pr o priate Astra Ze neca re prese ntati ves 
i m me diatel y, b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec ome s a ware of it.
T he desi g nate d Astra Ze neca re pres e ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e, wit hi n 
o ne or 5 cale n dar da ys f or o ver d oses ass ociate d wit h a n S A E (see Secti o n  8. 3. 1 ) a n d wit hi n 
3 0 d a y s for all ot her o ver d oses.
8. 5 
H u m a n  Bi ol o gic al S a m ples
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bi o l o gical sa m ples will be pr o vi de d i n t he st u d y 
s pecific La b orat or y Ma n ual. Sa mples s h o ul d be st ore d i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de nt iality.  F or f urt her details o n Ha n dlin g of  H u ma n Biol o gical 
S a m ple see  A p pe n di x C.
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he iss ue of t he C S R i n 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 7 of 1 5 5
li ne wit h c o nse nt a n d lo c al  re q uire me nts, after w hic h t he y will be destr o ye d/re patriate d. 
 
P har mac o ki net ic sa m ples will be dis p ose d of after t he Bi oa nal ytical Re p ort fi nalisati on or 
6 m o nt hs after iss ua nce of t he draft Bi oa nal y tical Re p ort ( w hic he ver is earlier), u nless 
c o nse nte d f or f ut ure a nal yses. 
 
P har mac o ki net ic sa m ples ma y be dis p ose d of or a n o n y mise d b y p o oli n g. A d diti onal 
a nal yses ma y be c o n d ucte d o n t he a n o n y mise d, p o ole d P K sa m ples t o f urt her 
e val uate a n d vali date t he a nal yt ical met h o d. A n y r es ults fr o m s uc h anal yses m a y be 
re p orte d se paratel y fr o m t he C S R.
8. 5. 1 
P h ar m ac o ki netics
 
Pl as ma sa mples will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of 
osi mert i ni b, sa v oliti ni b a n d t heir meta b olites as s pecifie d i n t he S o As (Ta ble 1 a n d 
Ta ble 2 ) a n d Ta ble 1 0 .
 
S a m ples ma y  be c ollecte d at a d ditio n al  time p oi nts d uri n g t he st u d y  if warra nte d a n d 
a gree d u p o n bet wee n t he i n vest i gat or a n d t he s p o ns or, e g, f or safet y reas o ns. T he ti mi n g 
of  sa m pli n g ma y be altere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a vaila ble data 
(e g, t o o btai n data cl oser t o t he ti me of pea k or tr o u g h matri x c o nce ntrati o ns) t o e ns ure 
a p pr o priate m o nit ori n g. 
 
S a m ples will  be c ollecte d, la belle d, st ore d, a n d s hi p pe d as detaile d in t he La b orat or y  
Ma n ual.
Ta ble 1 0 
P h ar m ac o ki netic S a m pli n g Sc he d ule
C ycle n u m ber 
S a m pli n g p oi nt a
C y cle 1, Da y 1 
Pre -d ose, a n d 1 a n d 3 h o urs p ost -d ose
C y cle 2, Da y 1 
Pre -d ose, a n d 1 a n d 3 h o urs p ost -d ose
C y cle 3, Da y 1 
Pre -d ose, a n d 1, 3, 4, a n d 6 h o urs p ost -d ose b
C y cle 6, Da y 1 
Pre -d ose
Disc o nti n uati o n
Disc o nti n uati o n P K sa m ples will be c ollecte d as s o o n as feasi ble if a patie nt disc o nti n ues 
d ue t o a n A E reacti o n.
a
Sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts.
b
Tri plicate E C Gs t o be c ollecte d at t hese ti me p oi nts as descri be d i n Secti o n  8. 2. 3 .
P K sa m ple c ollecti o n wi n d o ws are: Pre -d ose, u p t o 2 h o urs pre -d ose; 1 h o ur p ost -d ose, ± 5 mi n utes; 3 h o urs 
p ost -d ose, ± 1 0 mi n utes; 4 h o urs a n d 6 h o urs p ost -d ose, ± 3 0 mi n utes.
P K sa m ples are c ollecte d f or b ot h treat me nt peri o ds. Ti mi n gs are relati ve t o t he start of st u d y i nter ve nti o n ie, 
ra n d o mise d treat me nt or cr oss-o ve r. 
A E = A d verse e ve nt; E C G = Electr ocar di o gra m; P K = P har mac o ki netics.
O n P K da ys patie nts s h o ul d c o me t o t he cli nic faste d w here t he y will first be gi ve n a m o derate 
brea kfast (t he sa me brea kfast s h o ul d be gi ve n o n all P K da ys) a n d will a d mi nister t he 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 8 of 1 5 5
sav o liti ni b a n d osi merti ni b/ place b o d ose at t he sa me ti me. Fasti n g state will be c ollecte d i n t he 
e C R F. Pr e-d ose P K sa m ple ma y be dra w n u p t o 2 h o urs pre - d ose ( bef ore or after brea kfast).
S a m ples will  be use d t o a nal yse t he P K of sa v olit i ni b, osi merti ni b a n d t heir meta b olites a n d 
a p pr o priate P K para meters will be deter mi ne d a n d s u m marise d. S u m mar y c o nce ntrati o ns f or 
a p pr o priate P K para meters will be re p orte d i n t he C S R se paratel y f or ra n d o mise d a n d 
cr oss-o ver treat m e nt. T he c o nce ntrati o n data fr o m t his st u d y ma y be c o m bi ne d wit h data fr o m 
ot her st u di es i n a p o p ulatio n P K a nal ysis a n d, if c o n d ucte d, will be re p orte d se paratel y  fr o m 
t he C S R.
A n y c ha n ges i n t he ti mi n g or a d dit i on of t i me p oi nts f or a n y pla n ne d st u d y assess me nts f or 
i n di vi d ual patient s must be d oc u me nte d a n d a p pr o ve d b y t he rele va nt st u d y  tea m me m ber a n d 
t he n arc hi ve d i n t he s p o ns or a n d site st u d y files, a n d ma y not c o nsti t ute a C S P a me n d me nt. 
T he I R B/I E C will be i nf or me d of a n y safet y iss ues t hat re q uire alterati o n of t he safety 
m o nit ori n g sc he me or a m e n d me nt of t he I C F a n d C S P.
8. 5. 1. 1 
Deter mi n ati o n of Dr u g C o nce ntr ati o n
S a m ples f or deter mi nati o n of i n di vi d ual dr u g a n d/ or meta b o lite c o nce ntratio ns i n plas ma will 
be assa ye d b y  bioa nal y tical test sites o perate d b y or o n be half o f Astra Ze neca, usi n g a n 
a p pr o priatel y vali date d bi oa nal yt ical met h o d. F ull details o f t he a nal ytical met h o d use d will be 
descri be d i n a se parate bi oa nal yt ical re p ort.
Dr u g c o nce ntrati o n i nf or mat i on t hat w o ul d u n bli n d t he st u d y  will not be re p orte d t o 
i n vesti gati ve sites or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d. 
I nc urre d sa m ple re pr o d uci bility a nal ysis, if a n y, will be perf or me d alo n gsi de t he bi oa nal ysis 
of  t he test sa m ples. T he res ults fr o m t he e val uati on, if perf or me d, will be re p orte d i n a 
se parate Bi oa nal ytical Re p ort. 
8. 5. 2 
I m m u n o ge nicit y Assess me nts
I mm u n o ge nicit y is n ot e val uate d i n t his st u d y.
8. 5. 3 
P h ar m ac o d y n a mics
P har mac o d y na mic para meters are n ot e val uate d i n t his st u d y .
8. 6 
H u m a n  Bi ol o gic al S a m ple Bi o m ar kers
8. 6. 1 
C ollecti o n of M a n d at or y S a m ples f or Bi o m ar ker A n al ysis
B y  c o nse nti n g t o partici pate i n t he st u d y t he patie nt c o nse nts t o partici pate i n t he ma n dat or y 
researc h c o m p o ne nts of t he st u d y. T he f oll owi n g sa m ples f or bi o m ar ker researc h are re q uire d 
a n d will be c o llecte d fr om all pat ient s i n t his st u d y as s pecifie d i n t he S o As (Ta ble 1 a n d 
Ta ble 2 ):

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
7 9 of 1 5 5
 
T u m o ur s peci me n, ta ke n f oll o wi n g pr o gressi o n o n pri or treat me nt wit h osi merti ni b, will 
be re q uire d at Pre -scree ni n g t o assess eli gi bilit y. T he M E T a m plificat i on stat us of t he 
pati e nts’ t u mo ur s peci me n b y  FI S H will be deter mi ne d at a ce ntral la b orat or y. T his 
a nal ysis is re q uire d t o i n vest i gate t he prese nce of M E T ge ne a m plificati o n t hat is nee de d 
t o i ncl u de t he patie nt i n t he st u d y. 
 
T u m o ur sa m ple 
re q uire me nts f or bi o mar ker testi n g will be defi ne d i n t he s u p p orti n g La b orat or y Ma n ual. 
 
S a m pli n g s h o ul d be u n derta ke n b y e x perie nce d p h ysicia ns i n a p pr o priate me dical 
facilities i n acc or da nce wit h sta n dar d cli nical practice f or patie nts wit h a d va nce d 
N S C L C.
 
Pati e nts will o nl y u n der g o t u mo ur s peci me n c ollecti o n w he n t he ris ks are c o nsi dere d 
me dicall y acce pt a ble b y t heir cari n g p h ysicia ns. W here p ossi ble, hi g h-ris k sites (s uc h 
as brai n, pa ncreas, etc) s h o ul d be a v o i de d.
 
S u p p orte d b y  N C C N/ E ur o pea n S ociety f or Me dical O n c olo g y  g uideli nes, t u m o ur 
re-bi o ps y at P D is a n o pti o n f or sta n dar d cli nical practice at ma n y sites i n or der t o 
e val uate t he a p pr o priate t hera pe utic o pti o ns, i ncl u di n g i n t he e ve nt of alter nat i ve 
mec ha nis ms of resista nce t o E G F R -T KI treat m e nt.
 
Bl o o d sa m ples will be c ollecte d at Pre -Scree ni n g a n d Scree ni n g t o a nal yse plas ma 
bi o mar kers. 
 
As t he rate of cleara nce of ct D N A  aft er 6-wee ks of  t hera p y is a sec o n dar y e n d p oi nt, t hese data 
will be prese nte d i n t he C S R. T he res ults of t he ot her e x pl orat or y researc h ma y be re p orte d 
se paratel y fr o m t he C S R.
T he res ults of t his e x pl orat or y  researc h ma y be p o ole d wit h data fr o m ot her st u dies wit h t he 
st u d y int er ve ntio ns t o ge nerate h y p ot heses t o be teste d i n f ut ure st u dies.
8. 6. 2
 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 0 of 1 5 5
 
 
8. 6. 3
 
 
 
 
 
8. 7
 
 
 
 
8. 8 
Me dic al Res o urce Utilis ati o n a n d He alt h Ec o n o mics
Me dical res o urce utilisat i on a n d healt h ec o n o mics are n ot e val uate d i n t his st u d y . 
9 
S T A TI S TI C A L C O N SI D E R A TI O N S
9. 1 
St atistic al H y p ot heses
T he pri mar y  o bjecti ve of t his st u d y is t o assess t he O R R of sa v o liti ni b i n c o m bi nati on wi t h 
osi mert i ni b vers us sa v o liti ni b i n c o m bi nat i on wi t h place b o i n patie nts wit h E G F R m +, M E T 
a mplifie d l ocall y a d va nce d or metastatic N S C L C w h o ha ve pr o gresse d o n pre vi o us 
osi mert i ni b t hera p y. T he n ull h y p ot hesis is t hat t here is n o differe nce bet wee n treat me nt 
gr o u ps o n O R R base d o n i n vesti gat or assess me nt per R E CI S T 1. 1 w he n all patie nts ha ve ha d 
t he o p p ort u nit y t o be treate d f or 6 m o nt hs. T he alter nati ve h y p ot hesis is t hat t here is a 
differe nce bet wee n treat me nt gr o u ps i n t his re gar d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 1 of 1 5 5
9. 2 
S a m ple Size Deter mi n a ti o n
Pri or t o C S P  V 3. 0, a p pr o xi matel y 2 0 0 pat ient s were pla n ne d t o be scree ne d t o ac hie ve 
5 6 pati e nts ra n d o ml y assi g ne d t o st u d y int er ve nt i on, wi t h t he pri mar y a nal ysis t o occ ur 
6 m o nt hs after t he last patie nt was ra n d o mise d. W it h 5 6 patie nts ( 2 8 per ar m) pl a n ne d,   
 
 
 
. At least half o f t he 
pati e nts i n t he st u d y ( 2 8 pati e nts) will be sec o n d -li ne patient s w h o were treate d wit h 
osi mert i ni b i n t he first-li ne setti n g. 
U n der C S P V 3. 0, t he pla n ne d n u m ber of ra n d o mise d patie nts will n ot be met. T his is a res ult 
of  the decisi o n b y Astra Ze neca t o ter mi nate st u d y recr uit me nt  earl y.
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 2 of 1 5 5
9. 3 
P o p ul ati o ns f or A n al yses
T he f o ll owi n g p o p ul at i ons are defi ne d:
Ta ble 11 
P o p ul ati o ns f or  An al ysis
P o p ul ati o n/ A n al ysis set 
Descri pti o n
F ull A nal y sis Set
T he F A S will i ncl u de all ra n d o mise d patie nts wit h treat me nt gr o u ps 
assi g ne d i n acc or da nce wit h t he ra n d o misati o n, re gar dless of t he treat me nt 
act uall y recei ve d. Patie nts wh o are ra n d o mise d b ut di d n ot s u bse q ue ntl y 
recei ve treat me nt will be i ncl u de d i n t he F A S. T he a nalysis of data usi n g t he 
F A S t heref ore f oll o ws t he pri nci ples of i nte nti o n t o treat. T he F A S will be 
t he pri mar y p o p ulati o n f or re p orti n g efficac y data a n d t o s u m marise 
baseli ne c haracteristics.
Safet y A nal ysis Set
T he S A S will c o nsist of all ra n d o mise d patie nts w h o recei ve d a n y a m o u nt 
of st u d y i nter ve nti o n. If a patie nt recei ves a n y a m o u nt of a n e x peri me ntal 
t hera p y, t he y will be s u m marise d i n t he treat me nt gr o u p c orres p o n di n g t o 
t he first e x peri me ntal treat me nt t hey recei ve d.  
T he S A S will be use d as t he pri mar y p o p ulati o n f or re p orti n g safet y data
Cr oss -o ver A nal ysis Set
T he Cr oss -o ver A nal ysis Set will c o nsist of all patie nts w h o cr osse d o ver t o 
sa v oliti ni b pl us osi merti ni b w h o ha ve recei ve d at least o ne d ose of
sa v oliti ni b pl us osi merti ni b.
It will be use d as t he p o p ulati o n f or re p orti n g t he efficac y a n d safet y data 
f or patie nts w h o cr osse d o ver t o treat me nt wit h sa v oliti ni b pl us osi merti ni b 
f oll o wi n g o bjecti ve pr o gressi o n o n sa v oliti ni b pl us place b o. 
P K A nal y sis Set
All patie nts w h o recei ve at least 1 d ose of sa v oliti ni b or osi merti ni b as per 
t he C S P , f or w h o m t here are at least o ne re p orta ble P K c o nce ntrati o n will 
be i ncl u de d i n t he P K A nal ysis Set. 
I nteri m F utilit y A nal ysis Set
T he I nteri m F utilit y A nal ysi s Set will i ncl u de t he patie nts w h o ha ve ha d t he 
o p p ort u nit y t o be treate d f or 2 R E CI S T p ost baseli ne sca ns ( 1 2 wee ks). T his 
a nal ysis set will o nl y be use d f or t he i nteri m f utilit y a nal ysis.
C S P = Cli nical St u d y Pr ot oc ol; F A S = F ull A nal ysis Set; P K = P h ar mac o ki netics; 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; S A S = Safet y A nal ysis Set.
9. 4 
St atistic al A n al yses
U n der C S P V 3. 0, t he S A P will be fi nalise d pri or t o t he u n bli n di n g of t he st u d y t hat is t o occ ur 
f oll owi n g earl y  st u d y recr uit me nt ter mi nati on, f or t he p ur p ose of a n earl y re vie w of t he st u d y 
data b y  Astra Ze neca. 
T he S A P will i ncl u de a m ore tec h nical a n d detaile d descri pt i on of t he statistical a nal yses 
descri be d i n t his sect i on. T his sect i on is a s u m mar y of t he pla n ne d statist ical a nal yses of t he 
m o st i mp orta nt e n d p oi nts i ncl u di n g pri mar y a n d ke y  sec o n dar y e n d p oi nts.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 3 of 1 5 5
9. 4. 1 
Ge ner al C o nsi der ati o ns
Descri pt i ve statistics will be use d f or all varia bles as a p pr o priate a n d will be prese nte d b y 
treat me nt ar m. C o nti n u o us varia bles will be s u m marise d b y t he n u m ber of o bser vati ons, 
mea n, sta n dar d de viat i on, m e dia n, mi ni m u m, a n d ma xi m u m. Cate g orical varia bles will be 
s u m marise d b y fre q ue nc y c o u nts a n d perce nta ges f or eac h cate g or y. U nless ot her wise state d, 
perce nta ges will be calc ulate d o ut of t he p o p ulati o n t otal f or t he c orres p o n di n g treat me nt ar m.
Res ults of all statist ical a nal yses will be prese nte d usi n g a 9 5 % CI a n d p-val ue, u nless 
ot her wi se state d.
A d dit i onal s u b gr o u p a nal yses of efficac y a n d safet y ma y be perf or me d a n d will be s pecifie d 
i n t he S A P.
De pe n di n g o n t he e xte nt of a n y i m pact, s u m maries of data relat i n g t o patie nts dia g n ose d wit h 
C O VI D -1 9, a n d i m pact of C O VI D- 1 9 o n st u d y  c o n d uct (i n partic ular misse d visits, dela ye d or 
di sc o nti n ue d st u d y int er ve ntio n, a n d ot her pr ot oc ol de viat i ons) ma y be ge nerate d. M ore detail 
will be pr o vi de d i n t he S A P .
Baseli ne f or patie nts o n ra n d o mise d treat me nt will be t he last assess m e nt of t he varia ble u n der 
c o nsi derati o n pri or t o t he i nta ke of t he first d ose, e xce pt f or efficac y varia bles. F or efficac y 
varia bles, baseli ne is defi ne d as t he last visit pri or t o ra n d o misat i on. F or patie nts w h o 
cr oss-o ver fr o m sa v oliti ni b pl us place b o t o sa v oliti ni b pl us osi merti ni b, t heir data will be c ut 
of f f or t he p ur p oses of a n y sa v olitini b pl us place b o assess me nt at t he last assess me nt of t he 
varia ble u n der c o nsi derati o n pri or t o t he i nta ke of t he first d ose of t he c o m bi nati o n t hera p y . 
Ef ficac y data will be s u m marise d a n d a nal yse d o n t he FA S, safet y data will be s u m marise d o n 
t he S A S a n d P K data will be s u m marise d o n t he P K A nal ysis Set. 
Baseli ne f or O R R, P F S, D o R a n d t u m o ur size assess me nts of patie nts w h o cr oss -o ver t o 
sa v oliti ni b pl us osi merti nib f r o m sa v oliti ni b pl us place b o will be t he pr o gressi o n sca n o n 
sa v oliti ni b pl us place b o, ac q uire d wit hi n 2 8 da ys of t he start of treat me nt i n t he cr oss-o ver 
p eri o d. 
 
Baseli ne f or safet y assess me nts of patie nts w h o cr oss -o ver t o 
sa v oliti ni b pl us osi merti ni b fr om sa v oliti ni b pl us place b o will be set as t he last assess me nt 
pri or t o fi rst d ose of osi merti ni b.
A Cr oss -o ver A nal ysis Set is i ncl u de d f or patie nts ra n d o mise d t o sa v o liti ni b pl us place b o w h o 
cr oss-o ver t o sa v o liti ni b pl us osi merti ni b u p o n o bjecti ve P D per R E CI S T 1. 1.
9. 4. 1. 1 
Str atific ati o n F act ors
T he stratif icati on i n t he statistical a nal yses will be base d o n t he val ues e ntere d i n t he I W R S at 
ra n d omisat i on, e ve n if it is s u bse q ue nt l y disc o vere d t hat t hese val ues were i nc orrect. If t here 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 4 of 1 5 5
are a n y patient s w h o were mis-stratifie d, a se nsiti vity a nal ysis o n t he pri mar y e n d p oi nt ma y be 
carrie d o ut usi n g t he c orrect baseli ne data c ollecte d i n t he e C R F.
9. 4. 1. 2 
M ulti plicit y Str ate g y f or Pri m ar y a n d Ke y Sec o n d ar y E n d p oi nts
Pri or t o C S P  V 3. 0, t he pri mar y a nal ysis was t o occ ur 6 m o nt hs after t he last patie nt was 
ra n d omise d. T hi s will be base d o n a c o m paris o n of t he pri mar y e n d p oi nt (ie, O R R) bet wee n 
treat me nt gr o u ps a n d will be teste d at t he 2 -side d 5 % si g nifica nce le vel.
 
 t he sec o n dar y 
efficac y e n d p oi nts will be teste d at a 2-side d si g nifica nce le vel of 5 %. T here will be n o 
a djust m e nt for m ul tiplici t y as t he st u d y is n ot desi g ne d t o s u p p ort la belli n g clai ms o n a n y of  
t he e n d p o i nts.
Fi nal a nal ysis was t o be perf or me d after t he earlier of 1 8 m o nt hs after t he last patie nt was 
ra n d omise d or w he n 7 0 % of t he patie nts ha ve pr o gresse d or die d d ue t o a n y ca use.  
 
 
U n der C S P V 3. 0, as a res ult of Astra Ze neca ’s decisio n t o ter mi nate st u d y  recr uit me nt earl y, 
t here will be n o pri mar y a nal ysis at t he ori gi nall y pla n ne d t i me p oi nt. F oll o wi n g earl y 
ter mi nati o n of st u d y recr uit me nt, a n i nitial D C O will occ ur t o allo w a n earl y re vie w of data b y  
Astra Ze neca. A fi nal D C O will occ ur 9 m o nt h s after t he last patie nt has bee n ra n d omi se d,
after w hic h t he fi nal a nal ysis will be perf or me d. 
9. 4. 2 
Effic ac y 
I n vesti g at or R E CI S T B ase d Assess me nts
Fr o m  t he i n vesti gat ors re vie w of t he i ma gi n g sca ns, t he R E CI S T t u m o ur res p o nse data will be 
use d t o deter mi ne eac h pat ient ’s visit res p o nse acc or di n g t o R E CI S T 1. 1. It will be use d t o 
deter mi ne t he e n d p o i nts of O R R, P F S, D o R a n d t u m o ur size c ha n ge.
At  eac h t u m o ur assess me nt, patie nts will be pr o gra m maticall y assi g ne d a R E CI S T 1. 1 visit 
res p o nse of C R, P R, S D or P D de pe n di n g o n t he stat us of t heir disease c o m pare d wit h 
baseli ne a n d pre vi o us assess m e nts. If a patie nt has ha d a t u m o ur assess me nt w hic h ca n n ot be 
e val uate d, t he patie nt will be assi g ne d a visit res p o nse of N E ( u nless t here is e vi de nce o f 
pr o gressi o n i n w hic h case t he res p o nse will be assi g ne d as P D).
I n vesti gat or-assess me nt of P D per R E C I S T 1. 1 of patie nts recei vi n g sa v o liti ni b pl us place b o 
is re q uire d pri or t o cr oss-o ver t o sa v o liti ni b pl us osi merti ni b.
Pl ease refer t o  A p pe n di x H f or t he defi niti on s of C R, P R, S D, P D a n d N E.
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 5 of 1 5 5
Ce ntr al Re vie w of R E CI S T 1. 1 B ase d Assess me nts
T he BI C R of ra di o l ogi cal i ma gi n g data will be carrie d o ut usi n g R E CI S T 1. 1. All ra di o l ogical 
sca ns f or all patient s (i ncl u di n g t h ose u nsc he d ule d visit s, or o utsi de visit wi n d o ws) will be 
pr o vi de d t o t he BI C R. T he i ma gi n g sca ns will be re vie we d b y 2 i n de pe n de nt ra di ol o gists 
usi n g R E CI S T 1. 1 criteria a n d will be a dj u dicate d if re q uire d. T he i n de pe n de nt re vie wers will 
be bli n de d t o st u d y  int er ve nt i on. Bli n de d i n de pe n de nt ce ntral re vie w data will be use d t o 
deter mi ne e n d p oi nts: O R R a n d P F S as a se nsit i vity a nal ysis.
F urt her details of t he BI C R will be d oc u me nte d i n t he BI C R c harter .
9. 4. 2. 1 
A n al ysis of Pri m ar y E n d p oi nt
O bject i ve res p o nse rate b y in vesti gat or assess me nt i n acc or da nce wit h R E CI S T 1. 1 is t he 
pri mar y  e n d p oi nt f or t his st u d y.
T he O R R is defi ne d as t he pr o p orti o n of patie nts wit h a n i n vest i gat or-assesse d res p o nse o f C R 
or P R b y  R E CI S T 1. 1. 
Data o btai ne d u p u nt il pr o gressi o n, or last e val ua ble assess me nt i n t he a bse nce of pr o gressi o n, 
will be i ncl u de d i n t he assess me nt of O R R. Patie nts w h o disc o nt i n ue treat me nt wit h o ut 
pr o gressi o n, recei ve a s u bse q ue nt a nti -ca ncer t hera p y ( n ote t hat f or t his a nal ysis ra di ot hera p y 
is n ot c o nsi dere d a s u bse q ue nt a nt i-ca ncer t hera p y) a n d t he n res p o nd will n ot be i ncl u de d as 
res p o n ders i n t he O R R.
T he O R R will be a nal yse d usi n g a l o gistic re gressi o n m o del a dj ust i n g f or t he stratificati on 
use d i n t he ra n d o misat i on. T he res ults of t he a nal ysis will be prese nte d i n ter ms of a n o d ds 
r atio (a n o d ds rati o g reater t ha n 1 will fa v o ur sa v oliti ni b i n c om bi nat i on wi t h osi merti ni b 
vers us sa v o liti ni b i n c o m bi nati on wi t h place b o) t o get her wit h its ass ociate d pr ofile li keli h o o d 
9 5 % CI a n d p -val ue ( base d o n t wice t he c ha n ge i n l o g -li keli h o o d res ulti n g fr o m t he a d diti on 
of  a treat me nt fact or t o t he mo d el ). 
If t here are n ot e n o u g h res p o nses f or a mea ni n gf ul a nal ysis usi n g l o gistic re gressi o n t he n a 
C M H test will be prese nte d. 
S u m maries will be pr o d uce d t hat prese nt t he n u m ber a n d perce nta ge of patie nts i n eac h 
treat me nt gr o u p wit h a t u mo ur res p o nse ( C R/ P R).
A se nsitivit y a nal ysis o f t he O R R will be perf or me d base d o n t he BI C R assess me nt of disease 
pr o gressi o n b y  R E CI S T 1. 1. F urt her se nsiti vity a nal yses will be descri be d i n t he S A P.
S u m maries will be pr o d uce d t hat prese nt t he n u m ber a n d perce nta ge of patie nts i n eac h 
treat me nt gr o u p wit h a t u m o ur res p o nse ( C R/ P R). S u m maries will als o be pr o d uce d f or O R R 
per BI C R.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 6 of 1 5 5
S u b gr o u p A n al ysis
S u b gr o u p a nal yses will be c o n d ucte d c o m pari n g O R R bet wee n t he treat me nt ar ms i n eac h 
strat u m use d i n t he ra n d omisat i on. If t here are s ufficie nt patie nts i n eac h strat u m, a l o gist ic 
re gressi o n c om par i n g treat me nts ma y be use d t o c o m pare treat me nts. T he res ults of t he 
a nal ysis will be prese nte d i n ter ms of a n o d ds rati o i n a nal o g y wit h t he pr i mary l ogist ic 
re gressi o n descri be d a b o ve. If t here are n ot e n o u g h res p o nses f or mea ni n gf ul s u b gr o u p 
a nal ysis usi n g l o gistic re gressi o n, t he n a C M H test ma y  be use d i nstea d. O bject i ve res p o nse 
rate wit hi n eac h strat u m will be prese nte d wit h a t w o-si de d 9 5 % CI usi n g t he Cl o p per -Pears o n 
met h o d. 
T he o d ds rati os a n d ass ociate d t w o -si de d 9 5 % pr ofile li keli h o o d CIs will be s u m marise d a n d 
prese nte d o n a f orest pl ot, al o n g wit h t he res ults of t he o verall pri mar y a nal ysis.
N o a dj ust me nt  t o t he sig nifica nce le vel f o r testi n g of s u b gr o u ps will be ma de si nce t he 
s u b gr o u p a nal yses 
 ma y o nl y be s u p p orti ve of t he pri mar y 
a nal ysis of O R R.
9. 4. 2. 2 
A n al ysis of Sec o n d ar y Effic ac y E n d p oi nts
Pr o gressi o n -free S ur vi v al
Pr o gressi o n -free s ur vi val is defi ne d as t he ti me fr o m ra n d o misati o n u nt il t he date of o bjecti ve 
di sease pr o gressio n per R E CI S T 1. 1 as assesse d b y  t he i n vestigat or or deat h d ue t o a n y  ca use 
re gar dless of w het her t he patie nt wit h dra ws fr o m t hera p y or recei ves a n ot her a nti-ca ncer 
t hera p y prior t o p r o gressi o n. Patie nts w h o ha ve n ot pr o gresse d or die d at t he ti me of a nal ysis 
will be ce ns ore d at t he ti me of t he latest date of assess me nt fr o m t heir last e val ua ble R E CI S T 
assess me nt.
H o we ver, if t he pat ient  pr o gresses or dies after 2 or m ore misse d visits, t he patie nt will be 
ce ns ore d at t he ti me of t he latest e val ua ble R E CI S T assess me nt. If t he patie nt has n o 
e val ua ble visit s or d oes n ot ha ve baseli ne data t he y will be ce ns ore d at Da y 1 u nless t he y die 
wi t hi n 2 visits of baseli ne: i n s uc h a case, t he death date will be use d as t he e ve nt date. 
T he P F S ti me will al wa ys be deri ve d base d o n sca n/assess me nt dates, n ot visit dates.
T he R E CI S T assess me nts/sca ns c o ntri b ut i n g t o war ds a partic ular visit ma y be perf or me d o n 
differe nt dates. T he f o ll owi n g r ul es will be a p plie d:
 
Date of pr o gressi o n will be deter mi ne d base d o n t he earliest of t he dates of t he c o m p o ne nt 
t hat trig gere d t he pr o gressi o n.
 
