A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of Oleclumab (MEDI9447) With or Without Durvalumab in Combination With Chemotherapy in Subjects With Metastatic Pancreatic Ductal Adenocarcinoma
Phase: PHASE1
Conditions: Carcinoma, Metastatic Pancreatic Adenocarcinoma
Sponsor: MedImmune LLC

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
A P h ase 1 b/ 2 St u d y t o E v al u ate t he S afet y , P h ar m ac o ki netics, a n d 
Cli nic al Acti vit y of Olecl u m a b ( M E DI 9 4 4 7) wit h or wit h o ut 
D ur v al u m a b i n C o m bi n ati o n wit h C he m ot her a p y i n S u bjects wit h 
Met ast atic P a ncre atic D uct al A de n oc arci n o m a
S p o ns or Pr ot oc ol N u m ber:
D 6 0 7 0 C 0 0 0 0 5
A p plic ati o n N u m ber:
I N D n u m ber 1 3 8 1 4 3
N C T n u m ber N C T 0 3 6 1 1 5 5 6
E u dra C T n u m ber 2 0 1 8- 0 0 1 0 2 8- 2 1
I n vesti g ati o n al Pr o d uct:
Ol ecl u ma b (i n vest i gati onal na me M E DI 9 4 4 7)
D ur val u ma b
S p o ns or:
Me dI m m u ne, L L C, a w h oll y o w ne d s u bsi diar y o f 
Astra Ze neca P L C
O ne Me dI m m u ne Wa y
G ai t hers b ur g, Mar yla n d, 2 0 8 7 8, U S A
Me dic al M o nit or:
, Cli nical De vel o p me nt,
O nc o l og y , Me dI m m u ne
P h o ne: 
 ( office); 
 ( mo bile) ;
Fa x: 
C o ntr act Rese arc h Or g a niz ati o n:
I C O N Cli nical Researc h Lt d
Pr ot oc ol Hist or y, D ate :
Ori gi nal  Pr ot oc ol, 2 2 Mar 2 0 1 8
A me n d me nt 1, 0 6J u n 2 0 1 9
A me n d me nt 2, 2 0 Dec 2 0 1 9
A me n d me nt 3, 2 4J u n 2 0 2 2
T his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat is pri vile ge d or 
c o nfi de nt ial a n d ma y n ot be discl ose d wit h o ut pri or a ut h orizat i on fr om Me dI m m u ne.
P P D
P P D
P P D
P P D
P P D

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
P R O T O C O L S Y N O P SI S
TI T L E
A P hase 1 b/ 2 St u d y t o E val uate t he Safet y, P har mac o ki netics, a n d Cli nical Acti vit y of Olecl u ma b ( M E DI 9 4 4 7) 
wit h or wit h o ut D ur val u ma b i n C o m bi nati o n wit h C he m ot hera p y i n S u bjects wit h Metastatic Pa ncreatic D uctal 
A de n ocarci n o ma
H Y P O T H E SI S
T he c o m bi nati o n of olecl u ma b (a nti -cl uster of differe ntiati o n [C D ]7 3) wit h or wit h o ut d ur val u ma b 
(a nti-pr o gr a m med cell deat h li ga n d -1 [ P D -L 1 ]) pl us c he m ot hera p y will de m o nstrate a de q uate safet y, 
t olera bilit y, a n d a ntit u m or acti vit y i n s u bjects wit h metastatic pa ncreatic d uctal a de n ocarci n o ma ( P D A C ) t hat 
has bee n pre vi o usl y u ntreate d or has pr o gresse d f oll o wi n g ge mci ta bi ne-base d c he m ot hera p y.
O B J E C TI V E S A N D S T U D Y E N D P OI N T S
Pri mar y  o bjecti ves a n d e n d p oi nts:
Part 1 ( D ose Escalati o n)
•
T o assess t he safet y a n d t olera bilit y of olecl u ma b pl us d ur val u ma b i n c o m bi nati o n wit h c he m ot hera p y 
a d mi nistere d i n s u bjects wit h metastatic P D A C

D ose -li miti n g t o xicities ( D L Ts), i nci de nce of a d verse e ve nts ( A Es) a n d seri o us a d verse e ve nts 
( S A Es), a n d cli nicall y mea ni n gf ul c ha n ges fr o m baseli ne i n cli nical la b orat or y para meters, vital 
si g ns, a n d electr ocar di o gra m ( E C G) res ults
Part 2 ( D ose E x pa nsi o n)
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d na b -paclita xel c o m pare d t o ge mcita bi ne a n d na b -paclita xel a d mi nistere d i n s u bjects 
wit h first-li ne (1 L) metastatic P D A C

O bjecti ve res p o nse ( O R) acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 
versi o n 1. 1 ( v 1. 1)
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n 
wit h a m o difie d re gi me n of le uc o v ori n, 5- fl u or o uracil ( 5-F U) a n d o xali plati n (m F O L F O X ) c o m pare d t o 
m F O L F O X a d mi nistere d i n s u bjects wit h sec o n d-li ne (2 L) metastatic P D A C

O R acc or di n g t o R E CI S T v 1. 1
Sec o n dar y o bjecti ves a n d e n d p oi nts:
Part 1 ( D ose Escalati o n)
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b pl us d ur val u ma b i n c o m bi nati o n wit h 
ge mcita bi ne a n d na b -paclita xel a d mi nistere d i n s u bjects wit h 1 L metastatic P D A C

O R a n d disease c o ntr ol ( D C ) acc or di n g t o R E CI S T v 1. 1
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b pl us d ur val u ma b i n c o m bi nati o n wit h 
m F O L F O X a d mi nistere d i n s u bjects wit h 2 L metastatic P D A C

O R a n d D C acc or di n g t o R E CI S T v 1. 1
Part 2 ( D ose E x pa nsi o n)
•
T o assess t he safet y a n d t olera bilit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
c he m ot hera p y a d mi nistere d i n s u bjects wit h metastatic P D A C

I nci de nce of A Es a n d S A Es a n d cli nicall y mea ni n gf ul c ha n ges fr o m baseli ne i n cli nical la b orat or y 
para meters, vital si g ns, a n d E C G res ults
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n 
wit h ge mcita bi ne a n d na b -paclita xel c o m pare d t o ge mcita bi ne a n d na b -paclita xel a d mi nistere d i n s u bjects 
wit h 1 L metastatic P D A C

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

O verall s ur vi val ( O S); pr o gressi o n -free s ur vi val ( P F S), d urati o n of res p o nse ( D o R), a n d D C 
a cc or di n g t o R E CI S T v 1. 1
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n 
wit h m F O L F O X c o m pare d t o m F O L F O X a d mi nistere d i n s u bjects wit h 2 L metastatic P D A C

O S; P F S, D o R, a n d D C acc or di n g t o R E CI S T v 1. 1
•
T o e val uate t he preli mi nar y a ntit u m or acti vit y of olecl u ma b wit h or wit h o ut d ur val u ma b i n c o m bi nati o n 
wit h c he m ot hera p y c o m pare d t o c he m ot hera p y al o ne i n t he p o p ulati o n defi ne d b y C D 7 3 e x pressi o n

O S; O R a n d P F S acc or di n g t o R E CI S T v 1. 1 b y C D 7 3 e x pressi o n at baseli ne
Part 1 ( D ose Escalati o n) a n d Part 2 ( D ose E x pa nsi o n)
•
T o assess t he i m m u n o ge nicit y of olecl u ma b a n d d ur val u ma b i n c o m bi nati o n wit h c he m ot hera p y 
a d mi nistere d i n s u bjects wit h metastatic P D A C

De vel o p me nt of detecta ble a nti -dr u g a nti b o dies ( A D As ) f ollo wi n g olecl u ma b a n d d ur val u ma b
•
T o deter mi ne t he p har mac o ki netic ( P K ) pr ofile of olecl u ma b a n d d ur val u ma b i n c o m bi nati o n wit h 
c he m ot hera p y a d mi nistere d i n s u bjects wit h metastatic P D A C

S u m mar y P K f or olecl u ma b, d ur val u ma b, a n d selecte d c he m o t hera pies a n d/ or t heir meta b olites
E x pl o rat or y o bjecti ves a n d e n d p oi nts:
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
S T U D Y D E SI G N
T his is a P hase 1 b/ 2, m ultice nter, o pe n -la bel, d ose-escalati o n a n d d ose-e x pa nsi o n st u d y t o assess t he safet y, 
preli mi nar y  a ntit u m or acti vit y, i m m u n o ge nicit y, a n d P K of olecl u ma b wit h or wit h o ut d ur val u ma b i n 
c o m bi nati o n w it h c he m ot hera p y a d mi nistere d i n s u bjects wit h metastatic P D A C. S u bjects wit h pre vi o usl y 
u ntreate d metastatic P D A C ( 1 L metastatic P D A C) will be e nr olle d i n C o h ort A. S u bjects wit h metastatic P D A C 
pre vi o usl y treate d wit h ge mcita bi ne -base d c he m ot hera p y ( wit h o ut e x p os ure t o 5 -F U, ca pecita bi ne, or 
o xali plati n; 2 L metastatic P D A C) will be e nr olle d i n C o h ort B. T he st u d y c o nsists of 2 parts, d ose escalati o n 
( Part 1) a n d d ose e x pa nsi o n ( Part 2). 
P art 1 ( D ose Esc al ati o n)
D uri n g Part 1, d ose escalati o n of olecl u ma b will be perf or me d i n c o m bi nati o n wit h d ur val u ma b a n d 
c he m ot hera p y ( ge mcita bi ne + na b-paclita xel f or s u bjects wit h 1 L metastatic P D A C [ C o h ort A]; m F O L F O X f or 
s u bjects wit h 2 L metastatic P D A C [ C o h ort B]) t o deter mi ne eit her t he ma xi m u m t olerate d d ose ( M T D) or t he 
hi g hest pr ot oc ol -defi ne d d ose f or eac h re gi me n. S u bjects will be e nr olle d i n c o h orts t o be treate d wit h i ncreasi n g 
d ose le vels of olecl u ma b wit h t he p ote ntial t o be treate d at a l o wer d ose le vel. A si n gle d ose le vel f or 
d ur val u ma b a n d c he m ot hera p y will be use d i n c o m bi nati o n wit h olecl u ma b. T he D ose -escalati o n C o m mittee 
will m o nit or s u bjects f or D L Ts d uri n g t he 2 8 -da y D L T -e val uati on p e ri o d a n d will ma ke decisi o ns f or 
e nr oll me nt of a d diti o nal s u bjects at a d ose le vel, d ose escalati o n t o t he ne xt d ose le vel, or d ose de -escalati o n.
D ose escalati o n will be gi n wit h e nr oll me nt of at least 3 s u bjects (a n d u p t o 6 s u bjects) at D ose L e vel 1. If n o 
D L Ts are o bser ve d i n a c o h ort of 3 t o 6 e val ua ble s u bjects , t he n d ose escalati o n t o t he ne xt hi g her d ose c o h ort 
will be per mitte d after re vie w of all a vaila ble safet y data. If 1 s u bject i n a d ose -le vel c o h ort of 3 or m ore 
e val ua ble s u bjects e x perie nces a D L T, t hat d ose-le vel c o h ort will be e x pa n de d t o a t otal of 6 s u bjects. If n o 
m ore t ha n 1 of 6 s u bjects i n t he d ose -le vel c o h ort e x perie nces a D L T, d ose escalati o n will c o nti n ue t o t he ne xt 
hi g her d ose -le vel c o h ort. If ≥ 2 s u bjects i n a d ose -le vel c o h ort e x perie nce a D L T, t he M T D will be e xcee de d a n d 
n o f urt her s u bjects will be e nr olle d i nt o t hat d ose -le vel c o h ort. If t his occ urs, t he prece di n g d ose-le vel c o h ort 
will be e val uate d f or t he M T D a n d a t otal of 6 s u bjects will be treate d at t he prece di n g d ose le vel if n ot alrea d y 
e x pa n de d. If ≤ 1 of 6 s u bjects e x perie nces a D L T at t he prece di n g d ose le vel, t he n t his d ose le vel will be t he 
M T D. If t he M T D is e xcee de d at t he starti n g d ose le vel, t he n a l o wer d ose le vel of olecl u ma b ( d ose le vel
-1) 
m a y  be e val uate d. 
P art 2 ( D ose E x p a nsi o n)
O nce t he rec o m me n de d P hase 2 d ose ( R P 2 D) f or a c o h ort has bee n i de ntifie d, e nr oll me nt i nt o Part 2 d ose 
e x pa nsi o n ma y pr ocee d. C o h orts A a n d B ma y be o pe ne d f or e nr oll me nt at t he discreti o n of t he s p o ns or 
i n de pe n de ntl y of eac h ot her.
D uri n g Part 2 ( d ose e x pa nsi o n), t he R P 2 D of olecl u ma b i de ntifie d i n Part 1 f or eac h re gi me n will be e val uate d 
wit h or wit h o ut d ur val u ma b i n c o m bi nati o n wit h c he m ot hera p y. S u bjects e nr olle d i n Part 2 will be stratifie d 
acc or di n g t o t u m oral e x pressi o n of C D 7 3 b y i m m u n o hist oc he mist r y (I H C) a n d ra n d o mize d t o a treat me nt ar m. 
S u bjects i n C o h ort A ( 1 L metastatic P D A C) will be ra n d o mize d 1: 1: 1 t o o ne of 3 treat me nt ar ms: ge mcita bi ne 
a n d na b-paclita xel ( Ar m A 1); olecl u ma b + ge mcita bi ne a n d na b -paclita xel ( Ar m A 2); or olecl u ma b + 
d ur val u m a b + ge mcita bi ne a n d na b-paclita xel ( Ar m A 3). S u bjects i n C o h ort B ( 2 L metastatic P D A C) will be 
ra n d o mize d 1: 1: 1 t o o ne of 3 treat me nt ar ms: m F O L F O X ( Ar m B 1); olecl u ma b + m F O L F O X ( Ar m B 2); or 
olecl u ma b + d ur val u ma b + m F O L F O X ( Ar m B 3). T here will be n o cr os s o ver bet wee n treat me nt ar ms.
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T A R G E T S U B J E C T P O P U L A TI O N
S u bjects ≥ 1 8 y ears of a ge dia g n ose d wit h hist ol o gicall y or c yt ol o gicall y c o nfir me d pa ncreatic a de n ocarci n o ma. 
S u bjects wit h pre vi o usl y u ntreate d metastatic P D A C ( 1 L metastatic P D A C) will be e nr olle d i n C o h ort A. 
S u bjects wit h metastatic P D A C pre vi o usl y treate d wit h ge mcita bi ne -base d c he m ot hera p y ( wit h o ut e x p os ure t o 
5 -F U, ca pecita bi ne, or o xali plati n [if c o nsi dere d a li ne of t hera p y]; 2 L metastatic P D A C) will be e nr olle d i n 
C o h ort B.
T R E A T M E N T G R O U P S A N D R E GI M E N S
U p t o a p pr o xi matel y 3 3 9 s u bjects will be e nr olle d i n t his st u d y: u p t o a p pr o xi matel y 2 4 s u bjects i n Part 1 ( d ose 
escalati o n) a n d u p t o a p pr o xi matel y 3 1 5 s u bjects i n Part 2 ( d ose e x pa nsi o n). All s u bjects i n b ot h c o h orts will be 
treate d until disease pr o gressi o n (a n d t he treat me nt criteria i n t he setti n g of pr o gressi ve disease are n ot met), 
i nt olera ble t o xicit y, wit h dra wal of s u bject c o nse nt, or a n ot her disc o nti n uati o n criteri o n is met.
A n y  st u d y s u bject still recei vi n g i n vesti gati o nal pr od uct at t he ti me of data e ntr y c ut -off will c o nti n ue t o recei ve 
i n vesti gati o nal pr o d uct wit hi n t he c urre nt st u d y t hr o u g h a c o nti n ue d treat me nt peri o d after data c ut -off f or 
a nal ysis of fi nal st u d y data as l on g as, i n t he I n vesti gat or’s o pi ni o n, t he st u d y s u bject is deri vi n g cli nical be nefit 
a n d has n ot f ulfille d a n y treat me nt disc o nti n uati o n criteria.
P art 1 ( D ose Esc al ati o n)
U p t o a p pr o xi matel y 2 4 s u bjects will be e nr olle d i n Part 1 ( d ose escalati o n): 9 t o a p pr o xi matel y 1 2 s u bjects wit h 
1 L metastatic P D A C will be e nr olle d i n C o h ort A a n d 9 t o a p pr o xi matel y 1 2 s u bjects wit h 2 L metastatic P D A C 
will be e nr olle d i n C o h ort B a n d treate d wit h i ncreasi n g d ose le vels of olecl u ma b. A si n gle d ose le vel f or 
d ur val u ma b a n d c he m ot hera p y ( ge mcita bi ne/ na b -paclita xel f or C o h ort A; m F O L O X f or C o h ort B) will be use d 
i n c o m bi nati o n wit h olecl u ma b as detaile d bel o w.
•
Olecl u ma b at o ne of 3 d ose le vels:

D ose le vel -1 ( 3 -6 s u bjects):  
 e ver y 2 wee ks ( Q 2 W ) f or 4 d oses, t he n e ver y 4 wee ks 
(Q 4 W ); if t he M T D is e xcee de d at t he starti n g d ose le vel (D ose L e vel 1)

D ose le vel 1 ( 3 -6 s u bjects)
 Q 2 W f or 4 d oses, t he n Q 4 W (starti n g d ose le vel)

D ose le vel 2 ( 6 s u bjects):  
 Q 2 W f or 4 d oses, t he n Q 4 W ( hi g hest pla n ne d d ose le vel)
•
D ur val u ma b  
 I V Q 4 W
•
C o h ort A: G e mci ta bi ne 
I V a n d na b-paclita xel 
I V on D a ys 1, 8, a n d 1 5 a n d t he n 
re peate d o n a Q 4 W sc he d ule
•
C o h ort B: m F O L F O X o n Da ys 1 a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule : o xali plati n 
I V; 
le uc o v ori n 
I V; 5-F U 
I V b ol us f oll o we d b y 5-F U 
a d mi nistere d b y 
c o nti n u o us I V i nf usi o n o ver 4 6 t o 4 8 h o urs
P art 2 ( D ose E x p a nsi o n)
U p t o a p pr o xi matel y 3 1 5 s u bjects will be e nr olle d i n Part 2 ( d ose e x pa nsi o n), u p t o a p pr o xi matel y 2 1 0 s u bjects
i n C oh ort A a n d u p t o a ppr o xi matel y 1 0 5 s u bjects i n C o h ort B . S u bjects will be stratifie d b y C D 7 3 e x pressi o n 
le vel a n d ra n d o mize d 1: 1: 1 t o o ne of 3 treat me nt ar ms per c o h ort (a p pr o xi matel y 7 0 s u bjects per treat me nt ar m
i n C oh ort A; a p pr o xi matel y 3 5 s u bjects per treat me nt ar m i n Co h ort B ). T he d ose le vel f or olecl u ma b will be 
deter mi ne d d uri n g Part 1 ( d ose escalati o n). T he d ose a n d treat me nt re gi me ns f or d ur val u ma b a n d c he m ot hera p y 
are t he sa me as i n d ose escalati o n. T he treat me nt ar ms f or eac h co h ort are detaile d bel o w:
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
•
C o h ort A

Ar m A 1 ( 7 0 s u bjects): ge mcita bi ne/ na b-paclita xel

Ar m A 2 ( 7 0 s u bjects): olecl u ma b a n d ge mcita bi ne/ na b-paclita xel

Ar m A 3 ( 7 0 s u bjects): olecl u ma b, d ur val u ma b, a n d ge mcita bi ne/ na b-paclita xel
•
C o h ort B

Ar m B 1 ( 3 5 s u bjects): m F O L F O X 

Ar m B 2 ( 3 5 s u bjects): olecl u ma b a n d m F O L F O X 

Ar m B 3 ( 3 5 s u bjects): olecl u ma b, d ur val u ma b, a n d m F O L F O X
S T A TI S TI C A L M E T H O D S 
S a m ple size: U p t o a p pr o xi matel y 3 3 9 s u bjects will be e nr olle d i n t he st u d y: u p t o a p pr o xi matel y 2 4 s u bjects i n 
Part 1, D ose Escalati o n a n d u p t o a p pr o xi matel y 3 1 5 s u bjects i n Part 2, D ose E x pa nsi o n (u p t o a p pr o xi matel y 
2 1 0 s u bjects i n C o h ort A a n d u p t o a p pr o xi matel y 1 0 5 s u bjects i n C o h or t B).
St atistic al a n al yses:
Efficac y:
T he efficac y a nal yses of a ntit u m or acti vit y will be base d o n t he int e nt -t o-treat (I T T) po p ulati o n ( defi ne d as all 
s u bjects w h o are ra n d o mize d a n d recei ve a n y a m o u nt of i n vesti gati o nal pr o d uct, a nal yze d acc or di n g t o 
ra n d o mize d treat me nt assi g n me nt). T he rates of O R a n d D C base d o n R E CI S T v 1. 1 will be s u m marize d wit h 
9 5 % c o nfi de nce i nter val base d o n t he e xact bi n o mial distri b uti o n. Ti me -t o-e ve nt e n d p oi nts ( D o R, P F S, a n d O S) 
will be a nal yze d usi n g t he Ka pla n -Meier met h o d. A d diti o nal a nal yses of a ntit u m or acti vit y ma y be c o n d ucte d i n 
t he as-treate d p o p ulati o n ( defi ne d as all s u bjects w h o recei ve a n y i n vesti gati o nal pr o d uct a nal yze d acc or di n g t o 
treat me nt recei ve d).
Safet y:
Safet y data, i ncl u di n g D L Ts, A Es, S A Es, la b orat or y e val uati o ns, vital si g ns, a n d E C G res ults will be 
s u m marize d base d o n t he as-treate d p o p ulati o n ( defi ne d as all s u bjects w h o recei ve a n y i n vesti gati o nal pr o d uct 
a nal yze d acc or di n g t o treat me nt recei ve d) . Descri pti ve statistics will be pr o vi de d f or A Es, S A Es, A E gra de 
(se verit y), a n d relati ons hi p t o i n vesti gati o nal pr o d uct(s), cli nical la b orat or y para meters, v ital si g ns, a n d E C G
res ults. A Es will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( N CI C T C A E) versi o n 4. 0 3. Descri pti ve statistics will be pr o vi de d f or t he cli nical la b orat or y 
res ults a n d c ha n ges fr o m baseli ne b y sc he d ule d ti me of e val uati o n a n d b y treat me nt ar m i ncl u di n g e n d of 
treat me nt visit as well as f or t he ma xi m u m a n d mi ni m u m p ost-baseli ne val ues. La b orat or y a b n or malities will be 
gra de d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3, if a p plica ble. Fre q ue ncies of w orst o bser ve d gra de will be 
prese nte d f or eac h la b orat or y para meter as well as t he rates of s u bjects wit h Gra de 3 -4 t o xicities.
I m m u n o ge nicit y a n d P har mac o ki netics:
O nl y s u bjects w h o recei ve at least 1 d ose of olecl u ma b a n d/ or d ur val u ma b a n d pr o vi de at least 1 p ost -treat me nt 
sa m ple will be e val uate d. 
F or eac h c o h ort, t he i m m u n o ge nic p ote ntial of c o m bi nati o ns will be assesse d b y s u m marizi n g t he n u m ber a n d 
perce nta ge of s u bjects w h o de vel o p detecta ble A D As. T he i m pact of A D As o n P K will be assesse d if data 
all o w. Sa m ples will be c ollecte d f or p ote ntiall y e val uati n g t he ne utralizi n g ca pacit y of A D As i n t he f ut ure. 
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
I n di vi d ual olecl u ma b a n d d ur val u ma b c o nce ntrati o ns will be ta b ulate d b y d ose c o h ort al o n g wit h descri pti ve 
statistics. N o n-c o m part me ntal P K data a nal ysis will be perf or me d fr o m eac h d ose c o h ort wit h sc he d ule d P K 
sa m ple c ollecti o n w here data all o w. Rele va nt descri pti ve statistics of n o n-c o m part me ntal P K para meters will be 
pr o vi de d a n d ma y i ncl u de: area u n der c o nce ntrati o n -ti me c ur ve, ma xi m u m o bser ve d c o nce ntrati o n ( C ma x ), ti me 
t o reac h Cma x , cleara nce, v ol u me of distri b uti o n, a n d ter mi nal half-life.
 
 
 
.
I nteri m A nal ysis:
A n i nte ri m a nal ysis will be perf or me d whe n a p pr o xi matel y 3 0 s u bjects i n eac h treat me nt ar m of Part 2 C o h ort A 
ha ve bee n d ose d a n d reac h t he data c ut -off criteria (ie, s u bjects w h o ha ve a baseli ne disease assess me nt, ha ve 
bee n d ose d at least 1 6 wee ks pri o r t o t he ti me of t he data c ut-off, a n d ha ve at least 1 p ost -baseli ne disease 
assess me nt a n d/ or disc o nti n ue d treat me nt d ue t o deat h or disease pr o gressi o n). Ra n d o mizati o n ma y be pa use d
d uri n g t he i nteri m a nal ysis bef ore t he decisi o n is ma de. If t he f utilit y criteria are met f or a n e x peri me ntal ar m, 
f urt her e nr oll me nt t o t hat ar m will be st o p pe d.
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T A B L E O F C O N T E N T S
P R O T O C O L S Y N O P SI S ......................................................................................................2
T A B L E O F C O N T E N T S ......................................................................................................8
LI S T O F A B B R E VI A TI O N S .............................................................................................1 4
1
I N T R O D U C TI O N ............................................................................................1 7
1. 1
Di sease Bac k gr o u n d .........................................................................................1 7
1. 1. 1
C he m ot h era p y in Pa ncreat ic D uctal Carci n oma .................................................1 7
1. 1. 2
I mm u n ot hera p y ................................................................................................. 1 8
1. 1. 3
I mm u n ot hera p y  in C o m bi nat i on wi t h C he mot h era p y ........................................1 8
1. 1. 4
C D 7 3 ................................................................................................................1 9
1. 2
Ol ecl u ma b a n d D ur val u ma b Bac k gr o u n d ..........................................................2 0
1. 2. 1
Ol ecl u ma b Bac k gr o u n d .....................................................................................2 0
1. 2. 2
D ur val u ma b Bac k gr o u n d ..................................................................................2 0
1. 3
S u m mar y  of N o ncli nical E x perie nce................................................................. 2 1
1. 3. 1
...................................................................2 1
1. 3. 2
D ur val u ma b N o ncli nical E x perie nce ................................................................. 2 1
1. 4
S u m mar y  of Cli nical E x perie nce.......................................................................2 1
1. 4. 1
Ol ecl u ma b Cli nical E x perie nce .........................................................................2 1
1. 4. 1. 1
St u d y  D 6 0 7 0 C 0 0 0 0 1.........................................................................................2 1
1. 4. 1. 2
St u d y  D 6 0 7 0 C 0 0 0 0 5.........................................................................................2 4
1. 4. 2
D ur val u ma b Cli nical E x perie nce .......................................................................2 7
1. 5
Rati o nale f or C o n d ucti n g t he St u d y ..................................................................2 8
1. 6
Be nefit -Ris k a n d Et hi cal Assess me nt ................................................................2 9
1. 6. 1
P ote nti al Ris ks..................................................................................................2 9
1. 6. 2
P ote nti al Be nefits..............................................................................................3 0
1. 7
Researc h H y p ot heses ........................................................................................3 1
2
O BJ E C TI V E S A N D E N D P O I N T S...................................................................3 1
2. 1
Pri mar y O bject i ve(s) a n d Ass ociate d E n d p oi nts................................................3 1
2. 1. 1
Sec o n dar y  O bjecti ves a n d Ass ociate d E n d p oi nts...............................................3 2
2. 1. 2
3
S T U D Y D E SI G N .............................................................................................3 4
3. 1
Descri pt i on of t he St u d y ...................................................................................3 4
3. 1. 1
O ver vie w ..........................................................................................................3 4
3. 1. 1. 1
Part 1: D ose Escalat i on .....................................................................................3 6
3. 1. 1. 2
Part 2: D ose E x pa nsi o n .....................................................................................3 7
3. 1. 2
Treat me nt Re gi me n ...........................................................................................3 8
3. 1. 2. 1
Part 1: D ose Escalat i on .....................................................................................3 8
3. 1. 2. 2
Part 2: D ose E x pa nsi o n .....................................................................................3 9
3. 1. 3
D ose Escal atio n, C o h ort Pr o gressi o n, D ose -li miti n g T o xicit y, a n d Safety 
Re vie w .............................................................................................................4 2
3. 1. 3. 1
D ose -escalat i on C o m mittee ( Part 1, D ose Escalat i o n).......................................4 2
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
5. 3. 3
A d verse E ve nts of S pecial I nterest f or D ur val u ma b ..........................................9 8
5. 4
Rec or di n g of A d verse E ve nts ............................................................................9 9
5. 4. 1
Ti me Peri o d f or C ollect i on of A d verse E ve nts ................................................1 0 0
5. 4. 2
F o ll ow- u p of  U nres ol ve d A d verse E ve nts .......................................................1 0 0
5. 4. 3
Deat hs ............................................................................................................1 0 0
5. 4. 4
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ..............................................1 0 0
5. 4. 5
A d verse E ve nts Base d o n E xa mi nat i on a n d Tests ............................................1 0 1
5. 4. 6
H y’s La w ........................................................................................................1 0 1
5. 4. 7
Di sease Pr o gressio n ........................................................................................1 0 1
5. 5
Re p orti n g of Seri o us A d verse E ve nts ..............................................................1 0 2
5. 6
Ot her E ve nts Re q uiri n g I m me diate Re p orti n g .................................................1 0 3
5. 6. 1
O ver d ose ........................................................................................................1 0 3
5. 6. 2
Pre g na nc y .......................................................................................................1 0 3
5. 6. 2. 1
Mater nal E x p os ure ..........................................................................................1 0 4
5. 6. 2. 2
Pater nal  E x p os ure...........................................................................................1 0 4
5. 6. 3
Me dicat i on Err or .............................................................................................1 0 4
6
S T U D Y A N D D A T A M A N A G E M E N T .........................................................1 0 6
6. 1
Trai ni n g of St u d y  Site Pers o n nel.....................................................................1 0 6
6. 2
M o ni t ori n g of t he St u d y..................................................................................1 0 6
6. 2. 1
S o urce Data ....................................................................................................1 0 6
6. 2. 2
St u d y  A gree me nts...........................................................................................1 0 6
6. 2. 3
Arc hi vi n g of St u d y  D o c u me nts .......................................................................1 0 7
6. 3
St u d y  Ti meta ble a n d E n d of St u d y..................................................................1 0 7
6. 4
Data Ma na ge me nt ...........................................................................................1 0 7
6. 5
Me dical M o nit or C o vera ge .............................................................................1 0 8
7
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S ....................................1 0 8
7. 1
S u bject Data Pr otecti o n ...................................................................................1 0 8
7. 2
Et hics a n d Re g ulat or y  Re vie w ........................................................................1 0 8
7. 3
I nf or me d C o nse nt ...........................................................................................1 0 9
7. 4
C ha n ges t o t he Pr ot oc ol a n d I nf or me d C o nse nt F or m ......................................1 0 9
7. 5
A u dits a n d I ns pect i ons ....................................................................................1 1 0
8
R E F E R E N C E S ...............................................................................................1 1 1
9
C H A N G E S T O T H E P R O T O C O L ................................................................. 1 1 5
9. 1
Pr ot oc ol  A me n d me nt 3...................................................................................1 1 5
9. 2
Pr ot oc ol  A me n d me nt 2...................................................................................1 1 5
9. 3
Pr ot oc ol  A me n d me nt 1...................................................................................1 1 7
1 0  
A P P E N DI C E S ................................................................................................1 2 0
1 0. 1
C o ntrace pti o n G ui da nce ..................................................................................1 2 0
1 0. 2
A d dit i onal Safet y G ui da nce ............................................................................1 2 1

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 of 1 4 4
Te m plate 1 8. 0
Ta ble 1 0 ( 4. 3. 3- 1) ...............................C ollect i on Ti mes f or Vital Si g ns D uri n g t he Treat me nt 
p eri o d ......................................................................................................7 5
Ta ble 1 1 ( 4. 3. 3- 2) ..................C ollect i on Ti mes f or El ectr ocar dio gr a m s D uri n g t he Treat me nt 
p eri o d ......................................................................................................7 6
Ta ble 1 2 ( 4. 5. 1- 1) .................................................................. I de ntificati o n of I n vesti gati onal 
Pr o d ucts ...................................................................................................8 2
Ta ble 1 3 ( 4. 8. 2- 1)
 
Ta ble 1 4 ( 9. 2-1) Hi g hl y  Effecti ve Met h o ds of C o ntrace pti o n ...........................................1 2 0
Ta ble 1 5 ( 9. 8-1) E val uat i on of O verall Res p o nse usi n g R E CI S T v 1. 1 ..............................1 3 7
Ta ble 1 6 ( 9. 9-1)
Ta ble 1 7 ( 9. 1 0-1) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes 
f or I m m u ne-me diate d Reacti o ns – Ge neral C o nsi derati o ns ....................1 4 1
Ta ble 1 8 ( 9. 1 0-3) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes 
f or I nf usio n -relate d Reactio ns................................................................ 1 4 3
Ta ble 1 9 ( 9. 1 0-4) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes 
f or N o n-i m m u ne-me diate d Reacti o ns .....................................................1 4 4
LI S T O F FI G U R E S
Fi g ure 1 ( 3. 1. 1 -1) .............................................................. St u d y  Flo w Dia gra m  ( Part 1: D ose 
Escal at i on) ...............................................................................................3 5
Fi g ure 2 ( 3. 1. 1 -2) .............................................................. St u d y  Flo w Dia gra m  ( Part 2: D ose 
E x pa nsi o n) ...............................................................................................3 6
Fi g ure 3 ( 3. 1. 2. 1- 1) .........................................................Treat me nt Re gi me n f or Part 1 ( D ose 
Escal at i on) ...............................................................................................3 9
Fi g ure 4 ( 3. 1. 2. 2- 1) Tr e at me nt Re gi me n f or C o h ort A ( Ar ms A 1, A 2, a n d A 3) i n Part 2 ( D ose 
E x pa nsi o n) ...............................................................................................4 1
Fi g ure 5 ( 3. 1. 2. 2- 2).Treat me nt Re gi me n f or C o h ort B ( Ar ms B 1, B 2, a n d B 3) i n Part 2 ( D ose 
E x pa nsi o n) ...............................................................................................4 1
Fi g ure 6
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 of 1 4 4
Te m plate 1 8. 0
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n or 
S peci alize d Ter m
Defi niti o n
δ
delta
1 L
first-li ne
2 L
sec o n d-li ne
5 -F U
5 -fl u or o uracil
A D A
a nti -dr u g a nti b o d y
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A M P
a de n osi ne m o n o p h os p hate
A S T
as partate a mi n otra nsferase
A T P
a de n osi ne tri p h os p hate
A U C
area u n der c o nce ntrati o n -ti me c ur ve
C A P
C olle ge of A merica n Pat h ol o gists
C D
cl uster of differe ntiati o n
CI
c o nfi de nce i nter val
C LI A
Cli nical La b orat or y I m pr o ve me nt A me n d me nts 
C ma x
ma xi m u m o bser ve d c o nce ntrati o n 
C N S
ce ntral ner v o us s yste m
C R
c o m plete res p o nse
C R C
c ol or ectal ca ncer
C S R
cli nical st u d y re p ort
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 or D N A
C T L A - 4
c yt ot o xic T-l ym p h oc y te ass ociate d pr otei n- 4
D C
disease c o ntr ol
D C R
disease c o ntr ol rate
D E C
D ose -escalati o n C o m mittee
D L T
d ose -li miti n g t o xicit y
D o R
d urati o n of res p o nse
E C G
electr ocar di o gra m

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 of 1 4 4
Te m plate 1 8. 0
A b bre vi ati o n or 
S peci alize d Ter m
Defi niti o n
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
 