W he n ce ns ori n g a patie nt f or P F S, t he patie nt will be ce ns ore d at t he latest of t he dates 
c o ntri b uti n g t o a partic ular o verall visit assess me nt.
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 7 of 1 5 5
Pri or t o C S P  V 3. 0, t he pri mar y a nal ysis of P F S was t o occ ur 6 m o nt hs after t he last patie nt 
was ra n d o mise d. A  fi nal a nal ysis was t o occ ur after t he earlier of 1 8 m o nt hs after t he last 
pati e nt was ra n d o mise d or w he n 7 0 % of  patie nts ha d pr o gresse d or die d. U n der C S P V 3. 0, as 
a res ult of Astra Ze neca’s decisi on t o ter mi nate st u d y  recr uit me nt earl y, t here will be n o 
pri mar y  a nal ysis at t he ori gi nall y pla n ne d ti me p oi nt. F oll o wi n g earl y ter mi nati on of st u d y  
recr uit me nt, a n i nitial D C O will occ ur t o all o w a n earl y  re vie w of data b y Astra Ze neca. T he 
st u d y will be u n bli n de d after c o mplet i on of data clea ni n g act i vities o n t his i nitial D C O data, 
a n d pat ient s o n sa v oliti ni b m on ot hera p y  (sa v olitini b pl us pl ace b o) will be gi ve n t he 
o p p ort u nit y t o cr oss-o ver t o t he sa v o liti ni b pl us osi merti ni b ar m. If t he i n vest i gat or belie ves 
pati e nts are gai ni n g cli nical be nefit a n d pat ient s ha ve n ot re p orte d P D, patie nts ma y c o nti n ue 
t o recei ve sa v oliti ni b m on ot hera p y. All pat ient s will be f oll owe d u nt il t he fi nal a nal ysis. A 
fi nal D C O will occ ur 9 m o nt hs aft er t he last patie nt has bee n ra n d omise d , after w hic h t he fi nal 
a nal ys is will be perf or me d.
Pr o gressi o n -free s ur vi val base d o n i n vestigat or assess me nt will be a nal yse d usi n g a stratifie d 
l og- ra n k test a djust i n g f or t he sa me fact ors as f or O R R f or ge nerati o n of t he p-val ue. T he 
effect of treat me nt will be esti mate d b y t he H R t o get her wit h its c orres p o n di n g 9 5 % CI f or t he 
F A S. A n H R less t ha n 1 will fa v o ur sa v o liti ni b pl us osi merti ni b. T he H R a n d its CI will be 
esti mate d fr o m a stratifie d C o x Pr o p orti o nal Hazar ds m o del ( wit h ties = Efr o n a n d baseli ne 
stratificati on) a n d t he CI calc ulate d usi n g a pr ofile li keli h o o d a p pr oac h. If t here are 
ins ufficie nt e ve nts per strata, a l o g -ra n k test will be use d t o a nal yse P F S i nstea d of a stratifie d 
l og- ra n k test.
Ka pla n -Meier pl ots of  P F S will be prese nte d b y tr e at me nt ar m. 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 ype of e ve nt ( R E CI S T 1. 1 or deat h) 
will be pr o vi de d al o n g wit h s u m maries of P F S ( n, e ve nts, me dia ns, q uartiles, pr o p orti o n 
pr o gressi o n free at 3, 6, 9, a n d 1 2 m o nt hs a n d c orres p o n di n g 9 5 % CIs) b y  treat me nt gr o u p.
T he ass u m pt i on of pr o p orti o nalit y wil l be assesse d. Pr o p orti o nal hazar ds will be teste d first l y 
b y e xa mi ni n g plots of  c o mple me ntar y  lo g -l og (e ve nt ti mes) vers us l o g (ti me) a n d, if t hese 
r aise c o ncer ns, b y fitti n g a ti me de pe n de nt c o variate (a d di n g a treat me nt-b y- ti me or 
treat me nt - b y-l n[ti me] i nteractio n ter m ) t o assess t he e xte nt t o w hic h t his re prese nts ra n d o m 
variat i on. If a lac k o f pr o p orti o nali t y is e vi de nt, t he variati o n i n treat me nt effect ca n be 
descri be d b y prese nt i n g piece wise H R calc ulate d o ver disti nct ti me-peri o ds f or e xa m ple 
0 t o 6 m o nt hs, 6 t o 1 2 m o nt hs etc. I n s uc h circ u msta nces, t he H R fr o m t he pri mar y a nal ysis 
ca n st ill b e m ea ni n gf ull y int er prete d as a n a vera ge H R o ver ti me u nless t here is e xte nsi ve 
cr ossi n g of t he s ur vi val c ur ves. If lac k of pr o p orti o nalit y is f ou n d t his m a y be a res ult of a 
treat me nt - b y-c o variate i nteractio n, w hic h will be i n vesti gate d. 
T he treat me nt stat us at pr o gressi o n of patie nts at t he ti me of a nal ysis will be s u m marise d. T his 
will i ncl u de t he n u m ber ( %) of patie nts st u d y  int er ve nt i on pri or t o pr o gressi o n, t he n u m ber 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 8 of 1 5 5
( %) of patient s w h o ha ve n ot pr o gresse d a n d were o n treat me nt or disc o nt i n ue d treat me nt. 
T his will als o pr o vi de distri b uti o n o f n u m ber of da ys pri or t o pr o gressi o n f or t he patie nts w h o 
ha ve disc o nt i n ue d treat me nt.
Se nsiti vit y A n al ysis
Pr o gressi o n -free s ur vi val defi ne d b y t he BI C R i n t he F A S will be a nal yse d as descri be d f or 
t he i n vest i gat or-assesse d P F S e n d p o i nt (see a b o ve). F urt her se nsiti vity a nal yses will be 
descri be d i n t he S A P.
D ur ati o n of Res p o nse
T he D o R is defi ne d as t he ti me fr o m  t he date of first d oc u me nte d res p o nse u ntil date of 
d oc u m e nte d pr o gressio n or deat h i n t he a bse nce of P D (ie, date of P F S e ve nt or 
ce ns ori n g – date of first res p o nse + 1). T he e n d of res p o nse s h o ul d c oi nci de wit h t he date of 
pr o gressi o n or deat h fr o m a ny ca use use d f or t he P F S e n d p o i nt. T he ti me of t he i nitial 
res p o nse will be defi ne d as t he latest of t he dates c o ntri b uti n g t o war ds t he first visit res p o nse 
of  C R or P R.
If a patie nt d oes n ot pr o gress f oll owi n g a res p o nse, t he n t heir D o R will use t he res pe ct i ve P F S 
ce ns ori n g t i me.
If t here are s ufficie nt n u m bers of res p o n ders, a n d s ufficie nt n u m bers of res p o nses t hat ha ve 
pr o gresse d b y t he p oi nt of t he a nal ysis, Ka pla n -Meier pl ots of  D o R i n t he res p o n di n g patient  
will be pr o d uce d a n d a p pr o priate descri pti ve s u m mar y statistics will be prese nte d ( n, n u m ber 
of  res p o nses t hat ha ve pr o gresse d, me dia n, q uartile, mi ni m u m a n d ma xi m u m D o R) b y 
treat me nt gr o u p wit h o ut a n y for m al c o mparis o n or p -val ue attac he d.
Perce nt a ge C h a n ge fr o m B aseli ne i n T u m o ur Size
T u m o ur size assess me nt is defi ne d as t he perce nta ge c ha n ge i n T Ls at 1 2 wee ks per 
R E CI S T 1. 1. A bs o l ute c ha n ge a n d perce nta ge c ha n ge fr o m baseli ne i n T L ’s t u mo ur si ze at 
1 2 wee ks will be base d o n R E CI S T T Ls meas ure me nts ta ke n at baseli ne a n d at W ee k 1 2. 
T u m o ur size is t he s u m of t h e lo n gest di a meters of t he T Ls. Baseli ne f or R E CI S T is defi ne d as 
t he last e val ua ble assess me nt pri or t o ra n d o misat i on. 
T he perce nta ge c ha n ge i n T L  t u mo ur si ze at Wee k 1 2 will be o btai ne d f or eac h patie nt b y 
ta ki n g t he differe nce bet wee n t he s u m of t he T Ls at Wee k 1 2 a n d t he s u m o f t he T Ls at 
baseli ne di vi de d b y  t he s u m of t he T Ls at baseli ne ti mes 1 0 0 (ie, [ Wee k 1 2 - baseli ne] / 
baseli ne × 1 0 0).
T he a bs o l ute c ha n ge i n T L t u mo ur si ze at Wee k 1 2 will be o btai ne d f or eac h patie nt b y t he 
differe n ce bet wee n t he s u m of t he T L at Wee k 1 2 a n d t he s u m o f t he T L at baseli ne.
T he a bs o l ute c ha n ge i n T L t u mo ur si ze fr o m baseli ne a n d perce nta ge c ha n ge i n T L t u mo ur 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
8 9 of 1 5 5
size fr o m baseli ne will be s u m marise d usi n g descri pti ve statist ics b y ra n d omise d treat me nt 
gr o u p. Best perce nta ge c ha n ge will als o be s u m marise d.
T he effect of st u d y i nter ve nt i ons o n a bs o l ute a n d perce nta ge c ha n ge i n T L t u mo ur size will be 
esti mate d fr o m a n A N C O VA m o d el  incl u di n g a ter m f or treat me nt, t he a bs ol ute ( perce nta ge) 
c ha n ge i n Wee k 1 2 value, a c o vari ate f or baseli ne T L t u mo ur si ze, stratificat i on use d i n 
ra n d omisat i on, a n d a c o variate f or t he ti me fr o m t he baseli ne sca n t o ra n d o misat i on. T he 
n u m ber of patie nts, u na dj uste d mea n a n d least -s q uares mea ns f or eac h treat me nt gr o u p s h o ul d 
be pres e nte d, t o get her wit h t he differe nce i n least-s q uares mea ns, 9 5 % CI a n d c orres p o n di n g 
p- val ue.
Ha n dli n g of missi n g data will be descri be d i n t he S A P .
Wa t erfall plots s h o wi n g t he perce nta ge c ha n ge at Wee k 1 2 a n d t he best perce nta ge c ha n ge 
fr om baseli ne i n s u m of  t he dia meters of T Ls will be pr o d uce d. S pi der pl ots s h o wi n g t he 
act ual c ha n ge a n d t he perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size f or eac h patie nt o ver 
ti me ma y be pr o d uce d. 
M o del  c hec ki n g dia g n ostics f or t he A N C O V A will be descri be d i n t he S A P . If A N C O VA is 
dee m e d n ot t o be a p pr o priate, n o n-para m etric tec h ni q ues will be use d. F urt her details i n t his 
re gar d will be descri be d i n t he S A P.
O ver all S ur vi v al
O verall s ur vi val is defi ne d as t he ti me fr o m ra n d o misat i on u ntil deat h d ue t o a n y  ca use, 
re gar dless of w het her t he patie nt wit h dra ws fr om ra n d omise d t hera p y  or recei ves a n ot her 
a nt ica ncer t hera p y. A n y patie nt n ot k n o w n t o ha ve die d at t he ti me of a nal ysis will be ce ns ore d 
base d o n t he last rec or de d date o n w hic h t he patie nt was k n o w n t o be ali ve.
N o te: Patie nts will be c o ntacte d f or s ur vi val f oll ow- u p Q 1 2 W  u ntil deat h, wit h dra wal of 
c o nse nt, or t he e n d of t he st u d y ie, at t he ti me of fi nal a nal ysis, defi ne d as t he earlier of 
1 8 m o nt hs after t he last patie nt is ra n d o mise d or w he n 7 0 % of patie nts ha ve pr o gresse d or 
di e d. Patie nts s h o uld be c o ntacte d i n t he wee k after D C O f or eac h a nal ysis t o esta blis h 
s ur vi val stat us. If patie nts are c o nfir me d t o be ali ve or if t he deat h date is after t he D C O date, 
t hese patie nts will be ce ns ore d at t he date of t he D C O.
O verall s ur vi val will be a nal yse d as descri be d f or t he i n vest i gat or-assesse d P F S e n d p o i nt 
( me ntio ne d earlier i n t his sect i on).
 
 F urt her 
details will be pr o vi de d i n t he S A P.
S u m maries of O S ( n, e ve nts, me dia ns, q uartiles, pr o p orti o n ali ve at 3, 6, 9 a n d 1 2 m o nt hs a n d 
c orres p o n di n g 9 5 % CIs) a n d a Ka pla n- Meier pl ot will  be pr o vide d. 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 0 of 1 5 5
9. 4. 2. 3 
A n al ysis of Effic ac y E n d p oi nts of t he Cr o ss- o ver A n al ysis Set
F or t he Cr oss -o ver A nal ysis Set, efficac y e n d p o i nts i ncl u de O R R, P F S, D o R, t u m o ur size 
assess me nt  
. Details of t he baseli ne f or t hese e n d p o i nts are gi ve n i n Secti o n 9. 4. 1 . 
T hese e n d p o i nts will o nl y be s u m marise d descri pti vel y ( Secti o n 9. 4. 2. 2 ).
List i n gs, a n d p ossi bl y s u m maries of t he a b o ve e n d p oi nts depe n di n g o n t he n u m ber of patie nts, 
will be prese nte d f or patie nts w h o cr oss -o ver fr o m sa v o liti ni b pl us place b o t o sa v oliti ni b pl us 
osi mert i ni b, prese nti n g data fr o m t he baseli ne of t heir sec o n d p hase o n war ds (see Secti on 
9. 4. 1 ). 
F urt her details of h o w t he data f or t hese patie nts will be prese nte d will be descri be d i n t he 
S A P.
9. 4. 2. 4 
E x pl or at or y E n d p oi nts
Stati stical a nal ysis of t he e x pl orat or y e n d p oi nts will be s u m marise d in t he S A P.
9. 4. 3 
S afet y
S af et y a n d t olera bilit y will  be assesse d i n ter ms of A Es, S A Es, disc o nti n uat i on rate d ue t o 
A Es, deat hs, la b orat or y  data, vit al si g ns, E C H O data, E C G data a n d E C O G perf or ma nce 
stat us. All safety a nal yses will be perf or me d o n t he S A S. Data will als o be prese nte d 
se paratel y for p ati e nts w h o cr osse d o ver t o sa v olit i ni b pl us osi merti ni b u p o n 
i n vesti gat or-assesse d P D per R E CI S T 1. 1 o n sa v o liti ni b pl us place b o. Safety data will be 
prese nte d usi n g descri pt i ve statistics u nless ot her wise s pecifie d.
A d verse e ve nts will be c o de d usi n g t he m ost rece nt versi o n of Me d D R A t hat ha ve bee n 
r elease d f or e xec uti o n at Astra Ze neca. A d verse e ve nts will be gra de d acc or di n g t o t he 
Nati o nal Ca ncer I nst itut e C T C A E ( Versio n 5. 0).
T he n u m ber of pat ient s e x perie nci n g eac h A E will be s u m marise d b y t he Me d D R A s yste m 
or ga n class, preferre d ter m a n d treat me nt gr o u p. T he n u m ber a n d perce nta ge of patie nts wit h 
A Es i n differe nt cate g ories (e g, ca usall y relate d, C T C A E Gra de ≥ 3 et c) will be s u m marise d, 
a n d e ve nts i n eac h cate g or y  will be f urt her s u m marise d b y Me d D R A s yst e m or ga n class, 
preferre d ter m a n d treat me nt gr o u p. If t here are s ufficie nt S A Es, t he y will be s u m marise d 
se paratel y. F urt her details will be pr o vi de d i n t he S A P.
A d verse e ve nts occ urri n g pri or t o t he start of s t u d y i nter ve nti on, treat m e nt -e mer ge nt A Es a n d 
p ost -treat me nt e mer ge nt A Es will be prese nte d se paratel y . A d verse e ve nts occ urri n g i n t he 
sa v oliti ni b i n c om bi nat i on wi t h place b o gr o u p will be s plit i nt o 2 prese ntati o ns base d o n 
w het her t he y  occ urre d bef ore or after t he cr oss o ver i nt o t he sa v oliti ni b i n c om bi nat i on wi t h 
osi mert i ni b gr o u p.
A n y A E occ urri n g bef ore t he first d ose of st u d y i nt er ve nt i on will be i ncl u de d i n t he data 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 1 of 1 5 5
listi n gs b ut will n ot be i ncl u de d i n t he s u m mar y ta bles of A Es. A d verse e ve nt s u m mar y ta bles 
will i ncl u de o nl y  tr e at me nt -e mer ge nt A Es. T he f oll o wi n g e ve nts are c o nsi dere d treat me nt 
e mer ge nt:
 
A d verse e ve nts wit h a n o nset date o n or after t he first d ose of ra n d o mise d st u d y  
i nter ve nt i on a n d wit hi n t he safet y f oll ow- u p peri o d ( 2 8 da y s [ ± 7 da ys] after last d ose of 
all st u d y int er ve nt i on). A n y  e ve nts i n t his perio d t hat occ ur after a patie nt has recei ve d 
f urt her t hera p y for ca ncer (f oll o wi n g di sc o nti n uati o n of all st u d y int er ve nt i on) will be 
fla g ge d i n t he data listi n gs.
 
W o rse ni n g of pre-e xist in g e ve nts o n or after t he first d ose of st u d y  int er ve nt i on a n d 
wi t hi n t he safety f oll ow- u p peri o d.
A n y e ve nts i n t his peri o d t hat occ ur after a patie nt has recei ve d f urt her t hera p y f or ca ncer 
(f oll owi n g disc o nt i n uati on of all st u d y  int er ve ntio n) will  b e fla g ge d i n t he data listi n gs, b ut n ot 
i ncl u de d i n t he s u m maries.
A n o ver vie w of A Es will prese nt f or eac h treat me nt gr o u p t he n u m ber a n d perce nta ge of 
pati e nts wit h a n y A E, A Es wit h o utc o me of deat h, S A Es, a n d A Es lea di n g t o disc o nt i n uati on 
of  st u d y int er ve nt i on, as well as A Es lea di n g t o st u d y i nter ve nt i on d ose i nterr u pti o ns, a n d A Es 
lea di n g t o st u d y int er ve ntio n d ose re d ucti o n as well  as t he n u m ber of i n di vi d ual occ urre nces 
i n t h ose cate g ories.
Se parate A E ta bles will be pr o vi de d ta ke n i nt o c o nsi derati o n r elatio ns hi p as assesse d b y t he 
i n vesti gat or, C T C A E gra de, seri o us ness, deat h a n d e ve nts lea di n g t o disc o nti n uati on of st u d y  
i nter ve nt i on f or t he first 6 wee ks a n d at a n y ti me as well as ot her acti o n ta ke n relate d t o st u d y 
i nter ve nt i on.
A n a d dit i on al  ta ble will prese nt n u m ber a n d perce nta ge of patie nts wit h m ost c o m m o n A Es. 
M ost c o m m o n (e g, fre q ue nc y o f > x %, ≥x %) will be defi ne d i n t he S A P.
I n acc or da nce wit h t he re q uire me nts of t he F D A, a se parate ta ble will prese nt n o n-serio us A Es 
occ urri n g i n m ore t ha n 5 % of patie nts i n a n y treat me nt gr o u p.
Ke y pat ient  i nf or mati o n will be prese nte d f or patie nts wit h A Es wit h o utc o me of deat h, S A Es, 
a n d A Es lea di n g t o disc o nti n uati on of st u d y  int er ve nt i on.
A n A E listi n g f or t he S A S will c o ver details f or eac h i n di vi d ual AE;  a n A E listi n g f or patie nts 
w h o were n ot e x p ose d t o st u d y  int er ve nt i on is prese nte d se paratel y.
F ull details o f A E a nal yses will be pr o vi de d i n t he S A P.
D uri n g t he e val uat i on of t he A E data, a n Astra Ze neca me dicall y q ualifie d e x pert will re vie w 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 2 of 1 5 5
t he list of  A Es t hat were n ot re p orte d as S A Es or A Es lea di n g t o disc o nt i n uati on. Base d o n t he 
e x pert ’s ju d ge me nt, si g nifica nt A Es of partic ular cli nical i m p orta nce ma y , after c o ns ult atio n 
wi t h t he Glo bal Pati e nt Safet y P h ysicia n, be c o nsi dere d ot her si g nifica nt A E s a n d re p orte d as 
s uc h i n t he C S R. A si milar re vie w of la b orat or y/ vit al si g ns ( p ulse a n d B P)/ E C G data will be 
perf or m e d for i de ntificat i on of ot her si g nifica nt A Es. E xa m ples of t hese c o ul d be mar ke d 
hae mat ol o gical a n d ot her la b orat or y  a b n or malities, a n d certai n e ve nts t hat lea d t o i nter ve nti on 
( ot her t ha n t h ose alrea d y classifie d as seri o us), d ose re d ucti o n or si g nifica nt a d diti o nal 
treat me nt. Ta bles a n d fi g ures f or p ote ntial H y's La w cases will be pr o d uce d.
D urati o n of  e x p os ure will be s u m marise d. T he n u m ber a n d perce nta ge of patie nts wit h at least 
o ne d ose i nterr u pti o n/ d ose dela y a n d at least o ne d ose re d ucti o n will als o be s u m marise d 
se paratel y for t he first 6 wee ks a n d at a n y  ti me.  
Details o f a n y deat hs will be liste d f or all pat ient s.
Gra p hical prese n t atio ns of  safety data will be pre pare d as is dee me d a p pr o priate.
Ot her safet y data i ncl u di n g p h ysical e xa mi nati o ns, cli nical hae mat ol o g y, c he mistr y, uri nal ysis, 
vit al si g ns a n d E C Gs will be s u m marise d usi n g descri pti ve statistics. F or all la b orat or y 
varia bles, w hic h are i ncl u de d i n t he c urre nt versi o n of C T C A E, t he C T C A E gra de will be 
calc ulate d. T he a nal ysis will be perf or me d base d o n t he S A S f or t he o verall p o p ulat i on a n d 
t he Cr oss-o ver A nal ysis Set.
A fre q ue nc y ta ble prese nts n u m ber of patie nts re p orti ng at least o ne treat m e nt e mer ge nt 
c ha n ges i n la b orat or y para meters. F or all la b orat or y v aria bles, w hic h are i ncl u de d i n t he 
c urre nt versi o n of C T C A E, t he C T C A E gra de will be calc ulate d.  
Details o f vit al si g n a n d la b orat or y a nal yses will be pr o vi de d i n t he S A P.
9. 4. 4 
P h ar m ac o ki netic A n al yses
P har mac o ki net ic a nal yses of t he plas ma c o nce ntrati on data f or sa v olit i ni b, osi merti ni b a n d 
t heir meta b o lites ( M 2 a n d M 3 f or sa v olit i ni b; A Z 5 1 0 4 f or osi merti ni b) will be perf or me d b y 
C P Q P , Astra Ze neca or a dele gate o n be half of  C P Q P. T he act ual sa m pli n g ti mes will be use d 
i n t he para meter.
W here p ossi ble, t he f o ll owi n g P K para meters will be deter mi ne d f or sa v olit i ni b, osi merti ni b 
a n d t heir meta b o lites:

After si n gle d osi n g: C 1 h a n d C 3 h p ost -d ose.
 
After m ul tiple d osi n g: C pr e -d os e, a n d at C1 h, a n d C3 h, p ost-d ose. A p pr o priate P K para meters 
s uc h as A U C ss, Css ma x, Tss ma x, C Lss/ F at C ycle 3, Da y 1 m a y als o be calc ulate d f or 
sa v oliti ni b, osi merti ni b a n d t heir meta b olites. T hese para meters ma y be prese nte d 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 3 of 1 5 5
se paratel y for sa v oli tini b pl u s osi merti ni b, sa v oliti ni b pl us place b o a n d f or patie nts w h o 
cr osse d o ver.
If p ossi ble, t he ti me de pe n de nc y of t he P K o n m ulti ple d osi n g will be assesse d b y t he 
calc ulat i on of t he rati os of:
 
C 3 h C ycle 2 Da y  1/ C3 h C ycle 1 Da y  1 
 
C pr e -d ose C ycle 3 Da y  1/ Cpr e -d ose C ycle 2 Da y  1
 
C pr e -d ose C ycle 6 Da y  1/ Cpr e -d ose C ycle 2 Da y  1
W here p ossi ble, t he a p pr o priate P K para meters will als o be deter mi ne d f or t he meta b o lites of 
sa v oliti ni b a n d osi merti ni b. T he c o nce ntrati o n data fr om t his st u d y ma y be c o m bi ne d wit h 
ot her st u dies t o perf or m p o p ulati o n P K a nal ysis a n d if c o n d ucte d, will be re p orte d se paratel y 
fr om t he C S R.
9. 4. 5 
Ot her A n al yses 
Bi o m ar ker a nal yses f or t he C S R will be descri be d i n t he S A P. 
Ci rc ulati n g-t u mo ur D N A d y na mics will be e val uate d as a s urr o gate mar ker of  cli nical 
efficac y. F or t he sec o n dar y o bjecti ve, t he pre vale nce of ct D N A cleara nce of 6 wee ks treat me nt 
wi t h sa v oliti ni b a n d osi merti ni b will be deter mi ne d. 
T he perce nta ge c ha n ge i n E G F R m utati o n ct D N A allele fre q ue ncies at W ee k 6 will be 
o btai ne d f or e ac h patie nt ta ki n g t he differe nce bet wee n t he allele fre q ue nc y of E G F R 
se nsitisi n g m utati o ns i n ct D N A at Wee k 6 a n d t he ct D N A at baseli ne di vi de d b y t he allele 
fre q ue nc y of E G F R se nsitisi n g m utati o ns i n ct D N A at baseli ne m ultiplie d b y  o ne h u n dre d (ie, 
[ Week 6 baseli ne]/ baseli ne × 1 0 0). Pati e nts wit h u n detecta ble E G F R m utati o ns at baseli ne 
will be e xcl u de d fr o m t his a nal ysis. Sa m ples wit h u n detecta ble E G F R m utati o ns will be 
i nter prete d as 0 % allele fre q ue nc y s o t hat t he % c ha n ge is 1 0 0 %.
T he a bs o l ute c ha n ge i n ct D N A at Wee k 6 will be o btai ne d f or eac h patie nt b y t he differe nce 
bet wee n t he E G F R m utati o n ct D N A allele fre q ue ncies at Wee k 6 a n d at baseli ne.
Pati e nts wit h detecta ble E G F R mut ati o ns at baseli ne a n d a vaila ble data at 6 -wee ks will als o be 
cate g orise d i nto t he f oll o wi n g gr o u ps: ( 1) ct D N A cleara nce: defi ne d b y a 1 0 0 % c ha n ge i n 
E G F R m ut ati o ns i n ct D N A (ie, u n detecta ble at Wee k 6) a n d ( 2) ct D N A n o n-cleara nce: defi ne d 
b y a perce nt c ha n ge i n E G F R m utati o ns i n ct D N A less t ha n 1 0 0 % (ie, detecta ble at Wee k 6). 
Pati e nts wit h u n detecta ble E G F R m utati o ns at baseli ne will be cate g orise d as 
“u ni nf or m at i ve.”
Ha n dli n g of missi n g data will be descri be d i n t he S A P .

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 4 of 1 5 5
T he perce nta ge c ha n ge a n d a bs ol ute c ha n ge at W ee k 6 i n ct D N A fr o m baseli ne will be 
s u m marise d usi n g descri ptive statistics. Descri pt i ve s u m maries s h o wi n g t he act ual c ha n ge a n d 
t he perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size f or eac h pat ient  o ver ti me ma y be 
pr o d uce d. S u m mar y  statistics of t he cate g orise d ct D N A gr o u ps will als o be pr o d uce d. 
A nal ysis will als o be prese nte d f or patie nts i n t he Cr oss- o ver A nal ysis Set.
Wa t erfall plots s h o wi n g t he perce nta ge c ha n ge at Wee k 6 will be pr o d uce d f or t he FA S a n d 
Cr oss -o ver A nal ysis Set. S pi der pl ots s h o wi n g t he act ual c ha n ge a n d t he perce nta ge c ha n ge 
fr om baseli ne i n t u m o ur si ze for eac h pati e nt o ver ti me ma y be pr o d uce d.
 
 
 
 
 
 
 
  
 
 
9. 5 
I nteri m A n al yses 
Pri or t o C S P  V 3. 0, a n o n-c o mparati ve i nteri m f utilit y a nal ysis f or t he sa v olit i ni b pl us place b o 
ar m was pla n ne d t o occ ur after 2 0 patie nts o verall ( 1 0 per a r m) ha d t he o p p ort u nity t o be 
treate d f or 2 R E CI S T p ost -baseli ne sca ns ( 1 2 wee ks). T he o utc o me of t he i nteri m f ut ility 
a nal ysis was t o be as f o ll ows:
 
St o p f urt her e nr ol me nt i nt o t he st u d y  if n o res p o nses are o bser ve d
 
If tr ue rate = 5 %, t here is a 5 9. 9 % pr oba bilit y of  o bser vi n g n o res p o nses.
 
If tr ue rate = 1 0 %, t here is a 3 4. 9 % pr o ba bility of  o bser vi n g n o res p o nses.
 
If tr ue rate = 4 3 %, t here is a 0. 4 % pr o ba bility of  o bser vi n g n o res p o nses.
Recr ui t me nt was t o c o nti n ue d uri n g t he i nteri m f utilit y a nal ysis. 
If t he decisi on was ma de b y t he I D M C t hat t he st u d y  was f utile, n o ne w patie nts were t o be 
e nr o lle d i nt o t he st u d y a n d all ra n d omise d pat ient s were t o be u n bli n de d a n d t h ose ra n d omise d 
t o sa v oliti ni b pl us place b o were t o be gi ve n t he o p p ort u nity t o cr oss- over t o sa v o liti ni b pl us 
osi mert i ni b (see Secti o n 4. 1. 2 ). 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 5 of 1 5 5
T he S A P will descri be t he pla n ne d a nal yses i n greater detail.
U n der C S P V 3. 0, as a res ult of Astra Ze neca ’s decisio n t o ter mi nate st u d y  recr uit me nt earl y, 
t he pla n ne d i nteri m f ut ility a nal ysis will n ot be perf or me d a n d t here will be n o re q uire me nt f or 
data re vie w b y t he I D M C. Alt er nat i vel y, fol l owi n g t he ter mi nat i on of st u d y  recr uit me nt, a n 
i nitial D C O will occ ur t o all o w a n earl y re vie w of  t he data b y Astra Ze neca. T he st u d y will be 
u n bli n de d aft er c o mpleti o n of  data clea ni n g act i vities o n t he i nit ial D C O data, a n d patie nts o n 
sa v oliti ni b m o n ot hera p y (sa v oliti ni b pl us place b o) will be gi ve n t he o p p ort u nit y t o cr oss-o ver 
t o t he sa v oliti ni b plus osi merti ni b ar m . If t he i n vesti gat or belie ves patie nts are gai ni n g cli nical 
be nefit a n d pat ient s ha ve n ot re p orte d P D, patie nts ma y c o nti n ue t o recei ve sa v oliti ni b 
m o n ot hera p y. All pat ient s will b e f ol l owe d u nt il t he fi nal a nal ysis.  
9. 6 
D at a M o nit ori n g C o m mittees
9. 6. 1 
I n de pe n de nt D at a M o nit ori n g C o m mittee 
Pri or t o C S P  V 3. 0, a n I D M C f or t he ra n d o mise d peri o d was pla n ne d t o be utilise d f or t his 
st u d y t o mo ni t or efficac y. F or details o n t he I D M C, refer t o A p pe n di x  A 5 . U n der C S P V 3. 0, 
t he pla n ne d i nteri m f ut ility a nal ysis will n ot be perf or me d a n d he nce a n I D M C re vie w will n ot 
be re q uire d. T his is a res ult of t he decisi o n b y Astra Ze neca t o ter mi nate st u d y recr uit me nt 
earl y. 
9. 6. 2 
I n de pe n de nt He p atic Assess me nt C o m mittee (I- H A C)
A pr o gra m -wi de I -H A C will re vie w safet y data relate d t o he patic e ve nts as per case defi nit i on 
of  dr u g-i n d uce d li ver i nj ur y (Ait hal et al 2 0 1 1 ). 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 6 of 1 5 5
1 0 
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L
C O N SI D E R A TI O N S
A p pe n di x A
Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
A 1
Re g ul at or y a n d Et hic al C o nsi der ati o ns
 
T his st u d y  will be c o n d ucte d i n acc or da nce with t he C S P a n d wit h t he f o ll owi n g:
 
C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizat i ons of Me dical 
S ci e nces I nter na tio nal  Et hical G ui deli nes
 
A p plica ble I C H G C P G ui deli nes
 
A p plica ble la ws a n d re g ulati o ns
 
T he C S P , C S P a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e g, a d vertise me nts) 
m ust be s u b mitte d t o a n I R B/I E C b y  t he i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he
I R B/I E C bef ore t he st u d y is i nitiate d.
 
A n y a me n d me nts t o t he C S P will re q uire I R B/I E C a n d a p plica ble Re g ulat or y A ut h orit y 
a p pr o val b efore i m ple me ntati o n of  c ha n ges ma de t o t he st u d y d esig n, e xce pt f or c ha n ges 
necessar y  t o eli mi nate a n i m me diate hazar d t o stu d y patie nts.
 
Astra Ze neca will be res p o nsi ble f or o btai ni n g t he re q uire d a ut h orisati o ns t o c o n d uct t he 
st u d y fr o m t he c o ncer ne d Re g ulat or y Aut h ori t y. T his res p o nsi bility ma y be dele gate d t o a 
C R O b ut t he acc o u nta bilit y re mai ns wit h Astra Ze neca.
Re g ul at o r y Re p orti n g Re q uire me nts f or S A Es
 
Pr o m pt n otificat i on b y t he i n vest i gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le g al 
o bli gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of  patie nts a n d t he safety of  a 
st u d y int er ve ntio n u n der cli nical i n v est i gati on are met.
 
T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he lo c al  re g ulat or y a ut h orit y a n d 
ot her re g ulat or y  a ge ncies a b o ut t he safety of  a st u d y int er ve nt i on u n der cli nical 
i n vesti gati on. T he s p o ns or will c o m p l y wit h c o u ntr y-s pecific re g ulator y  re q uire me nts 
r elat i n g t o safety re p orti n g t o t he re g ulat or y a ut h ority,  I R B/I E C, a n d i n vesti gat ors.
 
F or all st u dies e xce pt t h ose utilisi n g me dical de vices, i n vest i gat or safety re p orts m ust be 
pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reactio ns acc or di n g t o l ocal re g ulat or y  
re q uire me nts a n d s p o ns or p olic y a n d f or war de d t o i n vesti gat ors as necessar y.
 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safety i nf or mati on (e g, s u m mar y or list i n g of S A Es) fr o m t he s p o ns or will re vie w 
a n d t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uire me nts.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 7 of 1 5 5
A 2
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nter ests d uri n g t he c o urse of t he st u d y 
a n d f or o ne ye ar after c o mplet i on of t he st u d y.
A 3
I nfor me d C o nse nt Pr ocess
 
T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he patie nt
or hi s/ h er le gall y a ut h orise d re prese ntati ve a n d a nswer all q uesti o ns re gar di n g t he st u d y .
 
Pati e nts must be i nf or me d t hat t heir partici pat i on is v ol unt ar y a n d t he y are free t o ref use
t o partici pate a n d ma y wit hdra w t hei r c o nse nt at a n y time a n d f or a n y  reas o n d uri n g t he
st u d y. P atie nts or t heir le gall y a ut hori se d re prese ntati ve ( defi ne d as a n y i n di vi d ual pers o n,
j u dicial b o d y or ot her b o d y of in di vi d uals w h o are le gall y a ut h orise d u n der state a n d
fe deral la w t o c o nse nt t o researc h partici pati on o n be half o f a desi g nate d pers o n) will be
re q uire d t o sig n a sta te me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of
Ti tle 2 1 of  t he C o de of Fe deral Re g ulati ons part 5 0, l ocal re g ulati o ns, I C H g ui deli nes,
Heal t h I ns ura nce P orta bility a n d Acc o u nta bilit y Act re q ui re me nts, w here a p plica ble, a n d
t he I R B/I E C or st u d y ce ntre.
 
T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d
bef ore t he patie nt was e nr olle d i n t he st u d y  a n d t he date t he writte n c o nse nt was o btai ne d.
T he a ut h orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t h e I C F.
 
Pati e nts must be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir
parti ci pat i on i n t he st u d y.
 
A c o p y  of t he I C F(s) must be pr o vi de d t o t he pati e nt or t he patie nt’s le gall y a ut h orise d
re prese ntati ve.
A pat ient  w h o is rescree ne d is n ot re q uire d t o si g n a n ot her I C F if t he rescree ni n g occ urs 
wi t hi n t he scree ni n g wi n d o w.
T he I C F will c o ntai n a se parate secti o n t hat a d dresses a n d d oc u me nts t he c ollect i on a n d use of 
a n y ma n dat or y 
 h u ma n bi ol ogical  s a mples. T he i n vest i gat or or a ut h orise d 
desi g nee will e x plai n t o eac h patie nt t he o bjecti ves of t he a nal ysis t o be d o ne o n t he sa m ples 
. 
 
 
If a patie nt decli nes t o partici pate i n a n y vol u nt ar y  e x pl orat or y  
 researc h c om p o ne nt of 
t he st u d y, t here will be n o pe nalty or l oss of be nefit t o t he patie nt a n d he/ s he will not be 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 8 of 1 5 5
e xcl u de d fr o m ot her as pects of t he st u d y.
If a patie nt’s part ner bec o mes pre g na nt d uri n g or wit hi n 6 m o nt hs after t he st u d y, t he part ner 
is as ke d t o si g n t he " A d ult St u d y I nfor m e d C o nse nt F or m f or Pre g na nt Part ners of St u d y  
Pati e nts" a n d pr o vi de i nf or m at i on a b o ut t he pre g na nc y acc or di n gl y.
A 4
D at a Pr otecti o n
 
Pati e nts will be assi g ne d a u ni q ue i de nt ifier b y t he s p o ns or. A n y patient  rec or ds or 
datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de nt ifier o nl y; patient  na mes 
or a n y  inf o r mat i on w hic h w o ul d ma ke t he patie nt i de nt ifia ble will n ot be tra nsferre d.
 
T he patie nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
s p o ns or i n acc or da nce with l ocal data pr otectio n la w. T he l e v el of dis clos ure a n d use of 
t heir data must al s o be e x plai ne d t o t he patie nt i n t he i nf or me d c o nse nt. 
 
T he patie nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orise d pers o n nel a p p o i nte d b y t he s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.
A 5
C o m mittees Str uct ure
Pri or t o C S P  V 3. 0, t he I D M C was t o meet f or t he pla n ne d i nteri m f utility a nal ysis t o pr o vide a 
rec o m me n dati on f or t he c o nti n uati on of t his st u d y  base d o n efficac y o bser ve d. F or f urt her 
i nf or mat i on, refer t o t he I D M C c harter . U n der C S P V 3. 0, n o i nteri m f utility a nal ysis will be 
perf or m e d a n d he nce n o I D M C re vie w will be re q uire d. T his is a res ult of t he decisi o n b y 
Astra Ze neca t o ter mi nate st u d y  recr uit me nt earl y. 
A pr o gr a m-wi de I -H A C will re vie w safet y data relate d t o he patic e ve nts as per case defi nit i on 
of  dr u g-i n d uce d li ver i nj ur y (Ait hal et al 2 0 1 1 ). 
A 6
Disse mi n ati o n o f Cli nic al St u d y D at a
A descri pt i on of t his cli nical st u d y  will be a vaila ble o n htt p://astraze necacli nicaltrials.c o m a n d 
ht t p:// w w w.cli nicaltrials. g o v as will t he s u m mar y of t he mai n st u d y res ults w he n t he y are 
a vaila ble. T he cli nical st u d y a n d/ or s u m mar y of  mai n st u d y res ults ma y als o be a vaila ble o n 
ot her we bsites acc or di n g t o t he re g ulat i ons of t he c o u ntries i n w hic h t he mai n st u d y  is 
c o n d ucte d.
A 7
D at a Q u alit y Ass ur a nce
 
All patie nt data relati n g t o t he st u d y  will be rec or de d o n e C R F u nless tra ns mitte d t o the 
s p o ns or or desi g nee electr o nicall y ( e g, la b orat or y data). T he i n vesti gat or is res p o nsi ble 
f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y 
sig ni n g t he e C R F.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
9 9 of 1 5 5
 
T he i n vest i gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he e C R F.
 
T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pectio ns a n d pr o vi de di rect access t o s o urce data d oc u me nts.
 
M o ni t ori n g details descri bi n g strate g y  (e g, ris k-base d i nit iati ves i n o perati o ns a n d q uality 
s uc h as Ris k Ma na ge me nt a n d Miti gati on Strate gies a n d A nal yt ical Ris k -Base d 
M o ni t ori n g), met h o ds, res p o nsi bilit ies a n d re q uire me nts, i ncl u di n g ha n dli n g of 
n o nc o m p lia nce iss ues a n d m onit ori n g tec h ni q ues (ce ntral, re m ote, or o n -sit e mo ni t orin g) 
are pr o vi de d i n t he M o nit ori n g Pla n.
 
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y  incl u di n g 
q ualit y c hec ki n g of t he data.
 
T he s p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals (e g, C R Os).
 
St u d y  mo ni t ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nto t he e C R F b y a ut h orise d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m 
s o urce d oc u me nts; t hat t he safet y a n d rig hts of  patie nts are bei n g pr otecte d; a n d t hat t he 
st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d C S P a n d a n y ot her 
st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
 
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he i n vest i gat or f or 1 0 years after st u d y  c o mplet i on u nless l ocal 
re g ulat i ons or i nst ituti o nal  p olicies re q uire a lo n ger rete nti o n peri o d. N o rec or ds m a y be 
destr o y e d d uri n g t he rete nti o n p erio d wi t ho ut t he wri tte n a p pr o val of t he s p o ns or. N o 
rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit ho ut wri tte n n otificati on t o t he 
s p o ns or.
A 8
S o urce D oc u me nts
 
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he patie nt a n d s u bsta nt iate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
 
Data re p orte d o n t he e C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce 
d oc u m e nts must be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be 
e x plai ne d. T he i n vest i gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer 
rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
 
Defi nit i on o f w hat c o nstit utes s o urce data ca n be f o u n d i n t he S o urce Data Verificat i on 
Pl a n.
A 9
St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uitme nt  of 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 0 of 1 5 5
pati e nts.
T he first act of recr uit me nt is t he first patie nt c o nse nte d a n d will be t he st u d y  start date.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti on of t he s p o ns or . St u d y sites will be close d u p o n st u d y  
c o mplet i on. A st u d y site is c o nsi dere d close d w he n all  re q uire d d oc u me nts a n d st u d y s u p plies 
ha ve bee n c o llecte d a n d a st u d y-sit e clos ure visi t has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y-sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o n s for t he earl y cl os ure of a st u d y  site b y t he s p o ns or or i n vesti gat or ma y incl u de b ut are 
n ot li mite d t o:
 
Fail ure of t he i n vest i gat or t o c o m pl y with t he C S P , t he re q uire me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g uideli nes
 
I na de q uate recr uitme nt  of patie nts b y t he i n vesti gat or
 
Di sc o nti n uatio n of  furt her st u d y  int er ve nt i on de vel o p m e nt
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat ory a ut h orit ies, a n d a n y C R O use d i n t he st u d y of t he 
reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y  re q uire me nts. 
T he i n vest i gat or s hall pr o m ptl y i nf or m t he patient  a n d s h o ul d ass ure a p pr o priate patie nt 
t hera p y a n d/ or f oll o w- u p.
Pati e nts fr o m ter mi nate d sites will ha ve t he o p p ort u nity t o be tra nsferre d t o a n ot her site t o 
c o nti n ue t he st u d y, if feasi ble. 
A 1 0
P u blic ati o n P olic y
 
T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie nt ific meet i n gs. If t his is 
f oresee n, t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or 
bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o prietar y  inf or mati o n a n d t o 
pr o vi de c o m me nts.
 
T he s p o ns or will c o m p l y with t he re q uire me nts f or p u blicati o n o f st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he s p o ns or will ge nerall y s u p p ort 
p u blicat i on of m ult i-ce ntre st u dies o nl y in t hei r e ntiret y a n d n ot as i n di vi d ual site data. I n 
t his case, a c o or di nati n g i n vesti gat or will be desi g nate d b y m utual  a gree me nt.
 
A ut h ors hi p will be deter mi ne d b y  mut u al  a gree me nt a n d i n li ne with I nter nat i onal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 1 of 1 5 5
A p pe n di x B
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g,
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
B 1
Defi niti o n of A d verse E ve nts
A n A E is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y 
pati e nt a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
r elat i ons hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v o ura ble a n d u ni nte n de d si g n 
(e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest pai n), or disease 
t e mp orall y  ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d 
t o t he me dici nal pr o d uct. 
T he ter m  A E is use d t o i ncl u de b ot h seri o us a n d n o n -serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical occ urre nce. A n A E ma y occ ur at a n y  ti me, i ncl u di n g 
r u n-i n or was h o ut peri o ds, e ve n if n o st u d y int er ve nt i on has bee n a d mi nistere d.
B 2
Defi niti o ns of Seri o us A d verse E v e nts
A n S A E is a n A E occ urri n g d uri n g a n y  st u d y p hase (ie, r u n-i n, treat me nt, was h o ut, 
f oll ow- u p), t hat f ulfils o ne or m ore of t he f oll o wi n g criteria:
 
Res ults i n deat h
 
Is i m me diatel y life-t hreate ni n g
 
Re q ui res i n-pat ient  h os pitalisati on or pr ol o n gat i on of e xist i n g h os pi talisati on 
 
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y. 
 
Is a c o n ge nital a b n or mality or bi rt h defect
 
Is a n i m p orta nt me dical e ve nt t hat ma y je o par dise t he patie nt or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve.
A d verse E ve nts f or m ali g n a nt t u m o urs
re p orte d d uri n g a st u d y s h o uld ge nerall y be assesse d 
as S A Es . If no ot her seri o us ness criteria a p pl y, t he ‘I mp orta nt Me di cal E ve nt ’ crit erio n s h o ul d 
be use d. I n certai n sit uat i ons, h o we ver, me dical j u d ge m e nt o n a n i n di vi d ual e ve nt basis s h o ul d 
be a p plie d t o clarif y t hat t he mali g na nt t u m o ur e ve nt s h o ul d be assesse d a n d re p orte d as a 
N o n -Seri o us A E. F or e xa m ple, if t he t u m o ur is i ncl u de d as me dical hist or y  a n d pr o gressio n 
occ urs d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or pr o g n osis of t he 
mali g na nt t u m o ur, t he A E m a y not f ulfil  t he attri b utes f or bei n g assesse d as seri o us, alt h o u g h 
re p orti n g of t he pr o gressi o n of t he mali g na nt t u m o ur as a n A E is vali d a n d s h o ul d occ ur . Als o, 
s o me t ypes of  mali g na nt t u mo urs, w hic h d o n ot s prea d re m otel y after a r o uti ne treat me nt t hat 
d oes n ot re q uire h os pitalisat i on, m a y be assesse d as n o n-S eri o us; e xa m ples i n a d ults i ncl u de 
Sta ge 1 basal cell carci n o ma a n d S ta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne bi o ps y.
T he a b o ve i nstr ucti o n a p plies o nl y w he n t he mali g na nt t u m o ur e ve nt i n q uest i on is a ne w 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti n i b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 2 of 1 5 5
mali g na nt t u m o ur (ie, it is n ot t he t u mo ur f or w hi c h e ntr y int o t he st u d y  is a criterio n a n d t hat 
is bei n g treate d b y  t he st u d y int er ve ntio n u n der st u d y  a n d is n ot t he de vel o p me nt of ne w or 
pr o gressi o n of e xist i n g metastasis t o t he t u m o ur u n der st u d y). Mali g na nt t u m o urs t hat – as 
part of n or mal, if rare, pr o gressi o n – u n der g o tra nsf or mat i on (e g, Ri c hter's tra nsf or mat i on of 
B cell c hr o nic l y m p h oc ytic le u kae mia i nto diff use lar ge B cell l y m p h o ma) s h o ul d n ot be 
c o nsi dere d a ne w mali g na nt t u m o ur.
Life t hre ate ni n g
‘Life -t hreate ni n g’ mea ns t hat t he patie nt was at i m me diate ris k of deat h fr o m t he A E as it 
occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ul t in t he patie nt ’s 
deat h. ‘Life -t hreate ni n g’ d oes n ot m ea n t hat ha d a n A E occ urre d i n a m ore se vere f or m it 
mi g ht ha ve ca use d deat h (e g, he patit is t hat res ol ve d wit h o ut he patic fail ure).
H os pit alis ati o n
O ut pati e nt treat me nt i n a n e mer ge nc y r o o m is n ot i n itself a n S A E, alt ho u g h t he reas o ns f or it 
ma y be (e g, br o nc h os pas m, lar y n geal oe de ma). H os pital a d missi o ns a n d/ or s ur gical o perati o ns 
pl a n ne d bef ore or d uri n g a st u d y are n ot c o nsidere d A Es if t he ill ness or disease e xiste d bef ore 
t he patie nt was e nr olle d i n t he st u d y, pr o vide d t hat it di d n ot deteri orate i n a n u ne x pecte d wa y  
d uri n g t he st u d y.
I m p ort a nt me dic al e ve nt or me dic al tre at me nt
Me dical a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit u atio ns w here i m p orta nt me dical e ve nts ma y  not be i m me diatel y life t hreate ni n g or res ult i n 
deat h, h os pi talisati on, di sa bilit y or i nca pacit y but ma y je o par dise t he patie nt or ma y  re q uire 
me dical treat me nt t o pre ve nt o ne or m ore o utc o mes liste d i n t he defi nit i on o f serio us. T hese 
s h o uld us uall y be c o nsi dere d as seri o us.
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; me dical 
j u d ge me nt m ust be use d.
 
A n gi oe de ma n ot se vere e n o u g h t o re q uire i nt u bati o n b ut re q uiri n g I V h y dr oc ortis o ne 
treat me nt
 
He pat ot o xicit y ca use d b y paraceta m o l (aceta mi n o p he n) o ver d ose re q uiri n g treat me nt wit h 
N- acet ylc ystei ne
 
I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m
 
Bl o o d d y scrasias (e g, ne utr o pe nia or a nae mia re q uiri n g bl o o d tra nsf usi o n, etc) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisat i on
 
De vel o p me nt of dr u g de pe n de nc y or dr u g a b use

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 3 of 1 5 5
I nte nsit y r ati n g sc ale:
T he gra di n g scales f o u n d i n t he re vise d Nati o nal Ca ncer I nst itut e C T C A E latest versi o n will 
be utilise d f or all e ve nts wit h a n assi g ne d C T C A E gra di n g. F or t h ose e ve nts wit h o ut assi g ne d 
C T C A E gra des, t he rec o m me n dati o n i n t he C T C A E criteria t hat c o n verts mil d, m o derate a n d 
se vere e ve nts i nt o C T C A E gra des s h o ul d be use d. A c o p y of t he C T C A E ca n be d o w nl oa de d 
fr om t he Ca ncer T hera p y E val uat i on Pr o gra m we bsi te ( htt p://cte p.ca ncer. g o v). T he a p plica ble 
versi o n of C T C A E s h o ul d be descri be d clearl y.
B 3
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
W he n ma ki n g a n assess me nt of ca usalit y c o nsider t he f oll o wi n g f act ors w he n deci di n g if t here 
is a ‘reas o na ble p ossi bilit y’ t hat a n A E m a y ha ve bee n ca use d b y t he dr u g.
 
Ti me C o urse. E x p os ure t o s us pect dr u g. Has t he patie nt act uall y recei ve d t he s us pect 
dr u g? Di d t he A E occ ur i n a reas o na ble te m p oral relat i ons hi p t o t he a d mi nistrati o n of t he 
s us pect dr u g?
 
C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wl e d ge of t he s us pect dr u g ( p har mac o l og y  a n d t o xic o l og y ) or dr u gs of t he same 
p har mac o l ogi cal class? Or c o ul d t he A E be a nt ici pate d fr o m its p har mac ol ogi cal 
pr o perties?
 
De -c halle n ge e x perie nce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he d ose 
of  t he s us pect dr u g?
 
N o al ter nati ve ca use. T he A E ca n n ot be reas o na bl y e x plai ne d b y a n ot her aeti ol og y  s uc h 
as t he u n derl yi n g disease, ot her dr u gs, ot her h ost or e n vir o n me ntal fact ors.
 
Re -c halle n ge e x perie nce. Did t he A E re occ ur if t he s us pecte d dr u g was rei ntr o d uce d after 
ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a 
re-c halle n ge.
 
La b orat or y  tests. A s pecific la b orat or y in vest i gati on (if perf or me d) has c o nfir me d t he 
r elat i ons hi p .
I n diffic ult cases, ot her fact ors c o ul d be c o nsi dere d s uc h as:
 
Is t his a rec o g nise d feat ure of o ver d ose of t he dr u g?
 