 
F O L F O X
le uc o v ori n, 5-fl u or o uracil, a n d o xali plati n
F O L FI RI
5 -fl u or o uracil a n d li p os o mal iri n oteca n
F O L FI RI N O X
le uc o v ori n, 5-fl u or o uracil, iri n oteca n, a n d o xali plati n
F TI H
first-ti me-i n-h u ma n
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m yl tra nsferase
H Cl
h y dr oc hl ori de
H M G B 1
hi g h -m o bilit y gr o u p b o x 1
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 nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I F N-γ
i nterfer o n-ga m ma
I g
i m m u n o gl o b uli n
I H C
i m m u n o hist oc he mical
I L D
i nterstitial l u n g disease
i m A E
i m m u ne-me diate d a d verse e ve nt
I R B
I nstit uti onal Re vie w B oar d
I R R
i nf usi o n-relate d reacti o ns
I R T
I nteracti ve Res p o nse Tec h n ol o g y
I V
i ntra ve n o us(l y)
m A b
m o n ocl o nal a nti b o d y
m F O L F O X
m o difie d re gi me n of le uc o v ori n, 5 -fl u or o uracil, a n d o xali plati n
M RI
ma g netic res o na nce i ma gi n g
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
A b bre vi ati o n or 
S peci alize d Ter m
Defi niti o n
M S S
micr osatellite sta ble
M T D
ma xi m u m t olerate d d ose
N CI C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
N S C L C
n o n- s mall cell l u n g ca ncer
O R
o bjecti ve res p o nse
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
P D
pr o gressi ve disease
P D - 1
pr o gra m me d cell deat h - 1
P D -L 1
pr o gra m me d cell deat h li ga n d- 1
P D A C
pa ncreatic d uctal a de n ocarci n o ma
P F S
pr o gressi o n -free s ur vi val
P K
p har mac o ki netic(s)
P R
partial res p o nse
Q 2 W
e ver y 2 wee ks
Q 4 W
e ver y 4 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 ors
R P 2 D
rec o m me n de d P hase 2 d ose
S A E
seri o us a d verse e ve nt
S D
sta ble disease
SI D
s u bject i de ntificati o n
SI R S
s yste mic i nfla m mat or y res p o nse s y n dr o me
S R C
Safet y Re vie w C o m mittee
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
ter mi nal half-life
T B L
t otal bilir u bi n
T M A
t u m or tiss ue micr oarra y
tma x
ti me t o reac h Cma x
T N B C
tri ple ne gati ve breast ca ncer
T V
tar get val ue
U L N
u p per li mit of n or mal
V d
v ol u me of distri b uti o n
w/ v
wei g ht/ v ol u me
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1
I N T R O D U C TI O N
1. 1
Dise ase B ac k gr o u n d
Pa ncreat ic ca ncer c o nstitutes a b o ut 2. 4 % of all ca ncers w orl d wi de b ut acc o u nts f or 4 % of all 
ca ncer -r elate d deat hs (G L O B O C A N, 2 0 1 2 ). O verall, it is t he se ve nt h m ost c o m m o n ca use of 
deat h fr o m ca ncer f or b ot h me n a n d w o me n (G L O B O C A N, 2 0 1 2 ). I n 2 0 0 0, t here were 
a p pr o xi matel y 2 1 6, 4 0 0 ne w cases of pa ncreatic ca ncer gl o ball y wit h 2 1 3, 5 0 0 re p orte d deat hs 
fr om t he disease (Par ki n et al, 2 0 0 1 ). B y 2 0 1 2, t he n u m ber of ne w cases ha d i ncrease d t o 
3 3 7, 9 7 2 wit h 3 3 0, 3 9 1 esti mate d deat hs w orl d wi de (G L O B O C A N, 2 0 1 2 ). T he hi g h m ortality 
r at e is a testa me nt t o t he a g gressi ve ness of t his disease a n d is f urt her c o m p o u n de d b y t he lac k 
of  effecti ve t hera pies. Gi ve n b ot h t he i ncreasi n g i nci de nce a n d let hality of  t his disease, it is 
esse nt ial t hat n o vel effecti ve t hera pies are de vel o pe d t o re d uce h uma n s ufferi n g a n d deat h.
Pa ncreat ic d uctal a de n ocarci n oma ( P D A C) is a mali g na nc y wit h a n e xtre mel y p o or pr o g n osis, 
as e xe m plifie d b y a 1 -ye ar s ur vi val rate of a p pr o xi matel y 1 8 % f or all sta ges of t he disease a n d 
a n est i mate d 5-year s ur vi val rate of less t ha n 4 % (Hi dal g o et al , 2 0 1 5). At t he ti me of 
di a g n osis, a p pr o xi matel y 5 0 % t o 6 0 % of P D A C pati e nts ha ve metastatic disease, a n d 
a p pr o xi matel y 3 0 % t o 4 0 % ha ve l ocall y a d va nce d disease n ot a me na ble t o resecti o n (Gille n et 
al, 2 0 1 0). T his u n dersc ores t he u n met me dical nee d f or m ore effecti ve t hera pies f or P D A C 
pati e nts, es peciall y i n t he metastatic setti n g.
1. 1. 1
C he m ot her a p y i n P a ncre atic D uct al C arci n o m a
C o m bi nat i on c he m ot hera p y  is t he mai nsta y of tr e at me nt for fi rst-li ne ( 1 L) a n d sec o n d-li ne 
( 2 L) metastatic P D A C. T he re gi me ns t y p icall y utilize d i n t he 1 L setti n g i ncl u de 1) 
g e m cita bi ne + na b-paclit a xel, 2) le uc o v ori n, 5 -fl u or o uracil ( 5-F U), i rin oteca n a n d o xali plat i n 
( F O L FI RI N O X), 3) ge mcita bi ne + ca pecita bi ne, a n d 4) ge mcita bi ne + d oceta xel + 
ca pecita bi ne. I n patie nts wit h g o o d perf or ma nce stat us, ge mcita bi ne + na b -pacli ta xel is o ne of 
t he most c o m m o nl y prescri be d re gi me ns gl o ball y . I n patie nts wit h p o or perf or ma nce stat us, 
g e m cit a bi n e mo n ot h era p y is ty p icall y use d. T he re gi me ns c o ntai ni n g m ore t ha n 2 acti ve 
a ge nts t ypicall y res ulte d i n sli g ht l y hi g her res p o nse rates a n d me dia n o verall s ur vi val ( O S) b ut 
at t he e x pe nse of i ncrease d t o xicit y.  T he most c o m m o nl y  use d of t hese is F O L FI RI N O X wit h 
a n o bject i ve res p o nse rate ( O R R) of 3 2 % a n d a me dia n O S of 1 1. 1 m o nt hs (C o nr o y  et al, 
2 0 1 1) . I n c o ntrast, ge mcita bi ne + na b-paclit a xel has a n O R R o f 2 3 % a n d a me dia n O S of 8. 5 
m o nt hs b ut a m or e f a v ora ble safet y pr ofile (V o n H off et al, 2 0 1 3 ).
T he re gi me ns t y p icall y utilize d i n 2 L P D A C patie nts t hat recei ve d a ge mcita bi ne-base d 
t hera p y in t h e 1 L i ncl u de 5 -F U + li p os o mal iri n oteca n ( F O L FI RI) or a m o difie d re gi me n of 
le uc o v ori n, 5- F U , a n d o xali plat i n ( m F O L F O X) f or patie nts wit h g o o d perf or ma nce stat us. 
P ati e nts wit h p o or perf or ma nce stat us t ypicall y  recei ve si n gle-a ge nt 5-F U or best s u p p orti ve 
care o nl y. I n a 3- ar m, ra n d o mize d, o pe n-la bel st u d y, li p os o mal iri n oteca n + 5-F U ha d a n O R R 
of  7. 7 % vers us 0. 8 % f or t he le uc o v ori n + 5 -F U ar m a n d de m o nstrate d a statist icall y 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 1 4 4
Te m plate 1 8. 0
sig nifica nt i m pr o ve me nt i n me dia n O S of 6. 1 m o nt hs vers us 4. 2 m o nt hs (Merri mac k 
P har mace ut icals, 2 0 1 5). T here ha ve bee n m ulti ple st u dies of m F O L F O X w here t he O R R has 
ra n ge d fr om 0 % t o 7 % wit h me dia n O S bet wee n 3. 4 t o 5. 1 m o nt hs (P el zer et al, 2 0 1 1; Y o o et 
al, 2 0 0 9). Gi ve n t he differi n g safety pr ofiles of t he 2 re gi me ns, ma n y cli nicia ns ha ve 
c o nti n ue d t o fa v or t he use of m F O L F O X i n t he 2 L setti n g f or patie nts wit h g o o d perf or ma nce 
stat us t hat recei ve d ge mcita bi ne-base d t hera p y i n 1 L.
1. 1. 2
I m m u n ot her a p y
Rece nt l y, c hec k p oi nt i n hi bit ors ( pr o gra m me d cell deat h-1 [ P D -1]/ pr o gra m me d cell deat h 
li ga n d-1 [ P D -L 1] a n d c y t ot o xic T-l y m p h oc yte ass ociate d pr otei n-4 [ C T L A -4] i n hi bit ors) ha ve 
s h o w n si g nifica nt a ntitu m or acti vit y a n d bec o me t he sta n dar d -of -care f or mul tiple t u m or 
t ypes. D ue t o t hei r n o n-re d u n da nt mec ha nis m of actio n ( Par d oll, 2 0 1 2 ), tar geti n g b ot h P D-L 1 
a n d C T L A-4 pat h wa ys si m ulta ne o usl y mi g ht ha ve a d dit i ve or s y ner gistic acti vity i n ter ms of 
t u mor res p o nse. H o we ver, d ur val u ma b ( P D -L 1 i n hi bit or) or tre meli m u ma b ( C T L A- 4 
i n hi bit or) m o n ot hera p y a n d i n c o m bi nati on t hera p y di d n ot s h o w mea ni n gf ul cli nical act i vity 
i n 2 L metastatic P D A C s u bjects (O' Reill y et al, 2 0 1 8 ).
1. 1. 3
I m m u n ot her a p y i n C o m bi n ati o n wit h C he m ot her a p y
I mm u n ot hera p y  in c o m bi nat i on wi t h c he mot h era p y has s h o w n t he p ote ntial f or a d diti ve or 
s y ner gistic effects o n cli nical res p o nse acr oss m ulti ple t u m or t y pes e ve n w he n t he 
i m m u n ot hera p y effect b y its elf was mi ni mal s uc h as i n c o l orectal ca ncer (C R C ). 
I n a P hase 1 b, o pe n-label, 2 -ar m st u d y, atez oliz u ma b ( P D -L 1 i n hi bit or) + be vaciz u ma b (a 
vasc ular e n d ot helial gr o wt h fact or i n hi bit or) i n refract or y metastatic C R C patie nts ( Ar m A) 
a n d atez oliz u ma b + be vaciz u ma b + (le uc o v ori n, 5-F U, a n d o xali plati n [F O L F O X ]) i n 
o xali plat i n-nai ve m etastatic C R C pat ient s ( Ar m B) were e valu at e d . T he u nc o nfir me d O R R 
was 8 % ( 1/ 1 3) i n Ar m A a n d 3 6 % ( 9/ 2 5) i n Ar m B f or s u bjects wit h ≥1 t u m or assess me nt. 
T he u nc o nfir me d O R R was 4 4 % ( 8/ 1 8) f or Ar m B 1 L s u bjects. It was c o ncl u de d t hat t here 
were n o u ne x pecte d t o xicit ies a n d t hat cli nical acti vity was de m o n strate d i n b ot h treat me nt 
re gi me ns (Be n dell et al, 2 0 1 5 ).
I n a P hase 2 st u d y, pe m br oliz u ma b ( P D-L 1 i n hi bit or) i n c o m bi nat i on wi t h mF O L F O X was 
e val uate d i n s u bjects wit h u ntreate d, u nresecta ble C R C. T he st u d y  re p orte d o utc o mes were 
1 c o mplete res p o nse ( C R), 1 5 partial res p o nses ( P Rs), ( O R R = 5 3 %) a n d 1 4 sta ble disease 
( S D). T he a ut h ors c o ncl u de d t hat t he c o m bi nati on ha d a n acce pt a ble safet y pr ofile i n s u bjects 
wi t h u ntreate d a d va nce d C R C a n d t hat cli nical acti vity was e nc o ura gi n g (S ha h da et al, 2 0 1 7 ).
I n a P hase 2, o pe n-label st u d y of c he mot h era p y-naï ve s u bjects wit h n o n -s mall cell l u n g ca ncer 
( N S C L C), s u bjects recei ve d 4 c ycles of pe m br oliz u m a b 2 0 0 mg pl us car b o pl at i n area u n der 
c o nce ntrati o n-ti me c ur ve ( A U C) 5 m g/ m L per mi n a n d pe metre xe d 5 0 0 m g/ m² e ver y 3 wee ks 
f oll owe d b y pe m br o liz u ma b f or 2 4 m o nt hs a n d i n defi nite pe metre xe d mai nte na nce t hera p y or 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4 c y cles o f car b o plat i n a n d pe metre xe d alo n e fol l owe d b y  in defi ni te pe metre xe d mai nte na nce 
t hera p y (La n ger et al, 2 0 1 6 ). Fifty- fi ve perce nt ( 3 3/ 6 0) s u bjects i n t he pe m br oliz u ma b pl us 
c he m ot hera p y gr o u p ac hie ve d a n o bject i ve res p o nse ( O R) c o m pare d wit h 2 9 % ( 1 8/ 6 3) 
s u bjects treate d wit h c he m ot hera p y alo n e ( p = 0· 0 0 1 6). Base d o n t he res ults o f t his st u d y, t his 
is n o w a n a p pr o ve d t hera p y  in t he U nite d States. 
I n a d diti on, preli mi nar y cli nical data of ge mcita bi ne a n d na b- paclita xel c o m bi ne d wit h 
d ur val u ma b a n d tre meli m u ma b i n 1 1 s u bjects wit h metastatic P D A C s h o we d a n O R R of 7 3 % 
a n d disease c o ntr ol rate ( D C R) of 1 0 0 %. T he fi n di n gs c om pare fa v ora bl y wit h t he O R R a n d 
D C R o bser ve d wit h a c urre nt sta n dar d-of -care, ge mcita bi ne a n d na b-pacli t a x el ( O R R 2 9 %, 
D C R 8 0 %). T hese preli mi nar y  data s u g gest s y ner gistic acti vity des pi t e t h e lac k of cli nical 
acti vity f or t he c o m bi nati on of d ur val u ma b a n d tre meli m u ma b i n metastatic P D A C s u bjects
b ut a wai t c o nfir matio n i n a lar ger c o h ort of s u bjects wit h a ra n d o mize d c o ntr ol , w hic h is 
o n g oi n g . T he majori t y of a d verse e ve nts ( A Es) o bser ve d i n t he c o m bi nati o n re gi me n were 
r elate d t o c he mot h era p y a n d were lo w gra de (Re n o uf et al , 2 0 1 8).
I n s u m mar y, t he a vaila ble cli nical acti vity a n d safet y  data s u p p ort f urt her de vel o p me nt of 
i m m u n ot hera p y c o m bi ne d with c he m ot hera p y t o le vera ge p ote ntial a d dit i ve or s y ner gistic 
effects i n t he treat me nt of metastatic P D A C.
1. 1. 4
C D 7 3
A de n os i ne is a re g ulat or y a ut ocri ne a n d paracri ne fact or t hat acc u m ulates i n t he t u m or 
micr oe n vir o n me nt, i nfl ue nci n g i m m u ne act i vity,  a n gio ge nesis, a n d metastasi s. U p o n a p o pt otic 
or necr otic cell deat h, t u m or cells release a de n osi ne tri p h os p hate ( A T P) i nt o t he e xt racell ular 
s pace. A T P has bee n s h o w n t o lea d t o a pr o-i nfla m mat or y res p o nse. T o pre ve nt a n i m m u ne 
reactio n st i m ulate d b y cell deat h, tiss ues e x press cl uster of differe ntiati on ( C D) 3 9 a n d C D 7 3 
t o e nz y maticall y c o n vert A T P t o a de n osi ne, w hic h i n d uces a l ocalize d i m m u n os u p pressi ve 
res p o nse t hr o u g h ple otr o pic effects u p o n m ulti ple i m m u ne cell t y pes. I n t he e xtracell ular 
s pace, C D 3 9 a n d C D 7 3 i n ta n de m meta b olize A T P t o a de n osi ne m o n o p h os p hate ( A M P), a n d 
A M P t o a de n osi ne, res pect i vel y, a n d are a major s o urce of e xtracell ular a de n osi ne. T he rate -
li miti n g ste p i n t he ge nerati on of e xtracell ular a de n osi ne is t he de p h os p h or ylat i on of A M P b y 
C D 7 3. 
O ne mec ha nis m b y w hic h t u m ors ma y  ha ve e v o l ve d t o e va de t he i m m u ne s yste m is via 
o vere x pressi o n of C D 7 3. O vere x pressi o n o f C D 7 3 has bee n ass ociate d wit h p o or pr o g n osis i n 
m ult i ple ca ncer t ypes (I n o ue et al, 2 0 1 7; L u et al , 2 0 1 3; T urc otte et al, 2 0 1 5 ; Wa n g et al, 
2 0 1 2 ; Ya n g et al , 2 0 1 3; Y u et al, 2 0 1 5 ). It is h y p ot hesize d t hat tar gete d i m m u n ot hera p y t o 
i n hi bit C D 7 3 acti vity will re d uce a de n osi ne pr o d ucti o n, t h us a u g me nt i n g h ost a n d/ or 
i m m u n ot hera p y res p o nse t o t u mor.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
I n-vit r o a n d i n-vi v o st u di es c o n d ucte d b y Z ha o et al in vest i gate d t he i mpact of  a ntica ncer 
t hera pies i ncl u di n g ge mcita bi ne o n t he i n d uct i on of i m m u n o ge nic cell deat h. T he a ut h ors 
f ou n d t hat ge m cita bi ne effecti vel y i n hi bite d t u m or gr o wt h b y in d uci n g i m m u n o ge nic cell 
deat h i n pa ncreatic ca ncer, a n d t hat it i ncrease d b ot h A T P a n d hi g h -m o bilit y gr o u p b o x 1 
(H M G B 1 ) r elease (Z ha o et al, 2 0 1 5 ). F urt her m ore, a n i n-vit r o st u d y b y Sa ma nta, et al 
d e m o nstrate d t hat f or m ult i ple c he m ot hera pe utic a ge nts a n d m ulti ple triple ne gat i ve breast 
ca ncer ( T N B C) cell li nes, c he m ot hera p y i n d uce d h y p o xia -i n d uci ble fact or-de pe n de nt 
c o or di nate d tra nscri pt i onal act i vati on of P D -L 1, C D 4 7, a n d C D 7 3 e x pressi o n. Cell s urface 
e x pressi o n of P D -L 1 a n d/ or C D 7 3 o n T N B C cells e na bles t he m t o i n d uce a ner g y or a p o pt osis 
of  effect or T cells with a c o nc o mita nt i ncrease i n re g ulat or y  T cells i n t he t u m or 
micr oe n vir o n me nt, t here b y i m pairi n g a da pt i ve a ntit um o r i m m u nity (Sa ma nta et al , 2 0 1 8). 
Ta ke n t o get her, t he res ults of t hese precli nical st u dies s u g gest t hat c he m ot hera p y  ca n i ncrease 
e xtracell ular A T P a n d increase C D 7 3 a n d P D -L 1 e x pressi o n s u p p orti n g t he c o m bi nat i on of 
i m m u n ot hera p y tar geti n g C D 7 3 a n d/ or P D -L 1 wit h c he m ot hera p y  t o i mpr o ve efficac y .
I mm u n o hist oc he mical (I H C) a nal ysis o f t u mor ti ss ue micr oarra ys ( T M As) f or C D 7 3 
e x pressi o n has de m o nstrate d t hat t here are t u m or hist ol o gies e nric he d f or pre vale nce of hi g h 
t u mor al  C D 7 3 e x pressio n , wit h hi g hest pre vale nce i n pa ncreatic T M As. T heref ore, a nti-C D 7 3 
i m m u n ot hera p y t hat tar gets a de n osi ne-me diate d i m m u n os u p pressi o n mi g ht i m pr o ve t he 
pr o g n osi s of P D A C pat ient s w he n use d i n c om bi nati o n wit h ot her a ntica ncer t hera pies.
1. 2
Olecl u m a b a n d D ur v al u m a b B ac k gr o u n d
Ol ecl u ma b (i n vest i gati onal na me M E DI 9 4 4 7) a n d d ur val u ma b are briefl y descri be d bel o w. 
Refer t o t he c urre nt I n vest i gat or’s Br oc h ures (I Bs) f or details. 
1. 2. 1
O lecl u m a b B ac k gr o u n d
Me dI m m u ne is p urs ui n g de vel o p me nt of olecl u ma b as a p ote ntial a nt ica ncer t hera p y f or 
pati e nts wit h a d va nce d s oli d t u m ors. Olecl u ma b is a h u ma n i m m u n o gl o b uli n (I g) G 1 la m b da 
(I g G 1 λ) mo n o cl o nal  a nti b o d y ( m A b) t hat select i vel y bi n ds t o C D 7 3 a n d i n hi bits a de n osi ne 
pr o d ucti o n f r o m C D 7 3-ass o ciate d ect o n ucle otidase acti vi t y a n d lea ds t o a re d uctio n i n C D 7 3 
e x pressi o n d ue t o b ot h i nter nalizati o n o f t he rece pt or a n d s he d di n g of t he e xtracell ular 
d o m ai n. It c o ntai ns a tri ple m utati o n i n t he hea v y c hai n c o nsta nt re gi o n f or re d uce d effect or 
f u ncti on. E xtracell ular a de n osi ne c o ntri b utes t o t he i m m u n os u p pressi ve effects of b ot h 
c yt ot o xic T l y m p h oc ytes a n d m yel oi d-deri ve d s u p press or cells, a m o n g ot hers. T he e nz y mat ic 
bl oc ka de o f C D 7 3 a n d decrease d e x pre ssi on ca use d b y  bi n di n g of olecl u ma b t o C D 7 3 ma y 
lea d t o i ncrease d a ntit u m or i m m u nity.
1. 2. 2
D ur v al u m a b B ac k gr o u n d
Me dI m m u ne has de vel o pe d d ur val u ma b as a p ote ntial a ntica ncer t hera p y  for t he treat m e nt of 
m ult i ple t u m or t ypes. D ur val u ma b is a h u ma n I g G 1 ka p pa ( I g G 1 κ) m A b t hat bl oc ks t he 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
i nteract i on of P D -L 1 ( b ut n ot pr o gra m me d cell deat h li ga n d -2) wi t h P D-1 o n T -l y m p h oc yt e 
( T cells) a n d C D 8 0 ( B 7. 1) o n i m m u ne cells a n d is e n gi neere d t o re d uce a nti b o d y-de pe n de nt 
cell-me diate d c y t ot o xicit y a n d c o mple me nt acti vati o n.
1. 3
S u m m ar y of N o ncli nic al E x perie nce
1. 3. 1
 
 
 
 
1. 3. 2
D ur v al u m a b N o ncli nic al E x perie nce
Refer t o t he c urre nt d ur val u ma b I B f or a c o m plete s u m mar y of n o ncli nical e x perie nce.
1. 4
S u m m ar y of Cli nic al E x perie nce
Cli nical e x perie nce wit h ol ecl u ma b a n d d ur val u ma b is briefl y  descri be d bel o w. Refer t o t he 
c urre nt I Bs f or a c o m plete s u m mar y of cli nical i nf or mati o n t hat i nclu des safety,  efficac y, a n d 
p har mac o ki net ics (P K ).
1. 4. 1
Olecl u m a b Cli nic al E x perie nce
1. 4. 1. 1
St u d y D 6 0 7 0 C 0 0 0 0 1
St u d y  D 6 0 7 0 C 0 0 0 0 1 is a first-ti me-i n-h u ma n ( F TI H), P hase 1, m ult ice nter, o pe n-lab el , 
d ose -escalat i on, a n d d ose -e x pa nsi o n st u d y  of ole cl u ma b t o be a d mi nistere d as a si n gle a ge nt 
or i n c o m bi nati o n wit h d ur val u ma b i n a d ult s u bjects wit h selecte d a d va nce d s o li d t u m ors. As 
of  t he 0 9 J u ne 2 0 1 9 data c ut -off, t he m o n ot hera p y  a n d c om bi nat i on t hera p y  d ose-escalat i on 
p hases were c o m plete d wit h a t otal e nr ol lme nt of 4 2 s u bjects a n d 2 4 s u bjects, res pecti vel y. I n 
t his st u d y, s u bjects recei ve d olecl u ma b 5, 1 0, 2 0, a n d 4 0 m g/ k g gi ve n I V e ver y 2 wee ks 
(Q 2 W ) as mo n ot hera p y  a n d i n c o m bi nati o n with d ur val u ma b 1 0 m g/ k g Q 2 W i n t he 
d ose -escalat i on p hase . T he c o m bi nat i on t hera p y  d os e-e x pa nsi o n p hase is o n g o i n g wit h a t otal 
of  1 1 1 s u bjects e nr olle d, i ncl u di n g 4 2 s u bjects wit h C R C, 4 2 s u bjects wit h P D A C , a n d 
2 7 s u bjects wit h e pid er m al gr o wt h fact or rece pt or m uta nt N S C L C. Base d o n a nal ysis o f 
safety,  P K , a n d preli mi nar y efficac y in St u d y D 6 0 7 0 C 0 0 0 0 1, a rec o m me n de d P hase 2 d ose 
( R P 2 D) of ol ecl u ma b 4 0 m g/ k g ( 3 0 0 0 m g i n a 7 5-k g i n di vi d ual) Q 2 W was selecte d.
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Olecl u m a b M o n ot her a p y ( D ose -esc al ati o n P h ase)
A m o n g t he 4 2 s u bjects wi t h a d va nce d C R C a n d P D A C w h o were treate d wit h olecl u ma b 
m o n ot hera p y , 3 9 s u bjects ( 9 2. 9 %) e x perie nce d at least 1 A E a n d 2 3 s u bjects ( 5 4. 8 %) 
e x perie nce d a t least 1 treat me nt -relate d A E. T he m ost fre q ue ntl y re p orte d A Es (i n ≥1 5 % of  
t otal s u bjects, re gar dless of ca usalit y ) were fati g ue (4 0. 5 %) , a ne mia a n d a b d o mi nal pai n
( 2 3. 8 % eac h), d ys p nea a n d decrease d a p petite ( 2 1. 4 % eac h), v o mit i n g ( 1 9. 0 %), a n d p yre xia 
( 1 6. 7 %). T here were n o cli nicall y mea ni n gf ul tre n ds i n i nci de nce of A Es acr oss d ose gr o u ps. 
T he m o st fre q ue ntl y re p orte d treat me nt-relate d A Es (i n ≥5 % t otal  s u bjects) were fati g ue 
( 1 6. 7 %) a n d na usea a n d a ne mia ( 9. 5 % eac h).
T hree s u bjects ( 7. 1 %) re p orte d at least 1 treat me nt -relate d Gra de 3 or Gra de 4 A E (e ve nts of 
i ncrease d a m ylase, i ncrease d ga m ma -gl uta m yl  tr a nsferase ( G G T ), i ncrease d li pase, a n d 
h y per gl yce mia). Fiftee n s u bjects ( 3 5. 7 %) e x perie nce d serio us a d verse e ve nts ( S A Es ). T hree 
s u bjects ( 7. 1 %) e x perie nce d t he S A E of ascites; t his was t he o nl y S A E re p orte d b y more t ha n 
1 s u bject. N o ne of t he S A Es were c o nsi dere d treat me nt-relate d. T hree s u bjects ( 7. 1 %) 
di sc o nti n ue d treat me nt d ue t o e ve nts of c h o lan git is, metastases t o ce ntral ner v o us s yste m
( C N S), a n d p ul m onar y  e mb o lis m. N o ne of t hese e ve nts were c o nsi dere d treat me nt-relate d.
Fi ve of t he 4 2 s u bjects ( 1 1. 9 %) re p orte d at least 1 a d verse e ve nt of s pecial i nterest ( A E SI ). 
F o ur s u bjects ( 9. 5 %) ha d peri p heral e de ma a n d 1 s u bject ( 2. 4 %) ha d p ul m o nar y  e mb o lism.
A t otal o f 3 2 ( 7 6 . 2%) s u bj ects die d o n st u d y; 3 of t hese deat hs were re p orte d w hile s u bjects 
were o n treat me nt ( deat h was t he reas o n f or e n d of treat me nt). O ne s u bject w h o die d o n 
treat me nt ha d a fatal A E of s mall i ntest i nal o bstr ucti o n; t his deat h was n ot c o nsi dere d relate d 
t o treat me nt wit h olecl u ma b. All ot her deat hs were d ue t o t he disease u n der st u d y. T here were 
n o d ose -li miti n g t o xicities (D L Ts ) re p orte d d uri n g t he ol ecl u ma b mo n ot hera p y  
d ose -escalat i on p hase, a n d t he ma xi m u m t ol erate d d ose ( M T D ) was n ot reac he d.
Olecl u m a b a n d D ur v al u m a b C o m bi n ati o n T her a p y ( D ose- esc al ati o n P h ase)
T we nt y- f our s u bjects wit h a d va nce d C R C a n d P D A C were treate d wi t h olecl u ma b a n d 
d ur val u ma b c o m bi nat i on t hera p y  in t he d ose -escalati o n p hase. All 2 4 s u bjects e x perie nce d 
A Es, a n d 1 3 s u bjects ( 5 4. 2 %) e x perie nce d at least 1 treat me nt -r elate d A E. T he m ost 
fre q ue ntl y re p orte d A Es (i n ≥ 1 5 % of t otal  s u bjects, re gar dless of ca usality)  were fati g ue a n d
v o mit i n g ( 2 9. 2 % eac h), a b d o mi nal pai n ( 2 0. 8 %), a n d na usea ( 1 6. 7 %). T here were n o 
cli nicall y mea n i n gf ul tre n ds i n i nci de nce of A Es acr oss d ose gr o u ps. T he m ost fre q ue ntl y 
re p orte d treat me nt-relate d A Es (i n ≥1 0 % of  t otal s u bjects) were fati g ue ( 2 5. 0 %) a n d na usea, 
i ncrease d as partate a mi n otra nsferase ( A S T ), a n d v o miti n g ( 1 2. 5 % eac h).
Fi ve s u bjects ( 2 0. 8 %) re p orte d at least 1 treat me nt -relate d Gra de 3 or Gra de 4 A E (e ve nts of 
t hr o mb oc y t o pe nia [ 1 s u bject], i ncrease d ala ni ne a mi n otra nsferase ( A L T ) [ 1 s u bject], i ncrease d 
A S T [ 2 s u bjects], h y per gl yce mia [ 1 s u bject], a n d hea dac he [ 1 s u bject]). Te n s u bjects ( 41. 7 %) 
e x perie nce d S A Es. P ul m o nar y e m b olis m ( 2 s u bjects) was t he o nl y S A E e x perie nce d b y mor e 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
t ha n 1 s u bject. O ne s u bject re p orte d a treat me nt-relate d S A E of t hr o m b oc yt o p e nia. T w o 
s u bjects (8. 3 %) disc o nt i n ue d treat me nt d ue t o e ve nts of i ncrease d A L T, i ncrease d A S T, 
i ncrease d bl o o d alkali ne p h os p hatase ( A L P ), a n d i ncrease d bl o o d bilir u bi n. O ne of  t hese 
2 s u bjects e x perie nce d e ve nts t hat were c o nsi dere d treat me nt -r elate d ( i ncrease d A S T a n d 
i ncrease d bl o o d bilir u bi n). Fi ve of t he 2 4 s u bjects ( 2 0. 8 %) e x perie nce d at least 1 A E SI. 
P eri p heral  e de ma a n d p ul m on ar y  e m b olism were t he o nl y  AE SIs re p orte d i n > 1 s u bject 
( 2 s u bjects eac h).
A t otal o f 1 9 ( 7 9 . 2%) s u bj ects die d o n st u d y; 2 of t hese deat hs were re p orte d w hile s u bjects 
were o n treat me nt. O ne s u bject w h o die d o n treat me nt ha d a fatal A E of re nal fail ure 
c o nsi dere d u nrelate d t o st u d y tr e at me nt b y t he i n vestigat or. All  ot her deat hs were d ue t o t he 
di sease u n der st u d y. T here were n o D L Ts re p orte d d uri n g t he olecl u ma b a n d d ur val u ma b 
c o m bi nat i on t hera p y  d ose-escalat i on p hase, a n d t he M T D was n ot reac he d.
Olecl u m a b a n d D ur v al u m a b C o m bi n ati o n T her a p y ( D ose- e x p a nsi o n P h ase)
S af et y
A m o n g t he 1 1 1 s u bjects treate d wit h olecl u ma b a n d d ur val u ma b c o m bi nat i on t hera p y i n t he 
d ose -e x pa nsi o n p hase of t he st u d y , 1 0 4 s u bjects (9 3. 7 %) e x perie nce d at least 1 A E , a n d
5 9 s u bjects (5 3. 2 %) e x perie nce d at least 1 treat me nt -relate d A E. T he m ost f re q ue ntl y re p orte d 
A Es b y  preferre d ter m (i n ≥ 1 5 % of t otal  s u bjects, re gar dless of ca usalit y ) were fatig ue 
(2 8. 8 %) , na usea ( 1 8.9 %), a b d o mi nal pai n a n d v o mit i n g (1 8. 0 % eac h), c o nsti pat i on ( 1 7. 1 %), 
i ncrease d A S T ( 1 6. 2 %) , a n d p yre xia a n d diarr hea ( 1 5. 3 % eac h) . T here were n o cli nicall y 
mea ni n gf ul patter ns i n t he i nci de nce o f A Es acr oss e x pa nsi o n c o h orts . T he most f re q ue ntl y 
re p orte d treat me nt-relate d A Es (in ≥ 5 % of t otal  s u bjects) were fati g ue (1 4. 4 %) , diarr hea 
( 9.0 %), p yre xia a n d v o mit i n g ( 6.3 %
eac h), a n d i ncrease d A S T ( 5. 4%).
A t otal o f 1 5. 3 % of s u bjects re p orte d at least 1 treat me nt -relate d Gra de 3 or Gra de 4 A E. T he 
f oll owi n g treat m e nt -relate d Gra de 3 or Gra de 4 A Es were re p orte d i n 2 s u bjects eac h: 
he pat itis, i ncrease d A S T, i ncrease d bl o o d A L P, a n d i ncrease d li pase. O verall, 4 5. 9 % of 
s u bjects e x perie nce d at least 1 S A E. T he m ost fre q ue nt l y re p orte d S A Es ( > 2 % s u bjects) were 
ascites, p ne u mo nia, a n d v o mit i n g ( 4.5 % eac h), a b d o mi nal pai n a n d p ul m o n ar y  e m b olis m 
( 3.6 % eac h), a n d ple ural eff usi o n a n d se psis ( 2.7 % eac h). Ei g ht (7. 2 %) of t hese s u bjects 
e x perie nce d S A Es t hat were c o nsi dere d treat me nt -r elate d. T he treat me nt -relate d S A E of 
he pat itis (1. 8 %) was t he o nl y  tr e at me nt -relate d S A E re p orte d i n m ore t ha n 1 s u bject. O verall, 
7. 2 % of s u bjects e x perie nce d A Es lea di n g t o disc o nt i n uati on of treat me nt wit h olecl u ma b a n d 
d ur val u ma b; he patit is (1. 8 %) was t he o nl y s uc h e ve nt t hat occ urre d i n m ore t ha n 1
s ubject. 
B ot h cases of he pat itis were c o nsi dere d treat me nt-r elate d. A n o t her s u bject e x perie nce d a 
treat me nt -relate d A E of fati g ue t hat le d t o disc o nti n uati on of treat me nt. A f ourt h s u bject 
di sc o nti n ue d treat me nt d ue t o a treat me nt -relate d fatal S A E of s yste mic i nfla m mat or y 
res p o nse s y n dr o me (SI R S ; a narrati ve f or t his s u bject is pr o vi de d i n t he o lecl u ma b I B).
T we nt y- fi ve of t he 1 1 1 s u bjects ( 2 2. 5 %) re p orte d at least 1 A E SI. T he m ost c o m m o n A E SIs 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
(≥ 2 % of e x pa nsi o n t otal) re p orte d were peri p heral e de ma ( 1 0. 8 %) , p ul m onar y  e m b olis m 
( 6. 3 %) a n d dee p vei n t hr o m b osis ( 3. 6 %).
A t otal o f 6 6 s u bjects (5 9. 5 %) die d o n st u d y ; 4 s u bjects die d w hile o n treat me nt . T he majori t y 
of  deat hs occ urre d d ue t o t he disease u n der st u d y ( 5 6. 8 %). Of t he 6 6 s u bjects w h o die d, 
3 s u bjects ha d A Es lea di n g t o deat h. Of t he 3 s u bjects w h o ha d A Es lea di n g t o deat h, 1 s u bject 
di e d of a treat me nt -r elate d S A E of SI R S, a n d t he ot her 2 s u bjects die d of A Es t hat were 
c o nsi dere d u nrelate d t o st u d y tr e at me nt.
Cli nical Act i vity
As of t he 0 9 J u ne 2 0 1 9 data c ut -off date, t he O R R (c o nfir me d) i n t he P D A C c o h ort ( n = 4 2) 
was 4. 8 % ( 9 5 % c o nfi de nce i nter val [ CI ]: 0. 6 %, 1 6. 2 %). T he D C R ( 8
wee ks) i n t his c o h ort 
was 2 3. 8 % ( 9 5 % CI: 1 2. 1 %, 3 9. 5 %). T he me d ia n O S i n t he P D A C c o h ort was 6. 3 m o nt hs.
As of t he 0 9 J u ne 2 0 1 9 data c ut -off date, t he O R R s (c o nfir me d) i n t he C R C c o h ort ( n = 4 2) 
a n d N S C L C c o h ort ( n = 1 8) were 2. 4 % ( 9 5 % CI: 0. 1 %, 1 2. 6 %) a n d 1 1. 1 % ( 9 5 % CI: 2. 4 %, 
2 9. 2 %), res pecti vel y. T he D C Rs ( 8 wee ks) i n t he C R C a n d N S C L C c o h orts were 2 1. 4 % ( 9 5 % 
CI: 1 0. 3 %, 3 6. 8 %) a n d 1 8. 5 % ( 9 5 % CI: 6. 3 %, 3 8. 1 %), res pecti vel y .
1. 4. 1. 2
St u d y D 6 0 7 0 C 0 0 0 0 5
As of 0 9 J u ne 2 0 1 9, 7 5 s u bjects wit h P D A C ha ve bee n e nr o lle d i n t he fol l owi n g c o h orts of  t he 
c urre nt o n g oi n g st u d y ( D 6 0 7 0 C 0 0 0 0 5):

D ose escalati on – C o h ort A

D ose 1 - Olecl u ma b  
 + d u r val u ma b + ge mcita bi ne + na b-paclita xel ( 
)

D ose 2 - Olecl u ma b  
 + d ur val u ma b + ge mcita bi ne + na b -paclita xel ( 
)

D ose escalat i on – C o h ort B

D ose 1 - Olecl u ma b  
 + d ur val u ma b + m F O L F O X ( 
)

D ose 2 - Olecl u ma b  
 + d ur val u ma b + m F O L F O X ( 
)

D ose e x pa nsi o n – C o h ort A

Ar m A 1 – g e m cita bi ne + na b-pacli t a x el ( 
)

Ar m A 2 – Ol e clu ma b 
 + ge mcita bi ne + na b-pacli t a x el ( 
)

Ar m A 3 – Ol e clu ma b 
g + d ur val u ma b + ge mcita bi ne + na b -pacli t a x el 
(
)
D ose E scalati o n - C o h ort A
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
 
 
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1. 4. 2
D ur v al u m a b Cli nic al E x perie nce
As of t he data c ut -off date of 1 2 J ul y 2 0 1 9 , ap pr o xi matel y  8 8 1 7 pat ient s ha ve recei ve d 
d ur val u ma b as m o n ot hera p y  or i n c o m bi nati on wi t h ot her a ntica ncer a ge nts i n Astra Ze neca or 
Me dI m m u ne -s p o ns ore d i nter ve nti onal st u dies i n m ulti ple t u m or t ypes, sta ges of disease , a n d 
li nes of t hera p y. A n esti mate d 8 3 4 3 patie nts ha ve bee n ra n d o mize d t o t he vari o us 
treat me nt/c o mparat or ar m s i n s p o ns or-bli n de d st u dies. I n a d dit i on, 2 4 8 2 patie nts ha ve 
parti ci pate d i n t he d ur val u ma b Earl y Access Pr o gra m ( St u d y D 4 1 9 4 C 0 0 0 0 2) f or patie nts wit h 
l ocall y a d va nce d, u nresecta ble N S C L C w h ose disease has n ot pr o gresse d f oll o wi n g 
pl at i n u m-base d c he m ora diat i on t hera p y . T he c u mulat i ve gl o bal p ost -mar ket i n g patie nt 
e x p os ure t o d ur val u ma b ( 1 0 m g/ k g) t o 3 0 J u ne 2 0 1 9 has bee n est i mate d t o be a p pr o xi matel y 
1 2 3 8 5 pati e nt -ye ars. D ur val u ma b has bee n a p pr o ve d i n bla d der a n d l u n g ca ncer i n a n u m ber 
of  c o u ntries. Details o n t he safet y pr ofile o f d ur val u m a b are briefl y s u m marize d bel o w.
T he safety pr ofile of d ur val u ma b as m o n ot hera p y  a n d c o m bi ne d wit h ot her a ntica ncer a ge nts 
is c o nsiste nt wit h t he p har mac ol og y  of t he tar get a n d ot her a ge nts i n t he i m m u ne c hec k p oi nt 
i n hi bit or class. M ost a d verse dr u g reacti o ns see n with t his class of a ge nts are t h o u g ht t o be 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
d ue t o effects of i nfla m mat or y  cells o n s pecific t iss ues a n d c o uld occ ur i n a n y or ga n s yste m .
S af et y data p o ol e d fr o m 8 d ur val u ma b m o n ot hera p y  st u dies i ncl u de d 2 7 6 9 pati e nts w h o 
recei ve d a d ur val u ma b d ose of 1 0 m g/ k g Q 2 W or 2 0 m g/ k g Q 4 W .