Is t here a k n o w n mec ha nis m?
Ca usalit y of  ‘relate d’ is ma d e if f o ll o wi n g a re vie w of t he rele va nt data, t here is e vi de nce f or a 
‘reas o na ble p ossi bilit y’ of  a ca usal relati o ns hi p f or t he i n di vi d ual case. T he e x pressi o n 
‘reas o na ble p ossi bility ’ of  a ca usal r el atio ns hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati ons hi p.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 4 of 1 5 5
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble data i ncl u di n g e n o u g h 
i nf or mat i on t o m a ke a n i nf or me d j u d g me nt. With n o a vail a ble facts or ar g u me nts t o s u g gest a 
ca usal relat i ons hi p, t he e ve nt(s) will be assesse d as ‘n ot rel ate d’.
Ca usal relat i ons hi p i n cases w here t he disease u n der st u d y  has deteriorate d d ue t o l ac k of 
effect s h o uld be classifie d as n o reas o na ble p ossi bilit y.
B 4
M e dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y  a me dicat i on err or is a n u ni nte n de d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n Astra Ze neca st u d y  int er ve nt i on t hat eit her ca uses har m t o t he 
pati e nt or has t he p ote ntial t o ca use har m t o t he p atie nt. 
A me dicat i on err or is n ot lac k of efficac y of t he dr u g, b ut rat her a h u ma n or pr ocess relate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y sit e st aff or pati e nt.
Me dicat i on err or i ncl u des sit uat i ons w here a n err or: 
 
occ urre d
 
was i de nt ifie d a nd i nterce pte d bef ore t he patie nt recei ve d t he dr u g
 
di d n ot occ ur, b ut circ u msta nces were rec o g nise d t hat c o ul d ha ve le d t o a n err or
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:
 
Dr u g na me c o nf usi o n
 
Di s pe nsi n g err or e g, me d icatio n pre pare d i nc orrectl y , e ve n if it was n ot act uall y gi ve n t o 
t he patie nt
 
Dr u g n ot a d mi nistere d as i n dicate d, f or e xa m ple, wr o n g r o ute or wr o n g site of 
a d mi nistrati o n
 
Dr u g n ot ta ke n as i n dicate d e g, ta blet diss o l ve d i n water w he n it s h o ul d be ta ke n as a 
s oli d ta blet 
 
Dr u g n ot st ore d as i nstr ucte d e g, ke pt i n t he fri d ge w he n it s h o ul d be at r o o m te m perat ure 
 
Wr o n g patie nt recei ve d t he me dicati o n (e xcl u di n g I V R S/I W R S err ors)
 
Wr o n g dr u g a d mi nistere d t o patie nt (e xcl u di n g I V R S/I W R S err ors)
E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me dicati on err ors i n cli nical st u dies:
 
Err ors relate d t o or res ulti n g fr o m I V R S/I W R S - i ncl u di n g t h ose w hic h lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicati o n err or 
 
Pati e nt  accide ntall y  misse d dr u g d ose(s) e g, f or g ot t o ta ke me dicati on

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 5 of 1 5 5
 
Acci de ntal  o ver d ose ( will be ca pt ure d as a n o ver d ose)
 
Pati e nt faile d t o ret ur n u n use d me dicat i on or e m pt y  pac ka gi n g
 
Err ors relate d t o bac k gr o u n d a n d resc ue me dicat i on, or sta n dar d of care me dicat i on i n 
o pe n l a bel st u dies, e ve n if a n Astra Ze neca pr o d uct 
Me dicat i on err ors are n ot re gar de d as A Es b ut A Es ma y occ ur as a c o nse q ue nce of t he 
me dicat i on err or.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 6 of 1 5 5
A p pe n di x C
H a n dli n g of H u m a n Bi ol o gic al S a m ples
C 1
C h ai n of C u st o d y
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m ples t hr o u g h o ut t heir lifec ycle.
T he i n vest i gat or at eac h ce ntre kee ps f ull tracea bilit y of c ollecte d bi ol ogi cal sa mples f r o m t he 
pati e nts w hile i n st ora ge at t he ce ntre u ntil s hi p me nt or dis p osal ( w he re a p pr o priate) a n d 
rec or ds rele va nt pr ocessi n g i nf or mati o n relate d t o t he sa m ples w hilst at site.
T he sa m ple recei ver kee ps f ull tracea bilit y of  t he sa mples w hile i n st ora ge a n d d uri n g use u nt il 
use d or dis p ose d of or u ntil f urt her s hi p me nt a n d kee ps rec o r d of recei pt of arri val a n d o n war d 
s hi p me nt or dis p osal.
Astra Ze neca or dele gate d re prese ntati ves will kee p o versi g ht of t he e nt ire life c ycle t hr o u g h 
i nter nal pr oce d ures, mo ni t orin g of st u d y  sites, a u diti n g or pr ocess c hec ks, a n d c o ntract ual 
re q uire me nts of  e xter nal la b orat or y pr o viders
S a m ples retai ne d f or f urt her use will be st ore d i n t he Astra Ze neca -assi g ne d bio b a n ks or ot her 
sa m ple arc hi ve facilities a n d will be trac ke d b y t he a p pr o priate Astra Ze neca T ea m d uri n g f or 
t he re mai n der of t he sa mple life c y cle.
If re q uire d, Astra Ze neca will e ns ure t hat re mai ni n g bi ol ogi c al s a mples are ret ur ne d t o t he site 
acc or di n g t o l ocal re g ulati o ns or at t he e n d of t he rete nti o n peri o d, w hic he ver is t he s o o ner.
C 2
Wit h dr a w al of I nf or me d C o nse nt f or D o n ate d Bi ol o gic al S a m ple s 
If a patie nt wit h dra ws c o nse nt t o t he use of d o nate d bi ol ogi c al s a mples, t he sa m ples will  b e 
di s p ose d of/ destr o ye d/re patriate d, a n d t he acti o n d oc u me nte d. If sa m ples are alrea d y a nal yse d ,
Astra Ze neca is n ot o bli ge d t o destr o y  t he res ults of t his research.
F o ll owi n g wi t hdra wal  of c o nse nt f or bi ol ogi c al sa m ples, f urt her st u d y particip ati o n s h o ul d be 
c o nsi dere d i n relat i on t o t he wi t hdra wal  pr ocesses o utli ne d i n t he i nf or me d c o nse nt.
T he i n vest i gat or:
 
E ns ures pat ient s’ wi t hdra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
hi g hli g hte d i m me diatel y t o Astra Ze neca or dele gate.
 
E ns ures t hat rele va nt h u ma n bi o l ogical sa m ples fr o m  t hat patie nt, if st ore d at t he st u d y 
site, are i m me diatel y ide ntifie d, dis p ose d of as a p pr o pri ate, a n d t he actio n d oc u me nte d
 
E ns ures t hat t he patie nt a n d Astra Ze neca are i nf or me d a b o ut t he sa m ple dis p osal.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 7 of 1 5 5
Astra Ze neca e ns ures t he or ga nisati o n(s) h ol di n g t he sa m ples is/are i nf or me d a b o ut t he 
wi t hdra w n c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d of or re patriate d as a p pr o priate, 
a n d t he acti o n d oc u me nte d a n d st u d y site n otifie d.
C 3
I nter n ati o n al Airli ne Tr a ns p ort ati o n Ass oci ati o n 6. 2 G ui d a nce 
D oc u me nt
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 oci at i on 
(htt ps:// w w w .i at a. or g/ w h at we d o/c ar g o/ d gr/ P a ges/ d o w nl o a d. as p x) classifies i nfecti ous 
s u bsta nces i nt o 3 cate g ories: Cate g or y A, Cate g or y B or E xe m pt
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 o cc 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 mals. 
C ate g or y A p at h o ge ns are e g, E b ola, Lassa fe ver vir us. I nfecti o us s u bsta nces meet i n g t hese 
criteria w hic h ca use disease i n h u ma ns or b ot h i n h u ma ns a n d a ni mals m ust be assi g ne d t o 
U N 2 8 1 4. I nfect i ous s u bsta nces w hic h ca use disease o nl y i n a ni mals m ust be assi g ne d t o 
U N 2 9 0 0:
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 patitis A, C, D, a n d E vir uses. T he y 
are assi g ne d t he f o ll owi n g U N n u m ber a n d pr o per s hi p pi n g na me
 
U N 3 3 7 3 – Bi o l ogi cal S u bsta nce, Cate g or y B
 
are t o be pac ke d i n acc or da nce wit h U N 3 3 7 3 a n d I A T A 6 5 0
E xe m pt - S u bsta nces w hic h d o n ot c o ntai n i nfect i o us s u bsta nces or s u bsta nces w hic h are 
u nli kel y t o ca use disease i n h u ma ns or a ni mals are n ot s u bject t o t hese Re g ulati o ns u nless t he y  
meet t he criteria f or i ncl usi o n i n a n ot her class.
 
Cli nical st u d y  sa m ples will fall i nt o Categ or y  B or e xe m pt u n der I A T A re g ulati ons
 
Cli nical st u d y  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 te m perat ure i n 
I A T A 6 5 0 c o m plia nt pac ka gi n g 
( htt ps:// w w w.iata. or g/ w hat we d o/car g o/ d gr/ D oc u me nts/ D G R- 6 0-E N -PI 6 5 0. p df).
 
Bi ol o gi cal sa m ples tra nsp orte d i n dr y  ice re q uire a d ditio nal  da n ger o us g o o ds s pecificati on 
f or t he dr y-ice c o nte nt

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 8 of 1 5 5
A p pe n di x D
D 1
D 2
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 0 9 of 1 5 5
 
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 0 of 1 5 5
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 1 of 1 5 5
A p pe n di x E
Acti o ns Re q uire d i n C ases of I ncre ases i n Li ver Bi oc he mistr y 
a n d E v al u ati o n of H y’s L a w
E 1
I ntr o d ucti o n
T his A p pe n di x descri bes t he pr ocess t o be f o ll owe d i n or der t o i de nt if y a n d a p pr o priatel y 
re p ort P H L cases a n d H L cases. It is n ot i nte n de d t o be a c o m pre he nsi ve g ui de t o t he 
ma na ge me nt of ele vate d li ver bi oc he mistries. 
D uri n g t he c o urse of t he st u d y  t he i n vesti gat or will re mai n vi gila nt f or i ncreases i n li ver 
bi oc he mistr y. T he i n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a patie nt meets p ote ntial 
P H L  criteria at a n y p oi nt d uri n g t he st u d y.
All s o urces of la b orat or y data are a p pr o priate f or t he deter mi nat i on of P H L  a n d H L e ve nts; 
t his i ncl u des sa m ples ta ke n at sc he d ule d st u d y visits a n d ot her visits i ncl u di n g ce ntral a n d all 
l ocal la b orat or y e val uati ons e ve n if c o llecte d o utsi de of t he st u d y visits; for e xa m ple, P H L  
crit eria c o uld be m et b y a n ele vate d A L T fr om a ce ntral la b orat or y a n d/ or ele vate d T B L fr o m 
a lo c al  la b orat or y. 
T he i n vest i gat or will als o re vie w A E data (f or e xa m ple, f or A Es t hat ma y i n dicate ele vat i ons 
i n li ver bi oc he mistr y) for p ossi ble P H L  e ve nts.
T he i n vest i gat or partici pates, t o get her wit h Astra Ze neca cli nical pr oject re prese ntati ves, i n 
re vie w a n d assess me nt of cases meeti n g P H L crit eria t o a gree w het her H L criteria are met. 
H y ’s La w criteria are met if t here is n o alter nati ve e x pla nati on f or t he ele v atio ns i n li ver 
bi oc he mistr y  ot her t ha n DI LI ca use d b y t he st u d y int er ve nt i on. 
T he i n vest i gat or is res p o nsi ble f or rec or di n g data pertai ni n g t o P H L/ H L cases a n d f or 
re p orti n g S A Es a n d A Es acc or di n g t o t he o utc o me of t he re vie w a n d assess me nt i n li ne wi t h 
sta n dar d safety re p orti n g pr ocesses.
E 2
Defi niti o ns
P ote nti al H y’s L a w
As partate a mi n otra nsferase or A L T ≥ 3 × U L N t o get her wit h T B L  ≥ 2 × U L N at a n y  p oi nt 
d uri n g t he st u d y  f oll owi n g t he start of st u d y  me dicatio n irres pecti ve of a n i ncrease i n A L P.
H y’s L a w
As partate a mi n otra nsferase or A L T ≥ 3 × U L N t o get her wit h T B L  ≥ 2 × U L N, w here n o ot her 
reas o n, ot her t ha n t he st u d y int er ve nt i on, ca n be f o u n d t o e x plai n t he c o m bi nat i on of 
i ncreases, e g, ele vate d A L P i n dicati n g c h olestasis, viral he patitis, a n ot her dr u g. 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 2 of 1 5 5
F or P H L  a n d H L t he ele vat i on i n tra nsa mi nases m ust prece de or be c oi nci de nt wit h (ie, o n t he 
sa me da y) t he ele v atio n i n T B L, b ut t here is n o s pecifie d ti mefra me wit hi n w hic h t he 
ele vat i ons i n tra nsa mi nases a n d T B L  must occ ur .
E 3
I de ntific ati o n of P ote nti al H y’s L a w C ases
I n or der t o ide ntif y  cases of P H L it is i m p orta nt t o perf or m a c o m pre he nsi ve re vie w of 
la b orat or y data f or a n y patient  w h o meets a n y of t he f oll owi n g i de ntificat i on cri t eria i n 
is olati on or i n c o m bi nat i on:
 
A L T ≥ 3 × U L N
 
A S T ≥ 3 × U L N
 
T B L ≥ 2 × U L N
T he i n vest i gat or will with o ut dela y  re vie w eac h ne w la b orat or y re p ort a n d if t he i de ntificati on 
criteria are met will:
 
N otif y  t he Astra Ze neca re prese ntati ve 
 
Deter mi ne w het her t he patie nt meets P H L criteria (see Secti o n  E 2 Defi nit i ons wi t hi n t his 
A p pe n di x f or defi nit i on) b y re vie wi n g la b orat or y  re p orts fr o m all pre vio us visi ts
 
Pr o m pt l y e nter t he la b orat or y data i nt o t he la b orat or y e C R F
E 4
F oll o w -u p
E 4. 1
P ote nti al H y’s L a w Criteri a N ot Met
If t he patie nt d oes n ot meet P H L criteria t he i n vesti gat or will:
 
I nf or m t he Astra Ze neca re prese ntati ve t hat t he patie nt has n ot met P H L criteria. 
 
Perf or m  fol l ow- u p o n s u bse q ue nt la b orat or y  res ults acc or di n g to t he g ui da nce pr o vi de d i n 
t he C S P .
E 4. 2
P ote nti al H y’s L a w Criteri a met
If t he patie nt d oes meet P H L crit eria t he i n vest i gat or will:
 
Deter mi ne w het her P H L criteria were met at a n y  st u d y visit prior t o starti n g st u d y  
i nter ve nt i on ( See Secti o n  E 6)
 
N otif y  t he Astra Ze neca re prese ntati ve w h o will t he n i nf or m t he ce ntral St u d y Tea m 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 3 of 1 5 5
 
Wit hi n o ne da y  of P H L crit eria bei n g met, t he i n vestigat or will re p ort t he ca se as a n S A E 
of  P ote ntial H y’s La w; serio us cri t eria ‘I m p orta nt me dical e ve nt’ a n d ca usalit y 
assess me nt ‘ yes/relate d’ acc or di n g t o C S P pr ocess f or S A E re p orti n g.
 
F or pati e nts t hat met P H L crit eria prior t o starti n g st u d y  int er ve ntio n, t he i n vest i gat or is 
n ot re q ui re d t o s u b mit a P H L S A E u nless t here is a si g nifica nt c ha n ge i n t he patie nt’s 
c o n ditio n
 
T he St u d y  P h ysicia n c o ntacts t he i n vesti gat or, t o pr o vi de g ui da nce, disc uss a n d a gree a n 
a p pr oac h f or t he st u d y patient s’ f oll ow- u p (i ncl u di n g a n y  furt her l a b or at or y testi n g) a n d 
t he c o nti n u o us re vie w o f data
 
S u bse q ue nt t o t his c o ntact t he i n vest i gat or will:
 
M o ni t or t he patie nt u ntil li ver bi oc he mistr y para meters a n d a p pr o priate cli nical 
s y m pt o ms a n d si g ns ret ur n t o n or mal or baseli ne le vels, or as l o n g as me dicall y 
i n dicate d. C o m pletes f oll ow- u p S A E F or m as re q uire d.
 
I n vesti gate t he aeti ol o g y of t he e ve nt a n d perf or m dia g n ostic i n vesti gat i ons as 
di sc usse d wit h t he St u d y P h ysicia n. 
 
C o m plete t he t hree Li ver e C R F M o d ules as i nf or mati o n bec o mes a vaila ble. 
A ‘si g nific a nt’ c h a n ge i n t he patient ’s c o n ditio n refers t o a cli nicall y  rele va nt c ha n ge i n a n y 
of  t he i n di vi d ual li ver bi oc he mistr y para meters ( A LT,  A S T or T B L) i n is olati o n or i n 
c o m bi nat i on, or a cli nicall y  rele va nt c ha n ge i n ass ociate d s y m pt o ms. T he deter mi nati o n of 
w het her t here has bee n a si g nifica nt c ha n ge will be at t he discret i on of t he i n vesti gat or, t his 
ma y be i n c o ns ultat i on wi t h t he St u d y P h ysicia n if t here is a n y u ncertai nty.
E 5
Re vie w a n d Assess me nt of P ote nti al H y’s L a w C ases
T he i nstr ucti o ns i n t his Sectio n s h o ul d be f ol l owe d f or all cases w here P H L  crit eria are met.
As s o o n as p ossi ble after t he bi oc he mistr y  a b n or mality was i ni tiall y detecte d, t he St u d y 
P h ysicia n c o ntacts t he i n vest i gat or i n or der t o re vie w a vaila ble data a n d a gree o n w het her 
t here is a n alter nat i ve e x pla nati on f or meet i n g P H L crit eria ot her t ha n DI LI ca use d b y t he 
st u d y int er ve ntio n, t o e ns ure ti mel y a nal ysis a n d re p orti n g t o healt h a ut h orities wit hi n 
1 5 cale n dar da ys fr o m date P H L criteria was met. T he Astra Ze neca Gl o bal Cli nic al Lea d or 
e q ui vale nt a n d Gl o bal Safet y P h ysicia n will als o be i n v ol ve d i n t his re vie w t o get her wit h 
ot her s u bject matter e x perts as a p pr o priate. 
Acc or di n g t o t he o utc o me of t he re vie w a n d assess me nt, t he i n vest i gat or will f oll o w t he 
i nstr uctio ns bel o w.
W her e t here is a n a gr ee d alter n ati ve e x pl a n ati o n f or t he A L T or A S T a n d T B L ele vat i ons, a 
deter mi nat i on of w het her t he alter nat i ve e x pla nati on is a n A E will be ma de a n d s u bse q ue nt l y 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 4 of 1 5 5
w het her t he A E meets t he criteria f or a n S A E:
 
If t he alter nati ve e x pla nati on is n ot a n A E, rec or d t he alter nati ve e x pla nati o n o n t he 
a p pr o priate e C R F.
 
If t he alter nati ve e x pla nati on is a n A E/ S A E: u p date t he pre vi o usl y s u b mitte d P ote ntial 
H y’s La w S A E a n d A E e C R Fs acc or di n gl y wit h t he ne w i nf or mat i on (reassessi n g e ve nt 
ter m; ca usality a n d serio us ness cri teria) f oll owi n g t he Astra Ze neca sta n dar d pr ocesses.
If it is a gree d t hat t here is n o e x pla nat i on t hat w o ul d e x plai n t he A LT or A S T a n d T B L  
ele vat i ons ot her t ha n t he st u d y  int er ve nt i on:
 
Se n d u p date d S A E (re p ort ter m ‘ H y’s La w’) acc or di n g t o Astra Ze neca sta n dar d 
pr ocesses. 
 
T he ‘ Me dicall y  I m p orta nt’ serio us cri t erio n s h o ul d be use d if n o ot her seri o us 
criteria a p pl y
 
As t here is n o alter nat i ve e x pla nati o n f or t he H L case, a ca usality assess me nt of 
‘relate d’ s h o ul d be assi g ne d.
If, t here is a n u na v oi da ble dela y, of o ver 1 5 cale n dar da ys i n o btai ni n g t he i nf or mati on 
necessar y  t o assess w het her or n ot t he case meets t he criteria f or H L, t he n it is ass u me d t hat 
t here is n o alter nat i ve e x pla nati o n u ntil s uc h ti me as a n i nf or me d decisi on ca n be m a de:
 
Pr o vi des a n y  furt her u p date t o t he pre vi o usl y s u b mitte d S A E of P ote ntial H y’s La w, 
(re p ort ter m n o w ‘ H y’s La w case’) e ns uri n g ca usality assess me nt is relate d t o st u d y 
i nter ve nt i on a n d seri o us ness criteria is me dicall y i m p orta nt, acc or di n g t o C S P pr ocess f or 
S A E re p orti n g.
 
C o nti n ue f o ll ow- u p a n d re vie w acc or di n g t o a gree d pla n. O nce t he necessar y  
s u p ple me ntar y inf or mat i on is o btai ne d, re peat t he re vie w a n d assess me nt t o deter mi ne 
w het her H L criteria are still met. U p date t he pre vi o usl y s u b mitte d P H L S A E re p ort 
f oll owi n g C S P pr ocess f or S A E re p orti n g, acc or di n g t o t he o utc o me of t he re vie w a n d 
a me n di n g t he re p orte d ter m if a n alter nat i ve e x pla nati on f or t he li ver bi oc he mistr y 
ele vat i ons is deter mi ne d.
E 6
Acti o ns Re q uire d W he n P ote nti al H y’s L a w Criter i a are Met 
Bef ore a n d After St arti n g St u d y I nter ve nti o n 
T his sect i on is a p plica ble t o patie nts wit h li ver metastases w h o meet P H L crit eria o n st u d y 
i nter ve nt i on, ha vi n g pre vi o usl y met P H L  crit eria at a st u d y visit prior t o starti n g st u d y  
i nter ve nt i on.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 5 of 1 5 5
At  t he first o n-st u d y int er ve nt i on occ urre nce of P H L  crit eria bei n g met t he i n vest i gat or will 
deter mi ne if t here has bee n a si g nific a nt c h a n ge i n t he patie nts’ c o n ditio n  c o mpare d wi t h t he 
last visit w here P H L crit eria were met.
 
If t here is n o si g nifica nt c ha nge n o acti o n is re q ui re d
 
If t here is a si g nifica nt c ha n ge, n otif y t he Astra Ze neca re prese ntati ve, w h o will i nf or m t he 
ce ntral St u d y T e a m, t he n f ollo w t he s u bse q ue nt pr ocess descri be d i n Sect i on  E 4. 2 .  
E 7
Acti o ns Re q uire d f or Re pe at E pis o des of P ote nti al H y’s L a w
T his sect i on is a p plica ble w he n a patie nt meets P H L crit eria o n st u d y int er ve nt i on a n d has 
alrea d y met P H L criteria at a pre vi o us o n st u d y i nter ve nt i on visit.
T he re q ui re me nt t o c o n d uct f oll ow- u p, re vi e w a n d assess me nt of a re peat occ urre nce(s) of 
P H L  is base d o n t he nat ure of t he alter nati ve ca use i de ntifie d f or t he pre vi o us occ urre nce. 
T he i n vest i gat or s h o ul d deter mi ne t he ca use f or t he pre vi o us occ urre nce of P H L crit eria bei n g 
met a n d a ns wer t he f o ll owi n g q uest i on:
Wa s t he alter nati ve ca use f or t he pre vi o us occ urre nce of P H L criteria bei n g met f o u n d 
t o be t he disease u n der st u d y e g, c hr o nic or pr o gressi n g mali g na nt disease, se vere 
i nfecti on or li ver disease or di d t he patie nt meet P H L  crit eria prior t o starti n g st u d y  
i nter ve nt i on a n d at t heir first o n -st u d y int er ve ntio n visi t as descri be d i n Secti on  E 6 of  
t his A p pe n di x?
If N o : fol l ow t he pr ocess descri be d i n Sect i on  E 4. 2 f or re p orti n g P H L as a n S A E.
If Ye s: Deter mi ne if t here has bee n a si g nifica nt c ha n ge i n t he pat ient ’s c o n ditio n c o m pare d 
wi t h w he n P H L crit eria were pre vi o usl y met.
 
If t here is n o si g nifica nt c ha n ge n o acti o n is re q uire d
 
If t here is a si g nifica nt c ha n ge f oll ow t he pr ocess descri be d i n Secti o n  E 4. 2 f or re p orti n g 
P H L as a n S A E
A ‘si g nifica nt’ c ha n ge i n t he patie nt ’s c o n ditio n refers t o a cli nicall y  rele va nt c ha n ge i n a n y of 
t he i n di vi d ual li ver bi oc he mistr y  para meters ( A LT,  A S T or T B L) i n is olati on or i n 
c o m bi nat i on, or a cli nicall y  rele va nt c ha n ge i n ass ociate d s y m pt o ms. T he deter mi nati o n of 
w het her t here has bee n a si g nifica nt c ha n ge will be at t he discret i on of t he i n vesti gat or, t his 
ma y be i n c o ns ultat i on wi t h t he St u d y P h ysicia n if t here is a n y u ncertai nty.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 6 of 1 5 5
E 8
Refere nces
Ait h al et al, 2 0 1 1
Ait hal G P , Wat ki ns P B, A n dra de RJ, Larre y  D, M olo k hia M, T a ki ka wa H, et al. Case 
defi nit i on a n d p he n ot y pe sta n dar dizat i on i n dr u g-i n d uce d li ver i nj ur y. Cli n Phar mac o l T her. 
2 0 1 1; 8 9( 6): 8 0 6 - 1 5.
F D A G ui d a nce f or I n d ustr y, J ul y 2 0 0 9
F D A  G ui da nce f or I n d ustr y (iss ue d J ul y 2 0 0 9) ‘Dr u g -i n d uce d li ver i nj ur y: Pre mar keti n g 
cli nical e val uat i on ’. Av aila ble fr o m; htt ps:// w w w .fda. g o v/re g ulat or y -i nf or mati on/searc h -f da-
g ui da nc e- d o c u m e nts/ dr u g -i n d uce d-li ver-i nj ur y-pre mar ket i n g-cli nical-e val uatio n. Accesse d 
0 6 A pril 2 0 2 0.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 7 of 1 5 5
A p pe n di x F
Ne w Y or k He art Ass oci ati o n cl assific ati o n of he art dise ase
F 1
N Y H A Cl assific ati o n of He art Dise ase
N Y H A cl ass 
S y m pt o ms
I
N o s y m pt o ms a n d n o li mitati o n i n or di nar y p h ysical acti vit y, e g, s h ort ness of breat h w he n 
wal ki n g, cli m bi n g stairs etc.
II
Mil d s y m pt o ms ( mil d s h ort ness of breat h a n d/ or a n gi na) a n d sli g ht li mitati o n d uri n g 
or di nar y acti vit y.
III
Mar ke d li mitati o n i n act i vit y d ue t o s y m pt o ms, e ve n d uri n g less-t ha n-or di nar y acti vit y, 
e g, wal ki n g s h ort dista nces ( 2 0 t o 1 0 0 m). C o mf orta ble o nl y at rest.
I V
Se vere li mitati o ns. E x perie nces s y m pt o ms e ve n w hile at rest. M ostl y be d b o u n d patie nts.
F 2
Refere nces
Ne w Y or k He art Ass oci ati o n 1 9 9 4
T he Cri t eria C o m mit t e e of t he Ne w Yor k Heart Ass ociati o n. N o me nclat ure a n d Criteria f or 
Di a g n osis of Diseases of t he Heart a n d Great Vessels. 9t h e dit i on. B ost o n, M A: Little, Br o w n 
& C o; 1 9 9 4. p. 2 5 3 -6.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 8 of 1 5 5
A p pe n di x G
Defi niti o n of W o me n of C hil d be ari n g P ote nti al a n d 
Acce pt a ble C o ntr ace pti ve Met h o ds
Defi niti o n of W o me n of C hil d be ari n g P ote nti al
Wo me n of C hil d beari n g P ote ntial:
Wo me n bet wee n me narc he a n d me n o pa use w h o ha ve n ot bee n per ma ne nt l y or s ur gicall y 
sterilise d a n d are ca pa ble of pr ocreati o n.
Wo me n N O T of C hil d beari n g P ote ntial:
Wo me n w h o are per m a ne nt l y or s ur gicall y sterilise d or p ost-me n o pa usal ( defi nit i ons bel o w): 
P er m a ne nt sterilisat i on i ncl u des h ysterect o m y a n d/ or bilateral o o p h orect o m y a n d/ or bilateral 
sal pi n gect o m y but e xcl u des bilateral  t u bal o c clusi o n . T u bal occl usi on is c o nsi dere d a hi g hl y 
effecti ve met h o d of birt h c o ntr ol b ut d oes n ot a bs ol utel y  e xcl u de p ossi bilit y of  pre g na nc y. 
( T he ter m occlusi o n  r efers t o b ot h occl u di n g a n d li gati n g tec h n i q ues t hat d o n ot p h ysicall y 
r e mo ve t he o vi d ucts).
 
W o me n w h o ha ve u n der g o ne t u bal occl usi o n s h o ul d be ma na ge d o n st u dies as if t he y are 
of  W o C B P (e g, u n der g o pre g na nc y testi n g etc, as re q uire d b y t he C S P ).
 
W o me n will  be c o nsi dere d p ost -me n o pa usal if t he y a re a me n orr h oeic f or 1 2 mo nt hs 
wi t ho ut a n al ter nati ve me d ical ca use. T he f oll o wi n g a ge-s pecific re q uire me nts a p pl y:
 
W o me n u n der 5 0 y ears old will  be c o nsidere d p ost -me n o pa usal if t he y ha ve bee n 
a me n orr h oeic f or 1 2 mo nt hs or m ore f o ll owi n g cessati o n o f e x o gen o us h or m o nal  
treat me nts a n d wit h lutei nizi n g h or m o ne a n d f o llicle-sti m ulati n g h or m o ne le vels i n t he 
p ost -me n o pa usal ra n ge.
 
W o me n o ver 5 0 y ears of a ge will be c o nsi dere d p ost -me n o pa usal if t he y ha ve bee n 
a me n orr h oeic f or 1 2 mo nt hs or m ore f o ll owi n g cessati o n of  all e x o ge n o us h or m o nal 
treat me nts.
Acce pt a ble c o ntr ace pti o n met h o ds
Hi g hl y  effecti ve met h o d of birt h c o ntr ol is defi ne d i n N ote 3 i n I C H G ui da nce M 3 
( N o ncli nical Safety St u di es for t he c o n d uct of H u ma n Cli nical trials f or P har mace uticals) as 
o ne t hat res ults i n a l o w fail ure rate (e g, less t ha n 1 perce nt per year) w he n use d c o nsiste ntl y 
a n d c orrectl y.
N ote t hat w o me n s h o ul d ha ve bee n sta ble o n t heir c h ose n met h o d of birt h c o ntr ol f or a 
mi ni m u m o f 2 wee ks bef ore e nteri n g t he st u d y. Ge neric na mes a nd e xa m ples of tra de na mes 
are gi ve n. As tra de na mes ma y  var y, i n vesti gat ors s h o ul d c hec k t he ge neric na me of a n y 
c o ntrace pti o n t o e ns ure s uita bilit y.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 1 9 of 1 5 5
Acce pta ble c o ntrace pti o n met h o ds are:
 
T otal  se x ual a bsti ne nce (a bsti ne nce m ust be f or t he t otal d urati o n of t he st u d y a n d t he 
f oll ow- u p peri o d)
 
Vasect o mise d se x ual part ner pl us male c o n d o m ( wit h patie nt ass ura nce t hat part ner 
recei ve d p ost-vasect o m y c o nfir mat i on of az o os per mia)
 
T u bal occl usi o n pl us m ale c o n d o m
 
I ntra-ut eri ne de vice - pr o vi de d c o ils are c o p per- ba n de d, pl us male c o n d o m
 
I ntra-ut eri ne s yste m - Le v o n or gestrel I ntra Uteri ne S yste m (e g, Mire na), pl us male 
c o n d o m
 
Me dr o x y pr o gester o ne i nject i ons ( De p o -Pr o vera) pl us male c o n d o m
 
Et o n o gestrel i m pla nts (e g, I m pla n o n, N or pla n) pl us male c o n d o m
 
N or m al a n d lo w d ose c o m bi ne d oral c o ntrace pti ve pills, pl us male c o n d o m
 
N orel gestr o mi n / et hi n ylestra di ol tra ns der mal s yste m pl us male c o n d o m
 
I ntra va gi nal de vice (e g et hi n ylestra di ol a n d et o n o gestrel) plus m ale c o n d o m
 
Cerazette ( des o gestrel) pl us male c o n d o m. Cerazette is c urre nt l y t he o nl y hi g hl y 
efficaci o us pr o gester o ne base d pill
U n acce pt a ble c o ntr ace pti o n met h o ds
T he f o ll owi n g m et h o ds are c o nsidere d n ot t o be hi g hl y  effecti ve a n d are t heref ore n ot 
acce pta ble c o ntrace pti ve met h o ds i n Astra Ze neca cli nical st u dies:
 
Tri p h asic c o m bi ne d oral c o ntrace pti ves 
 
All pr o gester o ne o nl y pills e xce pt, Cerazette
 
All barri er met h o ds, if i nte n de d t o be use d al o ne
 
N o n -c o p per c o ntai ni n g i ntra-uteri ne de vices
 
Fertilit y a ware ness met h o ds
 
C oi t us i nterr u pt us

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 0 of 1 5 5
A p pe n di x H
G u i deli nes f or E v al u ati o n of O bjecti ve T u m o ur Res p o nse 
usi n g R E CI S T 1. 1 Criteri a
H 1
I ntr o d ucti o n
T his a p pe n di x details t he i m ple me ntati o n o f R E CI S T 1. 1 g ui deli nes ( Ei se n ha uer et al 2 0 0 9). 
I n vesti gat or assess me nts will use t he R E CI S T 1. 1 g ui deli nes descri be d i n t his A p pe n di x.
H 2
I m a gi n g M o d alities a n d Ac q uisiti o n S pecific ati o ns f or 
R E CI S T 1. 1
A s u m mar y of t he i ma gi n g mo dali ties t hat ca n be use d f or t u mo ur assess me nt of T Ls, N T Ls, 
a n d N Ls is pr o vi de d i n  Ta ble H 1.
Ta ble H 1 
S u m m ar y of I m a gi n g M o d alities f or  Tu m o ur Assess me nt
T ar get lesi o ns
N o n -t ar get lesi o ns
Ne w lesi o ns
C T 
C T 
C T 
M RI
M RI
M RI
Plai n X -ra y 
Plai n X -ra y
C hest X -r a y
C hest X -r a y
B o ne sca n ( Sci nti gra p h y)
F D G -P E T/ C T
C T = C o m p ute d t o m o gra p h y; F D G -P E T/ C T = Fl u or o de o x y gl uc ose -p ositr o n e missi o n t o m o gra p h y/ C T; 
M RI
= Ma g netic res o na nce i ma gi n g.
H 2. 1
C T a n d M RI
C o m p ute d t o m o gra p h y  wit h I V c o ntrast is t he preferre d i ma gi n g m o dality (al t ho u g h M RI wi t h 
I V c o ntrast is acce pta ble if C T is c o ntrai n dicate d) t o ge nerate re pr o d uci ble a nat o mical i ma ges 
f or t u mo ur assess me nts (ie, f or meas ure me nt of T Ls, assess me nt of N T Ls, a n d i de nt ificati on 
of  N Ls). It is esse ntial t hat t he sa me c orrect i ma gi n g m o dalit y,  i ma ge ac q uisiti on para meters 
(e g, a nat o mic c o vera ge, i ma gi n g se q ue nces, etc), i ma gi n g facility,  t u mo ur assess or 
(e g, r a diol o gist), a n d m et h o d of t u mo ur assess me nt (e g, R E C I S T 1. 1) are use d c o nsiste ntl y f or 
eac h patie nt t hr o u g h o ut t he st u d y. T he use of t he sa me sca n ner f or serial sca ns is 
rec o m me n de d, if p ossi ble. It is i m p orta nt t o f oll ow t he i ma ge c ollect i on/t u m o ur assess me nt 
sc he d ule as cl osel y as p ossi ble (refer t o t he So A s; Ta ble 1 a n d Ta ble 2 ), a n d t his o n-st u d y 
i ma gi n g sc he d ule M U S T be f oll owe d re gar dl ess of a n y dela ys i n d osi n g or misse d i ma gi n g 
visit s. If a n u nsc he d ule d assess me nt is perf or me d (e g, t o i n vesti gate cli nical si g ns/s y m pt o ms 
of  pr o gressio n) a n d t he pati e nt has n ot pr o gresse d, e ver y atte m pt s h o ul d be ma de t o perf or m 
t he s u bse q ue nt sca n ac q uisit i ons at t he ne xt sc he d ule d i ma gi n g visit.
D ue t o i ts i n here nt ra pid ac q uisit i on (sec o n ds), C T is t he i ma gi n g m o dalit y of  c h oice. B o d y 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 1 of 1 5 5
sca ns s h o ul d be perf or me d with breat h -h o l d sca n ni n g tec h ni q ues, if p ossi ble. T heref ore, C T of 
t he c hest is rec o m me n de d o ver M RI d ue t o si g nifica nt m oti o n artefacts (e g, heart, maj or bl o o d 
vessels, breat hi n g) ass ociate d wit h M RI. Ma g net ic res o na nce i ma gi n g has e xcelle nt c o ntrast 
a n d s pat ial a n d te m p oral res ol uti ons; h o we ver, t here are ma n y i ma ge ac q uisit i on varia bles 
i n v ol ve d i n M RI, w hic h greatl y i m pact i ma ge q uality,  lesio n  c o ns pic uity,  a n d meas ure me nt. 
F urt her m ore, t he a vaila bilit y of M RI i s varia ble gl o ball y. T he mo dali t y use d at f oll o w- u p 
s h o uld be t he sa me as was use d at baseli ne, a n d t he lesi o ns s h o ul d be meas ur e d/assesse d o n 
t he sa me p ulse se q ue nce. I n ge neral, l ocal o nc ol o g y  dia g n ostic i ma gi n g para meters are 
a p plie d f or sca n ac q uisit i on.  
T he m ost cri tical C T a n d M RI i ma ge ac q uisiti on para m eters f or o pti mal t u m o ur e val uat i on are 
a nat o mic c o vera ge, c o ntrast a d mi nistrati o n, slice t hic k ness, a n d rec o nstr ucti o n i nter val.
a. A n at o mic c o ver a ge: O pti mal a nat o mic c o vera ge f or m ost s oli d t u m o urs is t he 
c hest -a b d o me n (a n d ofte n pel vis). C o vera ge s h o ul d e nc o m pass all areas o f k n o w n pre dilecti o n 
f or metastases i n t he di sease u n der e val uati o n a n d s h o ul d a d diti onall y  in vesti gate areas t hat 
ma y be i n v o l ve d base d o n si g ns a n d s y m pt o ms of i n di vi d ual patie nts. Beca use a lesi o n later 
i de ntifie d i n a b o d y part n ot sca n ne d at baseli ne w o ul d be c o nsi dere d as a ne w lesi on 
re present i n g disease pr o gressi o n, caref ul c o nsi derati o n s h o ul d be gi ve n t o t he e xte nt of 
i ma gi n g c o vera ge at baseli ne a n d at s u bse q ue nt f oll ow- u p ti me p oi nts. T his will e na ble better 
c o nsiste nc y n ot o nl y o f t u mo ur meas ure me nts b ut als o i de nt ificati on of ne w disea se.
Re q ui re d a nat o mical re gi o ns t o be i ma ge d f or assess me nt of t u m o ur b ur de n ( T Ls a n d/ or 
N T Ls) at baseli ne a n d f o ll ow- u p visit s var y acc or di n g t o t he st u d y, a n d t hese ti me p oi nts are 
s pecifie d i n t he S o As (Ta ble 1 a n d Ta ble 2 ). E xa m ples i ncl u de t he f oll o wi n g:
 
I V c o ntrast-e n ha nce d C T of c hest -a b d o me n (i ncl u di n g t he e nt ire li ver a n d b ot h a dre nal 
gl a n ds) ( -pel vis)
 
N o n -c o ntrast C T of c hest a n d I V c o ntrast -e n ha nce d a b d o me n (i ncl u di n g t he e nt ire li ver 
a n d b ot h a dre nal gla n ds) ( -pel vis)
 
I V c o ntrast-e n ha nce d M RI ( preferre d) or C T of t he brai n
F or c hest -a b d o me n ( -pel vis) i ma gi n g, t he f o ll owi n g a re sca n ni n g o pti o ns i n decreasi n g or der 
of  pr efere nce, wit h a d ditio nal o pti o ns ( 2 t o 4) f or c o nsi derati o n w he n patie nts ha ve se nsit i vity 
t o I V c o ntrast or ha ve c om pr o mise d re nal f u nct i on:
1 
C hest -a b d o me n ( -pel vis) C T wit h I V C T c o ntrast ( m ost preferre d)
2 
C hes t C T wit ho ut I V -c o ntrast + a b d o me n ( -pel vis) M RI wit h I V M RI c o ntrast, if C T I V 
c o ntrast (i o di ne base d) is me dicall y c o ntrai n dicate d at a n y t i me d uri n g t he st u d y
3 
C hest -a b d o me n ( -pel vis) C T wit h o ut I V c o ntrast, if b ot h I V C T a n d M RI c o ntrast are 
me dicall y c o ntrai n dicate d or t he patie nt has c o m pr o mise d re nal f u nct i on

Cli nica l St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 2 of 1 5 5
4 
C hest -a b d o me n ( -pel vis) M RI wit h I V M RI c o ntrast, if C T ca n n ot be perf or me d at a n y 
ti me d uri n g t he st u d y
b. I V c o ntr ast a d mi nistr ati o n: O pti mal vis ualisati o n a n d m eas ure me nt of metastases i n s o li d 
t u mo urs re q ui re c o nsiste nt a d mi nistrati o n ( d ose a n d rate) of I V c o ntrast as well as ti mi n g of 
sca n ni n g. A n a de q uate v o l ume of a s uita ble c o ntrast a ge nt s h o ul d be gi ve n s o t hat t he t u m o ur 
lesio ns are de m o nstrate d t o best effect a n d a c o nsiste nt met h o d is use d o n s u bse q ue nt 
e xa mi nat i ons f or a n y  gi ve n patie nt. Oral c o ntrast is rec o m me n de d t o hel p vis ualise a n d 
differe nt iate str uct ures i n t he a b d o me n a n d pel vis. 
c. Slice t hic k ness a n d rec o nstr ucti o n i nter v al: It is rec o m me n de d t hat e xtracra nial C T or 
M RI sc a ns be ac q uire d/rec o nstr ucte d as c o nti g u o us ( n o ga p) slices wit h ≤5- m m t hic k ness 
t hr o u g h o ut t he e ntire a nat o mic re gi o n of i nterest f or o pti mal lesi on me as ure me nts. 
E xce pt i onall y, partic ular i nst itut i ons m a y perf or m me dicall y acce pta ble sca ns at slice 
t hick nesses > 5 m m. If t his occ urs, t he mi ni m u m size of meas ura ble lesi o ns at baseli ne s h o ul d 
be t wi ce t he slice t hic k ness of t he baseli ne sca ns.
F or C T sca ns, all wi n d o w setti n gs s h o ul d be i ncl u de d i n t he assess me nt, partic ularl y i n t he 
t hora x w here l u n g a n d s oft tiss ue wi n d o ws s h o ul d be c o nsi dere d. W he n meas uri n g lesi ons, t he 
T L  s h o uld be m eas ure d o n t he sa me wi n d o w settin g f or re peate d e xa mi nat i ons t hr o u g h o ut t he 
st u d y.  
H 2. 1. 1 
Br ai n M RI
It is be yo n d t he sc o pe of t his a p pe n di x t o prescri be s pecific M RI p ulse se q ue nce para m eters 
f or all sca n ners, b o d y parts, a n d diseases. F or o pti mal brai n sca n ac q uisit i on h o we ver, t he 
rec o m me n de d M RI se q ue nces i ncl u de a T 1-wei g hte d sca n ( ≤1. 5 m m slice t hic k ness) bef ore 
ga d oli ni u m c o ntrast a d mi nistrati o n as well as a n i de nt ical T 1 se q ue nce after c o ntrast 
a d mi nistrati o n. Fl ui d-atte n uatio n i n versi o n -rec o ver y, diff usi on- wei g hte d a n d T 2- wei g hte d 
se q ue nces ca n hel p i n t he i de ntificat i on a n d assess me nt of brai n metastases.
H 2. 2
C hest X -r a ys
C hest X -ra y assess me nts will n ot be use d f or assess me nt of T Ls. C hest X -r a ys ca n, h o we ver, 
be use d t o assess N T Ls a n d t o i de nt if y t he prese nce of N Ls. H o we ver, t here is prefere nce t hat 
a hi g her res ol ut i on m o dalit y,  s uc h as C T, be use d t o c o nfir m t he prese nce of N Ls.
H 2. 3
Pl ai n X -r a y
Pl ai n X-r a y ma y be used as a met h o d of assess me nt f or b o ne N T Ls a n d t o i de nt if y t he 
prese nce of ne w b o ne lesi o ns.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 3 of 1 5 5
H 2. 4
Is ot o pic B o ne Sc a n
B o ne l esio ns i de nt ifie d o n a n is ot o pic b o ne sca n at baseli ne a n d c o nfir me d b y C T, M RI or 
X- r a y at baseli ne s h o ul d be rec or de d as N T Ls a n d f oll owe d b y t he sa me met h o d as per 
baseli ne assess me nt.
Is ot o pic b o ne sca ns ma y be use d as a met h o d of assess me nt t o i de nt if y t he prese nce of ne w 
b o ne lesi o ns at f oll o w -u p visi ts. Ne w lesio ns m a y be rec or de d i n case p osit i ve h ot- s p ots 
a p pear o n a b o ne sca n t hat w ere n ot prese nt o n a pre vi o us b o ne sca n; h o we ver, a ne wl y 
o bser ve d e q ui v ocal h ot -s p ot o n a b o ne sca n t hat ca n n ot be verifie d wit h c orrelat i ve i ma gi n g 
( C T, M RI, or X-ra y) of t he sa me a nat o mical re gi on s hall n ot be t he o nl y tri g ger f or a P D 
assess me nt at t hat ti me p oi nt.
H 2. 5
F D G -P E T
1 8F- Fl u or o de o x y gl uc ose p osi tr o n e missi on t o m o gra p h y/ C T sca ns ma y be use d as a met h o d f or 
i de ntif yi n g N Ls f or R E CI S T 1. 1 assess me nts acc or di n g wit h t he f oll owi n g al g ori t h m: N Ls 
will be rec or de d w here t here is p ositi ve 1 8F- Fl u or o de o x y gl uc ose u pta ke w hi c h is n ot prese nt 
o n t he baseli ne or pri or F D G -P E T sca n or w he n its l ocat i on c orres p o n ds t o N L  o n a 
c o mpa ni o n  C T/ M RI t hat has bee n c ollecte d cl ose i n ti me t o t he F D G-P E T sca n. A p osi tive 
F D G -P E T sca n lesi o n s h o ul d be re p orte d o nl y  w he n a n upta ke (e g, sta n dar dise d u pta ke 
val ues) greater t ha n t wice t hat of t he s urr o u n di n g tiss ue or li ver is o bser ve d. T he P E T p orti o n 
of  t he P E T/ C T i ntr o d uces a d diti onal data t hat ma y bias a n i n vest i gat or if it is n ot r o uti nel y or 
seriall y perf or me d. T heref ore, if t here is n o baseli ne or pri or F D G- P E T sca n a vaila ble f or 
c o mparis o n, a n d n o e vi de nce of N Ls o n c o m pa ni o n C T/ M RI sca ns, t he n f o ll ow- u p C T/ M RI 
assess me nts s h o ul d c o nt i n ue as per t he re g ular i ma gi n g sc he d ule t o verif y t he u ne q ui v ocal 
prese nce of N Ls.
At  prese nt, l o w-d ose or atte n uati o n c orrecti o n C T p orti o ns of a c o m bi ne d F D G -P E T/ C T sca n 
are of li mite d use i n a nat o micall y base d efficac y assess me nts, a n d it is t heref ore s u g geste d 
t hat t he y s h o uld n ot s u bst itute f or de dicate d dia g n ostic c o ntrast -e n ha nce d C T sca ns f or t u m o ur 
meas ure me nts b y  R E CI S T 1. 1. I n e xce pti onal sit u atio ns, if a si te ca n d oc u me nt t hat t he C T 
perf or m e d, as part of a P E T/ C T e xa mi nat i on, i s of i de ntical dia g n ostic q uality ( wit h I V 
c o ntrast) t o a de dicate d dia g n ostic C T sca n, t he n t he C T p orti o n of  t he P E T/ C T ca n be use d 
f or R E CI S T 1. 1 t u m o ur assess me nts. Ca uti o n t hat t his is n ot rec o m me n de d beca use t he P E T 
p orti o n of  t he C T i ntr o d uces a d diti onal ( P E T) data t hat ma y bias a n i n vest i gat or if it is n ot 
r o utinel y or seriall y rec or de d. 
H 2. 6
Ultr as o u n d
Ul tras o u n d e xa mi nati on will n ot be use d f or R E CI S T 1. 1 assess me nt of t u m o urs as it is n ot a 
re pr o d uci ble met h o d ( o perat or de pe n de nt), is s u bjecti ve i n i nter pretati o n, a n d ma y n ot pr o vi de 
a n acc urate assess me nt of t he tr ue t u m o ur size. T u m o urs i de ntifie d b y  ultras o u n d will nee d t o 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 4 of 1 5 5
be assesse d b y  c orr elat i ve C T or M RI a nat o mical sca n.
H 2. 7
Ot her T u m o ur Assess me nts
H 2. 7. 1 
Cli nic al E x a mi n ati o n
Cli nical e xa mi nat i on of s ki n/s urface lesi o ns ( b y  vis ual ins pect i on or ma n ual pal pat i on) will 
n ot be use d f or R E CI S T 1. 1 assess m e nts. T u m o urs i de ntifie d b y cli nical e xa mi nat i on will 
nee d t o be assesse d b y  c orr elat i ve C T or M RI a nat o mical sca ns.
H 2. 7. 2 
E n d osc o p y a n d L a p ar osc o p y
E n d osc o p y  a n d la par osc o p y will n ot be use d f or t u m o ur assess me nts as t he y are n ot vali date d 
i n t he c o nte xt of t u mo ur m eas ure me nts.
H 2. 7. 3   
Hist ol o g y a n d C yt ol o g y
Hi st olo g y  or t u mo ur m ar kers o n t u mo ur bi o ps y  sa m ples will n ot be use d as part of t he t u m o ur 
res p o nse assess me nts per R E CI S T 1. 1. Res ults of c yt ol o gical e xa mi nati on f or t he ne o plastic 
ori gi n o f a n y eff usi o n (e g, asci tes, pericar dial eff usi on, a n d ple ural eff usi o n) t hat a p pears or 
w orse ns d uri n g t he st u d y  will not be use d as part of t he t u m o ur res p o nse assess me nt as per 
R E CI S T 1. 1. F urt her m ore, a n o verall assess me nt of C R (all ot her disease disa p pears/re verts t o 
n or m al) w o uld be c ha n ge d t o P R if a n eff usi o n re mai ns prese nt ra di o l ogi call y.
H 2. 8
Me as ur a bilit y of T u m o ur Lesi o ns at B aseli ne
H 2. 8. 1 
R E CI S T 1. 1 Me as ur a ble Lesi o ns at B aseli ne
A t u mo ur l esio n  t hat ca n be acc uratel y meas ure d at baseli ne as ≥1 0 m m i n t he l o n gest 
di a meter f or n o n- n o dal  lesio n s or ≥1 5 m m i n s h ort a xis dia meter f or l y m p h n o de lesi o ns wit h 
I V c o ntrast-e n ha nce d C T or M RI a n d t hat is s uita ble f or acc urate re peate d meas ure me nts. T he 
s h ort a xis is defi ne d as t he l o n gest i n- pla ne a xis per pe n dic ular t o t he l o n g a xis.
H 2. 8. 2 
N o n -me as ur a ble Lesi o ns at B aseli ne
 
Tr ul y n o n -meas ura ble lesi o ns i ncl u de t he f oll o wi n g:
 
B o ne l esio ns (see e xce pt i on bel o w f or s oft tiss ue c o m p o ne nt)
 
Le pt o m e ni n geal disease
 
Ascites, ple ural eff usi o n, or pericar dial eff usi o n
 
I nfla m mat or y breast disease
 
L y m p ha n git ic i n v ol ve me nt of s ki n or l u n g
 
All ot her lesi o ns, i ncl u di n g s mall lesi o ns, ie, l o n gest dia meter < 1 0 m m or pat h ol o gical 
l y m p h n o des wit h ≥1 0- m m t o < 1 5 -m m s h ort a xis dia meter at baseli ne. Please n ote t hat 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 5 of 1 5 5
l y m p h n o des wit h < 1 0- m m s h ort a xis dia meter are c o nsi dere d n o n-pat h ol o gi cal a n d 
s h o uld n ot be rec or de d or f oll o we d as N T Ls.
 
Pre vi o usl y  irra diate d lesio n s. L ocalise d p ost-ra diati on c ha n ges t hat affect lesi o n size ma y  
occ ur. T heref ore, lesi o ns t hat ha ve bee n pre vi o usl y irra diate d are t y picall y  c o nsi dere d 
n o n -meas ura ble a n d as assesse d as N T L.
 
Brai n metastases s h o ul d be assesse d as N T Ls.
H 2. 8. 3 
S peci al C o nsi der ati o ns Re g ar di n g Lesi o n Me as ur a bilit y at B aseli ne
 
B o ne l esio ns
 
B o ne sca n, P E T sca n, or plai n X -r a y are n ot c o nsidere d a de q uate i ma gi n g tec h ni q ues 
t o me as ure b o ne lesio n s; h o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m t he 
prese nce or disa p peara nce of b o ne lesi o ns.
 
L y tic b o ne lesi o ns or mi xe d l y tic- blastic l esio n s, with i de ntifia ble s oft tiss ue 
c o mp o ne nts, ca n be c o nsi dere d meas ura ble if t he s oft tiss ue c o m p o ne nt m eets t he 
defi nit i on o f meas ura bilit y.  
 
Bl astic lesio n s are c o nsi dere d n o n-meas ura ble.
 
C yst ic lesio n s t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d meas ura ble 
lesio ns if t he y meet t he criteria f or meas ura bilit y fro m  a ra diol o gi cal p oi nt of  vie w, b ut if 
n o n- c yst ic lesi ons are prese nt i n t he sa me pat ient , t hese s h o ul d be selecte d o ver c ystic 
lesio ns as T Ls.
H 2. 8. 4 
R E CI S T 1. 1 T L Selecti o n at B aseli ne
A ma xi m u m o f 5 m eas ura ble lesi o ns, wi t h a ma xi m u m of 2 lesio ns per or ga n (i ncl u di n g 
l y m p h n odes c ollect i vel y c o nsi dere d as a si n gle or ga n), re prese ntati ve of all lesi ons i n v ol ve d, 
s h o uld be i de ntifie d as T Ls at baseli ne. T ar get lesi o ns s h o ul d be selecte d o n t he basis of t heir 
size (lo n gest di a meter f or n o n-n o dal  lesio n s or s h ort a xis f or n o dal lesio n s), b ut i n a d diti on 
s h o uld be t h ose t hat l e n d t he msel ves t o re pr o d uci ble re peate d meas ure me nts. It ma y be t he 
case t hat, o n occasi o n, t he lar gest lesi o n d oes n ot le n d itself t o re pr o d uci ble meas ure me nt, i n 
w hic h circ u msta nce t he ne xt lar gest lesi o n t ha t ca n be meas ure d re pr o d uci bl y, s h o uld be 
selecte d.
Ly m p h n o des, i n a n y l ocat i on (l o c al /re gio n al a nd dista nt), are c ollect i vel y c o nsi dere d as a 
si n gle or ga n, wit h a ma xi m u m of 2 l y m p h n o des as T Ls. A bilateral or ga n (e g, a dre nal gla n ds), 
a se g me nte d or ga n (e g, li ver), or a m ultil obe d or ga n (e g, l u n g) is eac h c o nsi dere d as a si n gle 
or ga n.
T he site a n d l ocat i on of eac h T L  s h o uld be d oc u m e nte d as well as t he l o n gest a xis dia meter 
f or n o n-n o dal  lesio ns ( or s h ort a xi s dia meter f or l y m p h n o des). All meas ure me nts s h o uld be 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 6 of 1 5 5
rec or de d i n w h ole (i nte ger) milli metres a n d calc ulate d val ues s h o ul d be r o u n de d t o w h ole 
n u m bers. At baseli ne, t he s u m of t he dia meters f or all T Ls will be calc ulate d a n d re p orte d as 
t he baseli ne s u m of dia meters. At  foll o w -u p visi ts, t he s u m of dia meters f or all T Ls will be 
calc ulate d a n d re p orte d as t he f oll o w -u p s u m  of dia meters.
S peci al C ases f or  T L Assess me nt at B aseli ne:
 
F or T Ls m eas ura ble i n 2 or 3 di me nsi o ns, al wa ys re p ort t he l o n gest dia meter. F or 
pat h ol o gi cal l y m p h n o des meas ura ble i n 2 or 3 di me nsi o ns, al wa ys re p ort t he s h ort a xis 
di a meter.
 
W he n l y m p h n o des are c oalesce d a n d n o l o n ger se para ble i n a c o n gl o merate mass, t he 
ma xi mal s h ort a xis dia meter of t he c oalesce d mass s h o ul d be rec or de d. N o n -n o dal  lesio n s 
t hat c oalesce s h o uld si milarl y be assesse d b y  t he lo n gest a xis di a meter.
 
T u m o ur lesi o n s selecte d f or fres h scree ni n g bi o ps y or F N A F F P E cell bl oc k s h o uld n ot be 
selecte d as T Ls, u nless i ma gi n g occ urre d at least a p pr o xi matel y 2 wee ks after bi o ps y, 
all o wi n g ti me f or heali n g.
 
If t he C T/ MRI slice t hi c k ness use d is > 5 m m , t he mi ni m u m size of meas ura ble disease at 
baseli ne s h o ul d be t wice t he slice t hic k ness of t he baseli ne sca n.
 
If a lesi on has c o m p letel y disa p peare d, t he l o n gest dia meter s h o ul d be rec or de d as 0 m m. 
If a lesi on a p pears i n t he sa me lo c ati o n o n a s u bse q ue nt sca n, it will be rec or de d as a N L.
H 2. 8. 5   
R E CI S T 1. 1 N T L Selecti o n at B aseli ne
All ot her lesi o ns, i ncl u di n g n o n -meas ura ble lesi o ns a n d s ur pl us meas ura ble lesi o ns, n ot 
rec or de d as T Ls s h o ul d be i de ntifie d as N T Ls at baseli ne. Meas ure me nts of t hese lesi o ns are 
n ot re q uire d, b ut t he prese nce or a bse nce of eac h s h o ul d be n ote d t hr o u g h o ut f oll o w - u p.
H 2. 9
E v al u ati o n of T u m o ur Res p o nse a n d Pr o gressi o n
H 2. 9. 1 
R E CI S T 1. 1 T L A ssess me nt at F oll o w -u p
T his sect i on defi nes t he criteria use d t o deter mi ne o bject i ve t u m o ur visit res p o nse f or 
R E CI S T 1. 1 -defi ne d T Ls. T he i ma gi n g m o dalit y,  locati o n, a n d sca n date of eac h T L  ide nt ifie d 
pre vi o usl y at baseli ne s h o ul d be d oc u me nte d at f o ll ow- u p visit s wit h t he lo n g a xis dia meter 
f or n o n-n o dal  lesio ns or s h ort a xis d iameter f or l y m p h n o de lesi o ns. All meas ure me nts s h o ul d 
be rec or de d i n w h ole milli metres . T he s u m of t he dia meters f or all T Ls at eac h f o ll ow- u p visi t 
will be c o m pare d t o t he baseli ne s u m of dia meters (f or res p o nse or S D) or t o t he s mallest pri or 
( na dir) su m  of dia meters (f or pr o gressi o n).

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 7 of 1 5 5
S peci al C ases f or  T L Assess me nt at F oll o w-u p
 
If a lesi on has c o m p letel y disa p peare d, t he dia meter s h o ul d be rec or de d as 0 m m. If a 
lesio n a p pears i n t he sa me l ocati o n o n a s u bse q ue nt sca n, it will be rec or de d as a n N L.
 