O verall, A Es re p orte d i n ≥1 5 % of  pati e nts, re gar dless of ca usalit y, were fat i g ue, 
decrease d a p pet ite, c o u g h, na usea, d y s p nea, c o nsti pati o n, a n d diarr hea. . T he m ost 
c o m m o n treat me nt -r elate d A Es re p orte d i n ≥5 % of pat ient s were fati g ue (1 3. 5 %) , 
di arr hea ( 8. 1 %), h yp ot h y r oidis m (8. 1 %) , pr urit us (7. 0 %) , na usea ( 6. 7 %) , decrease d 
a p petite ( 6. 6 %), a n d ras h (6. 2 %) .

A Es of Gra de 3 or hi g her c o nsi dere d relate d t o d ur val u ma b were re p orte d i n 1 1. 6 % of 
pati e nts: 9. 9 % of patie nts ha d Gra de 3 e ve nts, 1. 0 % of s u bjects ha d Gra de 4 e ve nts, a n d 
0. 6 % of s u bjects ha d Gra de 5 (fatal ) e ve nts. Gra de 3 or 4 treat me nt -relate d A Es occ urri n g 
i n ≥0. 5 % pati e nts were fat i g ue (1. 1 %), i ncrease d G G T ( 0. 8 %), p ne u m o nit is (0. 7 %), a n d 
i ncrease d A S T ( 0. 6 %) . T he o nl y Gra de 5 e ve nt s c o nsi dere d relate d t o d ur val u ma b 
occ urri n g i n ≥2 pati e nts were p ne u m o nit is (6 patie nts [ 0.2 %]) a n d res pirat or y fail ure 
( 2 patie nts [ < 0. 1 %]) .

A t otal o f 9. 4 % of  pati e nts disc o nti n ue d fr om st u d y tr e at me nt d ue t o a n A E. T he m ost 
c o m m o n e ve nts l ea di n g t o treat me nt disc o nt i n uati on were p ne u m o nit is (1. 2 %) , 
p ne u m o nia ( 0. 6 %), d ys p nea ( 0. 4 %), ge neral p h ysical health deteri orati o n (0. 3 %) , a n d 
i nterst itial l u n g disease (I L D), ra diati on p ne u m o nit is, se psis, a n d a ne mia (0. 2 %
eac h); all 
ot her disc o nt i n uati o n e ve nts occ urre d i n ≤4 pati e nts.

A t otal o f 6. 5 % of  pati e nts ha d S A Es t hat were c o nsi dere d relate d t o d ur val u ma b. T he 
m o st c o m mo n  treat me nt -relate d S A Es were p ne u m o nitis (1. 2 %), p ne u m o nia, diarr hea ,
a n d I L D ( 0. 3 % eac h), c olitis, i nf usi on- relate d reacti on (I R R) , a n d fati g ue ( 0. 2 % eac h), 
a n d d ys p nea , r a diat i on p ne u m o nit is, ac ute ki dne y i nj ur y, a dre nal ins ufficie nc y, i ncrease d 
A S T, de h y drati o n, h y p ot h y r oidis m , na usea, ner v o us s yste m dis or der , a n d 
t hr o mb oc y t o pe nia ( 0. 1 % eac h).
T he m ajori t y of treat me nt -relate d A Es were ma na gea ble with d ose del a ys, s y m pt o mat ic 
treat me nt a n d, i n t he case o f e ve nts s us pecte d t o ha ve a n i m m u ne basis, t he use of esta blis he d 
treat me nt g uideli nes f or i m m u ne -me diate d t o xicit y ( Secti o n 3. 1. 4 ).
1. 5
R ati o n ale f or C o n d ucti n g t he St u d y
Pa ncreat ic d uctal a de n ocarci n oma is a hi g hl y m or bi d disease wit h a hi g h m ortality d ue t o a 
lac k of effecti ve t hera pies. Acc or di n g t o gl o bal cli nical practice g ui deli nes ( Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k a n d E ur o pea n S ociet y f or Me dical O nc o lo g y ), g e mcita bi ne 
pl us na b -pacli t a x el a nd m F O L F O X are preferre d treat me nt re gi me ns f or 1 L a n d 2 L metastatic 
P D A C, res pect i vel y. H o we ver, t he effecti ve ness of t hese re gi me ns re mai ns li mite d. 
Precli nical i n -vit r o a n d i n-vi v o st u di es f o u n d t hat ge mcita bi ne ef fecti vel y in hi bi t e d t u mor 
gr o wt h b y  in d uci n g i m m u n o ge nic cell deat h i n pa ncreatic ca ncer, a n d t hat it i ncrease d A T P 
a n d H M G B 1 release (Z ha o et al, 2 0 1 5 ). A n ot her precli nical st u d y d e mo nstrate d t hat f or 
m ult i ple c he m ot hera pe utic a ge nts a n d m ulti ple T N B C cell li nes, c he m ot hera p y in d uce d 
tra nscript i onal acti vati o n o f P D -L 1, C D 4 7, a n d C D 7 3 e x pressi o n. Cell s urface e x pressi o n of 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
P D -L 1 a n d/ or C D 7 3 o n T N B C cells e na bles t he m t o i n d uce a ner g y or a p o pt osis of effect or 
T cells wit h a c o nc o mita nt i ncrease i n re g ulat or y T cells i n t he t u m or micr oe n vir o n me nt, 
there b y i m pairi n g a da pti ve a ntitu m or i m m u ni t y (S a m a nta et al, 2 0 1 8). T hese precli nical 
st u dies s u g gest t hat c he m ot hera p y ca n i ncrease e xtracell ular A T P a n d i ncrease C D 7 3 a n d 
P D -L 1 e x pressi o n s u p p orti n g t he c o m bi nat i on of i m m u n ot hera p y tar geti n g C D 7 3 a n d/ or 
P D -L 1 wi t h c he m ot hera p y t o i m pr o ve efficac y.
 
 
 
 
1. 6
Be nefit -Ris k a n d Et hic al Assess me nt
T he st u d y  will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he 
Declarati o n of Helsi n ki a n d are c o nsiste nt wit h I nter nati onal C o nfere nce o n Har m o ni satio n 
(I C H)/ G o o d Cli nical Practice ( G C P), a n d a p plica ble re g ulat or y re q uire me nts.
1. 6. 1
P ote nti al Ris ks
T here are c urre ntl y n o i de nt ifie d ris ks f or olecl u ma b. T he im p orta nt p ote ntial ris ks f or 
ol ecl u ma b i ncl u de t hr o m b osis a n d i ncrease d micr o vasc ular per mea bilit y,  a n d p ote ntial ris ks 
f or olecl u ma b i ncl u de arterial is c he mic dis or der . A d diti onal i m p orta nt p ote ntial ris ks i ncl u de 
I R Rs, a na p h yla xis, h y perse nsiti vity or aller gi c reactio ns, a n d i m m u ne c o m ple x disease , w hic h 
are ass ociate d wit h t he a d mi nistratio n of  m A bs . A d ditio nal  p ote ntial ris ks ass ociate d wit h a n y 
I V a d mi nistratio n are l ocalize d i nfect i on, re d ness, s welli n g, pai n, a n d i n d urat i on at t he 
a d mi nistrati o n site. F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h olecl u ma b, refer 
t o t he c urre nt olecl u ma b I B.
I de ntifie d ris ks with d ur val u ma b i ncl u de, b ut ar e n ot li mite d t o, p ne u m o nit is/I L D, he patitis, 
di arr hea/c olitis, e n d ocri n o pat hies (ie, e ve nts of h y p o p h ysitis/ h y p o pit uit aris m, t h yr oidi tis, 
a dre nal i ns ufficie nc y, h y p ot h yr oidis m, h y pert h yr oi dis m, t y pe 1 di a betes mellit us [w hic h ma y  
prese nt wit h dia bet ic ketoaci d osis] , a n d dia betes i nsipi d us), ne p hrit is, ras h/ der matitis 
(incl u di n g pe m p hi g o i d), m y ocar ditis, m yosi tis/ p ol y m y ositis, m yast he nia gra vis, i m m u ne 
t hr o mb oc y t o pe nia, I R Rs, pa ncreatitis, a n d e nce p halitis. P ote ntial ris ks i ncl u de 
h y perse nsit i vity react i ons a n d a na p h yla xis, s u bc uta ne o us i nject i on site react i ons, 
i m m u n o ge nicity,  c yt o ki ne release s y n dr o me, ot her i nfect i ons, a n d ot her rare or less fre q ue nt 
i m m u ne-me diate d A Es (i ncl u di n g, b ut n ot li mite d t o G uillai n -Barre S y n dr o m e, pericar ditis, 
sarc oi d osis, u veitis, c h olan git is scler osi n g, i m m u ne-me d iate d c ystitis, a n d ot her e ve nts 
i n v ol vi n g t he e ye, s ki n, hae mat olo gi cal, r he u mat olo gi cal e ve nts, vasc ulit is, a n d n o n-i nfecti ous 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
me ni n git is). F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h d ur val u ma b, refer t o t he 
c urre nt d ur val u ma b I B.
D ur val u ma b pl us olecl u ma b a n d o lecl u ma b as a m o n ot hera p y ha ve bee n well t olerate d t o date 
i n St u d y D 6 0 7 0 C 0 0 0 0 1. T he maj ority of  A Es ha ve bee n l o w gra de a n d n ot relate d t o 
treat me nt. T here are n o si g nifica nt o verla p pi n g t o xicit ies with c he m ot hera p y  base d o n eit her 
t he safet y pr ofile or t he mec ha nis ms of act i on of t he i n vesti gati onal pr o d ucts .
T he desi g n of t he c urre nt st u d y  ai ms t o mi ni mize p ote ntial ris ks t o s u bjects base d o n t he 
pr ot oc ol  incl usi o n a n d e xcl usi o n cri t eria, restrict i ons o n c o nc o mit a nt me dicat i on d uri n g t he 
st u d y, safety m o ni t ori n g (i nclu di n g re vie w of all safet y,  P K, a n d ot her rele va nt data b y t he 
D ose - escalati on C o m mittee [ D E C]), t o xicit y ma na ge me nt g ui deli nes, starti n g d ose selecti o n, 
d ose escalat i on sc he me, a n d st o p pi n g criteria. S pecific i nte nsi ve safet y m o nit ori n g is i n place 
f or t h ose ris ks dee me d t o be m ost li kel y.
1. 6. 2
P ote nti al Be nefits
Metastatic P D A C is a disease wit h a n e xtre mel y p o or pr o g n osis, w hic h u n dersc ores t he nee d 
f or n o vel t hera pies f or t his patient  p o p ulati on.
I n St u d y C D O N-M E DI 4 7 3 6 -1 1 0 8, a P hase 1 m ulti -ar m e x pa nsio n st u d y  of d ur val u ma b i n 
s u bjects wit h s oli d t u m ors, preli mi nar y efficac y data f or s u bjects wit h pa ncreatic ca ncer 
s h o we d 2 C R/ P Rs i n 3 0 e val ua ble s u bjects wit h u nselecte d P D -L 1 stat us a n d 2 C R/ P Rs i n 
1 9 e val ua ble s u bjects wit h P D -L 1 l o w/ ne gat i ve stat us ( defi ne d as t u m or cells < 2 5 %; 
D ur val u ma b I B). St u d y  D 4 1 9 8 C 0 0 0 0 1 ( A L P S), a P hase 2 st u d y  of d ur val u ma b i n 2 L P D A C 
s u bjects, s h o we d 2 u nc o nfir me d P Rs i n 3 3 e val ua ble s u bjects (O' Reill y et al, 2 0 1 8 ).
T he safet y a n d cli nical act i vity of  d ur valu ma b 1 0 m g/ k g pl us olecl u ma b 4 0 m g/ k g Q 2 W i n 2 L 
a n d 3 L P D A C s u bjects is bei n g e val uate d i n St u d y D 6 0 7 0 C 0 0 0 0 1. T he preli mi nar y  data 
s u g gest t hat treat me nt wit h olecl u ma b is well-t olerate d a n d lea ds t o a re d ucti o n i n C D 7 3 
e x pressi o n o n b ot h t u m or a n d circ ula tin g i m m u ne cells. As of t he 0 9 J u ne 2 0 1 9 data c ut -off, 
4 2 s u bjects wit h P D A C recei ve d t he c o m bi nati on t hera p y i n t he d ose -e x pa nsi o n c o h ort. T he 
O R R (c o nfir me d) was 4. 8 % ( 9 5 % CI: 0. 6 %, 1 6. 2 %)
a n d i ncl u de d 1 s u bject wit h C R a n d 1 
s u bject wit h P R. T he D C R ( 8 wee ks) was 2 3. 8 % ( 9 5 % CI: 1 2. 1 %, 3 9. 5 %). As of 0 9 J u ne 
2 0 1 9 , t he me dia n O S i n t his c o h ort was 6 . 3 m o nt hs. T hese data ac q uire d i n t he 2 -3 L 
metastati c pa ncreatic setti n g c o m pare well wit h t he acti ve sta n dar d -of -care bei n g 5 F U-
O n y vi de ( O S = 6. 1 m o nt hs) a n d pr o vi de a str o n g rati o nale f or i n vest i gati n g f urt her t he 
ol ecl u ma b-c o ntai ni n g re gi me ns i n pa ncreat ic ca ncer. Refer t o Secti o n 1. 4. 1 a n d t he c urre nt 
ol ecl u ma b I B for a d di tio nal  inf or m atio n.
T he pla n t o c o m bi ne ol ecl u ma b wit h or wit ho ut d ur val u ma b wit h ge mcita bi ne a n d 
na b -pacli ta xel ( C o h ort A) a n d m F O L F O X ( C o h ort B) i n t he c urre nt st u d y is s u p p orte d b y 
precli nical a n d cli nical st u dies w hic h ha ve de m o nstrate d i ncreases i n C D 7 3 e x pressi o n a n d 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
i ncreases i n e xtracell ular A T P i n res p o nse t o c he m ot hera p y (S a m a nta et al, 2 0 1 8; Z ha o et al , 
2 0 1 5) . I n a d diti on, precli nical st u dies ha ve de m o nstrate d s y ner gist ic be nefit of c he m ot hera p y 
wi t h C D 7 3 bl oc ka de (L oi  et al, 2 0 1 3). T heref ore, olecl u ma b with or wit h o ut d ur val u ma b 
c o m bi ne d wit h ge mcita bi ne a n d na b -paclit a xel or m F O L F O X t hera p y ma y de mo n strate a 
cli nicall y mea ni n gf ul be nefit a n d ma na gea ble safet y pr o file c o m pare d wit h ge mcita bi ne a n d 
na b -pacli t a x el or mF O L F O X. T he o verall be ne fit-ris k pr ofile of t he pr o p ose d treat me nt 
c o m bi nat i ons is e x pecte d t o be fa v ora ble f or s u bjects wit h P D A C, t heref ore s u p p orti n g t he 
c urre nt st u d y d esig n.
1. 7
Rese arc h H y p ot heses
T he c o m bi nat i on of o lecl u ma b (a nti-C D 7 3) wi t h or wit ho ut d ur val u ma b (a nti -P D -L 1) pl us 
c he m ot hera p y will de m o nstrate a de q uate safet y,  t olera bility,  a n d a ntitu m or acti vit y i n s u bjects 
wi t h metastatic P D A C t hat has bee n pre vi o usl y u ntreate d or has pr o gresse d f oll o wi n g 
g e m cita bi ne-base d c he m ot hera p y .
2
O B J E C TI V E S A N D E N D P O I N T S
2. 1
Pri m ar y O bject i ve(s) a n d Ass oci ate d E n d p oi nts
T a ble 1 ( 2. 1 - 1)
Pri m ar y O bjecti ve(s) a n d Ass oci ate d E n d p oi nts
T y pe
O bjecti ve
E n d p oi nt
Safet y
Part 1: T o assess t he safet y a n d t olera bilit y 
of olecl u ma b pl us d ur val u ma b i n 
c o m bi nati o n w it h c he m ot hera p y 
a d mi nistere d i n s u bjects wit h metastatic 
P D A C
•
D L Ts
•
I nci de nce of A Es a n d S A Es
•
Cli nicall y mea ni n gf ul c ha n ges fr o m 
baseli ne i n cli nical la b orat or y 
para meters, vital si g ns, a n d E C G 
res ults
Cli nical 
Acti vit y
Part 2: T o e val uate t he preli mi nar y 
a ntit u m or acti vit y of olecl u ma b wit h or 
wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
ge mcita bi ne a n d na b -paclita xel c o m pare d t o 
ge mcita bi ne a n d na b -paclita xel a d mi nistere d 
i n s u bjects wit h 1 L metastatic P D A C
•
O R acc or di n g t o R E CI S T v 1. 1
Part 2: T o e val uate t he pr eli mi nar y 
a ntit u m or acti vit y of olecl u ma b wit h or 
wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
m F O L F O X c o m pare d t o m F O L F O X 
a d mi nistere d i n s u bjects wit h 2 L metastatic 
P D A C
•
O R acc or di n g t o R E CI S T v 1. 1
1 L = first -li ne; 2 L = sec o n d-li ne; A E = a d verse e ve nt; E C G = electr ocar di o gra m; D L T = d ose -li miti n g t o xicit y; 
m F O L F O X = m o difie d re gi me n of le uc o v ori n, 5 -fl u or o uracil a n d o xali plati n; O R = o bjecti ve res p o nse; 
P D A C = pa ncreatic d uctal a de n ocarci n o ma; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; 
S A E = serio us a d verse e ve nt; v = versi o n
N ote: Part 1 is d ose escalati o n a n d Part 2 is d ose e x pa nsi o n.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
2. 1. 1
Sec o n d ar y O bjecti ves a n d Ass oci ate d E n d p oi nts
T a ble 2 ( 2. 1. 1 - 1)
Sec o n d ar y O bjecti ve(s) a n d Ass oci ate d E n d p oi nts
T y pe
O bjecti ve
E n d p oi nt
Safet y
Part 2: T o assess t he safet y a n d t olera bilit y 
of olecl u ma b wit h or wit h o ut d ur val u ma b i n 
c o m bi nati o n w it h c he m ot hera p y 
a d mi nistere d i n s u bjects wit h metastatic 
P D A C
•
I nci de nce of A Es a n d S A Es
•
Cli nicall y mea ni n gf ul c ha n ges fr o m 
baseli ne i n cli nical la b orat or y 
para meters, vital si g ns, a n d E C G 
res ults
Cli nical 
Acti vit y
Part 1: T o e val uate t he preli mi nar y 
a ntit u m or acti vit y of olecl u ma b pl us 
d ur val u ma b i n c o m bi nati o n wit h 
ge mcita bi ne a n d na b -paclita xel 
a d mi nistere d i n s u bjects wit h 1 L metastatic 
P D A C
•
O R a n d D C acc or di n g t o R E CI S T v 1. 1
Part 1: T o e val uate t he preli mi nar y 
a ntit u m or acti vit y of olecl u ma b pl us 
d ur val u ma b i n c o m bi nati o n wit h 
m F O L F O X a d mi nistere d i n s u bjects wit h 
2 L metastatic P D A C
•
O R a n d D C acc or di n g t o R E CI S T v 1. 1
Part 2: T o e val uate t he pr eli mi nar y 
a ntit u m or acti vit y of olecl u ma b wit h or 
wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
ge mcita bi ne a n d na b -paclita xel c o m pare d t o 
ge mcita bi ne a n d na b -paclita xel 
a d mi nistere d i n s u bjects wit h 1 L metastatic 
P D A C
•
O S
•
P F S, D o R, a n d D C acc or di n g t o 
R E CI S T v 1 . 1
Part 2: T o e val uate t he preli mi nar y 
a ntit u m or acti vit y of olecl u ma b wit h or 
wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
m F O L F O X c o m pare d t o m F O L F O X 
a d mi nistere d i n s u bjects wit h 2 L metastatic 
P D A C
•
O S
•
P F S, D o R, a n d D C acc or di n g t o 
R E CI S T v 1. 1
Part 2: T o e val uate t he preli mi nar y 
a ntit u m or acti vit y of olecl u ma b wit h or 
wit h o ut d ur val u ma b i n c o m bi nati o n wit h 
c he m ot hera p y c o m pare d t o c he m ot hera p y 
al o ne i n t he p o p ulati o n defi ne d b y C D 7 3 
e x pressi o n
•
O S
•
O R a n d P F S acc or di n g t o R E CI S T 
v 1. 1 b y C D 7 3 e x pressi o n at baseli ne 
I m m u n o ge nicit y
T o assess t he i m m u n o ge nicit y of olecl u ma b 
a n d d ur val u ma b i n c o m bi nati o n wit h 
c he m ot hera p y a d mi nistere d i n s u bjects wit h 
metastatic P D A C
•
De vel o p me nt of detecta ble A D As 
f oll owi n g olecl u ma b a n d d ur val u ma b

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 2 ( 2. 1. 1 - 1)
Sec o n d ar y O bjecti ve(s) a n d Ass oci ate d E n d p oi nts
T y pe
O bjecti ve
E n d p oi nt
P har mac o
ki netics
T o deter mi ne t he P K pr ofile of olecl u ma b 
a n d d ur val u ma b i n c o m bi nati o n wit h 
c he m ot hera p y a d mi nistere d i n s u bjects wit h 
metastatic P D A C
•
S u m mar y P K f or olecl u ma b, 
d ur val u ma b, a n d selecte d 
c he m ot hera pies a n d/ or t heir 
meta b olites
1 L = first -li ne; 2 L = sec o n d-li ne; A D A = a nti-dr u g a nti b o d y; A E = a d verse e ve nt; C D = cl uster of differe ntiati o n; 
D C = disease c o ntr ol; D o R = d urati o n of res p o nse; E C G = electr ocar di o gra m; m F O L F O X = m o difie d re gi me n of 
le uc o v ori n, 5-fl uor o ur acil, a n d o xali plati n; O R = o bjecti ve res p o nse; O S = o verall s ur vi val; P D A C = pa ncreatic 
d uctal a de n ocarci n o ma; P F S = pr o gressi o n -free s ur vi val; P K = p har mac o ki netic(s); R E CI S T = Res p o nse 
E val uati o n Criteria i n S oli d T u m ors; S A E = seri o us a d verse e ve n t; v = versi o n.
N ote: Part 1 is d ose escalati o n a n d Part 2 is d ose e x pa nsi o n.
2. 1. 2
T a ble 3 ( 2. 1. 2 - 1)
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 3 ( 2. 1. 2 - 1)
3
S T U D Y D E SI G N
3. 1
Descri pti o n of t he St u d y
3. 1. 1
O ver vie w
T his is a P hase 1 b/ 2, m ult ice nter, o pe n-lab el , d ose-escalat i on a n d d ose -e x pa nsi o n st u d y  t o 
assess t he safet y,  preli mi nar y a ntit u mor acti vit y, i m m u n o ge nicit y,  a n d P K of olecl u ma b wit h 
or wi t ho ut d ur val u ma b i n c o m bi nat i on wi t h c he mot h era p y a dmi nistere d i n s u bjects wit h 
metastati c P D A C. S u bjects wit h pre vi o usl y u ntreate d metastatic P D A C ( 1 L metastatic P D A C) 
will be e nr o lle d i n C o h ort A. S u bjects wit h metastatic P D A C pre vi o usl y treate d wit h 
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
g e m cita bi ne-base d c he m ot hera p y  ( wit ho ut e x p os ure t o 5 - FU, ca pecita bi ne, or o xali plati n; 2 L 
metastati c P D A C) will be e nr olle d i n C o h ort B. T he st u d y  c o nsists of 2 parts, d ose escalat i on 
( Part 1) a n d d ose e x pa nsi on ( Part 2). All s u bjects i n b ot h c o h orts will be treate d u ntil disease 
pr o gressi o n, i nt olera ble t o xi cit y, wit hdra wal of s u bject c o nse nt, or a n ot her disc o nt i n uati on 
crit erio n  is met.
U p t o a p pr o xi matel y  3 3 9 s u bjects will be e nr olle d i n t his st u d y at a p pr o xi matel y 3 0 sites 
gl o b all y: u p t o a p pr o xi matel y 2 4 s u bjects i n Part 1 ( d ose escalat i on) a n d u p t o a p pr o xi matel y 
3 1 5 s u bjects i n Part 2 ( d ose e x pa nsi o n). T he st u d y flo w di a gra m is prese nte d i n Fi g ure 1
(3. 1. 1 - 1) f or Part 1 ( d ose escalati o n) a n d i n Fi g ure 2 ( 3. 1. 1 - 2) f or Part 2 ( d ose e x pa nsi on).
Fi g ure 1 ( 3. 1. 1 - 1)
St u d y Fl o w Di a gr a m ( P art 1: D ose Esc al ati o n)
1 L = first -li ne; 2 L = sec o n d-li ne; m F O L F O X = m o difie d re gi me n of le uc o v ori n, 5 -fl u or o uracil, a n d o xali plati n; 
N = n u m ber; P D A C = pa ncreatic d uctal a de n ocarci n o ma.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Fi g ure 2 ( 3. 1. 1 - 2)
St u d y Fl o w Di a gr a m ( P art 2: D ose E x p a nsi o n)
1 L = first -li ne; 2 L = sec o n d-li ne; C D = cl uster of differe ntiati o n; m F O L F O X = m o difie d re gi me n of le uc o v ori n, 
5- fl u or o uracil a n d o xali plati n; N = n u m ber; P D A C = pa ncreatic d uctal a de n ocarci n o ma.
a
Stratificati o n f or C D 7 3.
F or C o h ort A, a n i nteri m a nal ys is will be perf or me d w he n a p pr o xi matel y 3 0 e val ua ble 
s u bjects i n eac h treat me nt ar m ha ve bee n d ose d a n d reac h t he data c ut-off criteria. Refer t o 
Secti o n 4. 8. 7 f or a d ditio n al details.
T he e n d p o i nts t o be meas ured i n t his st u d y  are descri be d i n Secti on 2 .
3. 1. 1. 1
P art 1: D ose Esc al ati o n
D uri n g Part 1, d ose escalat i on of o lecl u ma b will be perf or me d i n c om bi nat i on wi t h 
d ur val u ma b a n d c he mot h era p y ( ge mcita bi ne + na b-paclita xel f or s u bjects wit h 1 L metastatic 
P D A C [ C o h ort A]; m F O L F O X f or s u bjects wit h 2 L metastatic P D A C [ C o h ort B]) t o 
deter mi ne eit her t he M T D or t he hi g hest pr ot oc ol -defi ne d d ose f or eac h re gi me n. 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
S u bjects will be e nr o lle d i n c o h orts t o be treate d with i ncreasi n g d ose le vels of olecl u ma b wit h 
t he p ote ntial t o be treate d at a lo wer d ose l e v el. A si n gle d ose le vel f or d ur val u ma b a n d 
c he m ot hera p y will be use d i n c o m bi nat i on wi t h oleclu ma b (see Sect i on 3. 1. 2. 1 ). D ose 
escalat i on will be gi n wit h e nr oll me nt of at least 3 s u bjects (a n d u p t o 6 s u bjects) at D ose 
L e vel 1 ( Ta ble 4 ( 3. 1. 1. 1 - 1)). T he D E C ( Secti o n 3. 1. 3. 1 ) will m onit or s u bjects f or D L Ts 
d uri n g t he D L T -e val uat i on peri o d as def i ne d i n Secti o n 3. 1. 3. 3 . E nr oll me nt of a d diti on al  
s u bjects at a d ose le vel, d ose escalat i on t o t he ne xt d ose le vel, or d ose de -escalat i on will  
pr o gress acc or di n g t o t he r ul es o utli ne d i n Sect i on 3. 1. 3. 2 . If t he M T D is e xcee de d at t he 
starti n g d ose le vel, t he n a l o wer d ose le vel o f ol e cl u ma b 
 ( d ose le vel -1) m a y be 
e valuate d (Ta ble 4 ( 3. 1. 1. 1 - 1)).
T a ble 4 ( 3. 1. 1. 1 - 1)
Olecl u m a b D ose Le vels f or E v al u ati o n i n P art 1 ( D ose 
Esc al ati o n)
A ge nts
D ose Le vel - 1
N = 3 - 6 s u bjects
D ose Le vel 1
a
N = 3 -6 s u bjects
D ose Le vel 2
N = 6 s u bjects
Olecl u ma b
( C o h orts A a n d B)
 Q 2 W × 4
t he n Q 4 W
 Q 2 W × 4
t he n Q 4 W
 Q 2 W × 4
t he n Q 4 W
I V = i ntra ve n o usl y; Q 2 W = e ver y 2 wee ks; Q 4 W = e very 4 wee ks.
a
Starti n g d ose le vel.
3. 1. 1. 2
P art 2: D ose E x p a nsi o n
O nce t he R P 2 D f or a c o h ort has bee n i de nt ifie d, e nr oll me nt i nt o Part 2 d ose e x pa nsi on ma y 
pr ocee d. C o h orts A a n d B ma y be o pe ne d f or e nr oll me nt at t he discret i on of t he s p o ns or 
i n de pe n de ntl y of eac h ot her. Refer t o Secti o n 3. 1. 3. 1 f or details o n o n g oi n g safety 
s ur veilla nce.
D uri n g Part 2 ( d ose e x pa nsi o n), t he R P 2 D of olecl u ma b i de ntifie d i n Part 1 f or eac h re g i me n 
will be e val uate d wit h or wit h o ut d ur val u ma b i n c o m bi nat i on wi t h c he mot h era p y (see 
Secti o n 3. 1. 2. 2 ). S u bjects e nr olle d i n Part 2 will be stratifie d acc or di n g t o t u mor al  e x pressio n 
of  C D 7 3 b y I H C a n d ra n d o mize d t o a treat me nt ar m.
S u bjects i n C o h ort A ( 1 L metastatic P D A C) will be ra n d o mize d 1: 1: 1 t o o ne of 3 treat me nt 
ar ms:

Ar m A 1: ge mcita bi ne + na b -pacli ta xel or 

Ar m A 2: o lecl u ma b + ge mcita bi ne + na b-paclit a xel or 

Ar m A 3: o lecl u ma b + d ur val u ma b + ge mcita bi ne + na b-pacli t a x el
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 8 of 1 4 4
Te m plate 1 8. 0
S u bjects i n C o h ort B ( 2 L metastatic P D A C) will be ra n d o mize d 1: 1: 1 t o o ne of 3 treat me nt 
ar ms:

Ar m B 1: m F O L F O X or 

Ar m B 2: ol ecl u ma b + m F O L F O X or 

Ar m B 3: ol ecl u ma b + d ur val u ma b + m F O L F O X
T here will be n o cr oss o ver bet wee n treat me nt ar ms.
3. 1. 2
Tre at m e nt Re gi me n
T he treat me nt ar ms a n d re gi me ns are detaile d i n Secti o n 3. 1. 2. 1 f or Part 1 ( d ose escalati on) 
a n d i n Sect i on 3. 1. 2. 2 f or Part 2 ( d ose e x pa nsi on). All treat me nt will be a d mi nistere d 
be gi n ni n g o n Da y  1 u ntil c o nfir me d ra di o l ogi cal pr o gressi ve disease ( P D ) u nless t here is 
u nacce pta ble t o xicit y, wi t hdra wal of c o nse nt, or a n ot her disc o nt i n uati o n criteri o n is met.
If a n y c he m ot hera pe utic a ge nt is disc o nti n ue d d ue t o treat me nt-r elate d t o xicit y, olecl u ma b 
wi t h or wit ho ut d ur val u ma b a n d a n y  no n -res p o nsi ble c he m othera pe ut ic a ge nt ma y c o nti n ue at 
t he i n vest i gat or’s discreti o n w he n t o xicity res ol ves t o Gra de 2 or less. 
N ote: If t he i n vest i gat or feels a s u bject is rea d y t o restart t he ot her n o n- res p o nsi ble tr e at me nts 
pri or t o t he c he m ot hera pe ut ic t o xicity res o l vi n g to Gra de 2 or less, Me dI m m u ne s h o ul d be 
c o ns ulte d f or a n e xce pt i on t o t hi s r ule.
All s u bjects will be f oll ow e d f or s ur vi val u nt il t he e n d of t he st u d y ( defi ne d as t he last 
e x pecte d visit of t he last s u bject o n st u d y, a p pr o xi matel y 2 year s after t he last s u bject be gi ns 
treat me nt wit h in vest i gati onal pr o d uct or w he n t he s p o ns or st o ps t he st u d y , w hic he ver occ urs 
earlier [ Secti o n 6. 3 ]). 
At  t he c o ncl usi on of  t he st u d y, s u bjects w h o c o nti n ue t o de m o nstrate cli nical be nefit will be 
eli gi ble t o recei ve i n vest i gati onal pr o d uct via a r oll o ver st u d y  re q uirin g a p pr o val b y t he 
res p o nsi ble Healt h A ut h ority a n d et hics c o m mittee or t hr o u g h a n ot her mec ha nis m at t he 
di scretio n of  t he s p o ns or. T he s p o ns or reser ves t he ri g ht t o ter mi nate access t o i n vesti gati onal 
pr o d uct if a n y o f t he f o ll owi n g occ ur: a) t he mar keti n g a p plicati o n is rejecte d b y  t he 
res p o nsi ble Healt h A ut h ority; b) t he st u d y  is ter mi nate d d ue t o safet y c o ncer ns; c) t he s u bject 
ca n o btai n i n vest i gati onal pr o d uct fr o m a g o ver n me nt -s p o ns ore d or pri vate healt h pr o gra m; or 
d) t hera pe utic alter nati ves bec o me a vaila ble i n t he l ocal mar ket.
3. 1. 2. 1
P art 1: D ose Esc al ati o n
I n Part 1 ( d ose escalati o n), s u bjects will be e nr olle d i n either C o h ort A or B a n d recei ve t he 
f oll owi n g treat m e nt as detaile d bel o w a n d prese nte d i n  Fi g ure 3 ( 3. 1. 2. 1 - 1).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

C o h ort A 

Ar m A 1
o
G e m cita bi ne 
 a n d na b-pacli ta xel 
 o n Da ys 1, 8, 
a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule 

Ar m A 2
o
Ol ecl u ma b I V Q 2 W f or 4 d oses, t he n Q 4 W a n d
o
G e m cita bi ne 
 a n d na b-pacli ta xel 
 o n Da ys 1, 8, 
a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule 

Ar m A 3
o
Ol ecl u ma b I V Q 2 W f or 4 d oses, t he n Q 4 W a n d
o
D ur val u ma b  
 Q 4 W a n d
o
G e m cita bi ne 
 a n d na b-pacli ta xel 
 o n Da ys 1, 8, 
a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule 

C o h ort B

Ar m B 1
o
m F O L F O X o n Da ys 1 a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule: O xali platin 
 le uc o v ori n 
; 5-F U 
 b olus f ol l owe d b y  
5- F U 
a d mi nistere d b y c o nt i n u o us I V i nf usi on o ver 4 6 t o 4 8 h o urs

Ar m B 2
o
Ol ecl u ma b I V Q 2 W f or 4 d oses, t he n Q 4 W a n d
o
m F O L F O X o n Da ys 1 a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule: O xali plati n 
 le uc o v ori n 
; 5-F U 
 b olus f ol l owe d b y  
5- F U 
a d mi nistere d b y c o nt i n u o us I V i nf usi on o ver 4 6 t o 4 8 h o urs