If a T L s plit s i nt o 2 or m ore parts, t he s u m of t he dia meters of t h ose parts s h o ul d be 
rec or de d.
 
If 2 or m ore T Ls mer ge, t he n t he s u m of t he dia meters of t he c o m bi ne d lesi o n s h o ul d be 
rec or de d f or o ne of t he lesi ons a n d 0 m m rec or de d f or t he ot her lesi o n(s). If t he mer ge d 
T Ls are n o n -n o dal  lesio ns, rec or d t he l o n g a xis dia meter of t he mer ge d lesi o n. If 
pat h ol o gi c l y m p h n o des c oalesce a n d are n o l o n ger i n di vi d uall y se para ble wit hi n a 
c o n glo m erate mass, t he ma xi mal s h ort a xis dia meter is rec or de d.
 
If a T L is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult 
val ue of 5 m m s h o ul d be assi g ne d. If a n acc urate meas ure ca n be gi ve n, t his s h o ul d be 
rec or de d, e ve n if it is bel o w 5 m m.
 
If a T L ca n n ot be meas ure d acc uratel y d ue t o it bei n g t o o lar ge, pr o vi de a n esti mate of t he 
size of t he lesi on. T he c h o ice of “ T o o lar ge t o meas ure” i n t he case re p ort f or m will 
trig ger a n o verall visit res p o nse of P D.
 
W he n a T L has ha d a n u nsc he d ule d, n o n -pr ot oc ol  int er ve nt i on, t he f o ll owi n g a p pl y:
 
Tar get l esio n i nter ve ntio n ma y  incl u de ra di ot h era p y, e m b o lisati on, e xcisi o nal bi o ps y , 
s ur ger y, etc, t hat is n ot a part of st u d y int er ve ntio n a n d mi g ht a d versel y affect t he size 
of  t hat T L
 
If a n I nter ve nti on o n a T L is t ic ke d i n t he C R F, t he dia meter of t he lesi on is still 
rec or de d ( 0 m m if n o l o n ger prese nt) a n d i s i nclu de d i n t he s u m  of dia meters. 
 
If a T L I nter ve nti o n is tic ke d, t he i nter ve nti on m u st be re p orte d f or all s u bse q ue nt 
assess me nts of t hat T L. 
 
If a T L has a n I nter ve nti on, t he o nl y  o verall visit res p o nses allo we d t o be rec or de d b y  
t he i n vest i gat or are N E or P D, wit h P D if t he s u m of dia meters e xcee ds a 
2 0 % i ncrease a n d at least a 5 m m a bs o l ute i ncrease i n t he visit s u m o f di a meters 
c o mpare d t o t h e pre vi o us mi ni m u m ( na dir) s u m o f dia meters. 
 
N o visit wit h a rec or de d Tar get lesi o n i nter ve nt i on ca n be use d as t he mi ni m u m 
( na dir) s u m of dia meters.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 8 of 1 5 5
Ta ble H 2 
R E CI S T E v al u ati o n of T a r get Lesi o ns
C o m plete res p o nse ( C R)
Disa p peara nce of all T Ls si nce baseli ne. A n y pat h ol o gical l y m p h n o des selecte d 
as T Ls m ust ha ve a re d ucti o n i n s h ort a xis dia meter t o < 1 0 m m.
Partial res p o nse ( P R)
At least a 3 0 % decrease i n t he s u m of dia meters of T Ls, ta ki n g as refere nce t he 
baseli ne s u m of dia meters.
Sta ble disease ( S D)
Neit her s ufficie nt decrease i n t he s u m of dia meters t o q ualif y f or P R n or s ufficie nt 
i ncrease t o q ualif y f or P D.
Pr o gressi o n of disease 
( P D)
At least a 2 0 % i ncrease i n t he s u m of dia meters o f T Ls, ta ki n g as refere nce t he 
s mallest pre vi o us s u m of dia meters ( na dir)— T his i ncl u des t he baseli ne s u m if t hat 
is t he s mallest o n st u d y. I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust 
de m o nstrate a n a bs ol ute i ncrease of at least 5 m m fr o m na di r.
N ot e val ua ble ( N E)
O nl y rele va nt if a n y of t he T Ls at f oll o w -u p were n ot assesse d or N E (e g missi n g 
a nat o m y) or ha d a lesi o n i nter ve nti o n at t his visit.
N ote: If t he s u m of dia meters meets t he P D criteria, P D o verri des N E as a T L 
res p o nse.
N ot a p plica ble ( N A) 
O nl y rele va nt if n o T Ls prese nt at baseli ne.
C R = C o m plete res p o nse; N A = N ot a p plica ble; N E = N ot e val ua ble; P D = Pr o gr essi o n of disease; P R = Par tial 
res p o nse; 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; S D = Sta ble disease; T L = Ta r get lesi o n.
H 2. 9. 2 
R E CI S T 1. 1 N T L Assess me nt at F oll o w -u p
All ot her lesi o ns ( or sites of disease) n ot rec or de d as T L  s h o uld be i de ntifie d as N T Ls at 
baseli ne. Meas ure me nts are n ot re q uire d f or t hese lesi o ns, b ut t heir stat us s h o ul d be f o ll owe d 
at s u bse q ue nt visits. At  eac h visit a n o verall assess me nt of t he N T L res p o nse s h o ul d be 
rec or de d b y t he i n vesti gat or. 
To  ac hie ve ‘u ne q ui v ocal  pr o gressio n ’ o n t he basis of N T Ls, t here m ust be a n o verall le vel o f 
s u bsta ntial w orse ni n g i n n o n -tar get disease s uc h t hat, e ve n i n prese nce of S D or P R i n T Ls, 
t he o verall t u m o ur b ur de n has i ncrease d s ufficie nt l y t o merit u ne q ui v ocal pr o gressi o n b y 
N T Ls. A m o dest ‘i ncrease’ i n t he size of o ne or m ore N T Ls is us uall y n ot s ufficie nt t o q ualif y 
f or u ne q ui v ocal pr o gressi o n stat us. T he desi g nati on of o verall pr o gressi o n s o lel y o n t he basis
of  c ha n ge i n n o n-tar get disease i n t he face of S D or P R of tar get disease will t heref ore be 
e xtre mel y rare.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 2 9 of 1 5 5
Ta ble H 3 
R E CI S T 1. 1 E v al u ati o n of N o n -t ar get Lesi o ns
C o m plete res p o nse ( C R)
Disa p pea ra nce of all N T Ls si nce baseli ne. All l y m p h n o des m ust be 
n o n- pat h ol o gical i n size ( < 1 0 m m s h ort a xis).
N o n C R/ N o n P D
Persiste nce of 1 or m ore N T Ls.
Pr o gressi ve Disease ( P D)
U n e q ui v ocal pr o gressi o n of e xisti n g N T Ls. Une q ui v ocal pr o gressi o n ma y be 
d ue t o a n i m p orta nt pr o gressi o n i n 1 lesi o n o nl y or i n se veral lesi o ns. I n all cases 
t he pr o gressi o n M U S T be cli nicall y si g nifica nt f or t he p h ysicia n t o c o nsi der 
c ha n gi n g ( or st o p pi n g) t hera p y.
N ot e val ua ble ( N E)
O nl y rele va nt w he n 1 or s o me of t he N T Ls were n o t assesse d a n d, i n t he 
i n vesti gat or's o pi ni o n, t he y are n ot a ble t o pr o vi de a n e val ua ble o verall N T L 
assess me nt at t his visit.
N ote: F or patie nts wit h o ut T Ls at baseli ne, t his is rele va nt if a n y of t he N T Ls 
were n ot assesse d at t his visit a n d t he pr o gressi o n criteria ha ve n ot bee n met.
N ot a p plica ble ( N A) 
O nl y rele va nt if n o N T Ls prese nt at baseli ne.
C R = C o m plete res p o nse; N A = N ot a p plica ble; N E = N ot e val ua ble; N T L = N o n -tar get lesi o n; 
P D = Pr o gr essi o n of disease; 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 L = Tar get lesi o n.
H 2. 9. 3 
R E CI S T 1. 1 N L I de ntific ati o n at F oll o w -u p
Details, i ncl u di n g t he i ma gi n g m o dalit y,  t he date of sca n, a n d t he l ocati o n of a n y N Ls will als o 
be rec or de d i n t he C R F. T he prese nce of o ne or m ore N Ls is assesse d as pr o gressio n. T he 
fi n di n g of a n N L s h o uld be u ne q ui v ocal, ie, n ot attri b uta ble t o differe nces i n sca n ni n g 
tec h ni q ue, c ha n ge i n i ma gi n g m o dality or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her t ha n 
t u mo ur. If a n N L is e q ui v ocal, f or e xa m ple beca use of its s mall size, t he treat me nt a n d t u m o ur 
assess me nts s h o ul d be c o nt i n ue d u ntil t he pre vi o usl y ( pre-e xist i n g) ne w lesi on has bee n 
assesse d as u ne q ui v ocal at a f o ll ow- u p visit, a n d t he n t he pr o gressi o n date s h o ul d be declare d 
usi n g t he date of t he i nit ial sca n w he n t he N L  first a p peare d.
A lesi on i de ntifie d at a f oll ow- u p assess me nt i n a n a nat o mical l ocat i on t hat was n ot sca n ne d at 
baseli ne is c o nsi dere d a n N L  a n d will in dicate P D.
H 2. 9. 4 
R E CI S T 1. 1 E v al u ati o n of O ver all Visit Res p o nse at F oll o w -u p
Deri vat i on of o verall visit res p o nse as a res ult of t he c o m bi ne d assess me nt of T Ls, N T Ls, a n d 
N Ls uses t he al g orit h m s h o w n i n  Ta ble H 4.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 0 of 1 5 5
Ta ble H 4 
R E CI S T 1. 1 O ver all Visit Res p o nse
T ar get lesi o ns 
N o n -t ar get lesi o ns
Ne w lesi o ns 
O ver all visit res p o nse
C R
C R
N o
C R
C R
N A
N o
C R
C R
N o n -C R/ N o n -P D
N o
P R
C R
N E
N o
P R
P R
N o n -P D or N E or N A
N o
P R
S D
N o n -P D or N E or N A
N o
S D
N E
N o n -P D or N E
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D
N ote: A n o verall assess me nt of C R (all ot her disease disa p pears/re verts t o n or mal) w o ul d be c ha n ge d t o P R if 
ascites re mai ns prese nt ra di ol o gicall y.
C R = C o m plete res p o nse; N A = N ot a p plica ble ( o nl y rele va nt if t here were n o n o n -tar get lesi o ns at baseli ne, 
h o we ver at least o ne tar get lesi o n is a n e ntr y crite ri o n f or t he st u d y); N E = N ot e val ua ble; P D = Pr o gressi o n of 
disease; P R = Par tial res p o nse; 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; S D = Sta ble disease.
T he f o ll owi n g o verall visit res p o nses are p ossi ble de pe n di n g o n t he e xte nt of t u m o ur disease 
at baseli ne:
 
F or pati e nts wit h T Ls (at baseli ne): C R, P R, S D, P D, or N E
 
F or pati e nts wit h N T Ls o nl y (at baseli ne): C R, N o n-C R/ N o n -P D, P D, or N E
 
F or pati e nts wit h n o disease at baseli ne: N E D (a vaila ble as a n o pti o n i n t he e C R F), P D, or 
N E
H 2. 9. 5 
Ce ntr al I m a gi n g
I ma ges, i ncl u di n g u nsc he d ule d visit sca ns, will be c ollecte d o n a n o n g oi n g basis a n d se nt t o a n 
Astra Ze neca -a p p oi nte d i ma gi n g C R O f or q ualit y c o ntr ol , st ora ge, a n d f or BI C R. G ui deli nes 
f or i ma ge ac q uisiti on, de- i de ntificati on, st ora ge of di gital c o pi es at t he i n vest i gati ve site (as 
s o urce d oc u me nts), a n d tra nsfer t o t he i ma gi n g C R O will be pr o vi de d i n a se parate d oc u me nt. 
Electr o nic i ma ge tra nsfer fr o m t he sites t o t he i ma gi n g C R O is str o n gl y e nc o ura ge d. A BI C R 
of  ima ges will be perf or me d at t he dis cretio n of  Astra Ze neca. Res ults of t hese i n de pe n de nt 
re vie ws will n ot be c o m m u nicate d t o i n vesti gat ors, a n d res ults of i n vesti gat or R E CI S T 1. 1 
assess me nts will n ot be s hare d wit h t he ce ntral re vie wers. T he ma na ge me nt of patie nts will be 
base d i n part u p o n t he res ults of t he R E CI S T 1. 1 assess me nt c o n d ucte d b y t he i n vesti gat or. 
F urt her details of t he BI C R will be d oc u me nte d i n t he I n de pe n de nt Re vie w C harter .

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 1 of 1 5 5
H 3
Refere nces
Eise n h a uer et al 2 0 0 9
Eise n ha uer E A, T herasse P , B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, et al. Ne w res p o nse 
e val uat i on cri t eria i n s oli d t u mo urs: re vi se d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer . 
2 0 0 9; 4 5( 2): 2 2 8 - 4 7.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 2 of 1 5 5
A p pe n di x I
D ose M o dific ati o ns f or t he M a n a ge me nt of A d verse E ve nts
I 1
M a n a ge me nt of St u d y Tre at m e nt-rel ate d T o xicities
T he patie nt will be c o nt i n u o usl y e val uate d f or A Es d uri n g t he st u d y . A Es are t o be assesse d 
acc or di n g t o t he N CI C T C A E Versio n 5. 0. T he i n vesti gat or s h o ul d attri b ute t he A E t o a 
s pecific dr u g or t o t he c o m bi nat i on if it is n ot p ossi ble t o assi g n t he A E t o a s pecific st u d y  
i nter ve nt i on . T his is t o g ui de d ose m o dificati o ns t hat ma y lea d t o a treat me nt h ol d, d ose 
re d uctio n a n d/ or disc o nt i n uati on of a s pecific st u d y i nter ve nt i on . If t here are mul tiple or 
o verl a p pi n g t o xicities or w here t he relat i ons hi p is n ot clear, t he i n vesti gat or s h o ul d c o ns ult 
wi t h t he Astra Ze neca St u d y  Tea m.
D ose m o dificat i on g ui deli nes f or t o xi cities relate d t o osi merti ni b a n d sa v o liti ni b are s h o w n i n 
Ta ble I 1 a n d t o xicit ies t hat re q uire per ma ne nt disc o nti n uat i on of st u d y  treat me nt are s h o w n i n 
Ta ble I 2.
Ta ble I1 
St u d y T re at me nt D ose M o dific ati o n I nstr ucti o ns f or To xicities Rel ate d t o 
Osi merti ni b a n d/ or  Sa v oliti ni b (e xcl u di n g t o xicities t h at re q uire s pecific 
m a n a ge me nt g ui deli nes)
C T C A E Gr a de
a
I nstr ucti o ns f or osi merti ni b 
I nstr ucti o ns for s a v oliti ni b
Gr a de 2 or l o wer
C o nti n ue a n d treat wit h s u p p orti ve 
meas ures (as per l ocal practice)
C o nti n ue a n d treat wit h s u p p orti ve 
meas ures (as per l ocal practice)
Gr a de 3
Wit h h ol d osi merti ni b f or u p t o 
3 wee ks
If t he A E i m pr o ves t o ≤Gra de 2 
after wit h h ol di n g of osi merti ni b 
f or u p t o 3 wee ks, osi merti ni b ma y 
be restarte d at t he sa me d ose 
 or a l o wer d ose   
.
If t he A E d oes n ot i m pr o ve t o 
≤Gra de 2 after wit h h ol di n g f or u p 
t o 3 wee ks, per ma ne ntl y 
disc o nti n ue osi merti ni b.
See als o t o xicit y s pecific 
g ui da nce.
Wit h h ol d sa v oliti ni b
Sa v oliti ni b ma y be restarte d at t he 
sa me d ose or c o nsi der a d ose 
re d ucti on u p o n rec o ver y of t he A E 
t o ≤Gr a de 2 wit hi n 7 da ys b
Sa v oliti ni b s h o ul d be per ma ne ntl y 
disc o nti n ue d if t he A E d oes n ot 
rec o ver t o ≤Gra de 2 wit hi n 7 da ys.
If t his is a rec urre nce of t he sa me 
Gra de 3 t o xicit y, res u me d osi n g at 
o ne re d uce d d ose le vel ( ma xi m u m 
of 2 d ose re d ucti o ns) as cli nicall y 
a p pr o priate u p o n rec o ver y of t he 
A E t o ≤Gra de 2 wit hi n 7 da ys b
Gr a de 4
Per ma ne ntl y disc o nti n ue i f relate d 
t o osi merti ni b.
Wit h h ol d sa v oliti ni b a n d disc uss 
wit h t he Astra Ze neca St u d y Tea m. 
C o nti n uati o n of sa v oliti ni b 
de pe n ds o n w het her t he A E is 
re versi ble or ma na gea ble wit h a 
d ose re d ucti o n. If it is n ot 
e x pecte d t hat t he A E is 
ma na gea ble or re vers i ble wit h a 
d ose re d ucti o n, disc o nti n ue 
sa v oliti ni b.
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 3 of 1 5 5
C T C A E Gr a de
a
I nstr ucti o ns f or osi merti ni b 
I nstr ucti o ns for s a v oliti ni b
If t his is a rec urre nce of t he sa me 
Gra de 4 t o xicit y, per ma ne ntl y 
disc o nti n ue sa v oliti ni b.
a
A Es nee d t o be assesse d acc or di n g t o t he N CI C T C A E Versi o n 5. 0.
b
Res u m pti o n of sa v oliti ni b m ust f oll o w t he s pecific restart g ui deli nes if t he e ve nt is a c o nstellati o n of 
p y re xia, s ki n reacti o ns, m yal gia, art hral gia or h y perse nsiti vit y, see Secti o n I 3. 3
N ote: F or i nstr ucti o ns re gar di n g a n y A E t hat re q uires per ma ne nt disc o nti n uati o n see  Ta ble I 2. F or i nstr ucti o ns o n 
d ose re d ucti o n f or osi merti ni b, see  Ta ble I 4; f or i nstr ucti o ns o n d ose re d ucti o ns for  sa v oliti ni b, see Ta ble I 5. If 
t he st u d y i nter ve nti on has bee n re d uce d t o t he l o west d ose le vel i n t he pr ot oc ol, t he patie nt will be per ma ne ntl y 
disc o nti n ue d fr o m t he st u d y i nt er ve nti o n.
A E = A d verse e ve nt; C T C A E = C o m m o n Tec h n ol o g y Criteria f or A d verse E ve nts; N CI = Nati o nal Ca ncer 
I nstit ute.
Ta ble I 2 
To xicities t h at Re q uir e Per m a ne nt Disc o nti n u ati o n of St u d y T re at me nt
T o xicit y
I nstr ucti o ns f or osi merti ni b 
I nstr ucti o ns f or s a v oliti ni b
P ul m o n ar y:
I nterstitial l u n g disease or 
p ne u m o nitis
Per ma ne ntl y disc o nti n ue 
osi merti ni b
N ot a p plica ble
C ar di o v asc ul ar:
Q Tc i nter val pr ol o n gati o n wit h 
si g ns/s y m pt o ms of seri o us 
arr yt h mia
S y m pt o matic c o n gesti ve heart 
fail ure
Per ma ne ntl y disc o nti n ue 
Osi merti ni b
Per ma ne ntl y disc o nti n ue 
osi merti ni b
Per ma ne ntl y disc o nti n ue 
sa v oliti ni b
N ot a p plica ble
He p atic
N ot a p plica ble
See Secti o n  I 3. 2 f or dr u g-relate d 
he pat ot o xicit y meeti n g t he criteria 
f or disc o nti n uati o n
Der m at ol o gic al
Wit h h ol d osi merti ni b f or 
s us pecte d cases of SJ S or E M M. 
Per ma ne ntl y disc o nti n u e 
osi merti ni b f or c o nfir me d cases of 
SJ S or E M M.
Disc o nti n ue i n t he case of 
c o nfir me d or s us pecte d SJ S
Ac ute h y perse nsiti vit y
N ot a p plica ble
Disc o nti n ue i n t he case of ac ute
h y perse nsiti vit y
E M M = Er y t he ma M ultif or me Maj or; Q Tc = c orrecte d Q T i nter val; SJ S = Ste ve ns -J o h ns o n s y n dr o me.
Pati e nts e x perie nci n g I L D will n ot be per mitte d t o restart osi merti ni b. Patie nts e x perie nci n g 
Q T c pr ol o n gati o n wit h si g ns/s y m pt o ms o f serio us arr h yt h mia will  not be per mi tte d t o restart 
st u d y tr e at me nt.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 4 of 1 5 5
I 1. 1
G ui deli nes f or t he M a n a ge me nt of O verl a p pi n g T o xicities Bet wee n 
Osi m erti ni b a n d S a v oliti ni b
Q T c Pr ol o n gat i on
Q T c pr ol o n gati o n is a rec o g nise d t o xicit y of osi merti ni b a n d sa v o liti ni b; ma na ge me nt of t his 
t o xicit y is s u m marise d i n Ta ble I 3.
Ta ble I3 
M a n a ge me nt of Q T c Prol o n g ati o n
C T C A E Gr a de 
I nstr ucti o ns f or 
osi merti ni b
I nstr ucti o ns f or 
s a v oliti ni b
F urt her i n vesti g ati o n 
re q uire d
C T C A E Gr a de 1 or 
Gr a de 2
N o acti o n re q uire d   
N o acti o n re q uire d 
Re vie w c o nc o mita nt 
treat me nts a n d 
c o-m or bi dities f or ris ks 
of Q T pr ol o n gati o n or 
ris k f or T d P a
C T C A E Gr a de 3
( Q Tc i nter val > 5 0 0 msec 
or  > 6 0 msec c ha n ge fr o m 
baseli ne o n at least 2 
se parate E C Gs)
Wit h h ol d osi merti ni b 
u ntil Q Tc F i nter val is 
< 4 8 1 msec, or has 
rec o vere d t o baseli ne if 
baseli ne Q Tc was 
> 4 8 1 msec, wit hi n 
2 1 da ys of i nterr u pti o n.
T he n restart osi merti ni b 
at a re d uce d d ose   
 
 at t he 
discre ti on of t he 
i n vesti gat or, t o all o w 
f or sit uati o ns w here 
ca usalit y i n relati o n t o 
osi merti ni b ma y be 
diffic ult t o deter mi ne.
Wit h h ol d sa v oliti ni b 
u ntil Q Tc F i nter val is 
< 4 8 1 msec. If t he Q Tc F 
res ol ves t o < 4 8 1 msec i n 
2 1 da ys, restart 
sa v oliti ni b at a re duce d 
d ose.
Re vie w c o nc o mita nt 
treat me nts a n d 
c o-m or bi dities f or ris ks 
of Q T pr ol o n gati o n or 
ris k f or T d P a
C o ns ult wit h car di ol o gist 
t o vali date E C G fi n di n g. 
E ns ure car diac 
s ur veilla nce a n d ta ke 
acti o ns i n acc or da nce 
wit h cli nical sta n dar ds. 
Re g ular E C Gs perf or me d 
u ntil res ol uti o n t o Q Tc F 
< 4 8 1 msec.
If t he Q Tc F d oes n ot 
res ol ve t o < 4 8 1 msec 
i n 2 1 da ys, disc o nti n ue 
osi merti ni b.
If t he Q Tc F d oes n ot 
res ol ve t o < 4 8 1 msec i n 
2 1 da ys, disc o nti n ue 
sa v oliti ni b.
C o ns ult wit h a 
car di ol o gist f or f urt her 
ma na ge m e n t as cli nicall y 
i n dicate d.
C T C A E Gr a de 4
( T d P; p ol y m or p hic 
ve ntric ular tac h ycar dia; 
si g ns a n d s y m pt o ms of 
seri o us arr h yt h mia)
Disc o nti n ue 
osi merti ni b
Disc o nti n ue sa v oliti ni b 
C o ns ult wit h a 
car di ol o gist f or f urt her 
ma na ge me nt as cli nicall y 
i n dicate d.
a
F or g ui da nce re gar di n g p ote ntial i nteracti o ns wit h c o nc o mita nt me dicati o ns k n o w n t o pr ol o n g t he 
Q T i nter val, see Secti o n J 5.
C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; E C G = Electr ocar di o gra m; Q Tc = c orrecte d Q T 
i nter val; Q Tc F = Q T i nter val calc ulate d usi n g Fri dericia’s c orrecti o n; T d P = T o rsa des de P oi ntes.
I n li g ht of t he p ote ntial f or Q T c ha n ges ass ociate d wit h osi merti ni b, a n d i n accor da nce wi t h 
G C P , it is rec o m me n de d t hat c orrecti o n of cli nicall y si g nifica nt electr ol yte a b n or malities 
( h y p o kalae mia, h y p o ma g nesae mia, h y p ocalcae mia) t o wit hi n n or mal ra n ges ta kes place pri or 
t o first d ose a n d is m o nit ore d d uri n g treat me nt wit h osi merti nib.
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 5 of 1 5 5
T he Q T c i nter val pr o l on gat i on p ote ntial of sa v o liti ni b 6 0 0 m g was assesse d i n a t h or o u g h 
Q T stu d y i n heal t hy v o l unt eers. A nal ysis o f t he data s h o we d t hat it was a p osit i ve st u d y, as t he 
u p per b o u n ds of t he 2- side d 9 0 % CI f or t he m ea n Δ Δ Q T c F were u p t o 1 3. 6 msec a n d 1 4 msec, 
at 4 h o urs a n d 5 h o urs, res pecti vel y. Q Tc F will be assesse d fre q ue ntl y o n tri plicate E C G 
assess me nts perf or me d at re g ular i nter vals t hr o u g h o ut t he st u d y  acc or di n g t o t he S o A.
Er y t he ma M ultifor m e a n d Ste ve ns-J o h ns o n S y n dr o me
Case re p or ts of E M (i ncl u di n g Er yt he ma M ultif or me Major [ E M M]) a n d SJ S ha ve bee n 
u nc o m m o nl y  a nd rarel y  re p orte d, res pecti vel y, i n ass ociat i on wi t h osi merti ni b treat me nt. 
Bef ore i nit iati n g treat me nt, patie nts s h o ul d be a d vise d of si g ns a n d s y m pt o ms of E M/ E M M 
a n d SJ S. If si g ns a n d s y m pt o ms s u g gesti ve of E M/ E M M de vel o p, cl ose patie nt m o nit ori n g 
a n d dr u g i nterr u pti o n or disc o nt i n uati on of osi merti ni b s h o ul d be c o nsi dere d. If si g ns a n d 
s y m pt o ms s u g gesti ve of SJ S a p pear, osi merti ni b s h o ul d be i nterr u pte d or disc o nti n ue d 
i mme diatel y . 
A case of SJ S has bee n re p orte d i n te m p oral ass ociati o n wit h sa v o liti ni b. Patient s w h o s h o w 
s y m pt o ms or si g ns s u g gesti n g e mer gi n g SJ S w hile o n st u d y treat me nt (e g, pr o gressi ve s ki n 
ras h ofte n wit h blisters or m uc osal lesi ons) m ust disc o nti n ue s a v o liti ni b i m me diatel y a n d 
recei ve a p pr o priate treat me nt. If e mer gi n g SJ S is s us pecte d, re-c halle n ge wit h sa v o liti ni b m ust 
be a v o i de d.
I 2
Osi merti ni b D ose M o dific ati o n a n d G ui d a nce
Osi mert i ni b ma na ge me nt s h o ul d be i n acc or da nce wit h t he l ocal la bel i n t he fir st i nsta nce.
If a patie nt e x perie nces a C T C A E Gra de 3 a n d/ or u nacce pta ble t o xicity (e xcl u di n g I L D, Q T c 
pr ol o n gati o n, kerati tis, a n d E M M/ SJ S) i ncl u di n g a D L T n ot attri b uta ble t o t he disease or 
di sease-relate d pr ocesses u n der i n vesti gati on, d osi n g will be i n terr u pte d a n d s u p p orti ve 
t hera p y a d mi nistere d as re q uire d i n acc or da nce with l ocal practice/ g ui deli nes.
If a t o xicity (e xcl u di n g I L D, Q T c pr olo n gat i on, keratit is, a n d E M M/ SJ S) res ol ves or re verts t o 
≤ C T C A E Gra de 2 wit hi n 3 wee ks of o nset, treat me nt wit h o si merti ni b ma y be restarte d at t he 
sa me d ose   
 or a l o wer d ose   
 usi n g t he r ules bel o w f or d ose m o dificati o ns 
(Ta ble I 4) a n d wit h disc ussio n  a n d a gree me nt wit h t he Astra Ze neca St u d y  Tea m P h ysicia n as 
nee de d. T here will be n o i n di vi d ual m o dificat i ons t o d ose re gi me n i n res p o nse t o t o xicity,  o nl y 
p ote nti al d ose re d uctio n or d ose i nterr u pti o n. 
If t he t o xicity (e xcl u di n g I L D, Q T c pr olo n gati o n, kerati tis, a n d E M M/ SJ S) d oes n ot res ol ve t o 
≤ C T C A E Gra de 2 after 3 wee ks of wit h h o l di n g osi merti ni b, t he n t he patie nt s h o ul d be 
wi t hdra w n fr o m  t he st u d y a n d o bser ve d u ntil res ol uti o n of t he t o xicity (Ta ble I1 ).
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 6 of 1 5 5
Ta ble I 4 
D ose Re d ucti o n f or  Osi merti ni b t o M a n a ge A d verse E ve nts
St arti n g osi merti ni b d ose 
Re d uce d d ose - 1
O n res ol uti on of t o xicit y wi t hi n 3 wee ks:
 
If a n A E s u bse q ue ntl y re q uires d ose i nterr u pti o n, osi merti ni b ma y restart at t he sa me d ose 
or t he re d uce d d ose, o n res ol uti o n/i m pr o ve me nt of t he A E at t he discret i on of t he 
i n vesti gat or.  
I 2. 1
I L D/ P ne u m o nitis-li ke T o xicit y
If ne w or w orse ni n g p ul m o nar y s y m pt o m s (e g, d ys p n oea) or ra di o l ogi c al a b n or malit y 
s u g gesti ve of I L D is o bser ve d, a n i nterr u pti o n i n osi merti ni b d osi n g is rec om me n de d, a n d t he 
Astra Ze neca st u d y  t e a m s h o uld be i nf or m e d. It is str o n gl y rec o m me n de d t o perf o r m a full  
di a g n ostic w or k u p, t o e xcl u de alter nat i ve ca uses s uc h as l y m p ha n gitic carci n omat osi s, 
i nfecti on, aller g y, car dio ge nic oe de m a or p ul mo n ar y h a e morr ha ge. T he res ults of f ull 
di a g n ostic w or k u p (i ncl u di n g hi g h res ol ut i on C T, bl o o d a n d s p ut u m c ult ure, hae mat ol o gical 
para m eters) will be ca pt ure d b y e C R F. All i ma ge data s h o ul d be pr o vi de d t o Astra Ze neca. I n 
t he prese nce o f c o nfir mat or y hig h res ol ut i on C T sca ns w here ot her ca uses of res pirat or y 
s y m pt o ms ha ve bee n e xcl u de d, a dia g n osis of I L D s h o ul d be c o nsi dere d a n d osi merti ni b 
p er m a ne nt l y disc o nti n ue d.
I 2. 2
Ker atitis
Pati e nts prese nt i n g wit h si g ns a n d s y m pt o ms s u g gesti ve of keratitis s uc h as ac ute or 
w orse ni n g: e ye i nfla m mat i on, l acri mat i on, li g ht se nsit i vity,  bl urre d visi on, e y e pai n a n d/ or re d 
e ye s h o uld be r eferre d pr o mptl y t o a n o p ht hal m o l og y  s pecialist.
I 2. 3
C h a n ges i n C ar di ac C o ntr actilit y
Base d o n t he a vaila ble cli nical st u d y  data, a ca usal relati ons hi p bet wee n effects o n c ha n ges i n 
car diac c o ntractilit y a n d osi merti ni b has n ot bee n esta blis he d. I n patie nts wi t h car diac ris k 
fact ors a n d t h ose wit h c o n diti ons t hat ca n affect LV E F , car diac mo ni t ori n g, i ncl u di n g a n 
assess me nt of LV E F at baseli ne a n d d uri n g treat me nt, s h o ul d be c o nsi dere d. I n patie nts w h o 
de vel o p rele va nt car diac si g ns/s y m pt o ms d uri n g treat me nt, ca r dia c mo ni t ori n g i ncl u di n g 
L V E F assess me nt s h o ul d be c o nsi dere d.
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 7 of 1 5 5
I 3
S a v oliti ni b D ose M o dific ati o n a n d G ui d a nce
I 3. 1
S a v oliti ni b D ose M o dific ati o n a n d G ui d a nce
S u bsta nt ial ac ute t o xicities s h o uld be ma na ge d as me dicall y i n dicate d a n d wit h te m p orar y  
s us pe nsi o n of sav o liti ni b, as a p pr o priate u nless d ue t o s us pecte d h yperse nsi tivit y (see 
Secti o n I 3. 3 ). 
D ose re d ucti o ns or h ol ds are all o we d as cli nicall y i n dicate d b y  t he treati n g p h ysicia n a n d i n 
li ne wit h Ta ble I 5 a n d Ta ble I 1. F or eac h patie nt, a ma xi m u m of 2 d ose re d ucti o ns of 
sa v oliti ni b will be all owe d. N o d ose re -escalat i ons are all o we d. G ui da nce o n d ose le vel 
re d uctio n is prese nte d i n  Ta ble I 5.
Ta ble I5 
D ose Re d ucti o n f or  S a v oliti ni b A d verse E ve nts
St arti n g s a v oliti ni b d ose 
Re d uce d d ose - 1
 
Re d uce d d ose - 2
N ote: O nl y 2 d ose re d ucti o ns of sa v oliti ni b are per mitte d.
I 3. 2
He p at ot o xicit y M a n a ge me nt G ui deli ne
 
Pr o m pt l y e val uate patie nts wit h ele vate d L F Ts d uri n g treat me nt wit h sa v oliti ni b f or 
alter nati ve aet i ol ogies a n d P H L criteria, a n d disc o nti n ue p ote ntial c o ntri b uti n g 
c o nc o mita nt me dicat i ons or alter nat i ve ca usal a ge nts, as well as a nt i-c oa g ula nts, if 
a p pr o priate.
 
E ns ure a P K sa m ple is c ollecte d as s o o n as feasi ble w he n t he patie nt disc o nt i n ues d ue t o 
a n A E reacti o n (see  Ta ble 1 , Ta ble 2 a n d Sectio n 8. 5 ). 
 
If a patie nt disc o nti n ues d ue t o L F T a b n or malit y, L F T mo ni t orin g s h o ul d c o nt i n ue u ntil 
res ol ve d t o Gra de 1 or baseli ne or a n a p pare nt platea u has bee n reac he d.
I 3. 2. 1 
D ose M o dific ati o n D ue t o Dr u g -rel ate d He p at ot o xicit y
 
Di sc o nti n ue dr u g if:
 
A L T or A S T > 8 × U L N wit h T B L ele vati o n a b o ve baseli ne or U L N, o r
 
A L T or A S T > 5 × U L N f or u p t o o ne wee k ( < 7 da ys) wit h T B L ele vati o n a b o ve 
baseli ne or U L N, f o ll owi n g i m me diate wi t hh o l di n g of dr u g. Re peat L F T testi n g 
wi t hi n 2 t o 3 da ys a n d at least t wice a wee k u ntil i m pr o ve me nt t o Gra de 1 or 
baseli ne.
 
A L T or A S T > 3 × U L N a n d ( T B L > 2 × U L N or I N R > 1. 5 if n ot o n a ntic oa g ula nts 
t hat ele vate t he I N R), or
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 8 of 1 5 5
 
A S T or A L T > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia > 5 %
 
Wit h h o l d d osi n g if AL T or A S T > 5 × U L N f or > 2 wee ks or 8 × U L N wit h o ut T B L 
ele vat i on a b o ve baseli ne or U L N, re peat L F T testi n g t wice a wee k f or o ne wee k: 
 
If i m pr o ve d t o Gra de 1 or baseli ne i n o ne wee k, res u me at re d uce d d ose wit h L F T 
testi n g t wice a wee k f or 6 wee ks
 
If n ot, di sc o nti n ue
 
Wit h h o l d d osi n g if A L T or A S T > 3 × U L N a n d c o nc urre nt T B L > 1. 5 × U L N, re peat 
L F T testi n g t wice a wee k f or o ne wee k:
 
If b ot h A L T/ A S T a n d T B L i m pr o ve d t o Gra de 1 or baseli ne i n o ne wee k, res u me at 
re d uce d d ose wit h L F T testi n g t wice a wee k f or 6 wee ks
 
If n ot, di sc o nti n ue
 
Wit h h o l d d osi n g if A L T or A S T > 3 × U L N a n d c o nc urre nt T B L > 1 × U L N t o 1. 5 × 
U L N, re peat L F T testi n g t wice a wee k f or o ne wee k,
 
If b ot h A L T/ A S T a n d T B L i m pr o ve d t o n or mal ra n ge ( < Gra de 1) or baseli ne i n 
o ne wee k, res u me a t sa me d ose wit h L F T testi n g t wice a wee k f or 6 wee ks
 
If n ot, res u me at re d uce d d ose 
 
C o nti n ue d osi n g if A L T or A S T > 3 × U L N wit h o ut T B L ele vat i on a b o ve baseli ne or 
U L N, re peat L F T testi n g e ver y  wee k
 
If A L T or A S T tre n di n g u p war d, wit h h o l d d osi n g a n d re peat L F T t wice a wee k f or 
o ne wee k
 
If i m pr o ve t o Gra de 1 or baseli ne i n o ne wee k, res u me at sa me d ose wit h L F T testi n g 
e ver y wee k f or 6 wee ks
 
If i m pr o ve t o Gra de 1 or baseli ne i n 2 wee ks, res u me at re d uce d d ose wit h L F T 
testi n g e ver y w e e k for 6 wee ks
 
If n ot, disc o nt i n ue
 
Di sc o nti n ue f or rec urre nt A L T or A S T > 5 × U L N
 
Di sc o nti n ue f or rec urre nt A L T or A S T > 3 × U L N a n d T B L > 1. 5 × U L N
 
Wit h h o l d d osi n g f or rec urre nt A L T or A S T > 3 × U L N wit h o ut T B L ele vati on a b o ve 
baseli ne or U L N, re peat L F T testi n g t wice a wee k f or o ne wee k
 
If i m pr o ve t o Gra de 1 or baseli ne i n o ne wee k, res u me at re d uce d d ose wit h L F T 
testi n g e ver y w e e k for 6 wee ks; if n ot, disc o nt i n ue

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 3 9 of 1 5 5
I 3. 3
G ui d a nce f or M a n a ge me nt of S a v oliti ni b S pecific T o xicities
H y perse nsiti vit y: H y perse nsit i vity,  w hic h ma y ma nifest as a c o nstellati on of s y m pt o ms s uc h 
as b ut n ot li mit e d t o p yre xia, aller gic s ki n reacti on, i ncrease d li ver e nz y mes, c y t o pe nia, or 
m yal gia a n d/ or art hral gia has bee n re p orte d after sa v o liti ni b d osi n g. T hese reacti o ns ha ve 
occ urre d wit hi n da ys t o wee ks aft er t he first d ose b ut t he maj orit y of  reacti ons ha ve occ urre d 
i n t he first si x wee ks of t hera p y. P atie nts wit h s us pecte d sa v oliti ni b-relate d h yperse nsi tivi t y 
(e xcl u di n g c o nfir me d i nfecti ve aeti ol og y ), ma y be ma na ge d wit h c orti c oster oids, 
a nt i hista mi nes a n d a nt i pyret ics ( d oses a n d d urati o n of treat me nt acc or di n g t o l ocal practice at 
t he discret i on of t he i n vest i gat or). D ose i nterr u pti o n wit h sa v oliti ni b s h o uld be a v o i de d, if 
p ossi ble. S o me patie nts w h o e x perie nce d t he i nit ial h y perse nsit i vity reacti on als o r e p orte d 
se vere ac ute h yperse nsi tivi t y reacti ons, i ncl u di n g a na p h yla xis, u p o n restarti n g sa v o liti ni b 
treat me nt fol l owi n g a s h ort peri o d of i nterr u pti o n.
Rest arti n g s a v oliti ni b: ac ute h yperse nsi tivit y i ncl u di n g a na p h yla xis has bee n o bser ve d i n a 
n u m ber of pa tie nts mostl y u p o n sa v oliti ni b restart. If i nterr u pti o n of sa v o liti ni b occ urs i n t he 
first 6 wee ks of sa v oliti ni b d ue t o sa v oliti ni b-relate d ge neral t o xicities, or s pecific 
h y perse nsit i vity t o xi cities occ ur at a n y ti me, d osi n g wit h sa v oliti ni b may be res u m e d b ut at a 
re d uce d d ose, o nl y after c o ns ultati o n with a n d a p pr o val fr o m t he st u d y  p h ysicia n a n d wit h t he 
f oll owi n g ma na ge me nt:
 
Treat me nt:
 
Pre -treat me nt wit h s yste mic c ortic oster oi ds m ust be starte d at least 2 4 h o urs bef ore 
t he restart of sa v o liti ni b; 
 
Pre -treat me nt wit h a nti pyretics a n d a nti hista mi nes o n t he da y  of restart of sa v oliti ni b; 
 
D oses of a nt i hista mi nes, c ortic oster oi ds a n d a nti pyreti cs s h o uld be acc or di n g t o 
la belli n g i nstr ucti o ns/ pr o d uct i nf or mati on. 
 
T hese me dicat i ons m ust be c o nti n ue d dail y u nt il disc o nti n uati o n of sa v oliti ni b, b ut 
d oses of ster oi ds ma y  s u bse q ue ntl y be ta pere d acc or di n g t o l ocal practice
 
I nte nse me dical m o nit ori n g (restart at t he i nstitut i on) ;
 
T he restart of sa v o liti ni b m ust be perf or me d i n t he h os pital/i nstituti o n w here t he 
cli nical st u d y is carrie d o ut wit h me dical e q ui p me nt rea dil y a vaila ble f or res uscitati o n 
a n d ma na ge me nt of a na p h yla xis 
 
Vi t al stat us rec or di n g ( B P, te m perat ure, res pirat or y rate, heart rate, etc) bef ore 
a d mi nistrati o n of sa v o liti ni b, e ver y 1 5 mi n utes after sa v oliti ni b d osi n g f or t he first 
h o ur, e ver y  3 0 mi n utes f or t he ne xt h o ur a n d h o url y for a t otal  of at least 4 h o urs a n d
 
Pati e nt must be o bser ve d i n t he cli nic f or 2 4 h o urs bef ore disc har ge.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 0 of 1 5 5
 
S h o ul d t he s y m pt o m s rec ur, or a n ac ute a na p h ylactic react i on occ urs, i m me diate 
i nter ve nt i on m ust be i nst itut e d f or a p pr o priate ma na ge me nt of e ve nt a n d sa v o liti ni b 
m ust be per ma ne nt l y disc o nti n ue d.
A n y rec o m me n dat i ons re gar di n g h y perse ns iti vity ma na ge me nt or pre -treat me nt s h o ul d be 
use d as g ui deli nes o nl y. Fi nal decisio n s c o ncer ni n g ma na ge me nt of i n di vi d ual pat ient s reside 
wi t h t he i n vesti gat or or t he treati n g p h ysicia n.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 1 of 1 5 5
A p pe n di x J
G u i d a nce Re g ar di n g P ote nti al I nter acti o ns wit h C o nc o mit a nt 
Me dic ati o ns
T he use of a n y  nat ur al/ her bal pr o d ucts or ot her “f ol k re me dies” s h o uld be di sc o ura ge d, b ut 
use of t hese pr o d ucts, as well as use of all vita mi ns, n utriti o nal s u p ple me nts a n d all ot her 
c o nc o mita nt me dicat io ns m ust be rec or de d i n t he e C R F.
J 1
Dr u gs I n d uci n g C Y P 3 A 4 Met a b olis m t h at Astr a Ze nec a Str o n gl y 
Rec o m me n d are n ot C o m bi ne d wit h Osi merti ni b or S a v oliti ni b
Osi mert i ni b a n d sa v o liti ni b are meta b olise d b y C Y P 3 A 4 a n d C Y P 3 A 5 e nz y mes. 
A dr u g -dr u g i nteracti o n st u d y of  osi merti ni b e val uate d i n patie nts s h o we d t hat t here is 
p ote nti al for osi merti ni b bei n g a vict i m w he n c o-a d mi nistere d wit h str o n g i n d ucers of 
C Y P 3 A 4 ( osi merti ni b c o nce ntrati o ns are decrease d w he n c o -d ose d wit h rifa m pici n).
T he f o ll owi n g p ote nt i n d ucers of  C Y P 3 A 4 must n ot be use d d uri n g t his st u d y  for a n y  patient  
recei vi n g osi merti ni b or sa v oliti ni b.
Ta ble J 1 
Dr u gs I n d uci n g C Y P 3 A 4
C o ntr ai n dic ate d dr u gs
Wit h dr a w al peri o d pri or t o osi merti ni b 
or s a v oliti ni b st art
A vasi mi be, car ba maze pi ne, mit ota ne, p he n o bar bital 
( p he n o bar bit o ne), p he n yt oi n, rifa m pici n, rifa b uti n, rifa pe nti n
St J o h n’s W ort
3 wee ks
E nzal uta mi de
5 wee ks
C Y P = C yt oc hr o me P 4 5 0.
T his list is n ot i nte n de d t o be e x ha ust i ve, a n d a si milar restricti on will a p pl y  t o ot her a ge nts 
t hat are k n o w n t o str o n gl y m o d ulate C Y P 3 A 4 act i vity.  A p pr o priate me dical j u d g me nt is 
re q uire d. Please c o ntact Astra Ze neca wit h a n y q ueries y o u ha ve o n t his iss ue.
J 2
Dr u gs I n hi biti n g C Y P 1 A 2 Met a b olis m t h at Astr a Z e nec a Str o n gl y 
Rec o m me n d are n ot C o m bi ne d wit h S a v oliti ni b
Ta ble J 2 
Dr u gs I n hi biti n g C Y P 1 A 2
C o ntr ai n dic ate d dr u gs
Wit h dr a w al peri o d pri or t o s a v oliti ni b st art
Ci pr ofl o xaci n, E n o xaci n, Cli nafl o xaci n
Fl u v o xa mi ne
2 wee ks
C Y P = C yt oc hr o me P 4 5 0.
T his list is n ot i nte n de d t o be e x ha ust i ve, a n d a si milar restricti on will a p pl y  t o ot her a ge nts 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 2 of 1 5 5
t hat are k n o w n t o str o n gl y i n hi bit C Y P 1 A 2 acti vit y.  A p pr o priate me dical j u d g me nt is 
re q uire d. Please c o ntact Astra Ze neca wit h a n y q ueries y o u ha ve o n t his iss ue.
Sa v o liti ni b is a wea k i n hi bit or of Or ga nic A ni on Tra ns p orter Pr otei n B 1 a n d B 3, a n d B C R P. 
T he use of stati ns s h o ul d be a v o i de d as far as p ossi ble a n d if c o nsi dere d necessar y, t he patie nts 
s h o uld be gi ve n t he l o west a vaila ble d ose a n d cl osel y m o nit ore d f or t he effects of i ncrease d 
stati n e x p os ure.
J 3
Me dici nes w h ose E x p os ures m a y be Affecte d b y Osi merti ni b t h at 
Astr a Ze nec a C o nsi ders m a y be All o we d wit h C a uti o n
Osi mert i ni b ma y i ncrease t he c o nce ntrati o ns of se nsit i ve B C R P or P-g p s u bstrate 
(c o nce ntrati o ns of se nsiti ve B C R P s u bstrate, r os u vastati n or P-g p s u bstrate, fe x ofe na di ne is 
i ncrease d).
Ta ble J 3 
E x p os ur e, P h ar m ac ol o gic al Act i o n a n d To xicit y m a y be I ncre ase d o r  
Decr e ase d b y Osi merti ni b
W ar ni n g of p ossi ble i nter acti o n
A d vice
R os u vastati n 
S ulfasalazi ne
D o x or u bici n
Da u n or u bici n 
T o p oteca n
Alis kire n
Da bi gatra n eti xelate
Di g o xi n
Dr u gs are per mitte d b ut ca uti o n s h o ul d be e xercise d 
a n d patie nts m o nit ore d cl osel y f or p ossi ble dr u g 
i nteracti o ns. Please refer t o f ull prescri bi n g 
i nf or mati o n f or all dr u gs pri or t o c o-a d mi nistrati on 
wit h osi merti ni b.
J 4
Me dici nes w h ose E x p os ures m a y be Affecte d b y S a v oliti ni b t h at 
Astr a Ze nec a Str o n gl y Rec o m me n d are n ot C o m bi ne d wit h 
S a v oliti ni b
C y t oc hr o me P 4 5 0 3 A 4 s u bstrates w hic h ha ve a narr o w t hera pe utic ra n ge m ust n ot be ta ke n 
wi t hi n 2 wee ks of t he first d ose of sa v oliti ni b treat me nt ( 3 wee ks f or St J o h n’s Wort) a n d f or 
3 wee ks after t he last d ose of  sa v oliti ni b.
Pati e nts are n ot per mitte d t o recei ve warfari n w he n patie nts are treate d wit h sa v olit i ni b. L o w 
m o lec ular wei g ht he pari n is all o we d.
A n y c y t ot o xic c he mot h era p y, i n vestig ati o nal a ge nts or ot her a nti -ca ncer dr u gs f or t he 
treat me nt of a d va nce d N S C L C fr o m a pre vi o us treat me nt re gi me n or cli nical st u d y  wit hi n 
1 4 d a y s of t he first d ose of sa v o liti ni b.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 3 of 1 5 5
J 5
Dr u gs t h at m a y Pr ol o n g Q T I nter v al
T he dr u gs liste d i n t his secti o n are ta ke n fr o m i nf o r mat i on pr o vi de d b y  T he Ar iz o na Ce nter f or 
E d ucati o n a n d Researc h o n T hera pe ut ics o n t he Cre di ble Me ds® we bsite : 
ht t ps:// w w w.cre di ble me ds. or g. T he we bsite cate g orises dr u gs base d o n t he ris k of i n d uci n g 
T d P . 
D ur i n g scree ni n g, t he dr u gs t hat patie nts are c urre ntl y recei vi n g ( prescri be d a n d 
n o n- prescri pti o n) s h o ul d be c hec ke d a gai nst t he Ar iz o na Ce nter we bsite a b o ve. I n a d diti on, 
dr u gs i nte n de d f or use f o ll owi n g st u d y  int er ve ntio n i ni tiat i on s h o ul d be c hec ke d a gai n st t he 
we bsite.
J 5. 1
Dr u gs wit h a K n o w n Ris k of T d P
T he f o ll owi n g dr u gs pr ol o n g Q T i nter val a n d are clearl y  ass ociate d wit h a k n o w n ris k of T d P 
e ve n w he n ta ke n as rec o m me n de d. T hese dr u gs m ust ha ve bee n disc o nt i n ue d pri or t o t he start 
of  a d mi nistratio n of  st u d y i nter ve nt i on, i n acc or da nce wit h g ui da nce pr o vi de d i n  Ta ble J4 a n d 
s h o uld n ot be c o -a d mi nistere d wit h sa v o liti ni b or osi merti ni b a n d f or a peri o d of t w o wee ks 
after disc o nti n ui n g st u d y int er ve nt i on. 
T he list of dr u gs ma y  not be e x ha ust i ve a n d is s u bject t o c ha n ge as ne w i nf or mati on bec o me s 
a vaila ble. As s uc h, i n vest i gat ors are rec o m me n de d t o searc h t he Ar iz o na Ce nter we bsite t o 
c o nfir m t he m ost u p t o date i nf or mat i on. Rec o m me n de d wit h dra wal peri o ds f o ll owi n g 
cessat i on of treat m e nt wit h t hese a ge nts are pr o vi de d i n Ta ble J 4.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 4 of 1 5 5
Ta ble J 4 
Dr u gs wit h a K n o w n Ris k of T d P
C o ntr ai n dic ate d dr u gs
Wit h dr a w al peri o d pri or t o osi merti ni b 
a n d/ or s a v oliti ni b st art b
Aclar u bici n, a na greli de, ci pr ofl o xaci n, clarit hr o m yci n, 
c ocai ne, dr o peri d ol, er yt hr o m yci n, le v ofl o xaci n, o n da nsetr o n, 
pa pa veri ne h y dr oc hl ori de, pr ocai na mi de, s ul piri de, s ult o pri de, 
terfe na di ne, terli pressi n.
2 da y s
Cil ostaz ol, cisa pri de, dis o p yra mi de, d ofetili de, d o m peri d o ne, 
flecai ni de, gatifl o xaci n, gre pafl o xaci n, i b utili de, m o xifl o xaci n, 
o xali plati n, pr o p of ol, q ui ni di ne, r o xit hr o m yci n, se v ofl ura ne, 
s otal ol, s parfl o xaci n, t hi ori dazi ne
7 da y s
Azit hr o m y ci n, be pri dil, cital o pra m, c hl or pr o mazi ne, 
dr o ne dar o ne, escital o pra m, fl uc o naz ole, hal ofa ntri ne, 
hal o peri d ol, le v o me pr o mazi ne, le v os ul piri de, mes ori dazi ne
1 4 da ys
D o ne pezil, ter o dili ne
3 wee ks
Le v o met h a d yl, met ha d o ne, pi m ozi de
4 wee ks
Arse nic tri o xi de a, i b o gai ne
6 wee ks
Pe nta mi di ne
8 wee ks
Aste miz ole, pr o b uc ol, va n deta ni b
4 m o nt hs
A mi o dar o ne, c hl or o q ui ne
1 year
a
Esti mate d val ue as p har mac o ki netics of arse nic tri o xi de has n ot bee n st u die d.
b
Val ues deter mi ne d fr o m c o m pre he nsi ve re vie w (i nter nal t o Astra Ze neca) of eac h c o m p o u n d’s P K half -life 
a n d deter mi nati o n of t he was h -o ut peri o d.
T his list s h o ul d be c hec ke d a gai nst t he f ull a n d m ost c urre nt list prese nte d i n t he Cre di ble Me ds ® we bsite 
(htt ps:// w w w.cre di ble me ds. or g/ ).
P K = p har mac o ki netic; T d P = T orsa des de P oi ntes.
J 5. 2
Ot her T d P Ris k C ate g ories
Pati e nts recei vi n g dr u gs t hat pr ol o n g Q T i nter val or ma y i ncrease t he ris k of T d P fr o m ot her 
T d P  ris k cate g ories ca n be e nr o lle d, n ot wit hsta n di n g ot her e xcl usi ons a n d restri ct i ons, if t hese 
dr u gs are c o nsi dere d esse nt ial f or patie nt ma na ge me nt a n d t he patie nt has bee n sta ble o n 
t hera p y. Clos e m o ni t ori n g of E C Gs a n d electr ol yt es is rec o m me n de d.
Pati e nts wit h c o n ge nit al l o n g Q T s y n dro me ar e e xcl u de d fr o m t his st u d y.
J 5. 3
G ui d a nce Re g ar dless of T d P Ris k C ate g or y
D uri n g st u d y  int er ve nt i on a n d f or a peri o d of 2 wee ks after disc o nti n ui n g st u d y i nter ve nt i on if 
it is c o nsi dere d esse ntial f or patie nt ma na ge me nt t o c o -a d mi nister dr u gs k n o w n t o pr ol o n g 
Q T c i nter val, re gar dless of T d P ris k cate g or y, clos e m o ni t orin g of E C Gs a n d electr ol ytes is 
rec o m me n de d.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 5 of 1 5 5
J 5. 4
Dr u gs t h at m a y P ossi bl y Pr ol o n g Q T I nter v al
T he use of t he f o ll owi n g dr u gs is per mitte d ( n ot wit hsta n di n g ot her e xcl usi o ns a n d restrict i ons) 
pr o vi de d t he pati e nt has bee n sta ble o n t hera p y for t he peri o ds i n dicate d.
Ta ble J 5 
Dr u gs t h at m a y Pr ol o n g Q T I nter v al
Dr u g
Mi ni m u m tre at me nt peri o d o n me dic ati o n 
pri or t o osi mert i ni b st art
Alf uz osi n, c hl oral h y drate, ci pr ofl o xaci n, d olasetr o n, 
f oscar net, gala nta mi ne, ge mifl o xaci n, isri di pi ne, ket oc o naz ole, 
le v ofl o xaci n, me xileti ne, nicar di pi ne, octre oti de, ofl o xaci n, 
o n da nsetr o n, q uetia pi ne, ra n olazi ne, telit hr o m yci n, tiza ni di ne,
var de nafil, ve nlafa xi ne, zi prasi d o ne
2 da y s
A ma nta di ne, a mitri pt yli ne, a m o xa pi ne, cl oza pi ne, d o xe pi n, 
felba mate, flecai ni de, fl uc o naz ole, f os p he n yt oi n, gatifl o xaci n, 
gra nisetr o n, i mi pra mi ne, i n da pa mi de, lit hi u m, 
m oe xi pril/ H C T Z, m o xifl o xaci n, ris peri d o ne, r oxit hr o m yci n, 
sertrali ne, tri met h o pri m-s ulfa, tri mi pra mi ne, v oric o naz ole
7 da y s
Azit hr o m y ci n, cital o pra m, cl o mi pra mi ne, itrac o naz ole, 
n ortri pt yli ne, par o xeti ne, s olife naci n, tacr oli m us
1 4 da ys
Fl u o xeti ne 
5 wee ks
Pr otri pt yli ne
6 wee ks
Ta m o xife n
8 wee ks
J 6
Refere nces
T he Ariz o n a Ce nter f or E d uc ati o n a n d Rese arc h o n T her a pe utics o n t he Cre di ble Me ds ®
we bsite 
Av aila ble at U R L: ht t ps:// w w w.cre di ble me ds. or g. Accesse d o n 0 6 A pril 2 0 2 0.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 6 of 1 5 5
A p pe n di x K
A b bre vi ati o ns
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
A E
A d verse e ve nt
A L P
Al kali ne p h os p hatase 
A L T
Ala ni ne a mi n otra nsferase
A N C O V A
A nal y sis of c o varia nce
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve
A U C ss
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve at stea d y state
B
Bl o o d
B C R P
Br east ca ncer resista nce pr otei n
BI C R
Bli n de d i n de pe n de nt ce ntral re vie w
B P
Bl o o d press ure
C 1 h
Plas ma c o nce ntrati o n at 1 h o ur
C 3 h
Plas ma c o nce ntrati o n at 3 h o urs
C E P 7
Ce ntr o meric p orti o n of c hr o m os o me 7
CI
C o nfi de nce i nter val
C L ss/ F
A p pare nt cleara nce at stea d y state
C M H
C oc hra n – Ma ntel – Hae nszel
C O VI D - 1 9
C or o na vir us 2 0 1 9
C pr e -d ose
Plas ma c o nce ntrati o n pre -d ose
C P Q P
Cli nical P har mac ol o g y a n d Q ua ntitati ve P h ar mac ol o g y
C R
C o m plete res p o nse
C R O
C o ntract Researc h Or ga nisati o n
C S P
Cli nical St u d y Pr ot oc ol
C S R
Cli nical St u d y Re p ort
C ss ma x
Ma xi m u m plas ma c o nce ntrati o n at stea d y state
C T
C o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
ct D N A
Circ ulati n g t u m o ur D N A
C Y P
C y t oc hr o me P 4 5 0
D C O
Data c ut -off
DI LI
Dr u g i n d uce d li ver i nj ur y
D o R
D urati o n of res p o nse
E C G
Electr ocar di o gra m