Ar m B 3
o
Ol ecl u ma b I V Q 2 W f or 4 d oses, t he n Q 4 W a n d
o
D ur val u ma b 
 Q 4 W a n d
o
m F O L F O X o n Da ys 1 a n d 1 5 a n d t he n re peate d o n a Q 4 W sc he d ule: O xali plati n 
; le uc o v ori n 
; 5-F U 
 b olus f ol l owe d b y  
5- F U 
a d mi nistere d b y c o nt i n u o us I V i nf usi on o ver 4 6 t o 4 8 h o urs
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
3. 1. 3
D ose Esc al ati o n, C o h ort Pr o gressi o n, D ose -li miti n g T o xicit y, a n d S afet y 
Re vie w
3. 1. 3. 1
D ose -esc al ati o n C o m mittee ( P art 1, D ose Esc al ati o n)
S u bjects will be f o ll ow e d f or safet y d uri n g Part 1 of t he st u d y. A st u d y-s pecific D E C 
(incl u di n g at a mi n i m u m t he s p o ns or me dical m o nit or/cli nical lea d a n d all partici pati n g 
i n vesti gat ors w h o ha ve e nr olle d s u bjects i n t hat d ose le vel) will pr o vi de o n g oi n g safety 
s ur veilla nce of t he st u d y, wit h r e g ularl y sc he d ule d re vie ws of safet y a n d ot her rele va nt data. 
T hi s c o m mittee ma y als o meet t o re vie w data at ot her ti me p oi nts (e g, i n res p o nse t o A Es 
assesse d as me dicall y rele va nt b y t h e me dical mo ni t or). T his c o m mittee will be res p o nsi ble 
f or d ose-escalat i on or d ose de -escalati o n decisi o ns a n d rec o m me n dat i ons re gar di n g f urt her 
c o n d uct of t he st u d y d uri n g Part 1 . All decisi ons b y  t his c o m mittee will be d oc u me nte d a n d 
s hare d wit h all partici pati n g sites i n writ i n g.
3. 1. 3. 2
R ules f or D ose Esc al ati o n a n d C o h ort Pr o gressi o n ( P art 1)
I n Part 1 of t his st u d y, d ur val u ma b a n d olecl u mab i n c o m bi nat i on wi t h c he mot h era p y will be 
e x pl ore d. T he f o ll owi n g r ul es will be a p plica ble t o d ose escalat i on i n C o h orts A a n d B. 
1
T he M T D will be deter mi ne d base d o n t he assess me nt of D L Ts d uri n g t he 
D L T -e val uat i on peri o d ( Secti o n 3. 1. 3. 3 ). S u bjects w h o d o n ot meet t he criteria f or t he 
D L T -e val ua ble p o p ulat i on will be re place d ( Sect i on 4. 1. 8 ).
2
A d mi nistrati o n of  t he first d ose of i n vesti gati o nal pr o d uct m ust be sta g gere d b y a 
mi ni m u m o f 2 4 h o urs f or t he first 2 s u bjects i n eac h c o h ort. I ntra -s u bject d ose escalati o n 
will n ot be all o we d. I ntra -s u bject d ose de-escalat i on of o lecl u ma b or d ur val u ma b will n ot 
be all o we d.
3
A mi ni m u m of 3 s u bjects ( u p t o 6 s u bjects) will be e nr olle d i n eac h d ose -le vel c o h ort. If 
n o D L Ts are o bser ve d i n a c o h ort of 3 t o 6 e val ua ble s u bjects, t he n d ose escalat i on ma y 
occ ur. 
4 
If 1 s u bject i n a d ose- level c o h ort of 3 or m ore e val ua ble s u bjects e x perie nces a D L T, t hat 
d ose -lev el  c o h ort will be e x pa n de d t o a t otal of 6 s u bjects. If n o more t ha n 1 of 6 s u bjects 
i n t he d ose-lev el  c o h ort e x perie nces a D L T, d ose escalat i on will c o nti n ue t o t he ne xt 
hi g her d ose -level c o h ort.
5
If ≥ 2 s u bjects i n a d ose -level c o h ort e x perie nce a D L T, t he M T D will be e xcee de d a n d 
n o f urt her s u bjects will be e nr olle d i nt o t hat d ose le vel c o h ort. If t his occ urs, t he 
prece di n g d ose -level c o h ort will be e val uate d f or t he M T D a n d a t otal of 6 s u bjects will 
be treate d at t he prece di n g d ose le vel if n ot alrea d y e x pa n de d. If ≤ 1 of 6 s u bjects 
e x perie nces a D L T at t he prece di n g d ose le vel, t he n t his d ose le vel will be t he M T D. 
6
If ≥ 2 s u bjects i n t he first d ose c o h ort e x perie nce a D L T, t he n n o f urt her s u bjects will be 
e nr o lle d i nt o t hat d ose-lev el  c o h ort. A d ose de-escalat i on ( D ose Le vel -1) will t he n be 
e val uate d f or t he M T D i n 6 s u bjects. 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
7
If t he hi g hest pr ot oc ol-defi ne d d ose level is reac he d a n d n o D L Ts are o bser ve d i n a 
mi ni m u m o f 3 e val ua ble s u bjects, t he s p o ns or will e x pa n d t he hi g hest pr ot oc ol -defi ne d 
d ose l e vel t o 6 s u bjects. If ≤ 1 of 6 s u bjects e x perie nces a D L T, t he n t he hi g hest 
pr ot oc ol -defi ne d d ose le vel ma y  be selecte d for f urt her e val uati o n i n Part 2.
8
At  t he discretio n of  t he s p o ns or, d ose escalati on ma y be st o p pe d bef ore a n M T D is 
reac he d. I n t his case, a n e x pa n de d c o h ort d ose ma y be c h ose n base d o n a n assess me nt of 
P K, p har mac o d y na mic, bi o mar ker, safet y,  a n d a ntitu m or acti vit y d at a. 
9
D ose escalat i on pr ocee ds i n de pe n de nt l y bet wee n t he c o h orts of t his st u d y .
3. 1. 3. 3
D ose -li miti n g T o xicit y
D L Ts will be e val uate d d uri n g Part 1 ( d ose escalati o n) f or b ot h C o h orts A a n d B. T he peri o d 
f or D L T-e val uat i on will be fr o m t he first d os e of all st u d y treat me nts t hr o u g h Da y 2 8. 
S u bjects w h o d o n ot c o m plete t he D L T -e val uat i on peri o d or di d n ot recei ve all pla n ne d d oses 
of  olecl u ma b, d ur val u ma b, or c he m ot hera p y d uri n g t his ti me f or reas o ns ot her t ha n a D L T 
will be c o nsi dere d n o n- e val ua ble for D L T assess me nt a n d will be re place d wit h a n ot her 
s u bject at t he sa me d ose le vel, b ut will still be c o nsi dere d w he n re vie wi n g t o xicit y fr om t his 
c o h ort ( Secti o ns 4. 1. 8 a n d 4. 8. 1 ). Gra di n g of D L Ts will be acc or di n g t o t he Nati o nal Ca ncer 
I nstitute C o m m o n Ter mi n o l og y  Crit eria for A d verse E ve nts ( N CI C T C A E versi o n 4. 0 3). 
A D L T will be defi ne d as a n y  Gra de 3 or hig her t o xicit y or a n y  of t he e ve nts liste d bel o w t hat 
occ urs d uri n g t he D L T -e val uat i on peri o d. T o xi cit y t hat is clearl y a n d directl y relate d t o t he 
pri mar y  disease, c he m ot hera p y al one, or t o a n ot her eti o l og y  will n ot be c o nsi dere d D L Ts. T he 
f oll owi n g will be D L Ts:

I mm u ne- me d iate d a d verse e ve nts (i m A Es)

A n y Gra de 4 i m A E (e xcl u di n g as y m pt o mat ic li pase a n d/ or a m ylase ele vati o n)

A n y ≥ Gra de 3 c olit is

A n y ≥ Gra de 3 na usea, v o mit i n g, or diarr hea t hat d oes n ot res ol ve t o Gra de 2 or less 
wi t hi n 3 da ys of t he i nitiati on of ma xi mal s u p p orti ve care

A n y ≥ Gra de 3 p ne u m o nit is or I L D

A n y Gra de 2 p ne u m o nit is or I L D f or w hic h t he s y m pt o mat ol o g y d oes n ot res ol ve 
wi t hi n 7 da ys of t he i nitiati on of ma xi mal s u p p orti ve care

A ne mia

Gra de 4 a ne mia o f a n y d urati o n

Gra de 3 a ne mia if ass ociate d wit h cli nical se q uelae or re q uires tra nsf usi o n of 
> 2 u nits of re d bl o o d cells

T hr o m b oc y t o p e nia

Gra de 4 t hr o m b oc y t o p e nia ≥7 da y s 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

Gra de 3 or 4 t hr o m b oc y t o p e nia, re gar dless of d uratio n, ass oci ate d wit h Gra de 3 or 
hi g her he m orr ha ge

Ne utr o pe nia a n d/ or fe brile ne utr o pe nia

Gra de 4 fe brile ne utr o pe nia of  a n y d ur atio n

Gra de 3 fe brile ne utr o pe nia last i n g ≥5 da y s w hile recei vi n g ma xi mal s u p p orti ve care 

Gra de 4 ne utr o pe nia last i n g > 7 da y s 

Li ver f u ncti o n tests

Is olate d Gra de 3 li ver tra nsa mi nase ele vat i on or is ol ate d Gra de 3 t otal bilir u bi n 
( T B L) t hat d oes n ot d o w n gra de t o Gra de 1 or less wit hi n 1 4 da ys after o nset wit h 
o pti mal me dical ma na ge me nt, i ncl u di n g s yste mic c ortic oster oi ds. 

Is olate d Gra de 4 li ver tra nsa mi nase ele vat i on or T B L re gar dless of d urati o n.

A n y i ncrease i n A S T or A L T > 3 × u p per li mit n or mal ( U L N ) a n d c o nc urre nt 
i ncrease i n T B L > 2 × U L N ( H y’s La w) wit h o ut e vi de nce of c h o lestasis or alter nati ve 
e x pla nat i ons (e g, vi r al he pat itis, disease pr o gressio n i n t he li ver)

A n y ot her t o xicit y t hat is greater t ha n t hat at baseli ne, is cli nicall y si g nifica nt a n d/ or 
u nacce pta ble a n d is j u d ge d t o be a D L T b y  t he D E C 
A D L T e xcl u des t he f o ll owi n g:

Gra de 3 e n d ocri ne dis or der (t h y r oid, pi t uit ar y, a n d/ or a dre nal ins ufficie nc y ) t hat is 
ma na ge d wit h or wit h o ut s yste mic c ortic oster oi d t hera p y a n d/ or h or m o ne re place me nt 
t hera p y

Gra de 3 i nfla m mat or y  reacti on attri b ute d t o a l ocal a ntit u m or res p o nse (e g, i nfla m mat or y  
reactio n at si t es of metastatic disease, l y m p h n o des, et c) t hat res ol ve d t o Gra de 1 or less 
wi t hi n 3 0 da ys

C o nc urre nt vit ili g o or al o pecia of a n y A E gra de

Is olat e d la b orat or y c ha n ges of a n y gra de wit ho ut cli nical  se q uelae or cli nical si g nifica nce 
t hat are n ot defi ne d as a D L T a b o ve
I mm u ne- me d iate d A Es are defi ne d as A Es of a n i m m u ne nat ure (ie, i nfla m mat or y) i n t he 
a bse nce of a clear alter nat i ve eti ol og y . I n t he a bse nce of cli nical a b n or mality, re peat 
la b orat or y testi n g will be c o n d ucte d t o c o nfir m si g nifica nt la b orat or y fi n di n gs pri or t o 
desi g nati o n as a D L T . 
3. 1. 3. 4
S afet y Re vie w C o m mittee ( P art 2 , D ose E x p a nsi o n)
A S af et y Re vie w C o m mittee (S R C ) will c o n d uct safet y re vie ws of all e nr olle d s u bjects 
a p pr o xi matel y e v er y 3 mo nt hs . T he S R C ma y ma ke rec o m me n dat i ons re gar di n g c o nt i n uati on, 
m o dificati o n, or ter mi nat i on of a n y st u d y ar m for s af et y c o ncer ns. T he S R C ma y re q uest 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
a d ditio nal  data as nee de d. A d diti onal safety re vie ws ma y be c o n d ucte d at t he discreti o n o f t he 
S R C.
T he S R C will i ncl u de, b ut i s n ot li mite d t o, t he f oll o wi n g:

S R C C hair pers o n (Me dI m m u ne / Astra Ze neca Cli nical  Lea d)

St u d y  Me dical M o nit or

Gl o bal Safet y P h ysicia n

Pri nci pal I n vest i gat ors fr o m a s u bset of acti ve i n vesti gati onal sites ( 3- 5). T he n u m ber of 
s p o ns or re prese ntati ves will n ot e xcee d t he n u m ber of Pri nci pal I n vesti gat ors.

St u d y  St atisticia n

S R C c o or di nat or
T he Cli nical De vel o p m e nt S ci e nt ist, Patie nt Safet y Scie ntist, a n d ot her dele gates ma y als o be 
i n vite d as a p pr o priate. Ot her i nter nal a n d e xter nal e x perts ma y be c o ns ulte d b y t he S R C as 
necessar y . T he me m bers hi p, r oles, res p o nsi bilities, a n d details o n t he pr ocess 
flo w/c o m m u ni c ati o n pl a n are pr o vide d i n t he S R C C harter.
3. 1. 4
M a n a ge me nt of St u d y Me dic ati o n Rel ate d T o xicities
T he f o ll owi n g ge neral g ui da nce s h o ul d be f o ll owe d f or m a na ge me nt of t o xicities.

Treat eac h of t he t o xicit ies wit h ma xi m u m s u p porti ve care (i ncl u di n g h o l di n g t he a ge nt or 
a ge nts s us pecte d of ca usi n g t he t o xicit y if re q uire d). T he use of gr o wt h fact ors acc or di n g 
t o lo c al  practice will be all o we d.

S u bjects s h o ul d be t h or o u g hl y e val uate d t o r ule o ut a n y  alter nati ve etiol o g y  ( e g, disease 
pr o gressi o n, c o nc o mit a nt me dicat i ons, a n d i nfect i ons). 

If t he t o xicities are clearl y attri b ute d t o c he mot h era p y or i m m u ne t hera p y, eit her 
c he m ot hera p y or i m m u ne t hera p y ca n be dela ye d or disc o nti n ue d, a n d t he ot her o ne ma y 
be c o nt i n ue d. If t he ca usalit y of t o xicit y is u nclear, b ot h c he m ot hera p y a n d i m m u ne 
t hera p y s h o uld be dela ye d or disc o nti n ue d. 

I n t he e ve nt t hat t o xicities are clearl y attri b ute d t o c he m ot hera p y, b ot h c he m ot hera p y 
( g e mcita bi ne a n d na b-pacli t a x el or 5-F U a n d o xali plat i n) a n d t he re gime n c o m pr ise d of 
d ur val u ma b a n d o lecl u ma b s h o ul d be dela ye d f or u p t o 7 da ys; t he g oal of s y nc hr o nize d 
d el a y is t o preser ve t he ali g n me nt of c he m ot hera p y a n d i m m u n ot hera p y. If c he mot h era p y 
ca n n ot be res u me d wit hi n 7 da ys after t he ori gi nall y sc he d ule d da y, t he d ur val u ma b a n d 
ol ecl u ma b ma y be a d mi nistere d f or t hat c ycle.

If s u bjects e x perie nce a t o xicity clearl y relate d t o a n y c he mot h era pe ut ic a ge nt 
necessitat i n g t he per ma ne nt disc o nti n uati on of t hat a ge nt o nl y (e g, ne ur o pat h y  d ue t o 
o xali plat i n), t he n t he no n -offe n di n g c he m ot hera pe utic a ge nt, d ur val u ma b a n d o lecl u ma b 
ma y st ill be c o nt i n ue d u ntil t he s u bject meets t he g ui deli nes f or treat me nt disc o nti n uati o n. 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

I n t he a bse nce of clear alter nati ve eti ol og y , all e ve nts s h o ul d be c o nsi dere d p ote ntiall y 
i m m u ne-me d iate d, a n d t he t o xicity ma na ge me nt g ui deli nes detaile d bel o w s h o uld be 
f oll owe d .

I n t he e ve nt t hat d ur val u ma b a n d olecl u ma b is disc o nti n ue d or dela ye d as part of t he 
t o xicit y ma na ge me nt g uida nce, c he m ot hera p y  ma y still be a d mi nistere d as sc he d ule d. If 
d ur v al u ma b or olecl u ma b is dela ye d, t he n b ot h a ge nts m ust be dela ye d.
If u ns ure h o w t o ma na ge a s u bject, please c o ntact t he st u d y me dical m o nit or t o disc uss 
i n di vi d ual cases. All t o xicities will be gra de d acc or di n g t o N CI C T C A E versi on 4. 0 3.
3. 1. 4. 1
M a n a ge me nt of Ole cl u m a b -Rel ate d T o xicities
G ui deli nes f or m a na ge me nt of i m m u ne -me d iate d reacti o ns, I R Rs, a n d n o n-i m m u ne-me d iate d 
reactio ns f or ol ecl u ma b are pr o vi de d i n t he t o xicit y ma na ge me nt g ui deli nes i n Sect i on 1 0. 9 .
3. 1. 4. 2
M a n a ge me nt of D ur v al u m a b -Rel ate d T o xicities
C o m pre he nsi ve t o xi cit y ma na ge me nt g ui deli nes ha ve bee n de vel o pe d t o assist i n vest i gat ors 
wi t h t he rec o g nitio n a n d ma na ge me nt of t o xicit ies ass ociat e d wit h t he use of t he 
i m m u ne-c hec k p o i nt i n hi bit ors d ur val u ma b ( P D-L 1 i n hi bit or) a n d tre meli m u ma b ( C T L A - 4 
i n hi bit or). Gi ve n t he si milar u n derl yi n g mec ha nis ms of t o xicities o bser ve d with t hese 
2 c o mp o u n ds, t hese d ur val u ma b ± tr e meli m u ma b g ui deli nes are a p p lica ble t o t he ma na ge me nt 
of  p atie nts recei vi n g eit her dr u g as m o n ot hera p y  or i n c om bi nat i on. A d dit i onall y , t hese 
g ui deli nes are a p plica ble w he n eit her dr u g is use d al o ne or i n c o m bi nat i on a n d is a d mi nistere d 
c o nc urre nt l y or se q ue ntiall y wit h ot her a ntica ncer dr u gs (ie, a nt i ne o plastic c he m ot hera p y, 
tar gete d a ge nts), as part of a pr ot oc ol s pecific treat me nt re gi me n. T he t o xicity ma na ge me nt 
g ui deli nes pr o vi de i nf or mat i on f or t he ma na ge me nt of i m m u ne -me diate d reacti o ns, I R Rs, a n d 
n o n- i m m u ne me diate d reacti o ns t hat ma y be o bser ve d wit h c hec k p oi nt i n hi bit or m o n ot hera p y 
or c o m bi nat i on c hec k p o i nt i n hi bit or re gi me ns, wit h s pecific i nstr ucti o ns f or d ose 
m o dificati o ns (i ncl u di n g disc o nt i n uati ons) a n d treat me nt i nter ve nt i ons. I n vesti gat ors are 
a d vise d h o we ver t o use l o cal practice g ui deli nes a n d c o ns ult l ocal refere nces f or t he 
ma na ge me nt of t o xicit ies o bser ve d with ot her ca ncer treat me nt ( Secti o n 3. 1. 4. 3 ). T he m ost
c urre nt versi o n of t he d ur val u ma b ± tr e meli m u ma b t o xicit y ma na ge me nt g uideli nes, e nt itle d 
“ D osi n g M o dificat i on a n d T o xi cit y Ma na ge me nt G uideli nes f or I m m u ne -Me diate d, 
I nf usi on- Relate d, a n d N o n -I m m u ne Me diate d Reacti o ns ( M E DI 4 7 3 6 M o n ot hera p y or 
C o m bi nat i on T hera p y wit h Tre meli m u ma b or Tre meli m u ma b M o n ot hera p y )”, is pr o vide d t o 
t he i n vest i gati ve site as a n A n ne x d oc u me nt a n d is mai ntai ne d wit hi n t he Site Master File. I n 
a d ditio n, a versi o n of t he c urre nt D osi n g M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes
is a vaila ble t hr o u g h t he f oll owi n g li n k:  ht t ps://t mg. a zi rae.c o m. Please c o ntact t he st u d y 
re prese ntati ve f or i nf or mati on o n h o w t o gai n access t o t his we bsite.
P ati e nts s h o uld be t h or o u g hl y  e v aluate d a n d a p pr o pri at e eff orts s h o ul d be ma de t o r ule o ut 
ne o pl astic, i nfectio us, m eta b o lic, t o xi n, or ot her eti ol o gic ca uses of t he i m A E. Ser ol o gic, 
i m m u n ol ogic, a n d hist ol o gic ( bi o ps y) data, as a p pr o priate, s h o ul d be use d t o s u p p ort a n i m A E 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
di a g n osis. I n t he a bse nce of a clea r alter nati ve etiol o g y , e ve nts s h o uld be c o nsi dere d 
p ote nti all y i m m u ne relate d. I n a d ditio n, t here are certai n circ u msta nces i n w hic h d ur val u ma b 
s h o uld be per m a ne ntl y disc o nt i n ue d. F oll owi n g t he first d ose of i n vesti gat i onal pr o d uct, 
s u bse q ue nt a d mi nistrati on of d ur val u ma b ca n be m o difie d base d o n t o xicit ies o bser ve d as 
descri be d i n t he D osi n g M o dificat i on a n d T o xi cit y Ma na ge me nt G ui deli nes. T hese g ui deli nes 
ha ve bee n pre pare d b y t he s p o ns or t o assist t he I n vesti gat or i n t he e xercise of his/ her cli nical 
j u dg me nt i n treati n g t hese t y p es of  t o xicities. T hese g uideli nes a p pl y  t o A Es c o nsi dere d 
ca usall y relate d t o d ur valu ma b c o ntai ni n g re gi me n b y  t he re p orti n g i n vesti gat or.
D ose re d ucti o ns are n ot per mitte d. I n case of d o u bt, t he i n vesti gat or s h o ul d c o ns ult with t he 
me dical m o nit or .
3. 1. 4. 3
M a n a ge me nt of C he m ot her a p y Rel ate d T o xicities
T o xicit ies relate d t o c he mot h era p y s h o uld be ma na ge d b y  foll o wi n g i nst ituti o nal  lo c al  
sta n dar d-of -care g uideli nes i ncl u di n g d ose o missi o n, d ose m o dificat i on, a n d disc o nt i n uati on 
of  t hera p y.
He m at ol o gic E ve nts
F or he m at olo gi c t o xicities (e g, ne utr o pe nia a n d t hr o m b oc yt o p e nia), ma na ge me nt of t he 
t o xicit y, i ncl u di n g d ose mo dificat i ons or gr o wt h fact or s u p p ort, s h o ul d be perf or me d 
acc or di n g t o t he l ocal sta n dar d practice. 
N o n -he m at ol o gic E ve nts
F or n o n -he mat ol o gic t o xi cities (e g, perip heral  ne ur o pat h y, c uta ne o us t o xicity, gastr oi ntest i nal 
t o xicit y s uc h as mu c osi tis or diarr hea), ma na ge me nt of t he t o xicit y, i ncl u di n g d ose o missi ons, 
m o dificati o ns , a n d disc o nt i n uati ons, s h o ul d be perf or m e d acc or di n g t o t he l ocal sta n dar d 
practi ce.
A b n or m al He p atic F u ncti o n
C he m ot h era p y s h o uld o nl y  be a d mi nistere d if he patic f u nct i on is wit hi n t he l ocal or 
i nstituti o nal  p ar a m eters s pecifie d f or a d mi nistrati o n. He patic t o xicit y fr o m ta xa nes ma y occ ur 
b ut is u nc o m m o n. T heref ore, he patic d y sf u ncti on t hat occ urs w hile t he s u bject is o n st u d y 
s h o uld pr o m pt a n e val uat i on t o deter mi ne t he ca use, i ncl u di n g t he p ossi bilit y of  pr o gressi ve 
metastati c disease a n d he pat ot o xicit y fr o m c o nc urre nt me dicati ons. I n t he case of s u bjects 
w h o are recei vi n g olecl u ma b wit h or wit h o ut d ur val u ma b, i m m u ne -me diate d he pat itis s h o ul d 
be c o nsi dere d a n d ma na ge d acc or di n g t o t he t o xicit y  ma na ge me nt g uideli nes i n t he a bse nce of 
a clear alter nati ve etiol o g y  ( Sectio n 3. 1. 4 ).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
3. 2
R ati o n ale f or D ose, P o p ul ati o n, a n d E n d p oi nts
3. 2. 1
D ose R ati o n ale
3. 2. 1. 1
Olecl u m a b a n d D ur v al u m a b D ose R ati o n ale
T he ol ecl u ma b starti n g d ose of  
 Q 2 W × 4 t he n Q 4 W (e q ui vale nt t o  
 
Q 2 W × 4 t he n Q 4 W i n a 7 5 k g i n di vi d ual) was selecte d base d o n t he a vaila ble cli nical safet y,  
t olera bilit y, efficac y, a n d P K data fr o m t he o n g oi n g P hase 1 St u d y  D 6 0 7 0 C 0 0 0 0 1. I n t his 
st u d y olecl u ma b d oses of 
, a n d  
 Q 2 W were e xa mi ne d b ot h as a 
m o n ot hera p y  a n d i n c o m bi nati on wi t h d ur val u ma b 
 Q 2 W. Olecl u ma b was well 
t olerate d a n d t here were n o o bser ve d D L Ts eit her as m o n ot hera p y  or in c o m bi nat i on wi t h 
d ur val u ma b ( Secti o n 1. 4. 1 ). T he olecl u ma b 
 Q 2 W d ose (e q ui vale nt t o t he olecl u ma b 
 Q 2 W fi xe d d ose f or a 7 5 k g i n di vi d ual) was i de nt ifie d f or e val uati o n with 
d ur val u ma b 
 Q 2 W i n t he d ose-e xpa nsi o n  p hase of t his st u d y ( St u d y D 6 0 7 0 C 0 0 0 0 1). 
T he tar get d ose of  
 Q 2 W × 4 was c h ose n wit h t he i nte nt t o ac hie ve e x p os ures f or t he 
i nitial 7 0 da ys si milar t o t h ose o bser ve d at  
 Q 2 W d ose i n St u d y D 6 0 7 0 C 0 0 0 0 1 w here 
cli nical act i vity has bee n o bser ve d a n d C D 7 3 is e x pecte d t o ha ve bee n i n hi bite d ma xi mall y. 
S u bse q ue ntl y, a Q 4 W sc he d ule at  
 is pre dicte d t o res ult i n a de q uate l o n g -t er m 
e x p os ures wit h t he pre dicte d me dia n tr o u g h of 
 T he pre dicte d tr o u g h c o nce ntrati o n 
is a b o ve t he esti mate d C D 7 3 sat urati n g c o nce ntrati o n of a p pr o xi matel y  
 ( 1 0 0-f ol d of 
esti mate d Mic haelis -Me nte n c o nsta nt [ K m ] fr o m t he p o p ulati on P K m o del) t o mai ntai n 
o pti mal C D 7 3 sat urati o n at stea d y  state. At t he  
 Q 4 W mai nte na nce d ose le vel, t he 
pre di ct e d me dia n stea d y state tr o u g h c o nce ntrati o n at  
 will mai ntai n a de q uate 
c o nce ntrati o ns d uri n g t he maj orit y of  t he d osi n g i nter val. Ol ecl u ma b 
 is o ne 
d ose l e vel belo w t he hi g hest m o n ot hera p y  a n d c o m bi nati on wei g ht -base d d oses t hat ha ve bee n 
teste d a n d declare d t olera ble i n t he F TI H St u d y D 6 0 7 0 C 0 0 0 0 1. T heref ore, olecl u ma b  
 
× 4 t he n Q 4 W has bee n selecte d as t he starti n g d ose t o be use d i n c o m bi nat i on wi t h 
d ur val u ma b a n d sta n dar d-of -care c he m ot hera p y. A fi xe d d ose of olecl u ma b 
× 4 
t he n Q 4 W (e q ui vale nt t o 
× 4 t he n Q 4 W) is i ncl u de d as D ose L e vel -1, if 
nee de d.
T he d ose a n d sc he d ule of d ur val u ma b  
 Q 4 W i n c o m bi nat i on wi t h olecl u ma b was 
selecte d base d o n P K/ p har mac o d y na mics, safet y a n d efficac y data fr o m n u m er o us st u dies 
c o ntai ni n g d ur val u ma b. As detaile d i n Ta ble 4 6 ( D ur val u ma b I B, e dit i on 1 2), a fi xe d d ose of 
 Q 4 W (e q ui vale nt t o  
) is bei n g i n vesti gate d i n n u mer o us o n g oi n g st u dies. 
T his d ose was f o u n d t o be well t olerate d b ot h i n m o n ot hera p y  (Secti o n 5. 2. 2. 1; D ur val u ma b 
I B, e ditio n 1 2,) a n d i n c o m bi nat i on ( Secti o ns 5. 2. 2. 2 t o 5. 2. 2. 6; D ur val u ma b I B, e diti o n 1 2). 
D ur val u ma b P K e x p os ures o bser ve d i n c o m bi nati o n t hera p y were c o nsiste nt wit h t he 
o bser ve d m o n ot hera p y  e x p os ures ( Ta ble 4; D ur val u ma b IB, e di tio n 1 2). Si milarl y , i n t he 
o n g oi n g F TI H P hase 1 st u d y  ( St u d y D 6 0 7 0 C 0 0 0 0 1), d ur val u ma b  
 Q 2 W (e q ui vale nt 
t o 7 5 0 mg), a d mi nistere d i n c o m bi nati o n wit h ol ecl u ma b at 
 Q 2 W, was well 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
t olerate d wit ho ut a n y  D L Ts ( Sectio n 1. 4. 1 ). Als o, b ot h d ur val u ma b a n d olecl u ma b e x p os ures 
i n c o m bi nat i on di d n ot s h o w a n y  differe nces as c o m pare d t o m o n ot hera p y e x p os ures. 
Pre vi o us st u dies a n d P K si m ulat i ons o f d ur val u ma b ha ve i n dic ate d t hat a si milar A U C at 
stea d y state ( 4 wee ks) is e x pecte d f oll owi n g b ot h 1 0 m g/ k g Q 2 W a n d 
 Q 4 W. As 
s uc h, d ur val u ma b  
Q 4 W is c o nsi dere d t o be e q ui vale nt t o d ur val u ma b 
 
Q 2 W c urre nt l y bei n g utilize d i n t he o n g o i n g F TI H P hase 1 st u d y ( St u d y D 6 0 7 0 C 0 0 0 0 1). 
C o nsi deri n g all t he a vaila ble P K, safet y a n d t olera bilit y data, a 
 Q 4 W d ose of 
d ur val u ma b is pr o p ose d i n c o m bi nat i on wi t h ole cl u ma b a n d c he mot h era p y t o p ote ntiall y 
deri ve t he ma xi m u m be nefit. 
R ati o n ale f or Fi xe d D oses of I m m u n ot her a p y
Ma n y  p u blis he d articles ha ve pre vi o usl y re p orte d a si milarity of  e x p os ures f oll o wi n g eit her 
fi xe d or b o d y size-base d d osi n g of m A bs (Nar wal  et al, 2 0 1 3 ; N g et al, 2 0 0 6 ; Wa n g et al, 
2 0 0 9 ; Z ha n g et al, 2 0 1 2 ). Wa n g a n d c ollea g ues i n vesti gate d 1 2 m A bs a n d f o u n d t hat fi xe d a n d 
b o d y  size-base d d osi n g perf or m si milarl y, wit h fi xe d d osi n g bei n g better f or 7 of  1 2 m A bs 
(Wa n g et al, 2 0 0 9 ). I n a d diti on, t he y  in vest i gate d 1 8 t hera pe utic pr otei ns a n d pe pti des a n d 
s h o we d t hat fi xe d d osi n g perf or me d better f or 1 2 of 1 8 i n ter ms of re d uci n g t he 
bet wee n -pati e nt varia bilit y in P K/ p har mac o d y na mics para meters (Z ha n g et al, 2 0 1 2 ). A fi xe d 
d osi n g a p pr oac h is als o preferre d b y t he prescri bi n g c o m m u nit y d ue t o ease of use a n d 
re d uce d d osi n g err ors. Gi ve n t he e x pectati o n of si milar P K e x p os ure a n d varia bility,  it is 
c o nsi dere d feasi ble t o s wit c h t o fi xe d d osi n g re gi me ns. Base d o n a vera ge b o d y w eig ht of  
7 5 k g, t he fi xe d d ose of  
 Q 4 W d ur val u ma b (e q ui vale nt t o  
 Q 4 W) a n d t he 
fi xe d d oses of olecl u ma b 
 Q 2 W × 4 t he n Q 4 W (e q ui vale nt t o  
 Q 2 W × 4 
t he n Q 4 W) a n d olecl u ma b 
 Q 2 W × 4 t he n Q 4 W (e q ui vale nt t o  
 Q 2 W × 4 
t he n Q 4 W) are i nclu de d i n t he c urre nt st u d y . 
3. 2. 1. 2
R ati o n ale f or D oses of C he m ot her a p y
T he sta n dar d-of - care a ge nts bei n g a d mi nistere d eit her al o ne or i n c o m bi nati on wi t h olecl u ma b 
wi t h or wit ho ut d ur val u ma b w ill be d ose d acc or di n g t o sta n dar d practice f or t he re gi me ns. T he 
treat me nt re gi me ns are detaile d i n Sect i on 3. 1. 2 .
3. 2. 2
R ati o n ale f or St u d y P o p ul ati o n
D ur val u ma b or tre meli m u ma b m o n ot hera p y a n d i n c o m bi nati o n ha ve s h o w n m o dest 
a nt itu m or acti vit y i n t he 2 L metastatic P D A C p o p ulati on. H o we ver, t he c o m bi nat i on re gi me n 
of  t hese 2 a ge nts wit h ge mcita bi ne a n d na b-pacli ta xel de mo n strates cli nical acti vity i n t he 1 L 
metastati c P D A C p o p ulat i on. I n a d dit i on, ol ecl u ma b i n c o m bi nat i on wi t h d ur val u ma b has 
s h o w n cli nical acti vity i n 2 L a n d 3 L P D A C. T heref ore, olecl u ma b pl us d ur val u ma b c o m bi ne d 
wi t h ge mcita bi ne a n d na b-pacli t a x el ma y p ote ntiall y offer be nefit t o s u bject s wit h pre vio usl y  
u ntreate d metastatic P D A C.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T he P K para meters f or olecl u ma b, d ur val u ma b, a n d selecte d c he m ot hera pies t hat will be 
deter mi ne d f or t he sec o n dar y  o bjecti ve ma y i ncl u de o ne or m ore of t he f o ll owi n g: ma xi m u m 
o bser ve d c o nce ntrati o n ( C ma x), ti me t o reac h Cma x (tma x ), A U C, cleara nce, a p pare nt v o l ume of 
di stri b uti on ( Vd), a n d ter mi nal half-life (t1/ 2) if t he data all o w as well as ot hers if dee me d 
i m p orta nt. As d ur val u ma b a n d olecl u ma b will be a d mi nistere d o n a re peati n g d osi n g sc he d ule, 
t he de vel o p me nt of a nti-dr u g a nt i b o d y (A D A ) a n d its p ote ntial effect o n safety,  
p har mac o d y na mics, P K , a n d a nt itu m or acti vit y will als o be assesse d. 
As C D 7 3 has bee n s h o w n t o be pr o g n ostic a n d i s t he direct tar get of o ne of t he a ge nts utilize d 
i n t his st u d y, t he c orrelat i on bet wee n C D 7 3 e x pressi o n a n d cli nical o utc o me as assesse d b y 
O R R, D C R, D o R, P F S , a n d O S will be e val uate d. 
 
 
 
 
 
3. 2. 4
R a ti o n ale f or Str atific ati o n F act ors ( P art 2 [ D ose E x p a nsi o n])
C D 7 3 e x pressi o n has bee n ass ociate d wit h p o or pr o g n osis a n d w orse O S i n n u mer o us 
mali g na ncies i ncl u di n g C R C (Li u et al , 2 0 1 2; W u et al, 2 0 1 2 ), T N B C (L o i et al, 2 0 1 3), re nal 
cell carci no m a (Y u et al, 2 0 1 5 ), gastric ca ncer (L u et al , 2 0 1 3), hi g h-gra de ser o us o varia n 
ca ncer (T urc otte et al, 2 0 1 5 ), a n d hea d a n d nec k s q ua m o us cell carci n oma (Re n et al , 2 0 1 6).
 