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 7 of 1 5 5
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
E C H O
Ec h ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
Electr o nic Case Re p ort F or m
E D C
Electr o nic data ca pt ure
E G F R
E pi der mal gr o wt h fact or rece pt or
E G F R m
E pi der mal gr o wt h fact or rece pt or m utati o n
E G F R m +
E pi der mal gr o wt h fact or rece pt or m utati o n p ositi ve
E M
Er y t he ma m ultif or me
E M M
Er y t he ma M ultif or me Maj or
F A S
F ull A nal y sis Set
F D A
U S F o o d a n d Dr u g A d mi nistrati o n
F D G -P E T
Fl u or o de o x y gl uc ose -p ositr o n e missi o n t o m o gra p h y
F F P E
F or mali n -Fi xe d, Paraffi n -E m be d de d
FI S H
Fl u oresce nce i n sit u h y bri disati o n
F N A
Fi ne nee dle as pirati o n
G C P
G o o d Cli nical Practice
H Bs A g
He patitis B vir us s urface a nti ge n
H B V
He patitis B vir us
H C V
He patitis C vir us
H D P E
Hi g h -de nsit y p ol yet h yle ne
H G F
He pat oc yte gr o wt h fact or
HI V
H u ma n i m m u n o deficie nc y vir us
H L
H y’s La w
H R
Hazar d rati o
I A T A
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati o n
I B
I n vesti gat or’s Br oc h ure
I C F
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
I n de pe n de nt data m o nit ori n g c o m mittee
I E C
I n de pe n de nt Et hics C o m mittee 
I-H A C
I n de pe n de nt He patic Assess me nt C o m mittee
I L D
I nterstitial l u n g disease
I N R
I nter nati o nal N or malisati o n Rati o
I O
I m m u ne-on c ol o g y
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 8 of 1 5 5
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
I R B
I nstit uti onal Re vie w B oar d
I V
I ntra ve n o us
I V R S
I nteracti ve V oice Res p o nse S yste m
I W R S
I nteracti ve We b Res p o nse S yste m
L F T
Li ver f u ncti o n test
L L N
L o wer li mit of n or mal
L M W H
L o w m olec ular wei g ht he pari n
L V E F
Left ve ntric ular ejecti o n fracti o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M E T
He pat oc yte gr o wt h fact or rece pt or
M RI
Ma g netic res o na nce i ma gi n g
M U G A
M ulti -gate d ac q uisiti o n
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N E
N ot e val ua ble
N L
Ne w lesi o ns
N S C L C
N o n -s mall cell l u n g ca ncer
N T L
N o n -tar get lesi o ns
N Y H A
Ne w Y or k Heart Ass ociati o n
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val
P
Plas ma
P D
Pr o gressi o n of disease
P F S
Pr o gressi o n -free s ur vi val
P H L
P ote ntial H y’s la w
P K
P har mac o ki netics
P R
Partial res p o nse
Q 6/ 8/ 1 2 W
E ver y 6/ 8/ 1 2 wee ks
Q Tc
C orrecte d Q T i nter val
Q Tc F
Q T i nter val c orrecte d usi n g Fri dericia's f or m ula
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
S
Ser u m
S A E
Seri o us a d verse e ve nt 
S A P
Statistical A nal ysis Pla n
S A S
Safet y A nal ysis Set
C CI
C CI

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi mert i ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 4 9 of 1 5 5
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
S D
Sta ble disease
SJ S
Ste ve ns -J o h ns o n s y n dr o me
S o As
Sc he d ule of acti vities
T B L
T otal bilir u bi n
T d P
T orsa des de P oi ntes
T KI
T y r osi ne ki nase i n hi bit or
T L
Tar get lesi o ns
T ss ma x
Ti me of ma xi m u m plas ma c o nce ntrati o n at stea d y state
U
Ur i ne
U L N
U p per li mit of n or mal
W H O
W orl d Healt h Or ga nizati o n
W O C B P
W o me n of c hil d beari n g p ote ntial

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 0 of 1 5 5
A p pe n di x L
S u m m ar y of C h a n ges
L 1
A me n d me nt 1 ( 2 8 M a y
2 0 2 1)
Secti o n # a n d N a me 
Descri pti o n of C h a n ge 
Brief R ati o n ale
S u bst a nti al/
N o n -s u bst a nti al
A p pe n di x I: D ose 
M o dificati o ns f or t he 
Ma na ge me nt of A d verse 
E ve nts
D ose m o dificati o n 
g ui deli nes f or osi merti ni b 
a n d sa v oliti ni b were 
u p date d. T he mai n c ha n ges 
i ncl u de d a d diti on of Ta ble I 1 
( St u d y Treat me nt D ose 
M o dificati o n I nstr ucti o ns f or 
T o xicities Relate d t o 
Osi merti ni b a n d/ or 
Sa v olti ni b (e xcl u di n g 
t o xicities t hat re q uire 
s pecific ma na ge me nt 
g ui deli nes), Ta ble I 2 
( T o xicities t hat Re q uire 
Per ma ne nt Disc o nti n uati o n 
of St u d y Treat me nt), a n d 
Ta ble I 3 ( Ma na ge me nt of 
Q Tc Pr ol o n gati o n). Ta ble I 1 
was create d b y c o m bi ni n g 
i nf or mati o n i n pre vi o us 
Ta bles I 2 a n d I 4. C o nte nts i n 
pre vi o us Ta ble I 2 a n d 
Secti o ns I 2. 4 are mer ge d 
i nt o ne w Ta ble I 2. C o nte nts 
of pre vi o us Ta ble I 5 a n d 
Sec ti o n I 1. 2 were mer ge d t o 
create ne w Ta ble I 3.
D ose m o dificati o n 
g ui deli nes u p date d i n 
res p o nse t o t he F D A 
i nf or mati o n re q uest a n d 
i n li ne wit h t he 
prescri bi n g la bel f or 
osi merti ni b. 
S u bsta ntial
A p pe n di x I: D ose 
M o dificati o ns f or t he 
Ma na ge me nt of A d verse
E ve nts
I nstr ucti on f or rec urre nt 
Gra de 3 sa v oliti ni b -relate d 
t o xicities t hat res ol ve d t o 
baseli ne wit hi n 1 4 da ys of 
o nset was re m o ve d.
U p date d i n li ne wit h 
m ost rece nt P S S R.
S u bsta ntial

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 1 of 1 5 5
1 1 
R E F E R E N C E S
Ait h al et al 2 0 1 1
Ait hal G P , Wat ki ns P B, A n dra de RJ, L arre y D, M olo k hia M, T a ki ka wa H, et al. Case 
defi nit i on a n d p he n ot y pe sta n dar dizat i on i n dr u g-i n d uce d li ver i nj ur y. Cli n P har ma c ol T her. 
2 0 1 1; 8 9( 6): 8 0 6 - 1 5.
B all ar d et al 2 0 1 6
Ballar d P , Yates J W, Ya n g Z, Ki m D W, Ya n g J C, Ca ntari ni M, et al. Precli nical c o mparis o n of 
osi mert i ni b with ot her E G F R -T KIs i n E G F R -m ut a nt N S C L C brai n metastases m o dels, a n d 
earl y e vide nce of cli nical brai n metastases acti vit y.  Cli n Ca ncer Res. 2 0 1 6; 2 2( 2 0): 5 1 3 0- 4 0.
Be a n et al 2 0 0 7
Bea n J, Bre n na n C, S hi h J Y , Riel y G, Viale A, Wa n g L, et al. M E T a m plificati o n occ urs wit h 
or wi t ho ut T 7 9 0 m utati o ns i n E G F R m uta nt l u n g t u m ors wit h ac q uire d resista nce t o gefit i ni b 
or erl oti ni b. Pr oc Natl  Aca d Sci U S A. 2 0 0 7; 1 0 4( 5 2): 2 0 9 3 2 – 7.
Bec ker et al 2 0 1 1
Bec ker A, Cr o m ba g L, Hei de ma n D A M, T h u n nisse n F B, va n W ij k A W , P ost mus P E et al . 
Retreat me nt wit h erl oti ni b: Re gai n o f T KI se nsiti vity f oll o wi n g a dr u g h oli da y f or patie nts 
wi t h N S C L C w h o i nitiall y res p o n de d t o E G F R-T KI treat m e nt. E ur o pea n J o ur nal of Ca ncer 
2 0 1 1; 4 7( 1 7): 2 6 0 3 - 6.
C a mi d ge et al 2 0 1 4
Ca mi d ge D R, Pa o W , Se q uist LV.  Ac q uire d resista nce t o T KIs i n s oli d t u m o urs: lear ni n g fr o m 
l u n g ca ncer. Nat Re v Cli n O nc ol. 2 0 1 4; 1 1( 8): 4 7 3 – 8 1.
C h aft et al 2 0 1 1
C haft J E, O x nar d G R, Si ma C S, Kris M G, Miller V A, Ri el y GJ. Disease flare after t yr osi ne 
ki nase i n hi bit or disc o nt i n uati on i n patient s wit h E G F R-m uta nt l u n g ca ncer a n d ac q uire d 
resista nce t o erl oti ni b or gefiti ni b: i m plicati o ns f or cli nical trial desi g n. Cli n Ca ncer Res. 
2 0 1 1; 1 7( 1 9): 6 2 9 8 - 3 0 3.
C he n et al 2 0 1 3
C he n HJ, Y a n H H, Ya n g JJ, C he n Z H, S u J, Z ha n g X C, e t al. Disease flare after E G F R 
t yr osi ne ki nase i n hi bit or cessati on pre dicts p o or s ur vi val i n patie nts wit h n o n -s mall cell l u n g 
ca ncer. Pat h ol O nc ol Res. 2 0 1 3; 1 9( 4): 8 3 3 - 8.
C h o n g a n d J ä n ne 2 0 1 3
C h o n g C R a n d Jä n ne P A. T he q uest t o o verc o me resista nce t o E G F R -tar gete d t hera pies i n 
ca ncer. Nat Me d. 2 0 1 3; 1 9( 11): 1 3 8 9 -1 4 0 0.
C h o ueiri et al 2 0 1 7
C h o ueiri T K, Hala bi S, Sa nf or d B L, Ha h n O, Mic haels o n M D, Wals h M K, et al. Ca b oza nti ni b 

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 2 of 1 5 5
vers us s u nit i ni b as i nitial tar gete d t hera p y f or patie nts wit h metastatic re nal cell carci n o ma of 
p o or or i nter me diate ris k: T he Allia nce A 0 3 1 2 0 3 C A B O S U N Trial. J Cli n O nc o l. 
2 0 1 7; 3 5( 6): 5 9 1 - 7.  
Cr oss et al 2 0 1 4
Cr oss D A, As ht o n S E, G hi or g hi u S, E berlei n C, Ne b ha n C A, S pitzler PJ, et al. A Z D 9 2 9 1, a n 
irre versi ble E G F R T KI, o verc o mes T 7 9 0 M-me diate d resi sta nce t o E G F R i n hi bit ors i n l u n g 
ca ncer. Ca ncer Disc o v. 2 0 1 4: 4( 9); 1 0 4 6- 6 1.
E der et al 2 0 0 9
E der J P , Va n de Wo u de G F, B oer ner S A, L o R uss o P M. N o vel t hera pe utic i n hi bit ors of t he 
c- Met si g nali n g pat h wa y i n ca ncer . Cli n Ca ncer Res. 2 0 0 9; 1 5( 7): 2 2 0 7- 1 4.
E n gel m a n et al 2 0 0 7
E n gel ma n J A, Zej n ulla h u K, Mits u d o mi T , S o n g Y, H yla n d C, Par k J O, et al. M E T 
a mplificat i on lea ds t o gefiti ni b resista nce i n l u n g ca ncer b y acti vati n g E R B B 3 si g nali n g. 
S ci e nce. 2 0 0 7; 3 1 6( 5 8 2 7): 1 0 3 9 - 4 3.
G L O B O C A N 2 0 1 8
Av aila ble fr o m U R L: htt p:// gl o b oca n.i arc.fr/ Pa ges/fact _s heets _ca ncer.as p x. Accesse d 
0 6 A pril 2 0 2 0.
Gri delli et al 2 0 1 2 
Gri delli C, Ciar diell o F, Gallo C, Fel d R, B utts C, Ge b bia V, et al. First-li ne erl oti ni b f oll owe d 
b y sec o n d-li ne cis plati n-ge mci ta bi ne c he mot h era p y i n a d va nce d n o n-s mall-cell lu n g ca ncer: 
t he T O R C H ra n d o mize d trial. J Cli n O nc ol. 2 0 1 2; 3 0( 4): 3 0 0 2 -1 1.
He nr y et al 2 0 1 6
He nr y  R E, Barr y E R, Castriotta L, La d d B, Mar k o vets A, Bera n G, et al. Ac q ui re d sa v olitini b 
resista nce i n n o n-s mall c ell lu n g ca ncer arises via m ult i ple mec ha nis ms t hat c o n ver ge o n 
M E T- i n de pe n de nt m T O R a n d M Y C acti vati on. O nc otar get. 2 0 1 6; 7( 3 6): 5 7 6 5 1 -7 0. 
J ä n ne et al 2 0 1 5
Jä n ne PA, Feli p E, Ki m D -W,  J o h n T, Ha g gstr o m D E, A h n M -J, et al. C haracterizat i on of t he 
acti vit y of  A Z D 9 2 9 1 i n patie nts ( pts) wit h T 7 9 0 M ‘ne gat i ve’ a d va nce d n o n-s mall cell l u n g 
ca ncer (a N S C L C). [a bstract]. I n: Pr ocee di n gs of t he A A C R -N CI -E O R T C I nter nati o nal 
C o nfere nce: M o lec ular Tar gets a n d Ca ncer T hera pe utics; 2 0 1 5 N o v 5 -9; B ost o n, M A. 
P hila del p hia ( P A): A A C R; M o l Ca ncer T her 2 0 1 5; 1 4( 1 2 S u p pl 2): A bstract nr B 1 0 5. Av aila ble 
fr om U R L: htt ps:// m ct.aacrjo ur nals. or g/c o nte nt/ 1 4/ 1 2 _ S u p ple me nt _ 2/ B 1 0 5. Accesse d 
0 6 A pril 2 0 2 0.
Ji a et al 2 0 1 4
Jia H, Dai G, We n g J, Z ha n g Z, Wa n g Q, Z h o u F, et al. Disc o ver y of ( S)- 1-( 1-(I mi daz o[ 1, 2-

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 3 of 1 5 5
a] p yridi n - 6-yl)et h yl) -6 -( 1-met h yl- 1 H- p y r a z ol- 4-yl) -1 H- [ 1, 2, 3]triaz ol o[ 4, 5-b] p yrazi ne 
( v oliti ni b) as a hi g hl y p ote nt a n d selecti ve mese nc h y mal- e pit helial tra nsitio n  fact or (c-Met) 
i n hi bit or i n cli nical de vel o p me nt f or treat me nt of ca ncer. J Me d C he m. 2 0 1 4; 5 7( 1 8): 7 5 7 7- 8 9.
Kee d y et al 2 0 1 1
Kee d y V L, T e mi n S, S o merfiel d M R, Beasle y M B, J o h ns o n D H, Mc S ha ne L M, et al. 
A merica n S ociet y of  Cli nical O n c olo g y  pr o visio n al  cli nical o pi nio n : e pider mal gr o wt h fact or 
rece pt or ( E G F R) m utati o n testi n g f or patie nts wit h a d va nce d n o n- s mall-cell l u n g ca ncer 
c o nsi deri n g first -li ne E G F R tyr osi ne ki nase i n hi bit or t hera p y. J Cli n O nc ol. 
2 0 1 1; 2 9( 1 5): 2 1 2 1 - 7.
L a n ger et al 2 0 1 3
La n ger CJ, M o k T , P ost mus P E. T ar gete d a ge nts i n t he t hir d -/fo urt h -li ne treat me nt of patie nts 
wi t h a d va nce d (sta ge III/I V) n o n-s mall cell lu n g ca ncer ( N S C L C). Ca ncer Treat Re v . 
2 0 1 3; 3 9( 3): 2 5 2 - 6 0.
Lei g hl a n d C uri gli a n o 2 0 1 4
Lei g hl N B, C uri glia n o G. Earl y -sta ge lu n g ca ncer --w hat d o t he e x perts rec o m me n d? A n n 
O nc o l. 2 0 1 4; 2 5( 8): 1 4 5 1- 3.
M asters
et al 2 0 1 5
Masters G A, T e min S, Azz o li C G, Gi acc o ne G, Ba ker S Jr, Bra h mer J R, Ellis P M, Gajra A, 
Rac kear N, Sc hiller J H, S mit h TJ, Stra w n J R, Tre nt D, J o h ns o n D H; A merica n S ociet y of  
Cli nical O nc o l og y  Cli nical Pr a ctice. S yste mic T hera p y for Sta ge I V N o n -S mall -Cell L u n g 
Ca ncer: A mer ica n S ociet y of  Cli nical O n c olo g y  Cli nical Practice G uideli ne U p date. J Cli n 
O nc o l 2 0 1 5; 3 3( 3 0): 3 4 8 8 - 5 1 5.
M o k
et al 2 0 1 6
M o k T S, W u Y-L, A h n M -J, Garassi n o M C, Ki m H R, Ra mali n ga m S S, S he p her d FA, He Y , 
A ka mats u H, T heele n W S, Lee C K, Se bast ian M, T e m p let o n A, Ma n n H, Mar otti M, 
G hi or g hi u S, Pa pa di mitra k o p o ul o u V A; A U R A 3 I n vesti gat ors. Osi mert i ni b or 
Pl at i n u m-Pe metre xe d i n E G F R T 7 9 0 M -P osi tive L u n g Ca ncer . N E n gl J Me d. 
2 0 1 7; 3 7 6( 7): 6 2 9 - 4 0.
M o k
et al 2 0 1 7
M o k T S K, Ki m S W , Wu Y L, Na ka ga wa K, Ya n g JJ, A h n MJ, et al. Gefit i ni b Pl us 
C he m ot h era p y Vers us C he m ot hera p y i n E pi der mal Gr o wt h Fact or Rece pt or M utati o n- P osi tive 
N o n -S mall - Cell L u n g Ca ncer Resista nt t o First-Li ne Gefit i ni b (I M P R E S S): O verall S ur vi val 
a n d Bi o mar ker A nal yses. J Cli n O nc o l. 2 0 1 7; 3 5( 3 6): 4 0 2 7-3 4. 
N C C N 2 0 2 0
Nati o nal C o m pre he nsi ve Ca ncer Net w or k G ui deli nes f or T reat me nt of Ca ncer b y Site. 2 0 2 0. 
Av aila ble fr o m U R L: htt ps:// w w w . ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ defa ult.as p x # nscl.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 4 of 1 5 5
O h as hi et al 2 0 1 2
O has hi K, Se q uist L V,  Arcila M E, M ora n T, C h mielec ki J, Li n Y, et al. L u n g ca ncers with 
ac q uire d resista nce t o E G F R i n hi bit ors occasi o nall y har b or B R A F ge ne mut ati o ns b ut lac k 
m utati o ns i n K R A S, N R A S, or M E K 1. Pr oc Nat Aca d U S A  2 0 1 2; 1 0 9( 3 1): E 2 1 2 7- 3 3.
O x n ar d et al 2 0 2 0
O x nar d G R, Y a n g J C, Yu H, Ki m S W, Sa ka H, H or n L, et al. TA T T O N: a m ult i-ar m p hase I b 
trial of osi merti ni b c o m bi ne d wit h sel u meti ni b, sa v oliti ni b, or d ur val u ma b i n E G F R-m uta nt 
l u n g ca ncer. A n n O nc o l. 2 0 2 0; 3 1( 4): 5 0 7- 1 6.
P ar k et al 2 0 1 2
Par k S, C h oi Y L, S u n g C O, A n J, Se o J, A h n MJ, et al. Hi g h M E T c o p y  nu m ber a n d M E T 
o vere x pressi o n: p o or o utc o me i n n o n -s mall cell l u n g ca ncer patie nts. Hist ol Hist o pat h ol. 
2 0 1 2; 2 7( 2): 1 9 7 – 2 0 7.
Pi otr o ws k a et al 2 0 1 7
Pi otr o ws ka Z, T hress K S, M o ora dia n M, S u k Heist R, Azz oli C G, T e mel J S, et al. M E T 
a mplificat i on (a m p) as a resista nce mec ha nis m t o osi mert i ni b [a bstract]. J Cli n O nc ol 
2 0 1 7; 3 5( 1 5 s u p pl): 9 0 2 0. Av aila ble fr o m U R L: 
ht t ps://asc o p u bs. or g/ d oi/ 1 0. 1 2 0 0/J C O. 2 0 1 7. 3 5. 1 5 _s u p pl. 9 0 2 0. Accesse d 0 7 A pril 2 0 2 0.
Pisters a n d Le C he v alier 2 0 0 5
Pi sters K M, Le C he valier T. A d j u va nt c he m ot hera p y in c o m p letel y resecte d n o n-s mall-cell 
l u n g ca ncer. J Cli n O nc ol. 2 0 0 5; 2 3( 1 4): 3 2 7 0- 8.
R a m ali n g a m et al 2 0 1 8
Ra mali n ga m S S, Y a n g J C, Lee C K, K urata T, Ki m D W, J o h n T, et al. Osi merti ni b as first li ne 
treat me nt of E G F R m utatio n -p osi tive a d va nce d n o n-s mall-cell lu n g ca ncer . J Cli n O nc ol. 
2 0 1 8; 3 6( 9): 8 4 1 - 9
Rec k et al 2 0 1 4
Rec k M, P o pat S, Rei n m ut h N, De R u y ssc her D, Kerr K M, Peters S; E S M O G ui deli nes 
Wo r ki n g Gr o u p. Metastatic n o n-s mall-cell l u n g ca ncer ( N S C L C): E S M O Cli nical Practice 
G ui deli n es f or di a g n osis, treat me nt a n d f o ll ow- u p. A n n O nc o l. 2 0 1 4; S u p pl 3;iii 2 7- 3 9.
Sc h mi dt et al 1 9 9 7
Sc h mi dt L, D u h F M, C he n F , Kis hi da T, Gle n n G, C h o y k e P, et al. Ger mli ne a n d s omatic 
m utati o ns i n t he t yr osi ne ki nase d o mai n o f t he M E T pr ot o -o nc o ge ne i n pa pil lar y re nal 
carci n o ma s. Nat Ge net. 1 9 9 7; 1 6( 1): 6 8- 7 3.
Se q uist et al 2 0 1 1
Se q ui st LV,  Walt ma n B A, Dias-Sa nta gata D, Di g u mart h y  S, T ur ke A B, Fi dias P , et al. 
Ge n ot y pic a n d hist ol o gical  e v olut i on of l u n g ca ncers ac q uiri n g resista nce t o E G F R i n hi bit ors. 
S ci  Tra nsl Me d. 2 0 1 1; 3( 7 5): 7 5ra 2 6.

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
Sa v oliti ni b + Osi merti ni b - D 5 0 8 4 C 0 0 0 0 9
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
1 5 5 of 1 5 5
Se q uist et al 2 0 2 0
Se q ui st LV,  Ha n J Y, A h n MJ, C h o B C, Y u H, Ki m S W, et al. Osi merti ni b pl us sa v oliti ni b i n 
pati e nts wit h E G F R m utatio n -p osi tive, M E T-a mplifie d, n o n -s mall-cell l u n g ca ncer after 
pr o gressi o n o n E G F R t y r osi ne kinase i n hi bit ors: i nteri m res ult s fr o m a mul tice ntre, 
o pe n -label, p hase 1 b st u d y. La ncet O nc ol. 2 0 2 0; 2 1( 3): 3 7 3-8 6. 
S he p her d et al 2 0 1 8
S he p her d F A, Pa pa di mitra k o p o ul o u V , M o k T, Wu Y-L, Ha n J -Y,  Ah n M -J, et al. Earl y 
cleara nce of plas ma E G F R m utatio ns as a pre di ct or of res p o nse t o osi mert i ni b i n t he A U R A 3 
trial. J Cli n O nc ol 2 0 1 8; 3 6( 1 5 s u p pl): 9 0 2 7.  
S ori a et al 2 0 1 5
S oria J C, W u Y L, Na ka ga wa K, Ki m S W, Ya n g JJ, A h n MJ, et al. Gefiti ni b pl us c he m ot hera p y 
vers us place b o pl us c he m ot hera p y i n E G F R -m ut ati o n-p os iti ve n o n-s mall-cell l u n g ca ncer 
after pr o gressi o n o n first-li ne gefiti ni b (I M P R E S S): a p hase 3 ra n d omise d trial. La ncet O nc o l. 
2 0 1 5; 1 6( 8): 9 9 0 - 8.
S ori a et al 2 0 1 8
S oria J C, O he Y, Va nstee n kiste J, Re u n g wet watta na T, C he was k ul y on g B, Lee K H, et al. 
Osi mert ini b i n u ntreate d E G F R-m ut at e d a d va nce d n o n-s mall-cell lu n g ca ncer . N E n gl J Me d. 
2 0 1 8; 3 7 8( 2): 1 1 3 - 2 5.
Tr a vis et al 2 0 1 1
Tra vis W D, Bra m billa E, N o g uc hi M, Nic h o ls on A G, Geisi n ger K R, Yata be Y, et al. 
I nter nati o nal Ass ociati on f or t he St u d y of L u n g Ca ncer/ A merica n T h oracic S ociet y/ E ur o pea n 
Res pirat or y  S o ciet y i nter nat i onal m ult i disci pli nar y classificati on of l u n g a de n ocarci n o ma. J 
T h orac O nc ol. 2 0 1 1; 6( 2): 2 4 4 - 8 5.
Z h o u et al 2 0 1 9
Z h o u C, I ma m ura F , C he n g Y, O ka mot o I, C h o B C, Li n M C, et al. Earl y  cleara nce of plas ma 
E G F R m ut ati o ns as a pre di ct or of res p o nse t o osi merti ni b a n d c o m parat or E G F R -T KIs i n t he 
F L A U R A  trial [a bstract]. J Cli n O nc o l. 2 0 1 9; 3 7( 1 5 s u p pl): 9 0 2 0. Av aila ble fr o m U R L: 
ht t ps://asc o p u bs. or g/ d oi/a bs/ 1 0. 1 2 0 0/J C O. 2 0 1 9. 3 7. 1 5 _s u p pl. 9 0 2 0 Accesse d 0 7 A pril 2 0 2 0.

SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 5 0 8 4c 0 0 0 0 9-cs p- v 3
D oc u me nt Title:
D 5 0 8 4 C 0 0 0 0 9 Cli nical St u d y Pr ot oc ol versi o n 3
D oc u me nt I D:
Versi o n L a bel:
3. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
0 9- Ma y- 2 0 2 2 2 1: 3 7 U T C
C o nte nt A p pr o val
1 0- Ma y- 2 0 2 2 1 5: 5 0 U T C
C o nte nt A p pr o val
0 9- Ma y- 2 0 2 2 1 8: 2 7 U T C
C o nte nt A p pr o val
C CI
C CI
P P D
P P D
P P D