. S u bjects 
i n Part 2 will be re q uire d to s u b mit eit her arc hi val or fres h t u m or bi o ps y sa m ples f or C D 7 3 
I H C testi n g d uri n g scree ni n g. T hese res ults will be re q uire d f or stratifie d ra n d omizat i on t o 
ac hie ve bala nce d re prese ntati o n of t he 3 treat me nt ar ms i n eac h of t hese strata, t here b y 
mi ni miz i n g t he li keli h o o d of u n d ue bias o n treat me nt c o m paris o ns at t he e n d of t he st u d y . T he 
ra n d omizat i on will be stratifie d b y C D 7 3 e x pressi o n le vel (see Secti o n 4. 6. 1 ).
4
M A T E RI A L S A N D M E T H O D S
4. 1
S u bjects
4. 1. 1
N u m ber of S u bjects
U p t o a p pr o xi matel y  3 3 9 s u bjects will be e nr olle d i n t his st u d y: u p t o a p pr o xi matel y 
2 4 s u bjects i n Part 1 ( d ose escalat i on) a n d u p t o a p pr o xi matel y 3 1 5 s u bjects i n Part 2 ( d ose 
e x pa nsi o n).
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4. 1. 2
I ncl usi o n Criteri a
1
A ge ≥1 8 ye ars at t he ti me of scree ni n g or a ge of c o nse nt acc or di n g t o la w.
2
Wr itte n i nf or me d c o nse nt a n d a n y lo c all y re q uire d a ut h orizat i on (e g, data pri vac y) 
o btai ne d fr o m t he s u bject prior t o perf or mi n g a n y  pr ot oc ol-r elate d pr oce d ures, i ncl u di n g
scree ni n g e val uati ons.
3
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1.
4
Wei g ht ≥3 5 k g.
5
S u bjects dia g n ose d wit h hist o l ogicall y or c y t olo gi call y c o nfir me d pa ncreatic 
a de n ocarci n o ma:
(a) F or C o h ort A: S u bjects m ust n ot ha ve recei ve d s yste mic t hera p y f or metastatic 
pa ncreat ic a de n ocarci n oma. If s u bjects recei ve d pri or ne oa dj u va nt or a dj u va nt 
c he m ot hera p y a n d pr o gresse d wit hi n 6 m o nt hs o f t he last d ose, t he n t his s h o ul d be 
c o nsi dere d as a pri or li ne o f s yste mic t hera p y.
( b) F or C o h ort B: S u bject s must ha ve recei ve d a n d ra di o l ogicall y  pr o gresse d o n o nl y 
1 pri or li ne of s yste mic t hera p y  for m etastatic pa ncreatic a de n ocarci n o ma. T his m ust 
ha ve bee n a ge mcita bi ne -base d re gi me n a n d ma y  n ot ha ve c o ntai ne d 5-F U, 
ca pecita bi ne, or o xali plat i n (if c o nsid er e d a li ne of t hera p y) as a n y o f t he 
c o mp o ne nts. If s u bjects recei ve d pri or ne oa dj u va nt or a dj u va nt c he m ot hera p y  a n d 
pr o gresse d wit hi n 6 m o nt hs of t he last d ose , t he n t his s h o ul d be c o nsi dere d as a pri or 
li ne of s yste mic t hera p y.
6
S u bjects m ust ha ve at l east 1 m eas ura ble lesi o n acc or di n g t o R E CI S T v ersio n 1. 1.
(a) A pre vi o usl y  irra diate d lesio n  ca n be c o nsi dere d a tar get lesi on if t he lesi on is well 
defi ne d, m eas ura ble per R E CI S T, a n d has clearl y pr o gresse d.
( b) S u bjects m ust ha ve a n o n -tar get lesio n  t hat ca n be bi o psie d at acce pta ble ris k (if 
bi o ps y is re q uire d f or e nr oll me nt) as j u d ge d b y t he i n vest i gat or, or if n o ot her lesi on 
is s uita ble f or bi o ps y, t he n a R E CI S T tar get lesi on use d f or bi o ps y  must be ≥ 2 c m  in 
l on gest di a meter.
7
All s u bjects must c o nse nt t o pr o vi di n g arc hi val t u m or s peci me ns (c ore bi o psies or lar ger 
resecti o n, n o fi ne-nee dle as pirati o n sa m ples) f or c orrelati ve bi o mar ker st u dies a n d C D 7 3 
e x pressi o n testi n g f or stratificat i on if t u m or tiss ue is a vaila ble. If arc hi val s peci me n 
( ≤1 2 m o nt hs o l d) is n ot a vaila ble, s u bjects m ust c o nse nt t o a fres h bi o ps y.
8
A de q uate or ga n a n d marr o w f u nct i on as defi ne d i n  Ta ble 5 ( 4. 1. 2 - 1).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 5 ( 4. 1. 2 - 1)
Criteri a f or A de q u ate Or g a n a n d M arr o w F u ncti o n
P ar a meter
V al ue
He mat ol o gical
He m o gl o bi n
a
≥9 g/ d L
A bs ol ute ne utr o p hil c o u nt
a
≥1, 5 0 0 µ/ L
Platelet c o u nt a
≥1 0 0, 0 0 0 µ/ L
He patic
T otal bilir u bi n
C o h ort A: ≤ 1. 5 × U L N 
C o h ort B: ≤ 1. 5 × U L N if n o 
de m o nstra ble li ver metastases
C o h ort B: ≤ 3 × U L N is all o we d 
i n t he prese nce of d oc u me nte d 
Gil bert’s s y n dr o me or li ver 
metastases
Ala ni ne tra nsa mi nase a n d 
As partate tra nsa mi nase
≤ 2. 5 × U L N if n o de m o nstra ble 
li ver metastases
≤ 5 × U L N i n t he pr ese nce of li ver 
metastases
Al b u mi n
≥ 3 g/ d L
Re nal
Calc ulate d creati ni ne cleara nce
b
≥4 0 m L/ mi n ute
U L N = u p per li mit n or mal.
a
He mat ol o gical criteria ca n n ot be met wit h o n g oi n g or rece nt bl o o d tra nsf usi o ns ( wit hi n 1 4 da ys pri or t o 
t he sc he d ule d first d ose of st u d y treat me nt) or re q uire gr o wt h fact or s u p p ort ( wit hi n 2 1 da ys pri or t o t he 
sc he d ule d first d ose of st u d y treat me nt).
b
As deter mi ne d b y C oc kcr oft -Ga ult ( usi n g act ual b o d y wei g ht) or 2 4 -h o ur uri ne creati ni ne cleara nce.
9
Fe males of c hil d beari n g p ote ntial w h o are se x uall y acti ve wit h a n o nsterilize d male 
part ner m ust use at least 1 hi g hl y effect i ve met h o d of c o ntrace pti o n (see Sect i on  1 0. 1 f or 
defi nit i on o f females o f c hil d beari n g p ote ntial a n d f or a descri pt i on of hi g hl y effect i ve 
met h o ds of c o ntrace pti o n) fr o m scree ni n g t o 1 8 0 da ys after t he fi nal d ose of st u d y  
treat me nt. It is str o n gl y rec om me n de d f or t he male part ner of a fe male s u bject t o als o use 
male c o n d o m pl us s per mici de t hr o u g h o ut t his peri o d. Cessati o n of c o ntrace pti o n after t his 
p oi nt s h o ul d be disc usse d wit h a res p o nsi ble p h ysicia n. Peri o dic a bst i ne nce, t he r h yt h m 
met h o d, a n d t he wit h dra wal met h o d are n ot acce pta ble met h o ds of c o ntrace pti o n.
1 0
N o nsterilize d male s u bjects w h o are se x uall y acti ve wit h a fe male part ner of c hil d beari n g 
p ote nti al must use a m ale c o n d o m wit h s per mici de fr o m scree ni n g t o 1 8 0 da ys after 
receip t of t he fi nal d ose of st u d y treat me nt. It is str o n gl y rec o m me n de d f or t he fe male 
part ner of a male s u bject t o als o use a hi g hl y  effecti ve met h o d of c o ntrace pti o n 
t hr o u g h o ut t his peri o d, as descri be d i n Secti on 1 0. 1 . I n a d diti on, m ale s u bjects must 
refrai n fr om s per m d o nati on w hile o n st u d y  a n d for 1 8 0 da y s after t he fi nal d ose of st u d y 
treat me nt.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 4 of 1 4 4
Te m plate 1 8. 0
4. 1. 3
E xcl usi o n Criteri a
A n y of t he f o ll owi n g w o ul d e xcl u de t he s u bject fr o m  partici pat i on i n t he st u d y:
1
Recei pt of a n y  c o n ve nti onal or i n vest i gati onal a nt ica ncer t hera p y wit hi n 2 1 da ys or 
palliat i ve ra di ot hera p y withi n 1 4 da ys pri or t o t he sc he d ule d first d ose of st u d y treat me nt.
2
Pri or r e c ei pt of  a n y i m m u ne-me d iate d t hera p y inc l u di n g, b ut n ot li mite d t o, ot her 
a nt i-C T L A -4, a nt i-P D -1, a nti -P D -L 1 a nt i b o dies a n d a ge nts tar geti n g C D 7 3, C D 3 9, or 
a de n osi ne rece pt ors, e xcl u di n g t hera pe utic a nt ica ncer vacci nes.
3
C o nc urre nt e nr oll me nt i n a n ot her t hera pe utic cli nical st u d y . E nr oll me nt i n obser vat i onal 
st u dies will be all o we d.
4
A n y t o xicit y (e xcl u di n g alo pecia) fr o m  pri or sta n dar d t hera p y t hat has n ot bee n 
c o mpletel y res ol ve d t o baseli ne at t he ti me of c o nse nt. S u bjects wit h N CI C T C A E versi o n 
4. 0 3 Gra de 1 or 2 t o xicit ies t hat are dee me d sta ble or irre versi ble ca n be e nr olle d o n a 
case- b y-case basis wit h pri or c o ns ul t atio n a n d a gree m e nt wit h t he me dical m onit or.
5
S u bjects wit h a hist or y  of ve n o us t hr o m b osis wit hi n t he past 3 m o nt hs pri or t o t he 
sc he d ule d first d ose of st u d y treat me nt . N O T E: S u bj ects wit h t hr o m b osis d ue t o 
mec ha nical o bstr ucti o n b y  t he t u mor t hat i s fo u n d i nci de ntall y a n d is as y m pt o matic a n d 
d oes n ot re q uire t hera p y  ma y be e nr o lle d at t he i n vesti gat or’s discret i on a n d s h o ul d be 
clos el y  mo ni t or e d.
6
S u bjects wit h pri or hist or y  of my o car dial i nfarct i on, tra nsie nt isc he mic attac k, or str o ke 
wi t hi n t he past 3 m o nt hs pri or t o t he sc he d ule d first d ose of st u d y  treat me nt .
7
Act i ve or pri or d oc u me nte d a ut oi m m u ne dis or ders wit hi n t he past 3 years pri or t o t he 
sc he d ule d first d ose of st u d y treat me nt. T he f oll o wi n g are e xce pt i ons t o t his criteri o n:
(a) S u bjects wit h vit ili g o or al o pecia.
( b) S u bjects wit h h y p ot h y r oidis m  ( e g, fol l owi n g Has hi m ot o s y n dr o me) sta ble o n 
h or m o ne re pl ace me nt or ps oriasis n ot re q uiri n g s yste mic treat me nt.
(c) A n y c hr o nic s ki n c o n di tio n  t hat d oes n ot re q uire s yste mic t hera p y.
( d) S u bjects wit h celiac disease c o ntr olle d b y diet al o ne.
8
S u bjects wit h c o nfir me d h u ma n i m m u n o deficie nc y  vir us (e ve n if vir al loa d is 
u n detecta ble), c hr o nic or acti ve he pat itis B or C, or acti ve he patitis A.
9
Hi st or y of pri mar y i m m u n o deficie nc y, s oli d or ga n tra ns pla ntati o n, or acti ve t u berc ul osis. 
I n settin gs w here t here is a cli nical or ra di o gra p hic e vi de nce of t u berc ul osis, act i ve 
di sease m ust be e xcl u de d pri or t o e nr oll me nt. 
1 0
Ot her i n vasi ve mali g na nc y  wit hi n 2 years. N o ni n vasi ve mali g na ncies (ie, cer vical 
carci n o ma i n sit u, i n sit u pr ostate ca ncer, n o n-me la n omat o us carci n o ma of t he s ki n, d uctal 
carci n o ma i n sit u of t he breast t hat has bee n s ur gicall y c ure d) are e xclu d e d f r o m t his 
defi nit i on. 
1 1
K n o w n aller g y  or h y perse nsit i vity t o i n vesti gati on al  pr o d uct f or mulat i ons.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 2
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o o n g oi n g or acti ve i nfect i on 
re q uirin g a nt i bi otic t hera p y, u nc o ntr olle d h y perte nsi o n, blee di n g diat heses, or ps yc hiatric 
ill ness/s ocial sit uati ons t hat w o ul d li mit c o m p lia nce wit h st u d y re q uire me nts, 
s u bsta ntiall y increase ri s k of inc urri n g A Es, or c o m pr o mise t he a bilit y of  t he s u bject t o 
gi ve writte n i nf or me d c o nse nt.
1 3
A n y hist or y  of le pt o me ni n geal disease or c or d c o m pressi o n.
1 4
U ntreate d C N S metastatic disease. N ote: S u bjects pre vi o usl y treate d f or C N S metastases 
t hat are ra di o gra p hicall y a n d ne ur olo gicall y sta ble f or at least 2 8 da ys a n d d o n ot re q uire 
c ortic oster oids ( of a n y  d os e) for C N S s y m pt o m at ic ma na ge me nt f or at least 1 4 da ys prior
t o t he sc he d ule d first d ose of st u d y treat me nt will be eli gi ble.
1 5
C urre nt or pri or use of i m m u n os u p pressi ve me dicati o n wit hi n 1 4 da ys pri or t o t he 
sc he d ule d first d ose of st u d y treat me nt. T he f oll o wi n g are e xce pt i ons t o t his criteri o n:
(a) I ntra nasal, t o pical, i n hale d c ortic oster oi ds or l ocal ster oi d i njecti o ns (e g, 
i ntr a-artic ular i nject i on).
( b) S y ste mic c ortic oster oids at p h ysi o l ogi c d oses n ot t o e xcee d 1 0 m g/ da y of pre d nis o ne 
or e q ui vale nt.
(c) Ster oi ds as pre m e dicatio n f or h y perse nsi tivit y reacti o ns (e g, c o m p ute d t o mo gra p h y  
[ C T] sca n pre me dicati on).
1 6
Recei pt of li ve, atte n uate d vacci ne wit hi n 2 8 da ys pri or t o t he sc he d ule d first d ose of 
st u d y tr e at me nt ( N ote: S u bjects, if e nr olle d, s h o ul d n ot recei ve li ve vacci ne d uri n g t he 
st u d y a n d 1 8 0 da ys after t he last d ose of st u d y tr e at me nt). Vacci nat i on wi t h an i nacti vate d 
vacci ne is per mitte d at a n y  ti me.
1 7
Maj or s ur ger y  (as defi ne d b y t he i n vesti gat or) wit hi n 2 8 da ys pri or t o sc he d ule d first d ose 
of  st u d y tr e at me nt or still rec o veri n g fr o m pri or s ur ger y . L ocal pr oce d ures (e g, place me nt 
of  a s yste mic p ort, c ore nee dle bi o ps y, a n d pr ostate bi o ps y) are all o we d if c o m plete d at 
least 2 4 h o urs pri or t o t he a d mi nistrati o n of t he first d ose of st u d y treat me nt. 
1 8
Fe males w h o are pre g na nt, lactati n g, or i nte n d t o bec o me pre g na nt d uri n g t heir 
parti ci pat i on i n t he st u d y.
1 9
S u bjects w h o are i n v o l unt aril y i ncarcerate d or are u na ble t o willi n gl y pr o vi de c o nse nt or 
are u na ble t o c o m pl y wit h t he pr ot oc ol pr oce d ures.
2 0
A n y c o n dit i on t hat, i n t he o pi ni o n of t he i n vest i gat or, w o ul d i nterfere wit h safe 
a d mi nistrati o n or e val uat i on of t he i n vest i gati onal pr o d ucts or i nter pretati o n of s u bject 
safety or s t u d y res ults.
2 1
K n o w n aller g y  or h yperse nsi tivi t y t o ge mcita bi ne, na b-pacli ta xel, o xali plati n, le uc o v ori n, 
or 5 -F U.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4. 1. 4
S u bject E nr oll me nt a n d R a n d o miz ati o n
St u d y partici pat i on be gi ns (ie, a s u bject is “e nr o lle d”) o nce writte n i nf or me d c o nse nt is 
o btai ne d. O nce i nf or me d c o nse nt is o btai ne d, a s u bject i de nt ificati on ( SI D) n u m ber will be 
assi g ne d b y a ce ntral s yste m (e g, a n I nteracti ve Res p o nse Tec h n ol og y  [I R T]), an d t he 
scree ni n g e val uati ons m a y be gi n t o assess st u d y eli gi bility (incl usi o n/e xcl usi o n) cri t eria. T he 
SI D n u m ber will be use d t o i de nt if y t he s u bject d uri n g t he scree ni n g pr ocess a n d t hr o u g h o ut 
st u d y partici patio n, if a p plica ble. 
F or Part 2 ( d ose e x pa nsi o n ), o nce t he s u bject is c o nfir me d t o be eli gi ble, t he i n vesti gat or or 
s uita bl y trai ne d dele gate will p erfor m  ra n d o mizati o n i n I R T. T he s yste m will ra n d omize t he 
eli gi ble s u bject t o 1 of t he 3 treat me nt ar ms. S u bjects will be gi n treat me nt o n C ycle 1 Da y 1.
Treat me nt s h o ul d start n o m ore t ha n 3 w or ki n g da ys after bei n g ra n d o mize d. S u bjects m ust 
n ot be ra n d o mize d a n d treate d u nless all eli gi bilit y cri t eria ha ve bee n met. If t he s u bject is 
i neli gi ble a n d n ot ra n d o mize d, t he I R T s h o ul d be c o ntacte d t o wit h dra w t he s u bject i n t he 
s yste m.
A master l o g of all c o nse nte d s u bjects will be mai ntai ne d at t he site a n d will d oc u me nt all 
scree ni n g fail ures (ie, s u bjects w h o are c o nse nte d b ut d o n ot meet st u d y eli gi bility cri t eria 
a n d/ or are n ot ra n d o mize d), i ncl u di n g t he reas o n(s) f or scree ni n g fail ure. Site c o m pleti on of 
t he mi ni mal set of scree n fail ure i nf or mat i on i ncl u di n g de m o gra p h y, scree n fail ure details, 
eli gi bilit y crit eria, a n d a n y S A E are re q uire d.
S u bjects w h o d o n ot meet t he criteria f or partici pati o n i n t he st u d y (ie, scree ni n g fail ures) ma y 
be rescree ne d. S u bjects ca n be rescree ne d a si n gle ti me, b ut t he y  ca n n ot be re-ra n d o mize d. 
Rescree ne d s u bjects s h o ul d be assi g ne d a ne w s u bject n u m ber. H o we ver, rescree ni n g s h o ul d 
be d oc u m e 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 s u bjects s h o ul d ha ve t he reas o n f or scree n fail ure rec or de d i n t he electr o nic case re p ort 
f or m (e C R F).
4. 1. 5
Wit h dr a w al fr o m  t he St u d y
S u bjects are free t o wit h dra w t heir c o nse nt t o partici pate i n t he st u d y  (in vest i gati onal pr o d uct 
a n d assess me nts) at a n y ti me, wit ho ut pr ej u dice t o f urt her treat me nt. S u bjects w h o wit h dra w 
c o nse nt will 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  AEs. If  t he s u bject is 
willi n g, t he s u bject will be see n a n d assesse d b y t he i n vesti gat or a n d A Es will be f oll owe d u p. 
If a s u bject wit h dra ws fr om f urt her partici pati on i n t he st u d y, t he n n o f urt her st u d y visits or 
data c ollect i on s h o ul d ta ke pl ace.
4. 1. 6
Disc o nti n u ati o n of I n vesti g ati o n al Pr o d uct
A n i n di vi d ual s u bject will n ot recei ve a n y furt her i n vesti gati o nal pr o d uct if a n y o f t he 
f oll owi n g occ ur i n t he s u bject i n q uest i on:

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1
Wit h dra wal o f c o nse nt fr o m t he st u d y or fr o m furt her st u d y  treat me nt b y s u bject
2
U nacce pta ble t o xicit y/ A E t hat i n t he o pi ni o n o f t he i n vest i gat or or Me dI m m u ne, warra nts 
di sc o nti n uati on of f urt her d osi n g or meets criteria f or disc o nti n uati o n fr o m i n vesti gati onal 
pr o d uct as defi ne d i n Sect i on 3. 1. 3. 3 a n d Secti o n 3. 1. 4
3
Lac k of cli nical acti vit y or cli nical be nefit t o t he s u bject, i n t he o pi ni o n of t he i n vesti gat or
4 
C o nfir me d or u nc o nfir me d P D a n d t he treat me nt criteria i n t he setti n g of P D are n ot m et 
(ie, 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 decli ne 
i n E C O G perf or ma nce stat us i n dicati n g ra pi d decli ne; A N D a bse nce of ra pi d P D or t hreat 
t o vit al or ga ns/critical a nat o mical sit es r e q uirin g ur ge nt al ter nati ve me dical i nter ve nti o n)
5
I nitiatio n of  alter nati ve a ntica ncer t hera p y incl u di n g a n ot her i n vest i gati onal a ge nt
6
I nterc urre nt ill ness w hic h, i n t he j u d g me nt of t he in vesti gat or, w o ul d si g nifica nt l y affect 
assess me nts of cli nical stat us 
7
L ost t o foll o w - u p 
8
Pre g na nc y ( Secti o n 5. 6. 2 ) or i nte nt t o bec o me pre g na nt
9
S u bject is deter mi ne d t o ha ve met o ne or m ore of t he e xcl usi o n cri t eria for st u d y  
parti ci pat i on at st u d y  e ntr y a n d c o nti n ui n g treat me nt wit h in vest i gati onal pr o d uct mi g ht 
c o nstit ute a safet y ris k.
1 0
S u bject n o nc o m p lia nce (e g., ref usal t o a d here t o visit sc he d ule) t hat, i n t he o pi ni o n of t he 
I n vesti gat or or Me dI m m u ne, warra nts wit h dra wal
S u bjects w h o are per ma n e nt l y disc o nti n ue d fr om recei vi n g i n vesti gati onal pr o d uct will be 
f oll owe d f or pr ot oc ol -s pecifie d assess me nts i ncl u di n g f o ll ow- u p of  a n y A Es u nless c o nse nt is 
wi t hdra w n fr o m  furt her st u d y  p artici pat i on ( Secti o n 4. 1. 5 ) or t he s u bject is l ost t o f oll ow- u p. 
4. 1. 7
Tre at m e nt Be y o n d Pr o gressi o n
S u bjects i n all treat me nt ar ms ma y  c o nti n ue recei vi n g t heir ori gi nall y assi g ne d treat me nt, at 
t he i n vest i gat or’s discretio n, af ter t he first o verall ti me p oi nt assess me nt of P D b y 
R E CI S T v ersio n 1. 1 u ntil P D is c o nfir me d o n a f oll o w -u p sca n (c o nfir me d ra di o l ogi cal P D). 
A c o nfir mat or y  sca n is re q uire d f oll owi n g t he assess me nt of P D b y  R E CI S T versio n 1. 1, 
prefera bl y at t he n e xt sc he d ule d visit a n d n o earlier t ha n 4 wee ks after t he i m me diate pre vi o us 
assess me nt of P D.
F or all s u bjects w h o are treate d t hr o u g h pr o gressi o n t he i n vesti gat or s h o ul d e ns ure t hat t he 
s u bject d oes n ot ha ve a n y si g nifica nt, u nacce pta ble, or irre versi ble t o xicities t hat i n dicate t hat 
c o nti n ui n g treat me nt will n ot f urt her be nefit t he patie nts. S u bjects wit h u nc o nfir me d 
r a diol o gic P D w h o are eli gi ble t o c o nti n ue recei vi n g t heir assi g ne d treat me nt will be ma de 
a ware of t he p ote nti al be nefits a n d ris ks of c o nti n ui n g treat me nt i n t he setti n g of P D a n d m ust 
pr o vi de a se parate writte n i nf or me d c o nse nt pri or t o treat me nt.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T he cri t eria for c o nti n ui n g treat me nt des pite R E CI S T v ersio n 1. 1 -defi ne d pr o gressi o n are as 
f oll ows:

T here i s a bse nce of cli nical s y m pt o ms or sig ns i n dicat i n g cli nicall y si g nifica nt disease 
pr o gressi o n acc o m pa nie d b y a decli ne o f m o re t ha n 1 i n W H O/ E C O G perf or ma nce stat us.

T here i s a bse nce of ra pi d disease pr o gressi o n or t hreat t o vital or ga ns or crit ical 
a nat o mical sites (e g, C N S met astasis, res pir at or y fail ure d ue t o t u m or c o m pressi o n, or 
s pi nal c or d c o m pressi on) re q ui rin g ur ge nt alter nat i ve me dical i nter ve nt i on (c o nc urre nt 
r a diat i on treat me nt is n ot per mitte d). N O T E: If a s u bject re q uires palliati ve ra diati o n f or 
is olate d pr o gre ssi o n at a n i mm u n o l ogicall y pri vile ge d site (e g, brai n) w hile mai ntai ni n g 
di sease c o ntr ol o utside t he C N S, c o ns ult Me dI m m u ne f or a n e xce pti o n t o t his r ule: 
pr ot oc ol  t hera p y will nee d t o be hel d pri or t o a n d d uri n g t he ra diati o n.
S u bjects wit h c o nfir me d ra di ol o gi cal P D ma y c o nti n ue t o recei ve t heir assi g ne d treat me nt at 
t he discret i on of t he in vest i gat or (f oll owi n g c o ns ultati o n wi t h Me dI m m u ne) as l o n g as t he y 
are gai ni n g cli nical be nefit ; c ollecti on of a d dit i on al  sca ns s u bse q ue nt t o c o nfir me d 
r a diol o gical  PD will c o nt i n ue acc or di n g t o t he ori gi nal i ma gi n g sc he d ule.
S u bjects w h o Me d Im m u ne a n d t he i n vest i gat or deter mi ne ma y n ot c o nti n ue treat me nt after 
P D will be f o ll owe d u p f or s ur vi val. S u bjects w h o ha ve disc o nt i n ue d treat me nt d ue t o t o xicity 
or s y m pt o mat ic d et eri orati o n will  be fol l owe d u p u nt il ra di ol ogical  P D a n d f or s ur vi val. 
S u bjects w h o ha ve c o m me nce d s u bse q ue nt a ntica ncer t hera p y will be f o ll owe d u p o nl y f or 
s ur vi val.
4. 1. 8
Re pl ace me nt of S u bjects
I n Part 1 ( d ose escalati o n) s u bjects w h o d o n ot c o m plete t he D L T -e val uat i on peri o d as defi ne d 
i n Secti o n 3. 1. 3. 3 will be c o nsi dere d n o n -e val ua ble f or D L T assess me nt a n d will be re place d 
wi t h a n ot her s u bject at t he sa me d ose lev el . 
S u bjects e nr o lle d i n Part 2 ( d ose e x pa nsi on) will n ot be re place d.
4. 1. 9
Wit h dr a w al of I nf or me d C o nse nt f or D at a a n d Bi ol o gic al S a m ples
Me dI m m u ne e ns ures t hat bi ol o gical sa m ples are ret ur ne d t o t he s o urce or destr o ye d at t he e n d 
of  a s pecifie d peri o d as descri be d i n t he i nf or me d c o nse nt.
If a s u bject 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, a n d t he actio n d oc u me nte d. If sa m ples are alrea d y a nal yze d, 
Me dI m m u ne is n ot o bli ge d t o destr o y  t he res ults of t his researc h.
As c ollect i on of t he bi o l ogical sa m ples (
 
) is a n i nte gral part of t he st u d y, t he n t he s u bject is with dra w n fr o m f urt her st u d y  
parti ci pat i on.
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T he Pri nci pal I n vest i gat or:

E ns ures s u bjects’ wit h dra wal o f i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
n otifie d i m me diatel y t o Me dI m m u ne.

E ns ures t hat bi o l ogi cal sa m ples fr o m t hat s u bject, if st ore d at t he st u d y site, are 
i m me diatel y ide nt ifie d, dis p ose d of/ destr o ye d, a n d t he acti o n d ocu m e nte d.

E ns ures t he or ga nizat i on(s) h o l di n g t he sa m ples is/are i nf or me d a b o ut t he wit h dra 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/ destr o y e d, t he actio n d oc u m e nte d 
a n d t he si g ne d d oc u me nt ret ur ne d t o t he st u d y sit e.

E ns ures t hat t he s u bject a n d Me dI m m u ne are i nf or me d a b o ut t he sa m ple dis p osal.
Me dI m m u ne e ns ures t he or ga nizat i on(s ) h o l 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/ destr o y e d a n d t he act i on 
d oc u m e nte d a n d ret ur ne d t o t he st u d y sit e.
4. 2
Sc he d ule of St u d y Pr oce d ures
4. 2. 1
E nr oll me nt/ Scree ni n g Peri o d
Ta ble 6 ( 4. 2. 1- 1 ) s h o ws all pr oce d ures t o be c o n d ucte d at t he scree ni n g visit. 
W he ne ver vital si g ns, 1 2 -lea d E C Gs, a n d bl o o d dra ws are sc he d ule d f or t he sa me n omi nal 
ti me, t he bl o o d dra ws s h o ul d occ ur last. T he ti mi n g of t he first 2 assess me nts s h o ul d be s uc h 
t hat it allo ws t he bl o o d dra w (e g, P K bl o o d sa m ple) t o occ ur at t he pr o per n o mi nal ti me.
T a ble 6 ( 4. 2. 1 - 1)
Sc he d ule of Scree ni n g Pr oce d ures ( P art 1 [ D ose Esc al ati o n] a n d 
P art 2 [ D ose E x p a nsi o n] )
Pr oce d ure
Scree ni n g
Visit 1
D a y -2 8 t o D a y - 1
Writte n i nf or me d c o nse nt/ assi g n me nt of SI D n u m ber
X
De m o gra p hics (a ge, race, a n d et h nicit y)
X
Me dical hist or y (i ncl u di n g s m o ki n g, pri or t hera pies
a n d pri or 
i ma gi n g) a
X
Verif y  eli gi bilit y criteria
X
Assess me nt of A Es/ S A Es
X
C o nc o mita nt me dicati o ns
X
P h y sical e xa mi nati o n (f ull)
X
Hei g ht a n d wei g ht 
X
Vital si g ns 
X
E C G (i n tri plicate)
X

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 6 ( 4. 2. 1 - 1)
Sc he d ule of Scree ni n g Pr oce d ures ( P art 1 [ D ose Esc al ati o n] a n d 
P art 2 [ D ose E x p a nsi o n] )
Pr oce d ure
Scree ni n g
Visit 1
D a y -2 8 t o D a y - 1
E C O G perf or ma nce stat us
X
L oc al L a b or at or y Assess me nts
Cli nical c he mistr y 
X
He mat ol o g y
X
T S H a n d free T 4 (If T S H is n or mal t he n free T 4 is n ot 
re q uire d)
X
C- reacti ve pr otei n
X
Li pi d pa nel
X
Ur i nal ysis
X
Pre g na nc y test, ser u m β -H C G
b
X
C oa g ulati o n para meters (a P T T a n d I N R)
c
X
He patitis B, C; HI V - 1
X
Dise ase E v al u ati o n
d
C o ntraste d C T ( preferre d) of t he c hest, a b d o me n a n d pel vis
X
M RI ( preferre d) sca n of brai n if cli nical c o ncer n f or br ai n 
metastases
X
Ce ntr al L a b or at or y Assess me nts
T u m o r bi o ps y e
X
A E = a d verse e ve nt; a P T T = acti vate d partial t hr o m b o plasti n ti me; β -h C G = beta -h u ma n c h ori o nic g o na d otr o pi n; 
 C T = c o m p ute d t o m o gra p h y; 
; 
DI C O M = Di gital I ma gi n g a n d C o m m u nicati o ns i n Me dici ne; E C G = electr 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; HI V -1 = h u ma n i m m u n o deficie nc y vir us -1; I N R = i nter nati o nal n or malize d rati o; 
M RI = ma g netic res o na nce i ma gi n g; S A E = seri o us a d verse
e ve nt; SI D = s u bject i de ntificati o n; T 4 = t h yr o xi ne; 
T H S = t h y r oi d-sti m ulati n g h or m o ne.
a
If all o we d b y c o u ntr y: Pri or i ma gi n g i ncl u des ra w i ma gi n g data (e g DI C O M) of a pre vi o us disease 
assess me nt t hat has bee n perf or me d bet wee n 4 wee ks a n d 6 m o nt hs pri or t o baseli ne sca n o btai ne d d uri n g 
scree ni n g.
b
Fe males of c hil d beari n g p ote ntial o nl y .
c
If I N R is n ot a vaila ble, t he sites ma y s u bstit ute a pr ot hr o m bi n ti me.
C CI
C
C
C CI
C CI
C CI
C CI
C CI
C
C
CC
CC
CC
C
C
C
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
d
Disease assess me nts o btai ne d pri or t o i nf or me d c o nse nt as part of sta n dar d-of -care treat me nt b ut wit hin 2 8 
da y s of first d ose ma y be s u b mitte d i nstea d if t he c ollecti o n meets t he st u d y re q uire me nts, ot her wise re peat 
sca ns s h o ul d be o btai ne d.
e
All s u bjects m ust c o nse nt t o pr o vi di n g arc hi val t u m or s peci me ns f or c orrelati ve bi o mar ker st u dies a n d 
C D 7 3 e x pressi o n testi n g f or stratificati o n if t u m or tiss ue is a vaila ble. If arc hi val tiss ue is n ot a vaila ble or if 
t he arc hi val tiss ue was ta ke n o ver 1 2 m o nt hs a g o, t he n s u bjects m ust c o nse nt t o a n d pr o vi de a fres h bi o ps y 
as part of scree ni n g pri or t o first d ose of st u d y treat me nt.
4. 2. 2
Tre at m e nt Peri o d
All pr oce d ures t o be c o n d ucte d d uri n g t he treat me nt peri o d are s h o w n i n  Ta ble 7 ( 4. 2. 2 - 1) f or 
C o h ort A a n d i n  Ta ble 8 ( 4. 2. 2- 2) f or C o h ort B. 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 7 ( 4. 2. 2 - 1)
Sc he d ule of Tre at me nt Peri o d St u d y Pr oce d ures ( C o h ort A: P art 1 [ D ose Esc al ati o n] a n d P art 2 [ D ose 
E x p a nsi o n])
Pr oce d ure
C ycle 1
C ycle 2
C ycle 3
C ycle 4
C ycle 5
C ycle 6 a n d 
s u bse q ue nt c ycles
2 8 -d a y c ycle: Wi n d o w f or e ac h assess me nt after C ycle 1 D a y 1 is ± 3 d a ys, wi n d o w f or t u m or assess me nt ± 7 d a ys
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
Tar gete d p h ysical 
e xa mi nati o n ( base d o n 
s ym pt o ms) a n d at ot her 
visits as cli nicall y i n dicate d
X
X
X
D 1 Q 2 c ycles 
starti n g wit h C 6
Wei g ht
D 1 of eac h c ycle
Vital si g ns
a
All visits
E C G (i n tri plicate) b
X
X
C 8 D 1 o nl y
E C O G perf or ma nce stat us
X
X
X
D 1 Q 2 c ycles 
starti n g wit h C 6
C o nc o mita nt me dicati o ns
All Visits
Assess me nt of A Es/ S A Es
All Visits
Dise ase E v al u ati o n
Disease assess me nt (sca ns)
Ac q uire sca ns Q 8 W ± 7 da ys f or t he first 4 8 wee ks a n d t he n Q 1 2 W ± 7 da ys t hereafter relati ve t o t he date of first d ose u ntil 
c o nfir me d ra di ol o gical pr o gressi o n, u nless n ot cli nicall y feasi ble. T his i ma gi n g sc he d ule M U S T be f oll o we d re gar dless of a n y 
dela y s i n d osi n g
L oc al L a b or at or y Assess me nts
c
Cli nical c he mistr y
X
d
X  
X  
X  
X  
X
X
X
X
He m at ol o g y
X
d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 7 ( 4. 2. 2 - 1)
Sc he d ule of Tre at me nt Peri o d St u d y Pr oce d ures ( C o h ort A: P art 1 [ D ose Esc al ati o n] a n d P art 2 [ D ose 
E x p a nsi o n])
Pr oce d ure
C ycle 1
C ycle 2
C ycle 3
C ycle 4
C ycle 5
C ycle 6 a n d 
s u bse q ue nt c ycles
2 8 -d a y c ycle: Wi n d o w f or e ac h assess me nt after C ycle 1 D a y 1 is ± 3 d a ys, wi n d o w f or t u m or assess me nt ± 7 d a ys
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
D 1  
D 8
D 1 5
T S H a n d free T 4 (If T S H is 
n or mal t he n free T 4 is n ot 
re q uire d)
X
d
X
X
X
D 1 Q 2 c ycles starti n g wit h C 5
Ur i nal ysis
X
d
X
D 1 Q 2 c ycles starti n g wit h C 5
Pre g na nc y test e
X
As cli nicall y i n dicate d
C oa g ulati o n para meters 
(a P T T a n d I N R) f
As cli nicall y i n dicate d
P h ar m ac o ki netics g
Ser u m f or olecl u ma b P K
( Part 1 a n d Ar ms A 2 
a n d A 3)
X
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5 t hr o u g h 
C 1 1
Ser u m f or d ur val u ma b P K
( Part 1 a n d Ar m A 3)
X
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5 t hr o u g h 
C 1 1
Plas ma f or ge mcita bi ne P K
X
X
Plas ma f or na b -paclita xel 
P K
X
X
Ce ntr al L a b or at or y Assess me nts
c
Ser u m f or olecl u ma b A D A
( Part 1 a n d Ar ms A 2 
a n d A 3)
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
a
Vital si g ns: O n da ys of i n vesti gati o nal pr o d uct a d mi nistrati o n, vital si g ns will be meas ure d acc or di n g t o t he c ollecti o n ti mes i n  Ta ble 1 0 ( 4. 3. 3- 1 ).
b
E C Gs: O n da ys of i n vesti gati o nal pr o d uct a d mi nistrati o n, E C Gs will be meas ure d acc or di n g t o t he c ollecti o n ti mes i n  T a b l e 1 1 ( 4. 3. 3- 2 ).
c
L ocal a n d Ce ntral La bs: Assess me nts will be c ollecte d pri or t o a d mi nistrati o n of a n y i n vesti gati o nal pr o d uct. All safet y la b o r at or y res ults m ust be re vie we d 
b y t he i n vesti gat or or p h ysicia n desi g nee pri or t o a d mi nistrat i o n of a n y i n vesti gati o nal pr o d uct.
d
If scree ni n g assess me nts ha ve bee n perf or me d wit hi n t he 5 da ys pri or t o C ycle 1 Da y 1 ( Da ys -5 t o -1), t he n assess me nt d oes n ot nee d t o be perf or me d o n 
C y cle 1 Da y 1 pr e-d ose. 
e
Pre g na nc y test: F or w o me n of c hil d beari n g p ote ntial o nl y. A uri ne or ser u m pre g na nc y test is acce pta ble, if uri ne test is p ositi ve or e q ui v ocal t he n ser u m 
β- h C G testi n g s h o ul d be perf or me d f or c o nfir mati o n. W o me n of c hil d beari n g p ote ntial are re q uire d t o ha ve a pre g na nc y test wit hi n 7 da y s pri or t o t he first 
d ose of st u d y treat me nt. Pre g na nc y test ma y occ ur o n C ycle 1 Da y 1, b ut res ults m ust be a vaila ble a n d re vie we d b y t he treati n g p h ysicia n or i n vesti gat or 
pri or t o a d mi nistrati o n of a n y i n vesti gati o nal pr o d uct.
f
C oa g ulati o n tests: a P T T a n d I N R – o n l y perf or me d at scree ni n g a n d as cli nicall y i n dicate d. If I N R is n ot a vaila ble, t he sites ma y s u bstit ute a pr ot hr o m bi n 
ti me.
g
P K sa m ples: Ser u m sa m ples f or olecl u ma b a n d d ur val u ma b P K will be c ollecte d pre -d ose ( wit hi n 9 0 mi n utes pri or t o start of i nf usi o n) a n d 1 0 mi n utes 
( ± 5 mi n utes) p ost e n d of t he res pecti ve i nf usi o n. Plas ma sa m ples f or ge mcita bi ne a n d na b -paclita xel will be c ollecte d pre -d ose ( wit hi n 9 0 mi n utes pri or t o 
start of i nf usi o n) a n d 1 0 mi n utes ( ± 5 mi n utes) p ost e n d of t he res pecti ve i nf usi o n f or first d ose of C ycles 1 a n d 4.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 8 ( 4. 2. 2 - 2) 
Sc he d ule of Tre at me nt Pr oce d ures ( C o h ort B: P art 1 [ D ose Esc al ati o n] a n d P art 2 [ D ose E x p a nsi o n])
Pr oce d ure
C ycle 1
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5
C ycle 6 a n d s u bse q ue nt 
c ycles
2 8 -d a y c ycle: Wi n d o w f or e ac h assess me nt after C ycle 1 D a y 1 is ± 3 d a ys, wi n d o w f or t u m or assess me nt ± 7 d a ys
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
Tar gete d p h ysical e xa mi nati o n 
( base d o n s y m pt o ms) a n d at 
ot her visits as cli nicall y 
i n dicate d
X
X
X
D 1 Q 2 c ycles starti n g wit h C 6
Wei g ht
D 1 of eac h c ycle
Vital si g ns
a
All visits
E C G (i n tri plicate) b
X
X
C 8 D 1 o nl y
E C O G perf or ma nce stat us
X
X
X
D 1 Q 2 c ycles starti n g wit h C 6
 
C o nc o mita nt me dicati o ns
All visits
Assess me nt of A Es/ S A Es
All visits
Dise ase E v al u ati o n
Disease assess me nt (sca ns)
Ac q uire sca ns Q 6 W ± 7 da ys f or t he first 2 4 wee ks a n d t he n Q 8 W ± 7 da ys t hereafter relati ve t o t he date of first d ose u ntil 
c o nfir me d ra di ol o gical pr o gressi o n, u nless n ot cli nicall y feasi ble. T his i ma gi n g sc he d ule M U S T be f oll o we d re gar dless of 
a n y dela ys i n d osi n g.
L oc al L a b or at or y Assess me nts
c
Cli nical c he mistr y
X
d
X  
X  
X  
X
X
X
X
He mat ol o g y
X
d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 8 ( 4. 2. 2 - 2) 
Sc he d ule of Tre at me nt Pr oce d ures ( C o h ort B: P art 1 [ D ose Esc al ati o n] a n d P art 2 [ D ose E x p a nsi o n])
Pr oce d ure
C ycle 1
C ycle 2  
C ycle 3  
C ycle 4  
C ycle 5
C ycle 6 a n d s u bse q ue nt 
c ycles
2 8 -d a y c ycle: Wi n d o w f or e ac h assess me nt after C ycle 1 D a y 1 is ± 3 d a ys, wi n d o w f or t u m or assess me nt ± 7 d a ys
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
D 1
D 1 5
T S H a n d free T 4 (If T S H is 
n or mal t he n free T 4 is n ot 
re q uire d)
X
d
X
X
X
D 1 Q 2 c ycles starti n g wit h C 5
C A 1 9 - 9
X
d
X
X
X
D 1 Q 2 c ycles starti n g wit h C 5
Ur i nal ysis
X
d
X
D 1 Q 2 c ycles starti n g wit h C 5
Pre g na nc y test
e
X
As cli nicall y i n dicate d
C oa g ulati o n para meters (a P T T 
a n d I N R) f
As cli nicall y i n dicate d
P h ar m ac o ki netics
g
Ser u m f or olecl u ma b P K ( Part 1 
a n d Ar ms B 2 a n d B 3)
X
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5 t hr o u g h C 1 1
Ser u m f or d ur val u ma b P K
( Part 1 a n d Ar m B 3)
X
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5 t hr o u g h C 1 1
Ce ntr al L a b or at or y Assess me nts
c
Ser u m f or olecl u ma b A D A
( Part 1 a n d Ar ms B 2 a n d B 3)
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5
Ser u m f or d ur val u ma b A D A
( Part 1 a n d Ar m B 3)
X
X
X
D 1 Q 3 c ycles starti n g wit h C 5
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4. 2. 3
F oll o w- u p Peri o d
Ta ble 9 ( 4. 2. 3-1) s h o ws all pr oce d ures t o be c o n d ucte d d uri n g t he f o ll ow- u p peri o d. 
T a ble 9 ( 4. 2. 3 - 1)
Sc he d ule of F oll o w -u p Pr oce d ures ( P art 1 [ D ose Esc al ati o n] a n d 
P art 2 [ D ose E x p a nsi o n])
Pr oce d ure
F oll o w -u p Peri o d
F U P - 1
F U P - n
4 Wee ks P ost L ast D ose
( ± 7 D a ys)
Q 8 W ( ± 7 d a ys) St arti n g 
1 2 Wee ks P ost L ast D ose
Cli nic al Assess me nts
P h y sical e xa mi nati o n (a b bre viate d, 
s ym pt o m -directe d) 
X
Wei g ht
X
Vital si g ns
X
E C G (i n tri plicate)
X
O nl y F U P - 2
E C O G perf or ma nce stat us
X
C o nc o mita nt me dicati o ns
X
Assess me nt of A Es/ S A Es
X
O nl y F U P - 2
F oll o w -u p f or s ur vi val a n d s u bse q ue nt 
a ntica ncer treat me nt (tele p h o ne c o ntact if 
visits are disc o nti n ue d)
X
L oc al L a b or at or y Assess me nts
Cli nical c he mistr y
X
He mat ol o g y
X
T S H a n d free T 4 (If T S H is n or mal t he n 
free T 4 is n ot re q uire d)
X
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4. 3
Descri pti o n of St u d y Pr oce d ures
4. 3. 1
Effic ac y
T he pri mar y  assess me nt of t u mor res p o nse will be base d o n R E CI S T versi o n 1. 1 (Eise n ha uer 
et al, 2 0 0 9); see Secti o n 1 0. 7 ) a n d will be perf or me d acc or di n g t o t he sc he d ule s i n Secti o n 4. 2 . 
All i ma ges will be c ollecte d a n d st ore d f or p ossi ble f ut ure ce ntral re-a nal ysis. T he assess me nt 
sc he d ule als o a p plies t o t h ose s u bjects w h o c o nti n ue t o recei ve st u d y t hera p y in t he s etti n g of 
P D ( Secti o n 3. 1. 2 ). F or t h ose s u bjects w h o disc o nti n ue st u d y t hera p y as a res ult of c o nfir me d 
P D, di sease e val uati on will be perf or me d at t he e n d of treat me nt visit if cli nicall y a p pr o priate 
(ie, i n t he a bse nce of r a pidl y deteri orati n g cli nical stat us). After disc o nt i n uati on of 
i n vesti gati onal pr o d uct(s), all s u bjects will c o m p lete t he e n d of treat me nt visit a n d 
e nter f oll ow- u p; disease e val uat i on will be perf or me d acc or di n g t o t he sc he d ule i n 
Ta ble 9 (4. 2. 3. -1) . A d diti o nal disease assess me nts ma y be perf or me d as cli nicall y i n dicate d. 
T u m or assess me nts m a y incl u de t he f oll o wi n g e val uat i ons: cr oss -secti onal i ma gi n g usi n g C T 
or m a g net ic res o na nce i ma gi n g ( M RI) sca n of t he c hest, a b d o me n, pel vis; a n d brai n. C T or 
M RI sca n of t he c hest, a b d o me n, a n d pel vis will be perf or me d wit h eac h diseas e assess me nt 
f or all s u bjects. A d ditio nall y, C T or M RI sca n of t he brai n will be perf or me d at scree ni n g f or 
all s u bjects wit h cli nical c o ncer n f or brai n metastasis. A n y s u bjects wit h brai n metastases at 
scree ni n g or a n y s u bjects w h o de vel o p ne ur ol o gic or ot her cli nical s y m pt o ms t hat warra nt 
i ma gi n g m ust als o ha ve brai n i ma gi n g wit h eac h disease assess me nt. T he preferre d met h o d of 
di sease assess me nt is C T wit h c o ntrast; if C T wit h c o ntrast is c o ntrai n dicate d, C T wit h o ut 
c o ntrast is preferre d o ver M RI. T he preferre d met h o d f or C N S i ma gi n g is M RI; if C T sca n is 
perf or m e d, C T wit h c o ntrast is re q uire d. T he sa me met h o d is preferre d f or all s u bse q ue nt 
t u mor assess me nts. 
C o m p ute d t o m o gra p h y  sca n 

C T (c o ntrast preferre d) sca ns of t he c hest, a b d o me n, a n d pel vis s h o u l d be perf or me d with 
c o ntig u o us c uts i n slice t hic k ness of 5 m m or less. S piral C T s h o ul d be perf or m e d usi n g a 
5- m m c o nt i g u o us rec o nstr ucti o n al g orit h m. T he sa me i ma gi n g de vice s h o ul d be use d f or 
serial e val uat i ons.
Ma g net ic res o na nce i ma gi n g s c a n

M RI sca n of t he c hest, a b d o me n, a n d pel vis is acce pta ble f or meas ure me nt of lesi o ns 
pr o vi de d t hat t he sa me a nat o mical pla ne is use d f o r serial assess me nts. 

I n case of M RI, meas ure me nts will be prefera bl y perf or me d i n t he a xial (tra ns verse) pla ne 
o n c o ntrast -e n ha nce d T 1 -w ei g hte d i ma ges. H o we ver, t here are n o s pecific se q ue nce 
rec o m me n dati ons.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
4. 3. 3
Me dic al Hist or y a n d P h ysic al E x a mi n ati o n, Electr oc ar di o gr a m, 
Wei g ht, a n d Vit al Si g ns
Me dic al Hist or y
Me dical hist or y  will be c ollecte d at scree ni n g. Base d o n fi n di n gs fr o m me dical hist or y, 
o n g oi n g c urre nt c o n dit i ons will be gi ve n a baseli ne gra de acc or di n g t o t he pr oce d ure f or A Es. 
I ncreases i n se verity of  pre-e xist i n g c o n diti ons d uri n g t he st u d y  will be c o nsi dere d A Es, wit h 
res olut i on occ urri n g w he n t he gra de ret ur ns t o t he pre -st u d y gra de or belo w.
P h ysic al E x a mi n ati o ns
P h ysical e xa mi nat i ons will be perf o r me d acc or di n g t o t he sc he d ules i n Secti on 4. 2 . A 
c o mplete p h ysical e xa mi nat i on will be perf or me d at scree ni n g a n d s h o ul d i ncl u de assess me nts 
of  t he hea d, e yes, ear s, n ose, a n d t hr oat, res pirat or y, car di o vasc ular, gastr oi ntesti nal, 
m usc ul os keletal, ne ur o l ogi cal, ps yc hiatric, der mat olo gi cal, he mat olo gi c/l y m p hat ic, e n d ocri ne 
s yste ms, a n d weig ht t o 0. 1 k g; a n d hei g ht (at scree ni n g o nl y). A b bre viate d s y m pt o m -di recte d 
p h y sical e xa mi nati ons will be c o n d ucte d at s u bse q ue nt visits p ost d osi n g. 
Vit al Si g ns
Vi t al si g ns (te mperat ure, bl o o d press ure , p ulse rate, a n d res pirat or y rate) will be meas ure d 
acc or di n g t o t he sc he d ule s i n Secti on 4. 2 . C o llecti o n ti mes d uri n g t he treat me nt peri o d are 
detaile d bel o w i n  Ta ble 1 0 ( 4. 3. 3- 1) . F or all vital si g n meas ure me nts, s u bjects s h o ul d rest f or 
at least 1 0 mi n utes i n a s u pi ne or se mi -rec u m be nt p ositio n, a n d all  vital si g n meas ure me nts 
s h o uld be ta ke n pri or t o a n y  blo o d dr a w s or ot her pr oce d ures w he ne ver p ossi ble.
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 0 ( 4. 3. 3 - 1)
C ol lecti o n Ti mes f or Vit al Si g ns D uri n g t he Tre at me nt peri o d
Tre at me nt 
Ar m
Olecl u m a b
D ur v al u m a b
C he m ot her a p y
a
Pre -d ose
E OI
Pre -d ose
E OI
Pre -d ose
E OI
A 1 a n d B 1
N A  
N A  
N A  
N A
Wit hi n 3 0
mi n utes
Wit hi n 
1 5 mi n utes
A 2 a n d B 2
Wit hi n 
3 0 mi n utes
Wit hi n 
1 5 mi n utes
N A  
N A
Sa me as olecl u ma b 
E OI or wit hi n 
3 0 mi n utes o n 
c he m ot hera p y o nl y 
d osi n g da ys
Wit hi n 
1 5 mi n utes
Part 1, A 3, 
a n d B 3
Wit hi n 
3 0 mi n utes
Wit hi n 
1 5 mi n utes
Sa me as 
olecl u ma b 
E OI
Wit hi n 
1 5 mi n utes
Sa me as olecl u ma b 
or  d ur val u ma b E OI 
or  wit hi n 
3 0 mi n utes o n 
c he m ot hera p y o nl y 
d osi n g da ys
Wit hi n 
1 5 mi n utes
5 -F U = 5 -fl u or o uracil; E OI = e n d of i nf usi o n; N A = n ot a p plica ble.
a
E xcl u des 5 -F U c o nti n u o us i nf usi o n.
Electr oc ar di o gr a ms
Acc or di n g t o t he sc he d ule s i n Secti on 4. 2 , 1 2-lea d E C Gs will be o btai ne d b y t he site i n 
triplicate (all 3 wit hi n a 5 -mi n ute ti me peri o d) after t he s u bject has bee n i n s u pi ne or 
se mi-rec u m be nt rest f or 1 0 mi n utes. C ollect i on ti mes d ur i n g t he treat me nt peri o d are detaile d 
bel o w i n Ta ble 1 1 ( 4. 3. 3- 2) . 
I n case of cli nicall y si g nifica nt E C G a b n or malities i nclu di n g a n E C G t hat de m o nstrates a 
Q Tc F val u e > 5 0 0 ms ec, 2 a d dit i onal 1 2 -lea d E C Gs s h o ul d be o btai ne d o ver a brief peri o d 
(e g, 3 0 mi n utes) t o c o nfir m pr ol o n gati o n base d o n t he a vera ge Q Tc F val ue ma n uall y 
o ver -rea d b y a me dicall y q ualifie d pers o n.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 1 ( 4. 3. 3 - 2)  
C ollecti o n Ti mes f or Electr oc ar di o gr a ms D uri n g t he Tre at me nt 
peri o d
Tre at me nt 
Ar m
Olecl u m a b
D ur v al u m a b
C he m ot her a p y
a
Pre -d ose
E OI
Pre -d ose
E OI
Pre -d ose
E OI
A 1 a n d B 1
N A  
N A  
N A  
N A
Wit hi n 3 0
mi n utes
Wit hi n 
1 5 mi n utes
A 2 a n d B 2
Wit hi n 
3 0 mi n utes
Wit hi n 
1 5 mi n utes
N A  
N A
Sa me as olecl u ma b 
E OI or wit hi n 
3 0 mi n utes o n 
c he m ot hera p y o nl y 
d osi n g da ys
Wit hi n 
1 5 mi n utes
Part 1, A 3, 
a n d B 3
Wit hi n 
3 0 mi n utes
Wit hi n 
1 5 mi n utes
Sa me as 
olecl u ma b 
E OI
Wit hi n 
1 5 mi n utes
Sa me as olecl u ma b 
or  d ur val u ma b E OI 
or  wit hi n 
3 0 mi n utes o n 
c he m ot hera p y o nl y 
d osi n g da ys
Wit hi n 
1 5 mi n utes
5 -F U = 5 -fl u or o uracil; E OI = e n d of i nf usi o n; N A = n ot a p plica ble.
a
E xcl u des 5 -F U c o nti n u o us i nf usi o n.
4. 3. 4
Cli nic al L a b or at or y Tests
A La b orat or y  Ma n ual will be pr o vi de d t o t he sites t hat s pecifies t he pr oce d ures f or c ollecti on, 
pr ocessi n g, st ora ge, a n d s hi p me nt of sa m ples, as well as la b orat or y  c o ntact i nf or mati o n, 
s pecific t o t his cli nical researc h st u d y. 
Cli nical la b orat or y  safety tests will be perf or me d i n a lice nse d cli nical la b orat or y. Uri ne 
pre g na nc y tests ma y be perf or me d at t he site usi n g a lice nse d test ( di pst ic k). A b n or mal 
la b orat or y res ults s h o uld be re peate d as s o o n as p ossi ble ( prefera bl y wit hi n 2 4 t o 4 8 h o urs). 
T he f o ll owi n g cli nical la b orat or y  tests will be perf or me d (see Secti o n 4. 2 f or t he sc he d ules of  
tests): 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Ser u m / Pl as m a C he mistr y
•
S o di u m
•
A L T
•
P otassi u m
•
T otal bilir u bi n ( A direct bilir u bi n s h o ul d be 
o btai ne d if t otal bilir u bi n is > U L N)
•
Bicar b o nate
•
A L P
•
Bl o o d urea nitr o ge n
•
Al b u mi n
•
Creati ni ne
•
Ga m ma -gl uta m yl tra ns pe pti dase
•
Gl uc ose
•
T otal pr otei n
•
Calci u m
•
Lactate de h y dr o ge nase
•
Ma g nesi u m
•
A m ylase
•
A S T
•
Li pase
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 otra nsferase; U L N = u p per 
li mit n or mal
N ote f or ser u m / pl as m a c he mistr y: Tests f or A S T, A L T, A L P, a n d t otal bilir u bi n m ust be c o n d ucte d 
c o nc urre ntl y a n d assesse d c o nc urre ntl y.
Li pi d P a nel
•
T otal C h olester ol
•
Tri gl yceri des
He m at ol o g y
•
W hite bl o o d cells c o u nt 
•
A bs ol ute m o n oc yte c o u nt
•
A bs ol ute ne utr o p hil c o u nt
•
He m o gl o bi n
•
A bs ol ute l y m p h oc yte c o u nt
•
Platelet c o u nt
Uri n al ysis
•
Pr otei n
•
Bl o o d 
•
Ket o nes 
•
If a b n or mal, t he n micr osc o p y i ncl u di n g 
W B C/ H P F, R B C/ H P F 
H P F = hi g h p o wer fiel d; R B C = re d bl o o d cells; W B C = w hite bl o o d cells.
Pre g n a nc y Test (fe m ales of c hil d be ari n g p ote nti al o nl y)
•
Ur i ne h C G
•
Ser u m β -h C G (at scree ni n g o nl y a n d if a uri ne 
h C G is e q ui v o cal or p ositi ve d uri n g t he 
re mai n der of t he st u d y)
β- h C G = beta -h u ma n c h ori o nic g o na d otr o pi n; h C G = h u ma n c h ori o nic g o na d otr o pi n.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Ot her S afet y Tests
•
C oa g ulati o n tests: acti vate d partial t hr o m b o plasti n ti me a n d i nter nati o nal n or malize d rati o. If i nter nati o nal 
n or malize d rati o is n ot a vaila ble t he sites ma y s u bstit ute a pr ot hr o m bi n ti me. 
•
He patitis B testi n g: he patitis B s urface a nti ge n, he patitis B s urf ace a nti b o d y, he patitis B c ore a nti b o d y, I g M 
he patitis B c ore a nti b o d y. If he patitis B c ore (t otal) a nti b o d y testi n g is u na vaila ble, t he n t he he patitis B c ore 
I g G a n d I g M s h o ul d b ot h be o btai ne d i nstea d. If a test is n ot l ocall y a vaila ble, t he n sta n dar d l ocal practice 
f or assessi n g he patitis B stat us s h o ul d be utilize d. If scree ni n g tests are p ositi ve, a H B V-D N A test s h o ul d be 
o btai ne d t o assess i nfecti o n stat us. 
•
He patitis C a nti b o d y. If scree ni n g a nti b o d y is p ositi ve, a H C V -R N A tests s h o ul d be perf or me d t o assess 
i nfecti o n stat us. 
•
H u ma n i m m u n o deficie nc y vir us -1 a nti b o d y .
•
T h y r oi d f u ncti on tests: t h y r oi d-sti m ulati n g h or m o ne ( T S H) a n d free t h yr o xi ne ( T 4). N ote: If T S H is n or mal 
t he n free T 4 is n ot re q uire d.
• 
C-reacti ve pr otei n.
4. 3. 5
P h ar m ac o ki netic E v al u ati o n a n d Met h o ds
Bl o o d will be c ollecte d t o e val uate P K of olecl u ma b a n d d ur val u ma b i n ser u m (see 
Secti o n 4. 2 f or c ollecti o n ti me p oi nts). T he P K of olecl u ma b a n d d ur val u ma b i n ser u m will be 
meas ure d utilizi n g a vali date d assa y.
Bl o o d sa m ples will be c ollecte d f or deter mi nat i on of na b -pacli ta xel a n d ge mcita bi ne 
c o nce ntrati o n i n plas ma (see Secti o n 4. 2 f or c ollectio n ti me p oi nt s). Plas ma sa m ples will be 
a nal yze d usi n g a p pr o priate bi oa nal yt ical met h o ds. Details of sa m ple pr ocessi n g, ha n dli n g, 
s hi p me nt, a n d st ora ge are pr o vi de d i n t he La b orat or y Ma n ual. F ull details of t he a nal ytical 
met h o ds use d will be descri be d i n se parate bi oa nal yt ical re p orts.
4. 3. 6
I m m u n o ge nicit y E v al u ati o n a n d Met h o ds
Bl o o d sa m ples will be c ollecte d t o e val uate A D A res p o nses t o olecl u ma b a n d d ur val u ma b i n 
ser u m (see Secti on  4. 2 f or c ollecti on ti me p o i nts). T hese e val uati ons will be perf or me d 
utilizi n g a vali date d i m m u n oassa y met h o d.
4. 3. 7
4. 3. 8
T he s u bject’s c o nse nt t o t he use of d o nate d bi ol o gical sa m ples is ma n dat or y . 
 
 
 
 
 
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Details re ga r di n g s peci me n c ollecti on, pr ocessi n g, a n d testi n g will be pr o vi de d i n t he 
La b orat or y  Ma n ual.
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
 
 
 
.
4. 3. 8. 1
St or a ge, Re -use a n d Destr ucti o n of Bi ol o gic al S a m ples
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 Last S u bject’s Last 
Vi sit, after w hic h t he y will be destr o ye d. T he res ults of t his bi o mar ker researc h will be 
re p orte d eit her i n t he cli nical st u d y re p ort (C S R ) itself or as a n a d de n d u m, or se paratel y in a 
scie ntific re p ort or p u blicat i on. T he res ults of t his bi o mar ker researc h ma y be p o ole d wit h 
bi o mar ker data fr o m ot her st u dies wit h t he st u d y  dr u g t o ge nerate h yp ot heses t o be teste d i n 
f ut ure researc h.
4. 3. 9
Esti m at e of V ol u me of Bl o o d Be C ollecte d
A t otal o f n o m ore t ha n 7 0 m L ( 1 5 teas p o o ns) of bl o o d will be re q uire d f or all scree ni n g tests. 
N o m ore t ha n 5 0 m L ( 1 2 teas p o o ns) of bl o o d will be dra w n o n a n y visit da y after scree ni n g. 
T he t otal v ol u me t o be c ollecte d wil l de pe n d o n t he n u m ber of d oses a d mi nistere d a n d t he 
le n gt h of f oll ow- u p.
4. 4
St u d y or St u d y C o m p o ne nt S us pe nsi o n or Ter mi n ati o n
Me dI m m u ne reser ves t he ri g ht t o te m p oraril y s us pe n d or per ma ne nt l y ter mi nate t his st u d y or 
a n y c o m p o ne nt of t he st u d y at a n y t i me. T he reas o ns f or te m p oraril y  s us pe n di n g or 
p er m a ne nt l y ter mi nati n g t he st u d y ma y i ncl u de b ut are n ot li mite d t o t he f oll owi n g: 
1
T he i nci de nce or se verit y of  A Es i n t his or ot her st u dies i n dicates a p ote ntial healt h 
hazar d t o s u bjects
2
S u bject e nr oll me nt is u nsat isfact or y
3
N o nc o m plia nce t hat mi g ht si g nifica nt l y je o par dize t he vali dit y or i nte gri t y of t he st u d y 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4
S p o ns or decisi o n t o ter mi nate de vel o p me nt of t he i n vesti gati o nal pr o d uct f or t his 
i n dicati on
5
S p o ns or decisi o n t o ter mi nate t he st u d y  base d o n a pla n ne d f utility a nal ysis
If Me dI m m u ne deter mi nes t hat te m p orar y s us pe nsi o n or per ma ne nt ter mi nati on of t he st u d y  
or c o m p o ne nt of t he st u d y  is re q uire d, Me dI m m u ne will disc uss t he reas o ns f or ta ki n g s uc h 
actio n wi t h all p artici pat i n g i n vesti gat ors ( or hea d of t he me d ical i nstituti o n, w here 
a p plica ble). W he n feasi ble, Me dI m m u ne will pr o vi de a d va nce n otice t o all part ici pati n g 
i n vesti gat ors ( or hea d of t he me dical i nstituti o n, w here a p plica ble) of t he i m pe n di n g acti o n.
If t he st u d y or c o mp o ne nt of t he st u d y  is s us pen de d or ter mi nate d f or safet y reas o ns, 
Me dI m m u ne will pr o m ptl y i nf or m all i n vesti gat ors, hea ds of t he me dical i nstituti o ns ( w here 
a p plica ble), a n d/ or i nstit uti o ns c o n d uct i n g t he st u d y. Me dI m m u ne will als o pr o m ptl y i nf or m 
t he rele va nt re g ulat or y a ut h orities of  t he s us pe nsi on/ter mi nat i on al o n g wit h t he reas o ns f or 
s uc h acti o n. W here re q uire d b y a p plica ble re g ulat i o ns, t he i n vesti gat or or hea d of t he me dical 
i nstituti o n m ust i nf or m  t he I nstituti o nal  Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee 
(I E C) pr o m ptly a n d pr o vide t he reas o n(s) f or t he s us pe nsi o n/ter mi nat i on. If t he st u d y  or 
c o mp o ne nt of t he st u d y  is s us pe n de d f or safety reas o ns a n d it is dee me d a p pr o priate b y 
Me dI m m u ne t o res u me t he st u d y  or c o mp o ne nt of t he st u d y , a p pr o val fr o m t he rele va nt 
re g ulat or y a ut h orities (a n d I R Bs/I E Cs w he n a p plica ble) will be o btai ne d pri or t o res u mi n g t he 
st u d y.
4. 4. 1
C o nti n ue d Tre at me nt at St u d y C o m pleti o n
A n y st u d y  s u bject still recei vi n g i n vesti gati onal pr o d uct at t he ti me of data e ntr y  c ut-off will 
c o nti n ue t o recei ve i n vest igat i onal pr o d uct wit hi n t he c urre nt st u d y  t hr o u g h a c o nti n ue d 
treat me nt perio d aft er data c ut -off f or a nal ysis o f fi nal st u d y data as l o n g as, i n t he 
I n vesti gat or’s o pi ni on, t he st u d y  s u bject is deri vi n g cli nical be nefit a n d has n ot f ulfille d a n y 
treat me nt disc o nt i n uati on cri teria ( Sectio n 4. 1. 6 ). T he d urati o n of treat me nt will be u ntil 
di sease pr o gressio n, wi t hdra wal or u ntil c o nt i n ue d treat me nt is u nfeasi ble. D uri n g t his 
c o nti n ue d treat me nt peri o d aft er data c ut -off f or a nal ysis o f fi nal st u d y data, assess me nts will 
re vert t o t he sta n dar d of care f or eac h i n di vi d ual site.  
F o ll owi n g t he data c ut -off f or t he fi nal a nal ysis of t he st u d y data, t he I R T will be cl ose d a n d 
t he i n vest i gati onal pr o d uct dis pe nsat i on will be ma n uall y or dere d b y t he st u d y  site. T he 
i n vesti gati onal pr o d uct acc o u n ta bility i nf or mati on m ust c o nti n ue t o be mai ntai ne d a n d 
c ollecte d b y t he st u d y site u ntil all t he site’s st u d y s u bjects per ma ne ntl y c o m p lete receipt of  
i n vesti gati onal pr o d uct.
Data e x pecte d o n a n d afte r t he data c ut-off f or t he fi nal a nal ysis of t he st u d y  data will n ot be 
e ntere d i nt o t he cli nical st u d y data base b y sites. D uri n g a st u d y s u bject’s c o nti n ue d treat me nt 
p eri o d aft er data c ut -off f or a nal ysis o f fi nal st u d y d at a, S A Es, o ver d oses, a n d pre g na ncies 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
will be re p orte d usi n g pa per -base d C R Fs u nt il 2 8 da ys after t he st u d y s u bject’s last d ose of 
i n vesti gati onal pr o d uct. Re p orte d S A E data will be e ntere d b y  t he sp o ns or i nt o t he s p o ns or’s 
gl o bal  s af et y data base.
I n di vi d ual sites will be cl ose d after safety data base l oc k has occ urre d a n d si te’s fi nal st u d y 
s u bject c o m p letes t he 1 2- wee k f oll ow -u p visit. T he c o nti n ue d treat me nt peri o d after data 
c ut -off f or a nal ysis o f fi nal st u d y data will re mai n a vaila ble t o st u d y  s u bjects u ntil treat me nt 
di sc o nti n uati on, w hic h is defi ne d as t he date of t he last st u d y  s u bject’s 1 2- wee k f oll ow - u p 
visit.
4. 5
I n vesti g ati o n al Pr o d ucts
4. 5. 1
I de ntit y of I n vesti g ati o n al Pr o d uct(s)
Me dI m m u ne will pr o vi de t he i n vest i gat or(s) wit h i n vesti gati o nal pr o duct (Ta ble 1 2 ( 4. 5. 1 - 1) 
usi n g desi g nate d distri b ut i on ce nters. 
T a ble 1 2 (4. 5. 1 - 1)
I de ntific ati o n of I n vesti g ati o n al Pr o d ucts
I n vesti g ati o n al Pr o d uct
M a n uf act urer
C o nce ntr ati o n a n d F or m ul ati o n as 
S u p plie d
Olecl u ma b ( M E DI 9 4 4 7)
Me dI m m u ne
D ur val u ma b ( M E DI 4 7 3 6)
Me dI m m u ne
w/ v = wei g ht/ v ol u me.
 
 
.
 
 
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
Eac h i n vest i gati onal pr o d uct kit has a u ni q ue n u m ber t hat is pri nte d o n all la bels wit hi n t he kit 
(ie, t he o uter cart o n la bel a n d t he la bel o f eac h c o ntai ner wit hi n t he cart o n). Eac h cart o n a n d 
vial is la bele d wit h t he sa me u ni q ue se q ue nce n u m ber ra n ge. 
T he i n vest i gat or’s or site’s desi g nate d i n vesti gati onal pr o d uct ma na ger is re q uire d t o mai ntai n 
acc urate i n vesti gat i onal pr o d uct acc o u n ta bility rec or ds. U p o n c o m plet i on of t he st u d y, c o pies 
of  in vesti gati o nal pr o d uct acc o u nta bilit y rec or ds will be ret ur ne d t o Me dI m m u ne. All u n use d 
i n vesti gati onal pr o d ucts will be ret ur ne d t o a Me dI m m u ne -a ut h orize d de p ot or dis p ose d of 
u p o n a ut h orizat i on b y Me dI m m u ne acc or di n g t o t he i n vest i gati onal site p olic y. All 
i n vesti gati onal pr o d ucts s h o ul d be ke pt i n a sec ure a n d dr y  place. Vials s h o uld be st ore d at 
2° C t o 8° C (refri gerate d) a n d m ust n ot be fr oze n. Dr u g pr o d uct s h o ul d be ke pt i n ori gi nal 
pac ka gi n g u nt il use t o pre ve nt pr ol o n ge d li g ht e x p os ure.
4. 5. 1. 1
I n vesti g ati o n al Pr o d uct I ns pecti o n
Eac h vial selecte d f or d ose pre parati o n s h o ul d be i ns pecte d.
If a n y defects are n ote d wit h t he i n vesti gati onal pr o d uct(s), t he i n vesti gat or a n d site m o nit or 
s h o uld be n otifie d i m me diatel y. Refer t o t he Pr o d uct C o m plai nt sect i on ( Secti o n 4. 5. 1. 6 ) for 
f urt her i nstr ucti o ns.
D uri n g t he i ns pect i on if t he s ol uti on is t ur bi d or if a n y disc ol or atio n, or parti c ulates are 
o bser ve d, t he sit e mo ni t or s h o uld be n otifie d i m me diatel y a n d t he vial(s) s h o ul d be st ore d i n 
Q U A R A N TI N E at refri gerate d ( 2° C t o 8° C [ 3 6° F t o 4 6° F]) te m perat ure f or dr u g 
acc o u nta bilit y a n d p ote ntial f ut ure i ns pect i on.
After re m o vi n g t he re q uire d n u m ber of vials f or olecl u ma b ( M E DI 9 4 4 7) d ose pre parati o n 
( 2 vials f or t he 
 d ose; 3 vials f or t he 
 d ose; 6 vials f or t he 
 d ose) fr o m 
t he cart o n c o ntai ner, t he cart o n s h o ul d be i m me diatel y ret ur ne d t o st ora ge at 2° C t o 8° C ( 3 6° F 
t o 4 6° F).
4. 5. 1. 2
Olecl u m a b ( M E DI 9 4 4 7) I V B a g Pre p ar ati o n a n d A d mi nistr ati o n
T he ol ecl u ma b ( M E DI 9 4 4 7) d oses m ust be pre pare d b y  t he i n vesti gat or’s or site’s desi g nate d 
i n vesti gati onal pr o d uct ma na ger usi n g ase pt ic tec h ni q ue. 
T ot al  ti me fr om nee dle p u nct ure of t he olecl u ma b ( M E DI 9 4 4 7) vial t o t he start of 
a d mi nistrati o n s h o ul d n ot e xcee d:

2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F)

4 h o urs at r o o m te m perat ure
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
N o i nc o m pat i bilities bet wee n olecl u ma b ( M E DI 9 4 4 7) a n d p ol y vi n ylc hl ori de or p ol y olefi n 
ba gs ha ve bee n o bser ve d.
F or s u bjects > 3 0 k g i n weig ht , doses of  
 (i n t he e ve nt of a de- escalati o n),  
, 
a n d 
 will be a d mi nistere d usi n g a n I V ba g c o ntai ni n g 0. 9 % ( w/ v) sali ne, wit h a fi nal 
ol ecl u ma b ( M E DI 9 4 4 7) c o nce ntrati o n ra n gi n g fr o m 1. 5 t o 3 0 m g/ m L, a n d deli vere d t hr o u g h 
a n I V a d mi nistrati o n set wit h a 0. 2- or 0. 2 2 -μ m  filter. A d d 1 5 m L (ie,  
 d ose) , 3 0 m L 
(ie, 
 d ose), or 6 0. 0 m L (ie,  
 d ose) of olecl u ma b ( M E DI 9 4 4 7)) t o t he I V ba g. 
T he I V ba g size s h o ul d be selecte d s uc h t hat t he fi nal c o nce ntrati o n is wit hi n 1. 5 t o 3 0 
m g/ m L. Mi x t he ba g b y ge nt l y i n verti n g t o e ns ure h om o ge neit y of t he d ose i n t he ba g.
Ol ecl u ma b ( M E DI 9 4 4 7) will be a d mi nistere d at r o o m te m perat ure (a p pr o xi matel y  2 0 t o 
2 5° C) b y c o ntr olle d i nf usi o n i nto a peri p heral or ce ntral  vei n. Sta n dar d i nf usi on t i me f or 
ol ecl u ma b ( M E DI 9 4 4 7) is 1 h o ur ( + 1 5 mi n utes ); h o we ver , if t here are i nterr u pti o ns d uri n g 
i nf usi on, t he t otal all o we d i nf usi o n time s h o ul d n ot e xcee d 4 h o urs at r o o m te m perat ure.
D o n ot c o -a d mi nister ot her dr u gs t hr o u g h t he sa me i nf usi o n li ne.
F l us h t he I V li ne with a v o l ume of I V dil ue nt e q ual t o t he pri mi n g v o l ume of t he i nf usi o n set 
use d after t he c o nte nts of t he I V ba g are f ull y a d mi nistere d, or c o m plete t he i nf usi o n 
acc or di n g t o i nst ituti o nal  p olic y t o e ns ure t he f ull d ose is a d mi nistere d a nd d oc u me nt if t he 
li ne was n ot fl us he d.
If either pre parati o n ti me or i nf usi o n ti me e xcee ds t he ti me li mit s, a ne w d ose m ust be 
pre pare d fr o m ne w vials. Olecl u ma b ( M E DI 9 4 4 7) d oes n ot c o ntai n preser vat i ves, a n d a n y 
u n use d p orti o n m ust be discar de d.
4. 5. 1. 3
D ur v al u m a b ( M E DI 4 7 3 6) I V B a g Pre p ar ati o n a n d A d mi nistr ati o n
T he d ose of d ur val u ma b ( M E DI 4 7 3 6) f or a d mi nistrati o n m ust be pre pare d b y t he 
i n vesti gat or’s or site’s desi g nate d i n vesti gati o nal pr o d uct ma na ger usi n g ase ptic tec h ni q ue. 
T ot al  ti me fr om nee dle p u nct ure o f t he d ur val u ma b ( M E DI 4 7 3 6) vial t o t he start of 
a d mi nistrati o n s h o ul d n ot e xcee d: 

2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F)

4 h o urs at r o o m te m perat ure 
A d ose of 
 (for s u bjects > 3 0 k g i n wei g ht) will be a d mi nistere d usi n g a n I V ba g 
c o ntai ni n g 0. 9 % ( w/ v) sali ne or 5 % ( w/ v) de xtr ose, wit h a fi nal d ur val u ma b ( M E DI 4 7 3 6) 
c o nce ntrati o n ra n gi n g fr o m 1 t o 1 5 m g/ m L, a n d deli vere d t hr o u g h a n I V a d mi nistrati o n set 
wi t h a 0. 2- or 0. 2 2 -μ m  filter. A d d 3 0. 0 m L of d ur val u ma b ( M E DI 4 7 3 6) (ie, 
 of 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
A p h ysicia n m ust be prese nt at t he site or i m me diatel y a vaila ble t o res p o n d t o e mer ge ncies 
d uri n g all a d mi nistrati o ns of i n vest i gati onal pr o d uct. F ull y  fu nct i onal res uscitat i on facilit ies 
s h o uld be a vaila ble. I n vest i gati onal pr o d uct m ust n ot be a d mi nistere d via I V p us h or b ol us b ut 
as a slo w I V i nf usi o n. T he e nt ire c o nte nt of eac h I V ba g will be i nf use d usi n g a n i nf usi o n 
p u m p.
4. 5. 1. 5
M o nit ori n g of D ose A d mi nistr ati o n
S u bjects will be m o nit ore d d uri n g a n d after i nf usi o n of i n vesti gati onal pr o d uct . Vital si g ns 
will be meas ure d acc or di n g t o t he sc he d ule s descri be d i n Sect i on 4. 2. 2 a n d c ollect i on ti mes i n 
Ta ble 1 0 ( 4. 3. 3 - 1). 
Ma na ge me nt of olecl u ma b or d ur val u ma b -relate d t o xicities are descri be d i n Sect i on 3. 1. 4 . 
Aceta mi n o p he n a n d/ or a n a nt i hista mi ne (e g, di p he n h y dra mi ne) ma y be a d mi nistere d at t he 
di scretio n of  t he i n vesti gat or. If t he I R R is se vere or pr ol o n ge d, met h yl pre d nis ol one 1 0 0 m g 
( or t he e q ui vale nt) s h o ul d be a d mi nistere d as well. I n vesti gat ors ma y a d mi nister ster oi ds at 
t heir discretio n as cli nicall y  in dicate d a n d per t heir i nst itut i on’s g ui deli nes. T he me dical 
m o nit o r s h o ul d be i nf or me d if ster oi ds are utilize d f or ma na ge me nt of a n I R R.
As wi t h a n y biol o gic pr o d uct, aller gic react i ons t o d ose a d mi nistrati o n are p ossi ble. T heref ore, 
a p pr o priate dr u gs a n d me dical e q ui p me nt t o treat ac ute a na p h ylact ic reacti ons m ust be 
im me diatel y a vaila ble, a n d st u d y  pers o n nel m ust be trai ne d t o rec o g nize a n d treat 
a na p h yla xis.
4. 5. 1. 6
Re p orti n g Pr o d uct C o m pl ai nts
A n y defects wit h t he i n vest i gati onal pr o d uct m ust be re p orte d i m me di ately t o t he Me dI m m u ne 
Pr o d uct C o m plai nt De part me nt b y  t he sit e wit h furt her n otificat i on t o t he site m o nit or. All 
d ef ects will be c o m m u nicate d t o Me dI m m u ne a n d i n vesti gate d f urt her wit h t he Pr o d uct 
C o m plai nt De part me nt. D uri n g t he i n vest i gati on of t he pr o d uct c o m p lai nt, all i n vesti gati onal 
pr o d uct m ust be st ore d at la bele d c o n dit i ons u nless ot her wise i nstr ucte d.
Me dI m m u ne c o ntact i nf or mat i on f or re p orti n g pr o d uct c o m plai nts:
E mail: pr o d uctc o m plai nts @ me di m m u ne.c o m
P h o ne: + 1 - 3 0 1- 3 9 8- 2 1 0 5
+ 1 -8 7 7 -M E DI -4 1 1 ( + 1 - 8 7 7- 6 3 3- 4 4 1 1)
Fa x:
+ 1 - 3 0 1- 3 9 8- 8 8 0 0

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Mail:
Me dI m m u ne
At t n: Pr o d uct C o m plai nt De part me nt
O ne Me dI m m u ne Wa y,
G ai t hers b ur g, M D U S A 2 0 8 7 8
4. 5. 2
A d diti o n al St u d y Me dic ati o ns
Eac h sta n dar d -of -care a ge nt ( ge mcita bi ne, na b-pacli t a x el, a n d m F O L F O X [le uc o v ori n, 5- F U,
a n d o xali plati n]) will be s o urce d as c o m merciall y a vaila ble material/l ocall y  s o urce d, 
prescri be d acc or di n g t o l ocal re g ulat i ons, a n d will be a d mi nistere d acc or di n g t o prescri bi n g 
i nf or mat i on or treat me nt g ui da nce i n ge neral use b y t he i n vesti gati n g site. Pl ease refer t o 
T e m per o et al , 2 0 1 7 a n d D ucre u x et al, 2 0 1 5 treat me nt g ui deli nes f or t he ma na ge me nt of 
pati e nts wit h metastatic P D A C. U n der certai n circ u msta nces w he n l ocal s o urci n g is n ot 
feasi ble, a sta n dar d-of -care a ge nt will be s u p plie d ce ntrall y  b y Me dI m m u ne. T his will be 
la bele d with te xt tra nslate d i nt o l ocal la n g ua ges i n acc or da nce wit h re g ulat or y g uideli nes.
4. 5. 3
L a beli n g
La bels f or t he i n vesti gati o nal pr o d uct will be pre pare d i n acc or da nce wit h G o o d 
Ma n ufact ur i n g Practice a n d l ocal re g ulat or y g uideli nes. La bel te xt will be tra nslate d i nt o l ocal 
la n g ua ges, as re q uire d.
4. 5. 4
St or a ge
I n vesti gati onal pr o d uct vials are st ore d at 2° C t o 8° C ( 3 6° F t o 4 6° F) a n d m ust n ot be fr oze n. 
Dr u g pr o d uct s h o ul d be ke pt i n ori gi nal pac ka gi n g u nt il use t o pre ve nt pr ol o n ge d li g ht 
e x p os ure.
4. 5. 5
Tre at m e nt C o m pli a nce
I n vesti gati onal pr o d uct is a d mi nistere d b y st u d y  sit e pers o n nel, w h o will m onit or c o m plia nce.
4. 5. 6
Acc o u nt a bilit y
T he i n vest i gat or’s or site’s desi g nate d i n vesti gati onal pr o d uct ma na g er is re q uire d t o mai ntai n 
acc urate i n vesti gat i onal pr o d uct acc o u n ta bility rec or ds. U p o n c o m plet i on of t he st u d y , c o pies 
of  in vesti gati o nal pr o d uct acc o u nta bilit y rec or ds will be ret ur ne d t o Me dI m m u ne. All u n use d 
i n vesti gati onal pr o d uct will be ret ur ne d t o a Me dI m m u ne -a ut h orize d de p ot or dis p ose d of 
u p o n a ut h orizat i on b y Me dI m m u ne.
F or details o f acc o u nta bilit y d uri n g t he c o nti n ue d treat me nt peri o d aft er data c ut -off f or 
a nal ysis of fi nal st u d y d at a, see Secti o n 4. 4. 1 .

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
st u d y, i ncl u di n g tra nsf usi ons of bl o o d a n d bl o o d pr o d ucts, gr o wt h fact or s u p p ort, a n d 
treat me nt wit h a nti bi otics, a nti-e met ics, a nti-diarr heals, a n d a nal gesics, a n d ot her care as 
dee m e d a p pr o priate, a n d i n acc o r da nce with t heir i nst ituti o nal  g ui deli nes. Palliati ve 
r a diot h era p y is allo we d d uri n g t he st u d y  u p o n disc ussio n  wit h t h e me dical mo ni t or.
4. 7. 2
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Ot her t ha n t he me dicat i ons descri be d a b o ve, use of c o nc o mita nt me dicat i ons i ncl u di n g 
o ver -t he- c o u nter me dicat i ons, her bal s u p ple me nts, vita mi ns, etc is disc o ura ge d. S u bjects m ust 
be i nstr ucte d n ot t o ta ke a n y me dicat i ons, i ncl u di n g o ver -t he- c o u nter pr o d ucts, wit h o ut first 
c o ns ult i n g with t he i n vest i gat or. T he f o ll owi n g c o nc o mit a nt me dicatio ns are pr o hi bite d:

A n y i n vest i gati onal a ntica ncer t hera p y

A n y c o nc urre nt c he m ot hera p y, ra di ot hera p y  (e xce pt palliati ve ra di ot hera p y), 
i m m u n ot hera p y, biol o gi c or h or mo nal  t hera p y f or ca ncer treat me nt. 

I mm u n os u p pressi ve me dicati o ns i ncl u di n g, b ut n ot li m ite d t o s yste mic c ortic oster oi ds at 
d oses e xcee di n g 1 0 m g/ da y of pre d nis o ne or e q ui vale nt, met h otre xate, azat hi o pri ne, a n d 
t u mor necr osis fact or -alp ha bl oc kers. Use of i m m u n os u p pressi ve me dicat i ons f or t he 
ma na ge me nt of i n vesti gati o nal pr o d uct -relate d A Es, i n s u bjects wit h c o ntrast aller gies, or 
as pre me dicat i on pri or t o c he m ot h era p y, is acce pta ble. I n a d diti on, use of i n hale d a n d 
i ntra nasal c ortic oster oids is per mitte d. Te m p orar y  c o urses of c ortic oster oids f or treat m e nt 
of  u n derl yi n g or c o nc urre nt ill ness or i n t he setti n g of palliat i ve ra di ot hera p y ma y be 
per mitte d u p o n disc ussi o n wi t h t h e me dical mo ni t or. 

Li ve atte n uate d vacci nes d uri n g t he st u d y  t hr o u g h 1 8 0 da ys after t he last d ose of b ot h 
dr u gs

Ca n na bi n o i ds ( olecl u ma b treat me nt ar ms o nl y)

Her bal a n d nat ural  r e me dies s h o uld be a v o i de d
4. 8
St atistic al E v al u ati o n
4. 8. 1
Ge ner al C o nsi der ati o ns
Ta b ular s u m maries will be prese nte d b y treat me nt gr o u p. Cate g orical data will be s u m marize d 
b y t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y . C o nti n u o us varia bles will be 
s u m marize d b y descri pti ve statistics. A d diti onal details of statistical a nal yses will be 
descri be d i n t he statist ical a nal ysis pla n.
St u d y  p o p ulat i ons are defi ne d bel o w.

T he i nte nt -t o-treat (I T T) p o p ulati on is defi ne d as all s u bjects w h o are ra n d o mize d a n d 
recei ve a n y a m o u nt of i n vesti gati o nal pr o d uct, a nal yze d acc or di n g t o ra n d o mize d 
treat me nt assig n me nt. All a nal yses will be perf or me d o n t he I T T p o p ulat i on u nless 
ot her wi se s pecifie d.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 8. 3
Effic ac y
T he efficac y a nal yses of a nt itu m or acti vit y will  be base d o n t he I T T p o p ulati o n ( defi ne d i n 
Secti o n 4. 8. 1 ). T he rates of O R a n d D C base d o n R E CI S T versi o n 1. 1 will be s u m marize d 
wi t h 9 5 % CI base d o n t he e xact bi n omial distri b ut i o n. Ti me-t o-e ve nt e n d p oi nts ( D o R, P F S, 
a n d O S) will be a nal yze d usi n g t he Ka pla n-Meier met h o d. A d dit i onal a nal yses of a nt itu m or 
acti vit y ma y be c o n d ucte d i n t he as- treate d p o p ulatio n  ( defi ne d i n Secti on 4. 8. 1 ). A d diti onal 
details wi ll be pr o vi de d i n t he statist ical a nal ysis pla n. T he f o ll owi n g efficac y e n d p o i nts will 
be a nal yze d. 
4. 8. 3. 1
Pri m ar y Effic ac y A n al ysis
T he pri mar y  efficac y e nd p oi nt i s O R. O R is defi ne d as best o verall res p o nse of c o nfir me d C R 
or c o nfir me d P R acc or di n g t o R E CI S T v ersio n  1. 1. T he best o verall res p o nse is defi ne d as t he 
best res p o nse (i n t he or der of C R, P R, S D, P D, a n d n ot e val ua ble) a m o n g all o verall res p o nses 
rec or de d fr om t he start of treat me nt wit h i n vest i gati onal pr o d uct u ntil o bject i ve d oc u me ntati o n 
of  P D, or t he last e val ua ble disease assess me nt i n t he a bse nce of P D pri or t o t he i nit iati on of 
s u bse q ue nt a ntica ncer t hera p y or e n d of t he st u d y, w hic he ver occ urs first. T he best o verall 
res p o nse of C R or P R m ust be c o nfir me d, w hic h mea ns a res p o nse of C R/ P R is recor de d at a 
visit a n d c o nfir me d b y re peat i ma gi n g n ot less t ha n 2 8 da ys ( 4 wee ks) after t he visit w he n t he 
res p o nse was first o bser ve d wit h n o e vi de nce of pr o gressi o n bet wee n t he i nitial a n d C R/ P R 
c o nfir mat i on visit. T he O R R will be est i mate d b y t he pr o p orti on of O R, a n d its 9 5 % CI will 
be est i mate d usi n g t he e xact bi n omial distri b ut i on. C o m paris o n of ar m s for O R R will  be 
o btai ne d fr o m C oc hra n -Ma ntel -Hae nszel test .
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
4. 8. 3. 2
A d diti o n al A n al yses of t he Pri m ar y E n d p oi nt
If a p plica ble, a nal ysis of O R R b y C D 7 3 e x pressi o n at baseli ne as meas ure d b y I H C i n 
arc hi val a n d/ or fres h t u m or bi o psies ma y be c o n d ucte d. 
4. 8. 3. 3
Sec o n d ar y Effic ac y A n al yses
Sec o n dar y  efficac y e n d p oi nts i ncl u de D o R, D C, P F S, a n d O S.

D o R i s defi ne d as t he d urati o n fr o m t he first d oc u me ntati o n of O R t o t he first d oc u m e nte d 
di sease pr o gressio n or deat h d ue t o a n y  ca use, w hic he ver occ urs first. F or s u bjects w h o 
are ali ve a n d pr o gressi o n-free at t he ti me of data c ut-off f or a nal ysis, D o R will be 
ce ns ore d at t he last t u m or assess me nt date. T he D o R will o nl y be e val uat e d f or t he 
s u b gr o u p of s u bjects wit h a n O R usi n g t he Ka pla n-Mei er met h o d.

D C i s defi ne d as C R, P R, or S D (if s u bjects mai ntai n S D f or ≥ 8 wee ks [ ± 3 da y s]). D C 
will be a nal yze d b y est i mati n g t he D C R, defi ne d as t he pr o p orti o n of s u bjects wit h D C 
a n d its 2-side d 9 5 % CIs usi n g a n e xact pr o ba bilit y met h o d. 

P F S i s defi ne d as t he ti me fr o m ra n d o mizati on u nt il t he first d oc u me ntati o n of disease 
pr o gressi o n or deat h d ue t o a n y  ca use, w hic he ver occ urs first. F or s u bjects w h o are ali ve 
a n d pr o gressi o n- free at t he ti me of data c ut-off f or a nal ysis, P F S will be ce ns ore d at t he 
last t u mor assess me nt date. T he Ka pla n -Meier m et h o d ( Ka pla n a n d Meier, 1 9 5 8) will be 
use d t o esti mate t he P F S c ur ve a n d t he P F S rate at ti me p oi nts of i nterest.

O S is defi ne d as t he ti me fr o m ra n d o mizat i on u ntil deat h d ue t o a n y  ca use. F or s u bjects 
w h o are ali ve at t he ti me of data c ut -off, O S will be ce ns ore d o n t he last date w he n 
s u bjects are k n o w n t o be ali ve. T he Ka pla n-Meier met h o d will be use d t o esti mate t he O S 
c ur ve a n d t he O S rate at time p oi nts of i nterest.
4. 8. 3. 4
 
 
 
4. 8. 4
S afet y
4. 8. 4. 1
A n al ysis of S afet y E n d p oi nts
S af et y data, i ncl u di n g D L Ts, A Es, S A Es, la b orat or y  e val uat i ons, vital si g ns, a n d E C G res ults 
will be s u m marize d base d o n t he as- treate d p o p ul atio n. Descri pt i ve statistics will be pr o vi de d 
f or A Es, S A Es, A E gra de (se verity) , a n d relatio ns hi p t o i n vest i gati onal pr o d uct(s), cli nical 
la b orat or y para meters, vit al si g ns, a n d E C G res ults. A Es will be gra de d acc or di n g t o t he N CI 
C T C A E versi o n 4. 0 3.
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Descri pt i ve statistics will be pr o vi de d f or t he cli nical la b orat or y res ults a n d c ha n ges fr om 
baseli ne b y sc he d ule d ti me of e val uat i on a n d b y treat me nt ar m i ncl u di n g e n d o f treat me nt visit 
as well as f or t he ma xi m u m a nd mi ni m u m  p ost-baseli ne val ues. La b orat or y a b n or malit ies will 
be gra de d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3, if a p plica ble. Fre q ue ncies of w orst 
o bser ve d gra de will be prese nte d f or eac h la b orat or y  para meter as well as t he rates of s u bjects 
wi t h Gra de 3-4 t o xi cities.
4. 8. 4. 2
4. 8. 4. 3
 
 
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
4. 8. 5
A n al ysis of I m m u n o ge nicit y/ P h ar m ac o ki netics
O nl y s u bjects w h o recei ve at least 1 d ose of olecl u ma b a n d/ or d ur val u ma b a n d pr o vi de at least 
1 p ost -treat me nt sa mple will  be e val uate d. 
F or eac h c o h ort, t he i m m u n o ge nic p ote ntial o f c o m bi nat i ons will be assesse d b y  s u m marizi n g 
t he n u m ber a n d perce nta ge of  s u bjects w h o de vel op detecta ble A D As. T he i m pact of A D As 
o n P K will be assesse d if data all o w. Sa m ples will be c o llecte d f or p ote ntiall y e val uati n g t he 
ne utralizi n g ca pacit y of  AD As i n t he f ut ure.
I n di vi d ual olecl u ma b a n d d ur val u ma b c o nce ntrati o ns will be ta b ulate d b y  d ose c o h ort alo n g 
wi t h descri pti ve statistics. N o n-c o mpart me nt al P K data a nal ysis will be perf or me d fr om eac h 
d ose c o h ort wit h sc he d ule d P K sa m ple c o llecti on w here data all o w. Rele va nt descri pt i ve 
statistics of n o n-c o m part me ntal P K para mete rs will be pr o vide d a n d ma y i ncl u de: A U C, C ma x , 
tma x , cleara nce, Vd. a n d t1/ 2.
4. 8. 6
 
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
 
4. 8. 7
I nteri m An al ysis
I nteri m a nal ysis c om par i n g e x peri me ntal ar ms wi t h c o ntr ol will be perf or me d i n Part 2 
C o h ort A usi n g a j o i nt Ba yesia n pre dict i ve pr o ba bility,  w hic h all o ws f or i nteri m a nal ysis of  
t he delta ( δ), or differe nce, of t he O R R bet wee n e x peri me ntal a n d c o ntr ol ar ms (Lee a n d Li u, 
2 0 0 8 ; P ul kste nis et al , 2 0 1 7). F or i nteri m f ut ility a nal yses, a res p o nse is defi ne d as eit her a 
c o nfir me d or u nc o nfir me d C R or P R per R E CI S T v 1. 1. 
A n i nteri m a nal ysis will  be perf or me d w he n a p pr o xi matel y 3 0 s u bjects i n eac h tr e at me nt ar m
of  Part 2 C o h ort A ha ve bee n d ose d a n d reac h t he data c ut- off criteria (ie, s u bjects w h o ha ve a 
baseli ne disease assess me nt, ha ve bee n d ose d at  least 1 6 wee ks pri or t o t he ti me o f t he data 
c ut -off, a n d ha ve at least 1 p ost -baseli ne disease assess me nt a n d/ or disc o nt i n ue d treat me nt d ue 
t o deat h or disease pr o gressi o n). Ra n d o mizat i on ma y be pa use d d uri n g t he i nteri m a nal ysis 
bef ore t he decisi o n is ma de.
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
5
A S S E S S M E N T O F S A F E T Y
5. 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 s u bject or cli nical st u d y 
s u bject 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 ora 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 (e g, na usea, c hest pai n), or disease te m p orall y 
ass ociat e 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 d ici 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 nseri o 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 time, 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 treat me nt has bee n a d mi n istere d. 
Elect i ve treat me nt or s ur ger y or pre pla n ne d treat me nt or s ur ger y (t hat was sc he d ule d pri or t o 
t he s u bject bei n g e nr o lle d i nt o t he st u d y) for a d oc u m e nte d pre-e xisti n g c o n dit i on t hat di d n ot 
w orse n fr o m baseli ne is n ot c o nsi dere d a n A E (seri o us or n o nseri o us). A n u nt o war d me dical 
e ve nt occ urri n g d uri n g t he presc he d ule d elect i ve pr oce d ure or r o uti nel y sc he d ule d treat me nt 
s h o uld be rec or de d as a n A E or S A E.
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
5. 2
Defi niti o n of Seri o us A d verse E ve nts
A n S A E is a n y  AE t h at:

Res ults i n deat h

Is i m me diatel y life-t hreate ni n g

Re q ui res i n patient  h os pitalizati on or pr ol o n gat i on of  e xisti n g h os pi talizatio n 

Res ults i n persiste nt or si g nifica nt disa bilit y/ i nca pacity 

Is a c o n ge nital a n oma l y/ birt h defect i n offs pri n g of t he s u bject

Is a n i m p orta nt me dical e ve nt t hat ma y je o par dize t he s u bject or ma y re q uire me dical 
i nter ve nt i on t o pre ve nt o ne of t he o utc o mes liste d a b o ve
Me dical or scie nt ific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n t his sit uati o n. E xa m ples of me dicall y i mp orta nt e ve nts are 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 for aller gic br o nc h os pas m, bl o o d d y scrasias, or c o n v ulsi ons 
t hat d o n ot res ult i n h os pitalizat i ons , or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
5. 3
Defi niti o n of A d verse E ve nts of S pec i al I nterest
A n A E SI is o ne of scie ntific a n d me dical i nterest s pecific t o u n dersta n di n g of t he 
i n vesti gati onal pr o d uct a n d ma y  re q uire clos e m o ni t ori n g a n d ra pid c o m m u nicat i on b y t he 
i n vesti gat or t o Me dI m m u ne. A n A E SI ma y be seri o us or n o nseri o us. T he ra pi d re p orti n g of 
A E SIs all o ws o n g oi n g s ur veilla nce of t hese e ve nts i n or der t o c haracterize a n d u n dersta n d 
t he m in ass oci at i on wi t h t he use of t his i n vesti gati o nal pr o d uct.
5. 3. 1
A n a p h yl a xis a n d I nf usi o n -rel ate d Re acti o ns
I nf usi on of bi o l ogical pr o d ucts is c o m m o nl y ass ociate d wit h I R Rs. A na p h yla xis a n d I R Rs 
ha ve s o me c o m m o n ma nifestati o ns a n d m a y be diffic ult t o dist i n g uis h fr om eac h ot her. I R Rs 
are c o m m o nl y o bser ve d d uri n g or s h ortl y after t he first ti me of e x p os ure t o t he ra pe utic m A bs
deli vere d t hr o u g h I V i nf usi o n. T hese reacti o ns are less c o m m o n f oll owi n g s u bse q ue nt 
e x p os ures. U nli ke I R Rs, a na p h yla xis is a rare e ve nt, us uall y occ urri n g after s u bse q ue nt 
e x p os ure t o a n a nt i ge n, a n d it is m ost c o m m onl y  a c c o mpa nie d b y se vere s yste mic, s ki n a n d/ or 
m uc osal react i ons. T he i n vest i gat or is a d vise d t o caref ull y e xa mi ne s y m pt o ms of a d verse 
reactio ns o bser ve d d uri n g or s h ortl y  after e x p os ure t o olecl u ma b a n d d ur val u ma b, a n d 
c o nsi der t he a b o ve -me nti o ne d facts pri or t o ma ki n g a fi nal di a g n osis. React i ons occ urri n g at 
t he ti me o f or s h ortl y after s u bse q ue nt i nf usi o ns of i n vesti gat i onal pr o d uct are t o be j u d ge d b y 
t he i n vest i gat or at his/ her o w n discreti on. F or t he i n vesti gat or’s c o n ve nie nce a n d t o facilitate 
c o nsiste nc y i n j u d g me nts, a c o p y of t he Nat i onal I nst itute of Aller g y  a n d I nfecti ous Disease 
a n d F o o d a n d Aller g y A na p h yla xis Net w or k g ui da nce f or a na p h yla xis dia g n osis is pr o vi de d i n 
Secti o n  1 0. 3 . 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Refer t o Secti o n 3. 1. 4 f or gui deli nes f or ma na ge me nt of s u bjects wit h h y perse nsit i vity 
(incl u di n g a na p h ylactic reacti o n) a n d I R Rs. I n t he e ve nt of a n I R R, t he site s h o ul d d oc u me nt 
w hic h me dicat i ons ha ve bee n i nf use d at t he ti me of o nset of t he I R R i n a d dit i on t o si g ns a n d 
s y mp t o ms.
5. 3. 2
A d verse E ve nts of S peci al I nterest f or Olecl u m a b
5. 3. 2. 1
C ar di ac C hest P ai n, Tr a nsie nt Isc he mic Att ac k, a n d T hr o m b oe m b o lis m
A Es of car diac c hest pai n, tra nsie nt isc he mic attac k, a n d t hr o m b oe m b o lic e ve nts are of s pecial 
i nterest d ue t o olecl u ma b p ote ntial ris ks of arterial isc he mic dis or der, a n d t hr o m b osis. 
Beca use of t his p ote ntial ris k, p ote ntial s u bjects wit h a hist or y  of m y o car dial infarcti o n, 
str o ke, tra nsie nt isc he mic attac k, or t hr o m b oe m b o lis m i n t he pri or 3 m o nt hs are n ot eli gi ble 
(see Secti o n 4. 1. 3 ). T hese e ve nts re q uire ur gent  me dical ma na ge me nt, w hic h s h o ul d be 
perf or m e d acc or di n g t o c o nse ns us g ui deli nes de vel o pe d b y t he A merica n Heart Ass ociati on or 
a p pr o priate l ocal sta n dar ds of care.
5. 3. 2. 2
E de m a
E d e m a (e g, p ul m o nar y  or p erip heral) i s re gar de d as A E SI d ue t o olecl u ma b p ote ntial ris ks of 
i ncrease d micr o vasc ular per mea bility.  F or s u bjects w h o de vel o p ≥ Gra de 3 e de ma, d oses 
s h o uld be o mi tte d as per Sectio n 3. 1. 4 , a n d t hera p y ma y be disc o nti nue d at t he di screti on of 
t he i n vest i gat or.
5. 3. 2. 3
I m m u ne C o m ple x Dise ase
T he i m m u ne s yste m ca n res p o n d t o f orei g n pr otei n, e ve n t o h u ma nize d m A b b y pr o d uci n g 
h u ma n -a nt i-h u ma n a nt i b o dies, w hic h ma y res ult i n f or mati on of i m m u ne c o m p le xes a n d t heir 
de p osi tio n i n bl o o d vessels, j oi nt s, a n d gl omer uli ca usi n g s y m pt o mat ic disease (e g, vasc ulitis, 
gl o m er ulo n e p hri tis, art hritis, ser u m sic k ness). S u bjects will be m o nit ore d cli nicall y a n d f or t he 
prese nce of A D As. S u bjects w h o e x perie nce a n A E s us pecte d t o be i m m u ne c o mple x -relate d 
will disc o nt i n ue treat me nt. I m m u ne c o mple x disease will be ma na ge d i n acc or da nce wit h 
sta n dar d-of -care.
5. 3. 3
A d verse E ve nts of S peci al I nterest f or D ur v al u m a b
A E SIs f or d ur val u ma b i ncl u de b ut are n ot li mite d t o e ve nts wit h a p ote ntial i nfla m mat or y  or 
im m u ne -me diate d mec ha nis m a n d w hic h ma y re q uire m ore fre q ue nt m o nit ori n g a n d/ or 
i nter ve nt i ons s uc h as ster oi ds, i m m u n os u p pressa nts , a n d/ or h or m o ne re place me nt t hera p y. 
T hese A E SIs are bei n g cl o sel y mo ni t ore d i n cli nical st u dies wit h d ur val u ma b m o n ot hera p y 
an d c o m bi nat i on t hera p y . A n i m A E is defi ne d as a n A E t hat is ass ociate d wit h dr u g e x p os ure 
a n d is c o nsiste nt wit h a n i m m u ne-me diate d mec ha nis m of act i on a n d w here t here is n o clear 
alter nate etiol o g y . S er olo gi c, i m m u n olo gic, a n d hist ol o gic ( bi o ps y ) data, as a p pr o priate, 
s h o uld be use d t o s u p p ort a n i m A E dia g n osis. A p pr o priate eff orts s h o ul d be ma de t o r ule o ut 
ne o pl astic, i nfectio us, m eta b o lic, t o xi n, or ot her eti ol o gic ca uses of t he i m A E. 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
If t he i n vesti gat or has a n y q uesti ons i n re gar ds t o a n A E bei n g a n i m A E, t he i n vest i gat or 
s h o uld pr o m pt l y c o ntact t he me d ical m onit or .
A E SIs /i m A Es o bser ve d wit h a nt i-P D -L 1 / P D- 1 a ge nts s uc h as d ur val u ma b i ncl u de:

P ne u m o nit is

He pati tis 

Di arr hea/c olitis

I ntesti nal perf orati o n

E n d ocri n o pat hies (ie, e ve nts of h y p o p h ysit is/ h y p o pit uitaris m, t yp e 1 di a betes mellit us, 
a dre nal i ns ufficie nc y, h y pert h yr oidis m , a n d h y p ot h yr o i dis m)

Ne p hrit is

Ras h/ der mat itis

M y o c ar di tis

M y osi tis/ p ol y m y ositis

Pa ncreat itis

R are/less fre q ue nt  im A E s i ncl u di n g ne ur o m usc ular t o xi cities (e g, G uillai n-Barr e
s y n dr ome a n d m yast he nia gra vis)

Ot her i nfla m mat or y  res p o nses t hat are rare/less fre q ue nt wit h a p ote ntial 
i m m u ne-me diate d eti o l og y  incl u de, b ut are n ot li mite d t o, pericar dit is, sarc oi d osis, 
u veit is, a n d ot her e ve nts i n v o l vi n g t he e ye, s ki n, he mat ol o gical e ve nts, r he u mat ol o gical 
e ve nts, vasc ulitis, n o n-i nfecti ous m e ni n gitis, a n d n o n-i nfecti o us e nce p halitis. It is p ossi ble 
t hat e ve nts wit h a n i nfla m mat or y or i m m u ne me diate d mec ha nis m c o ul d occ ur i n nearl y 
all or ga ns.
I n a d diti on, I R Rs a n d h y perse nsit i vity/a na p h ylact ic reacti o ns with a differe nt u n derl yi n g 
p har mac o l ogi cal et i ol og y  are als o c o nsidere d A E SIs ( Secti o n 5. 3. 1 ).
F urt her i nf or mat i on o n t hese ris ks (e g , prese nt i n g s y m pt o ms) ca n be f o u n d i n t he c urre nt 
versi o n of t he d ur val u ma b I B. M ore s pecific g ui deli nes f or their e val uat i on a n d treat me nt are 
descri be d i n detail i n i n t he D ose M o dificati on a n d T o xicit y Ma na ge me nt G ui deli nes (refer t o 
Secti o n 3. 1. 4 ).
5. 4
Rec or di n g of A d verse E ve nts
A Es will be rec or de d o n t he e C R F usi n g a rec o g nize d me dical ter m or dia g n osis t hat 
acc uratel y reflects t he e ve nt. A Es will be assesse d b y t he i n vesti gat or f or se verit y,  relatio ns hi p 
t o t he i n vesti gati onal pr o d uct, p ossi ble et i ol ogi es, a n d w het her t he e ve nt meets criteria of a n 
S A E a n d t heref ore re q uires i m me diate n otificat i on t o Me dI m m u ne (see Sect i on 5. 5 ). See 
Secti o n 5. 2 f or t he defi niti on of S A Es a n d Sect i on  1 0. 2 f or g uideli nes f or assess me nt of 
se verity a n d relat i ons hi p. 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
If a n A E e v ol ves i nto a c o n di tio n t hat m eets t he re g ulat or y defi nitio n of  “serio us, ” i t will be 
re p orte d o n t he S A E Re p ort F or m.
5. 4. 1
Ti m e Peri o d f or C ollecti o n of A d verse E ve nts
A Es will be c o llecte d fr om ti me of si g nat ure of i nf or me d c o nse nt t hr o u g h o ut t he treat me nt 
p eri o d a n d i ncl u di n g t he f o ll ow- u p peri o d 1 2 wee ks p ost l ast d ose.
All S A Es will be rec or de d fr o m t he ti me of i nf or me d c o nse nt.
5. 4. 2
F oll o w- u p of U nres ol ve d A d verse E ve nts
A n y A Es t hat are u nres ol ve d at t he s u bject’s last A E assess me nt or ot her assess me nt/ visit as 
a p pr o priate i n t he st u d y ar e fol l 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. Me dI m m u ne retai ns t he ri g ht t o re q uest a d dit i onal 
i nf or mat i on f or a n y s u bject wit 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 .
5. 4. 3
De at hs
All deat hs t hat occ ur d uri n g t he st u d y , i n clu di n g t he pr ot oc ol -defi ne d f o ll ow- u p peri o d m ust 
be re p orte d as f oll o ws:

Deat h cl earl y t he res ult of disease pr o gressio n s h o ul d be re p orte d a n d d oc u me nte d o n t he 
state me nt of deat h e C R F b ut s h o ul d n ot be re p orte d as a n S A E.

W here deat h is n ot d ue ( or n ot clearl y  d ue) t o disease pr o gressio n, t he A E ca usi n g t he 
deat h m ust be re p orte d as a n S A E wit hi n 2 4 h o urs. T he re p ort s h o ul d c o ntai n a c o m me nt 
re gar di n g t he c o-i n v ol ve me nt of disease pr o gressi o n, if a p pr o priate, a n d s h o ul d assi g n 
mai n a n d c o ntri b ut or y  ca uses of deat h.

Deat hs wit h a n u n k n o w n ca use s h o ul d al wa ys be re p orte d as a n S A E. A p ost -m o rt e m 
(a ut o ps y) ma y be hel pf ul i n t he assess me nt of t he ca use of deat h, a n d if perf or me d , a c o p y 
of  t he p ost-m o rte m res ults s h o ul d be f or war de d t o Me dI m m u ne re prese ntati ve(s) wit hi n 
t he us ual ti mefra mes (refer t o Secti o n  5. 5 f or a d ditio n al inf or m atio n).
5. 4. 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 s u bject or re p orte d i n res p o nse t o t he o pe n q uesti o n 
fr om t he st u d y site staff: ‘ H ave y o u h a d a ny he alt h pr o ble ms si nce t he previ o us visit/y o u were 
l ast aske d ?’, or re veale d b y o bser vati on will be c ollecte d a n d rec or de d i n t he e C R F. W he n 
c ollect i 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 
sig 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 si g ns or s y m pt o ms 
t hat are n ot ge nerall y part of t he dia g n osis, 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.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
5. 4. 5
A d verse E ve nts B ase d o n E x a mi n ati o n a n d Tests
T he res ults fr o m  t he pr ot oc ol-ma n date d la b orat or y tests a n d vital si g ns will be s u m marize d i n 
t he C S R. A n a b n or mal la b orat or y fi n di n g (i ncl u di n g E C G fi n di n g) t hat re q uires me dical 
i nter ve nt i on b y t he i n vesti gat or, or a fi n di n g j u d ge d b y t he i n vest i gat or as me dicall y 
sig nifica nt s h o ul d be re p orte d as a n A E. If cli nical se q uelae are ass ociate d wit h a la b orat or y  
a b n or malit y, t h e dia g n osis or me dical c o n dit i on s h o ul d be re p orte d (e g, re nal fail ure, 
he mat uri a) n ot t he la b orat or y a b n or malit y (e g, ele vate d creati ni ne, uri ne re d bl o o d cell 
i ncrease d).
If deteriorati o n i n a la b orat or y  val ue/ vit al 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 sig 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/ vit al si g n 
will be c o nsi dere d as a d dit i onal i nf or ma tio n. W here ver p ossi ble , t he re p orti n g i n vest i gat or 
uses t he cli nical, rat her t ha n t he la b orat or y  t er m (e g, a ne mia vers us l o w he 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 orati o ns i n n o n -ma n date d 
para m eters s h o ul d be re p orte d as A E(s).
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
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 dis ease pr o gressio n, s h o ul d 
n ot be re p orte d as a n A E/ S A E.
5. 4. 6
H y’s L a w
Cases w here a s u bject 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 s h o ul d be re p orte d 
as S A Es ( Secti o n 5. 5 ). Please refer t o A p pe n di x 1 0. 4 f or furt 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 y’s La w. 
5. 4. 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 s u bject’s c o n dit i on attri b uta ble t o 
t he disease f or w hic h t he i n vesti gati onal pr o d uct 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 a ne w metastasis or pr o gressi o n of e xist i n g met astasis relate d t o t he pri mar y 
ca ncer u n der st u d y s h o uld n ot be c o nsi dere d a n A E. Deat h clearl y res ult i n g fr om di sease 
pr o gressi o n s h o ul d n ot be re p orte d as a n S A E (see re p orti n g g ui deli nes i n Sect i on 5. 4. 3 ).
T he ter m  disease pr o gressi o n s h o ul d n ot be re p orte d as a n A E or S A E, h o we ver, me dicall y 
sig nifica nt i n di vi d ual e ve nts a n d/ or la b orat or y  a b n or malit ies ass ociate d wit h disease 
pr o gressi o n (see defi nit i on of disease pr o gressi o n a b o ve) t hat f ulfill t he A E or S A E defi nit i on 
s h o uld be re p orte d.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
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 S A E. 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 a d mi nistrati o n of t he i n vest i gati onal pr o d uct a n d ha ve bee n 
i de ntifie d after t he s u bject’s i ncl usi on i n t he st u d y. Ne w metastatic lesio n (s) of t he s u bject’s 
k n o w n ca ncer s h o ul d n ot be re p orte d as a ne w ca ncer.
5. 5
Re p orti n g of Seri o us A d verse E ve nts
Pr o m pt n otificat i on b y t he in vest i gat or t o t he s p o ns or of  a S A E is esse ntial s o t hat le gal 
o bli gat i ons a n d et hical res p o nsi bilit ies t o war d t he safety of  partici pa nts a n d t he safet y of  a 
st u d y int er ve ntio n u n der cli nical i n vest 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 gul at 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 o n. 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 ulat or y re q uire me nts relati n g t o safety re p ortin g 
t o t he re g ulat or y a ut h orit y, I R Bs/I E Cs, a n d i nvest i gat ors.
F or all st u di es e xce pt t h ose utilizi n g me dical de vices i n vesti gat or safet y re p orts must be 
pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A R s) acc or di n g t o lo c al  
re g ulat or y r e 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 S A E or ot her s pecific 
safety i nf or mati on (e g, s u m mar y  or listi n g of S A Es) fr om t he s p o ns or will re vie w a n d t he n 
file it al o n g with t he I B a n d/ or 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.
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 i n vest i gati onal 
pr o d uct, 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 m ust 
i nf or m t he a p pr o priate s p o ns or re prese ntati ve(s) wit hi n 1 da y, ie, i m me diatel y b ut n o later 
t ha n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.
T he desi g nate d st u d y  re prese ntative w or ks wi t h t he i n vesti 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 t o t he s p o ns or’s P atie nt S afet y data e ntr y  sit e wit hi n 
1 cale n dar da 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 cale n dar da ys 
of  i nitial 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 s p o ns or 
re prese ntati ves of a n y foll o w -u p i nf o r mat i on o n a pre vi o usl y re p orte d S A E wit hi n 1 cale n dar 
d a y , ie, i m me diatel y b ut n o later t ha n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
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 is seri o us i n t he electr o nic data 
ca pt ure ( E D C) s yst e m, a n a ut o mat e d e mail alert is se nt t o i nf or m t he desi g nate d s p o ns or 
re prese ntati ve(s).
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 site pers o n nel re p orts 
a n S A E t o t he a p pr o priate s p o ns or re prese ntati ve b y tele p h o ne. T he s p o ns or re prese ntati ve 
will a d vise t he i n vesti gat or/st u d y  site pers o n nel h o w t o pr ocee d. 
F or details o f S A E re p orti n g d uri n g t he c o nti n ue d treat me nt peri o d aft er data c ut -off f or 
a nal ysis of fi nal st u d y d at a, see Secti o n 4. 4. 1 .
T he refere nce d oc u me nt f or defi nit i on o f e x pecte d ness/liste d ness is t he I B f or t he 
Astra Ze neca / Me dI m m u ne dr u g a n d t he l ocal c o u ntr y la bel f or t he acti ve c om parat or pr o d uct 
(c he m ot hera p y dr u gs ). 
5. 6
Ot h er E ve nts Re q uiri n g I m me di ate Re p orti n g
5. 6. 1
O ver d ose
A n o ver d ose is defi ne d as a s u bject recei vi n g a d ose of i n vest i gati onal pr o d uct i n e xcess of 
t hat s pecifie d i n t he I B, u nless ot her wise s pecifie d i n t his pr ot oc ol.

A n o ver 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 Me dI m m u ne i n vesti gati onal pr o d uct occ urs d uri n g 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 s h o ul d i nf or m t he a p pr o priate s p o ns or 
re prese ntati ves i m me diatel y, b ut n o later t ha n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.
T he desi g nate d s p o ns or 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 rele va nt 
i nf or mat i on is pr o vi de d t o t he s p o ns or’s Patie nt Safety data e ntr y  sit e.
F or o ver d oses ass ociate d wit h a n S A E, t he sta n dar d re p orti n g ti meli nes a p pl y; see Secti on  5. 5 . 
F or ot her o ver d oses (ie, t h ose n ot ass ociate d wit h a n A E or S A E), re p orti n g m ust occ ur wit hi n 
3 0 da y s.
F or details o f o ver d ose re p orti n g d uri n g t he c o nti n ue d treat me nt peri o d aft er data c ut -off f or 
a nal ysis of fi nal st u d y d at a, see Secti o n 4. 4. 1 .
5. 6. 2
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 ho ul d be re p orte d t o t he s p o ns or e xce pt if t he 
pre g na nc y is disc o vere d bef ore t he st u d y  s u bject has recei ve d a n y st u d y dr u g.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
F or details o f pre g na nc y re p orti n g d uri n g t he c o nti n ue d treat me nt peri o d aft er data c ut -off f or 
a nal ysis of fi nal st u d y d at a, see Secti o n 4. 4. 1 .
5. 6. 2. 1
M ater n al E x p os ure
If a s u bject bec omes pre g na nt d uri n g t he c o urse of t he st u d y, i n vesti gati onal pr o d uct 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 i n vest i gati onal 
pr o d uct u n der st u d y  ma y ha ve i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicat i on. 
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 uld be re p orte d a n d 
ha n dle d as S A Es. Electi ve a b orti o ns wit h o 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 
s u bject was disc o nti n ue d fr o m t he st u d y.
If a n y pre g na nc y occ urs d uri n g 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 will i nf or m t he a p pr o priate s p o ns or re prese ntati ves wit hi n 1 da y, ie, i m me diatel y 
b ut n o l ater t h a n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.
T he desi g nate d st u d y  re prese ntative w or ks wi t h t he i n vesti gat or t o e ns ure t hat all rele va nt 
i nf or mat i on is pr o vi de d t o t he s p o ns or’s P atie nt S afet y data e ntr y  sit e wit hi n 1 or 5 cale n dar 
da ys f or S A Es (see Secti o n  5. 5 ) 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 pre g na nc y re p orti n g 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 
pre g na nc y o utc o me m o d ule is use d t o re p ort t he o utc o me of t he pre g na nc y .
5. 6. 2. 2
P ater n al E x p os ure
Pre g na nc y of t he s u bject’s part ners is n ot c o nsi dere d t o be a n A E. H o we ver, t he o u t co m e of 
all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, 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 t he date of t he first d ose u ntil 1 8 0 da ys after 
t he last d ose of i n vest i gati onal pr o d uct s h o ul d, if p ossi ble, be f oll owe d u p a n d d oc u m e nte d. 
5. 6. 3
Me 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 dicatio n err or i s 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 Me dI m m u ne st u d y dr u g t hat eit her ca uses har m t o t he s u bject or 
has t he p ote nti al t o ca use har m t o t he s u bject. 
A me dicat i on err or is n ot lac k of efficac y o f t he dr u g, b ut rat her a h u ma n- or pr ocess -r elate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or s u bje ct.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
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 n d i nterce pte d bef ore t he s u bject recei ve d t he dr u g

Di d n ot occ ur, b ut circ u msta nces were rec o g nize 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 (ie, i nstea d of recei vi n g t he i n vesti gati o nal pr o d uct, t he s u bject 
recei ve d a dr u g t hat has a si milar-s o u n di n g na me)

Di s pe nsi n g err or, e g, me dicati on 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 s u bject

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 refri gerat or w he n it s h o ul d be at r o o m 
t e mperat ur e 

Wr o n g s u bject recei ve d t he me dicat i on (e xcl u di n g I R T err ors)

Wr o n g dr u g a d mi nistere d t o s u bject (e xcl u di n g I R T 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 R T - 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 on err or 

Acci de ntal  o ver d ose ( will be ca pt ure d as a n o ver d ose)

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 -label st u dies, e ve n if a n Astra Ze neca or Me dI m m u ne 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.
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 in vesti gat or or ot her site
pers o n nel i nf or ms t he a p pr o priate Me dI m m u ne re prese ntati ves wit hi n 1 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 Me dI m m u ne re prese ntati ve w or ks wit h t he in vest i gat or t o e ns ure t hat all 
r ele va nt i nfor m at i on is c om p lete d wit hi n 1 or 5 cale n dar da ys if t here is a n S A E ass ociate d 
wi t h t h e me dicat i on err or (see Secti o n  5. 5 ) a n d wit hi n 3 0 da ys f or all ot her me dicati on err ors. 
Me dicat i on err ors s h o ul d be re p orte d usi n g a Me dicati o n Err or Re p ort F or m.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
6
S T U D Y A N D D A T A M A N A G E M E N T
6. 1
Tr ai ni n g of St u d y Site Pers o n nel
Bef ore t he first s u bject is e ntere d i nt o t he st u d y , a Me dI m m u ne re prese ntati ve will re vie w a n d 
di sc uss t he re qui re me nts of t he pr ot oc ol a n d relate d d oc u me nts wit h t he i n vesti gati onal staff 
a n d als o trai n t he m i n a n y st u d y-s pecific pr oce d ures a n d s yste m(s) utilize d.
T he Pri nci pal I n vest i gat or will e ns ure t hat a p pr o priate trai ni n g rele va nt t o t he st u d y is gi ve n t o 
a ll of t hese staff, a n d t hat a n y ne w i nf or matio n rele va nt t o t he perf or m a nce of t his st u d y is 
f or war de d t o t he staff i n v ol ve d.
T he Pri nci pal I n vest i gat or will mai ntai n a rec or d of all i n di vi d uals i n v ol ve d i n t he st u d y 
( me dical, n ursi n g, a n d ot her staff).
6. 2
M o nit ori n g of t he St u d y
D uri n g t he st u d y , a Me dI m m u ne re prese ntati ve will ha ve re g ular c o ntacts wit h t he st u d y sit e, 
i ncl u di n g visits t o:

Pr o vi de i nf or m at i on a n d s u p p ort t o t he i n vest i gat or(s).

C o nfir m t hat facilit ies re mai n acce pta ble.

C o nfir m t hat t he i n vesti gati onal tea m  is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc uratel y a n d ti mel y rec or de d i n t he e C R Fs, t hat bi o l ogical  sa m ples are ha n dle d i n 
acc or da nce wit h t he La b orat or y Ma n ual, a n d t hat st u d y dr u g acc o u nta bility c hec ks are 
bei n g perf or me d .

Perf or m  s o urce data verificati o n (a c o m paris o n of t he data i n t he e C R Fs wit h t he s u bject’s 
me dical rec or ds at t he h os pital or practice, a n d ot her rec or ds rele va nt t o t he st u d y ) 
i ncl u di n g verificati on of i nf or me d c o nse nt of partici pat i n g s u bjects. T his will re q uire 
di rect access t o all ori gi nal rec or ds f or eac h s u bject (e g, cli nic c harts).

E ns ure wit h dra wal of i nf or me d c o nse nt t o t he use of t he s u bject’s bi o l ogical  sa m ples is 
re p orte d a n d bi ol ogical  sa m ples are ide nt ifie d a n d dis p ose d of/ destr o ye d acc or di n gl y, a n d 
t he actio n is d oc u m e nte d, a n d re p orte d t o t he s u bject.
T he Me dI m m u ne re prese ntati ve will be a vaila ble bet wee n visit s if t he i n vesti gat or(s) or ot her 
staff at t he ce nter nee ds i nf or mati o n a n d a d vice a b o ut t he st u d y c o n d uct.
6. 2. 1
S o urce D at a
Ref er t o t he Cli nical St u d y Agree me nt f or l o c ati o n of  s o urce data.
6. 2. 2
St u d y A gree me nts
T he Pri nci pal I n vest i gat or at eac h/t he ce nter s h o ul d c o m pl y with all t he ter ms, c o n dit i ons, a n d 
o bli gat i ons of t he Cli nical St u d y  A gree me nt, or e q ui vale nt, f or t his st u d y. I n t he e ve nt of a n y 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
i nc o nsiste nc y bet wee n t his pr ot oc ol a n d t he Cli nical St u d y Agree me nt, t he ter ms o f pr ot oc ol  
s hall pre vail with res pect t o t he c o n d uct of t he st u d y a n d t he treat me nt of s u bjects a n d i n all 
ot her res pects, n ot relati n g t o st u d y  c o n d uct or treat me nt of s u bjects, t he ter ms of t he Cli nical 
St u d y  A gree me nt s hall pre vail.
A gree me nts bet wee n Me dI m m u ne a n d t he Pri nci pal I n vest i gat or m ust be i n place bef ore a n y 
st u d y-relate d pr oce d ures ca n ta ke place, or s u bjects are e nr olle d.
6. 2. 3
Arc hi vi n g of St u d y D oc u me nts
T he i n vest i gat or f oll o ws t he pri nci ples o utli ne d i n t he Cli nical St u d y A gree me nt.
6. 3
St u d y Ti met a ble a n d E n d of St u d y
A n i n di vi d ual s u bject will be c o nsi dere d t o ha ve c o m plete d t he st u d y if t he s u bject was 
f oll owe d t hr o u g h t heir last pr ot oc ol -s pecifie d visi t/assess me nt (i ncl u di n g tele p h o ne c o ntact), 
re gar dless of t he n u m ber of d oses of i n vest i gati onal pr o d uct t hat was recei ve d. 
S u bjects will be c o nsi dere d n ot t o ha ve c o m p lete d t he st u d y if c o nse nt was wit h dra w n or t he 
s u bject was l ost t o f oll ow- u p (see Secti o ns  4. 1. 5 a n d 4. 1. 6 ).
T he e n d o f t he st u d y ( “st u d y c o mplet i on”) is defi ne d as t he date of t he last pr ot oc ol -s pecifie d 
visit/assess me nt (i ncl u di n g tele p h o ne c o ntact) f or t he last s u bject i n t he st u d y . T his date will 
be a p pr o xi matel y 2 years after t he last s u bject be gi ns treat me nt or w he n t he s p o ns or st o ps t he 
st u d y, w hic he ver occ urs earlier. A fi nal data c ut -of f f or t he pri mar y a nal ysis will occ ur at t his 
ti me.
6. 4
D at a M a n a ge me nt 
Data m a na ge me nt will be perf or me d b y Me dI m m u ne Data Ma na ge me nt staff or ot her part y
acc or di n g t o t he Data Ma na ge me nt Pl a n.
A n E D C s yste m will be use d f or data c ollecti on a n d q uer y  ha n dli n g. T he i n vesti gat or will 
e ns ure t hat data are rec or de d i n t he e C R Fs as s pecifie d i n t he st u d y  pr ot oc ol a n d i n acc or da nce 
wi t h t he e C R F i nstr ucti o ns pr o vi de d.
T he i n vest i gat or e ns ures t he acc urac y, c o mplete ness, a n d ti meli ness of t he data rec or de d a n d 
of  t he pr o visi on of a ns wers t o data q ueries acc or di n g t o t he Cli nical St u d y  Agree me nt. T he 
i n vesti gat or will si g n t he c o m plete d e C R Fs. A c o p y of t he c o mplete d e C R Fs will be arc hi ve d 
at t he st u d y sit e.
Data will n ot be e ntere d i nt o t he E D C s y st e m after t he fi nal data c ut-off (see Secti o n 4. 4. 1 ).
D uri n g a st u d y  s u bject’s c o nti n ue d treat me nt peri o d aft er data c ut -off f or a nal ysis o f fi nal 
st u d y d at a, S A Es, o ver d oses, a n d pre g na ncies will be re p orte d usi n g pa per -base d C R Fs u nt il 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
2 8 da y s after t he st u d y s u bject’s last d ose of i n vesti gati onal pr o d uct. Re p orte d S A E data will 
be e ntere d b y  t he s p o ns or i nt o t he s p o ns or’s gl o bal safety data base. 
6. 5
Me dic al M o nit or C o ver a ge
Eac h s u bject will be pr o vi de d wit h c o ntact i nf or mati o n f or t he Pri nci pal I n vest i gat or. I n 
a d ditio n, eac h s u bject will recei ve a t oll-free n u m ber i nte n de d t o pr o vi de t he s u bject’s 
p h ysicia n access t o a me dical m o nit or 2 4 h o urs a da y , 7 d a ys a wee k i n t he e ve nt of a n 
e mer ge nt sit u atio n w here t he s u bject’s healt h is dee me d t o be at ris k. I n t his sit uati o n, w he n a 
s u bject prese nts t o a me dical facility w here t he treati n g p h ysicia n or healt h care pr o vi der 
re q uires access t o a p h ysicia n w h o has k n o wle d ge of t he i n vest i gati onal pr o d uct a n d t he 
cli nical st u d y pr ot oc ol a n d t he Pri nci pal I n vesti gat or is n ot a vaila ble, t he treati n g p h ysicia n or 
healt h care pr o vi der ca n c o ntact a me dical m o nit or t hr o u g h t his s yste m, w hic h is ma na ge d b y  
t he s p o ns or .
7
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S
7. 1
S u bject D at a Pr otecti o n
Eac h s u bject will be assi g ne d a SI D t o e ns ure t hat pers o nall y i de ntifia ble i nf or mati on is ke pt 
se parate fr o m t he st u d y data. S u bject data t hat are rele va nt t o t he trial, e g, de mo gra p hic 
i nf or mat i on, p h ysical or me ntal healt h c o n dit i on, dia g n osis, c o m or bi dit ies, la b orat or y t est 
res ults, etc. will o nl y be c ollecte d wit h t he s u bject’s i nf or me d c o nse nt. T he I C F will 
i nc or p orate ( or, i n s ome cases, be acc o m pa nie d b y a se parate d oc u me nt i nc or p orati n g) 
w or di n g t hat descri bes h o w s u bject data will be c ollecte d, use d, a n d distri b ute d i n c o m plia nce 
wi t h r ele va nt data pr otecti o n a n d pri vac y le gislat i on.
7. 2
Et hics a n d Re g ul at or y Re vie w
T he I R B/I E C res p o nsi ble f or eac h site m ust re vie w a n d a p pr o ve t he fi nal st u d y  pr ot oc ol, 
i ncl u di n g t he fi nal versi on of t he I C F a n d a n y ot her writte n i nf or mat i on a n d/ or m at erials t o be 
pr o vi de d t o t he s u bjects. T he I R B/I E C m ust als o a p pr o ve all a d vert isi n g use d t o recr uit 
s u bjects f or t he st u d y. T he i n vesti gat or is res p o nsi ble f or s u b mitti n g t hese d oc u me nts t o t he 
a p plica ble I R B/I E C, a n d distri b ut i n g t he m t o t he st u d y site staff.
T he o pi ni o n of t he I R B/I E C m ust be gi ve n i n writ i n g. T he i n vesti gat or m ust pr o vi de a c o p y of 
t he writte n a p pr o val t o Me dI m m u ne bef ore e nr ollme nt of a n y  s u bject i nt o t he st u d y. 
Me dI m m u ne s h o ul d a p pr o ve a n y
s u bsta nti ve m o dificat i ons t o t he I C F t hat are nee de d t o meet 
l ocal re q uire me nts.
If re q uire d b y lo c al  re g ulati ons, t he pr ot oc ol m ust be re -a p pr o ve d b y t he I R B/I E C a n n uall y.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
Bef ore t he st u d y  is i nitiate d, Me dI m m u ne will e ns ure t hat t he nati o nal re g ulat or y a ut h orit y in 
eac h c o u ntr y has bee n n otifie d a n d t heir a p pr o val has bee n o btai ne d, as re q uire d. Me dI m m u ne 
will pr o vi de safet y u p dates/re p orts acc or di n g t o l ocal re q uire me nts, i ncl u di n g S U S A Rs w here 
r ele va nt, t o re g ulat or y a ut h orities, I R B/I E C, a n d pri nci pal i n vesti gat ors.
Eac h Pri nci pal I n vesti gat or is res p o nsi ble f or pr o vi di n g re p orts of a n y seri o us a n d u ne x pecte d 
a d verse dr u g reacti o ns fr o m a n y ot her st u d y c o n d ucte d wit h t he i n vesti gati onal pr o d uct t o t he 
I R B/I E C. Me dI m m u ne will pr o vi de t his i nf or mati o n t o t he Pri nci pal I n vesti gat or s o t hat 
he/s he ca n meet t hese re p orti n g re q uire me nts.
7. 3
I nfor me d C o nse nt
I nf or me d c o nse nt of eac h s u bject will be o btai ne d t hr o u g h a writte n a n d ver bal e x pla nat i on 
pr ocess t hat a d dresses all ele me nts re q uire d b y I C H/ G C P. Me dI m m u ne will  d e v elo p a c ore 
I C F f or use b y all in vesti gat ors i n t he cli nical st u d y . Me dI m m u ne m ust a p pr o ve a n y 
m o dificati o ns t o t he I C F t hat are nee de d t o meet l ocal re q uire me nts.
T he Pri nci pal I n vest i gat or(s) at eac h ce nter will:

E ns ure eac h s u bject is gi ve n f ull a n d a de q uate oral a n d writte n i nf or mati o n a b o ut t he 
nat ure, p ur p ose, p ossi ble ris k a n d be nefit of t he st u d y .

E ns ure eac h s u bject is n otifie d t hat t he y  ar e free t o disc o nti n ue fr om t he st u d y at a n y time .

E ns ure t hat eac h s u bject is gi ve n t he o p p ort u nit y t o as k q uestio ns a n d all o we d ti me t o 
c o nsi der t he i nf or mati o n pr o vi de d.

E ns ure eac h s u bject pr o vi des si g ne d a n d date d i nf o r me d c o nse nt bef ore c o n d ucti n g a n y 
pr oce d ure s pecificall y  for t he st u d y .

E ns ure t he ori gi nal, si g ne d I C F(s) is/are st ore d i n t he i n vest i gat or’s St u d y File.

E ns ure a c o p y  of t he si g ne d I C F is gi ve n t o t he s u bject.

E ns ure t hat a n y  ince nti ves f or s u bjects w h o partici pate i n t he st u d y  as well as a n y 
pr o vi sio n s for s u bjects har me d as a c o nse q ue nce of st u d y  p artici pat i on are descri be d i n 
t he I C F t hat is a p pr o ve d b y a n I R B/I E C.
7. 4
C h a n ges t o t he Pr ot oc ol a n d I nf or me d C o nse nt F or m
St u d y  pr oce d ures will n ot be c ha n ge d wit h o ut t he m ut ual a gree me nt of t he Pri nci pal 
I n vesti gat or a n d Me dI m m u ne. A n y c ha n ges m ust be d oc u me nte d i n a st u d y pr ot oc ol 
a me n d me nt. 
F or a s u bsta ntial c ha n ge t o t he pr ot oc ol, Me dI m m u ne will distri b ute a me n de d versi o ns of t he 
pr ot oc ol  t o t he Pri nci pal I n vest i gat or(s). Bef ore i m ple me ntati o n, a me n de d pr ot oc ols m ust be 
a p pr o ve d b y t he r ele va nt I R B/I E C (see Secti o n 7. 2 ) a n d re vie we d as per l ocal re g ulat or y 
a ut h orit y r e q uire me nts. T he I R B/I E C m ust als o a p pr o ve re visi o ns t o t he I C F, a d vertisi n g, a n d 
a n y ot her writte n i nf or mat i on a n d/ or m aterials res ult i n g fr o m t he c ha n ge t o t he pr ot oc ol.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
A n y n o n -s u bsta ntial c ha n ges will be c o m m u nicate d t o or a p pr o ve d b y eac h I R B/I E C.
7. 5
A u dits a n d I ns pecti o ns
A ut h ori ze d re prese ntati ves of Me dI m m u ne, a re g ulat or y a ut h orit y, or a n I R B/I E C ma y 
perf or m  a u dits or ins pect i ons at t he ce nter, i ncl u di n g s o urce data verificat i on. T he p ur p ose of 
a n a u dit or i ns pect i on is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y-relate d 
acti vit ies a n d d oc u me nts, t o deter mi ne w het her t hese acti vities were c o n d ucte d, a n d data were 
rec or de d, a nal yze d, a n d acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, G C P, g ui deli nes of t he 
I C H, a n d a n y a p plica ble re g ulat or y re q uire me nts. T he i n vesti gat or will c o ntact Me dI m m u ne 
i m me diatel y if c o ntacte d b y a re g ulat or y a ge nc y a b o ut a n i ns pect i on at t he site.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
8
R E F E R E N C E S
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C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
I n o ue Y, Y os hi m ura K, K ura be N, Ka h y o T, Ka wase A, Ta na has hi M, et al. Pr o g n ostic 
i m pact of C D 7 3 a n d A 2 A a de n osi ne rece pt or e x pressi on i n n o n- s mall-cell lu n g c a ncer. 
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2 0 1 5.
Nar wal  R, R os k os L K, R o b bie GJ. P o p ulati o n p har mac o ki netics of sifali m u ma b, a n 
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Cli n P har mac o ki n et. 2 0 1 3; 5 2( 1 1): 1 0 1 7 - 2 7.
N g C M, L u m  B L, Gi me nez V, Kelse y S, Allis on D. Rati o nale f or fi xe d d osi n g of pert uz u ma b 
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2 0 0 6; 2 3( 6): 1 2 7 5 - 8 4.
O' Reill y E, O h D, D ha ni N, Re n o uf D, Lee M, S u n W, et al. A ra n d o mize d P hase 2 st u d y o f 
d ur val u ma b m o n ot hera p y  a n d i n c o m bi nati on wi t h tre meli m u ma b i n pat ient s wit h metastatic 
pa ncreat ic d uctal a de n ocarci n oma ( m P D A C): A L P S St u d y. Prese nte d at t he 2 0 1 8 
Gastr oi ntesti nal Ca ncers S y m p osi u m ( A S C O GI). 1 8- 2 0 Ja n 2 0 1 8; Sa n Fra ncisc o, C A. P oster 
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Par d oll D M. T he bl oc ka de of i m m u ne c hec k p o i nts i n ca ncer i m m u n ot hera p y. Nat Re v Ca ncer. 
2 0 1 2; 1 2( 4): 2 5 2 -6 4.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T urc otte M, S pri n g K, P o m me y S, C h o ui nar d G, C o usi nea u I, Ge or ge J, et al. C D 7 3 is 
ass ociat e d wit h p o or pr o g n osis i n hi g h-gra de ser o us o varia n ca ncer. Ca ncer Res. 
2 0 1 5; 7 5 ( 2 1): 4 4 9 4- 5 0 3.
V o n H off D D, Er vi n T, Are na F P, C hi orea n E G, I nfa nte J, M o ore M, et al. I ncrease d s ur vi val 
i n pa ncreatic ca ncer wit h na b-pacli t a x el pl us ge mcita bi ne. N E n gl J Me d. 2 0 1 3; 3 6 9( 1 8): 1 6 9 1-
7 0 3.
Wa n g D D, Z ha n g S, Z ha o H, Me n A Y, Pari var K. Fi xe d d os i n g vers us b o d y size-base d 
d osi n g of m o n ocl o nal  a nti b o dies i n a d ult cli nical trials. J Cli n P har mac ol. 2 0 0 9; 4 9( 9): 1 0 1 2-
2 4.
Wa n g M, Z ha o J, Z ha n g L M, Li H, Y u J P, Re n X B, et al. C o m bi ne d Erl oti ni b a n d Cet u xi ma b 
o verc o m e t he ac q uire d resista nce t o e pider mal  gr o wt h fact or rece pt ors t y r osi ne ki nase 
i n hi bit or i n n o n-s mall-cell lu n g ca ncer. J Ca ncer Res Cli n O nc o l. 2 0 1 2; 1 3 8( 1 2): 2 0 6 9- 7 7.
W u X R, He X S, C he n Y F, Y ua n R X, Ze n g Y, Lia n L, et al. Hi g h e x pressi o n of C D 7 3 as a 
p o or pr o g n ostic bi o mar ker i n h u ma n c o l orectal ca ncer. J S ur g O nc ol. 2 0 1 2; 1 0 6( 2): 1 3 0 - 7.
Ya n g Q, D u J, Z u L. O vere x pressi o n of C D 7 3 i n pr ostate ca ncer is ass ociate d wit h l y m p h 
n o de m etastasis. Pat h ol O n c ol Res. 2 0 1 3; 1 9( 4): 8 1 1- 4.
Y o o C, H wa n g J Y, Ki m J E, Ki m T W, Lee J S, Par k D H, et al. A ra n d o mise d p hase II st u d y  of 
m o difie d F O L FI RI. 3 vs m o difie d F O L F O X as sec o n d -li ne t hera p y i n patient s wit h 
g e m cita bi ne-r efr a ct or y a d va nce d pa ncreatic ca ncer. Br J Ca ncer. 2 0 0 9; 1 0 1( 1 0): 1 6 5 8- 6 3.
Y u YI, Wa n g W, S o n g L, H u W, D o n g C, Pei H, et al. Ect o- 5'- n ucle oti dase e x pressi o n  is 
ass ociat e d wit h t he pr o gressio n of  re nal cell carci n o ma. O nc o l Lett. 2 0 1 5; 9( 6): 2 4 8 5 -9 4.
Z ha n g S, S hi R, Li C, Pari var K, Wa n g D D. Fi xe d d osi n g vers us b o d y  size-base d d osi n g of 
t hera pe utic pe pt i des a n d pr otei ns i n a d ults. J Cli n P har mac ol. 2 0 1 2;5 2( 1): 1 8 - 2 8.
Z ha o T, Re n H, Jia L, C he n J, Xi n W, Ya n F, et al. I n hi bit i on of HI F - 1 α b y P X-4 7 8 e n ha nces 
t he a nt i-t u mor effect of ge mcita bi ne b y i n d uci n g i m m u n o ge nic cell deat h i n pa ncreatic d uctal 
a de n ocarci n o ma. O nc otar get. 2 0 1 5; 6( 4): 2 2 5 0 - 6 2.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
9
C H A N G E S T O T H E P R O T O C O L
9. 1
Pr ot oc ol A me n d me nt 3
Te xt re vi sio ns r es ul tin g fr o m t his a me n d me nt are i nc or p orate d i n t he b o d y of Pr ot oc ol 
A me n d me nt 3. T he pri nci pal reas o n f or t his a me n d me nt is t o all o w a n y st u d y s u bject still 
recei vi n g i n vesti gati onal pr o d uct at t he ti me of  t he data e ntr y  c ut-off t o c o nt i n ue t o recei ve 
i n vesti gati onal pr o d uct wit hi n t he c urre nt st u d y  t hr o u g h a c o nti n ue d treat me nt peri o d. 
S u bsta nt ial c ha n ges t o t he pr ot oc ol are s u m marize d bel o w.
1
Secti o n 4. 4. 1 ( C o nti n ue d Treat me nt at St u d y  C o m pl et i on) : Ne w secti o n descri bi n g t he 
c o nti n ue d treat me nt peri o d f or s u bjects still recei vi n g i n vesti gati onal pr o d uct at t he ti me 
of  data e ntr y c ut-off. A s u m mar y  of Sectio n 4. 4. 1 has als o bee n a d de d t o t he pr ot oc ol 
s y n o psis. 
2
Secti o ns 1. 6. 1 ( P ote nti al Ris ks) a n d 5. 3. 2.1 ( Car diac C hest Pai n, Tra nsie nt Isc he mic 
At tac k, a n d T hr o m b oe m b olis m): T he k n o w n a n d p ote ntial ris ks f or olecl u ma b a n d 
d ur val u ma b were u p date d i n li ne wit h t he m ost rece nt i nf or mati on.
C ha n ges t o t he pr ot oc ol c o nsi dere d t o be n o n- s u bsta ntial are s u m marize d belo w.
1
Secti o n 6. 5 ( Me dical M o nit or Co vera ge) : Te xt was u p date d t o i n dicate t he s yste m for 
c o ntacti n g a me dical m o nit or w he n t he Pri nci pal I n vesti gat or is n ot a vaila ble will be 
ma na ge d b y  t he s p o ns or, n ot a t hir d-part y  ve n d or as pre vi o usl y.
2
Secti o ns 4. 5. 6 ( Acc o u nta bility) , 5. 5 ( Re p ortin g of Seri o us A d verse E ve nts) , 5. 6. 1
( O ver d ose), 5. 6. 2 ( Pre g na nc y), a n d 6. 4 ( Data Ma na ge me nt): Cr oss refere nces t o t he ne w 
Secti o n 4. 4. 1 ( C o nti n ue d Treat me nt at St u d y  C o m pl et i on ) were a d de d w here rele va nt . 
3
Secti o n 6. 3 ( St u d y  Ti meta ble a n d E n d of St u d y): Te xt was a d de d clarif yi n g t he p oi nt of 
t he data c ut -off f or t he pri mar y  a nal ysis.
9. 2
Pr ot oc ol A me n d me nt 2
Te xt re vi sio ns r es ul tin g fr o m t his a me n d me nt are i nc or p orate d i n t he b o d y of Pr ot oc ol 
A me n d me nt 2. T he pri nci pal reas o n f or t hi s a me n d me nt is t o re vise Secti on 1 0. 9 ( pre vi o usl y 
n u m bere d 1 0. 1 0) t o reflect g ui deli nes t o f oll o w f or olecl u ma b -r elate d t o xicities. T he t o xicit y 
ma na ge me nt g ui deli nes f or d ur val u ma b are t o be mai ntai n e d wit hi n t he Site Master File a n d 
t hr o u g h t he f oll owi n g li n k: htt ps://t m g.azirae.c o m. A d dit i onall y, t he sa m ple size f or C o h ort A 
( Part 2 [ D ose E x pa nsi on]) was i ncrease d t o 7 0 s u bjects per treat me nt ar m ( pre vi o usl y 
6 0 s u bjects per treat me nt ar m) d ue t o a dr o p -o ut rate of a p pr o xi matel y 2 0 % ( pre vi o usl y 
esti mate d as 1 0 %).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
S u bsta nt ial c ha n ges t o t he pr ot oc ol are s u m marize d bel o w.
1
Secti o n 1. 6. 1 ( P ote ntial Ris ks): Re vise d arterial calcificat i ons a n d arterial isc he mic 
di s or der t o p ote ntial ris ks for ol ecl u ma b ( pre vi o usl y i m p orta nt p ote ntial ris ks) per 
ol ecl u ma b I B e ditio n 6. 0. Re vise d ris ks f or d ur val u ma b per d ur val u ma b I B e d 1 5. 0.
2
Secti o ns 3. 1. 1 ( O ver vie w), 4. 1. 1 ( N u m ber of S u bjects), 4. 8. 2 ( Sa m ple Size), a n d Fi g ure 2 
( 3. 1. 1-2; St u d y Fl o w Dia gra m [ Part 2: D ose E x pa nsi o n]): Re vise d t o reflect a sa m ple size 
of  7 0 s u bjects per treat me nt ar m ( pre vi o usl y  6 0 s u bjects per treat me nt ar m) f or C o h ort A 
( Part 2 [ D ose E x pa nsi on]).
3
Secti o n 3. 1. 4. 1 ( Ma na ge me nt of Ol ecl u ma b-Relate d T o xi cities) a n d 1 0. 9 ( Olecl u ma b 
D osi n g M o dificat i on f or T o xicit y Ma na ge me nt [ pre vi o usl y n u m bere d 1 0. 1 0] ): Re vise d 
t o xicit y ma na ge me nt g uideli nes i n Secti o n 1 0. 9 t o reflect g ui deli nes t o f oll o w f or 
ol ecl u ma b-related t o xi cities.
4
Secti o n 3. 1. 4. 2 ( Ma na ge me nt of D ur val u ma b -Relate d T o xi cities): A d de d n e w sect i on 
wi t h inf or mati o n re gar di n g t o xicit y ma na ge me nt g ui deli nes f or d ur val u ma b. T he t o xi cit y 
ma na ge me nt g ui deli nes f or d ur val u ma b are t o be mai ntai ne d wit hi n t he Site Master File 
a n d t hr o u g h t he f o ll owi n g li n k: htt ps://t m g.azirae.c o m. T he d ur val u ma b t o xicit y 
ma na ge me nt g ui deli nes s h o ul d be f o ll owe d f or s u bjects w h o recei ve d ur val u ma b i n 
c o m bi nat i on wi t h olecl u ma b. Re n u m bere d s u bse q ue nt secti o ns acc or di n gl y.
5
Secti o n 4. 1. 7 ( Treat me nt Be y o n d Pr o gressi o n): A d de d state me nt i n t he sec o n d para gra p h 
t hat s u bjects wit h u nc o nfir me d ra di o l ogi c P D w h o are eli gi ble t o c o n ti n ue recei vi n g t heir 
assi g ne d treat me nt will be ma de a ware of t he p ote nt ial be nefit s a n d ris ks of c o nti n ui n g 
treat me nt i n t he setti n g of P D a n d m ust pr o vi de a se parate writte n i nf or me d c o nse nt pri or 
t o treat me nt.
6
Secti o n 4. 2. 3 ( F oll o w -u p Peri o d): A d d e d assess me nt f or pre g na nc y testi n g Q 4 W starti n g 
8 wee ks t hr o u g h 2 8 wee ks p ost last d ose d uri n g f o ll ow- u p i n Ta ble 9 ( 4. 2. 3 -1; Sc he d ule 
of  F oll ow- u p Pr oce d ures [ Part 1 (D o se Escalati on) a n d Part 2 (D o se E x pa nsi on) ]).
Cl arifie d i n t he f o ot n ote t hat uri ne pre g na nc y tests will be perf or me d eit her o n site or at 
h o me, a n d t he st u d y  site will c o ntact t he s u bject b y p h o ne t o o btai n res ults for tests 
perf or m e d at h o me. T he fre q ue nc y o f t he pre g na nc y testi n g was u p date d t o alig n wi t h 
c o ntrace pti o n re q uire me nts i n t he i ncl usi o n cri t eria a n d t he S u m mar y of Pr o d uct 
C haracteristics f or t he c he m ot hera p y dr u gs.
7
Secti o ns 4. 5. 1. 2 ( Ol ecl u ma b [ M E DI 9 4 4 7] I V Ba g Pre parati o n a n d A d mi nistrati o n) a n d 
4. 5. 1. 3 ( D ur val u ma b [ M E DI 4 7 3 6] I V Ba g Pre p arati o n a n d A d mi nistrati o n): Re vise d t o 
re q uire t hat s u bject w ei g h t is > 3 0 k g f or fi xe d d osi n g of olecl u ma b a n d d ur val u ma b d ue 
t o e n d ot o xi n le vels.
8
Secti o n 5. 3. 3 ( A d verse E ve nts of S pecial I nterest f or D ur val u ma b): A d de d A E SIs of 
vasc ulit is, n o n-i nfecti ou s me ni n gitis, a n d n o n-i nfecti o us e nce p halitis per d ur val u ma b I B 
e d 1 5. 0.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
9
Secti o n 5. 5 ( Re p orti n g of Seri o us A d verse E ve nts): U p date d t his sect i on t o e ns ure t hat 
c o u ntr y-s pecific re g ulat or y re p ortin g re q uire me nts f or S A Es are met, acc or di n g t o 
u p date d s p o ns o r g uideli nes.
C ha n ges t o t he pr ot oc ol c o nsi dere d t o be n o n- s u bsta ntial are s u m marize d bel o w.
1
Ti tle pa ge: U p date d me dical m o nit or a n d a d de d N C T a n d E u dra C T n u m bers.
2
S y n o psis: U p date d t o ali g n wit h c ha n ges t o t he b o d y  of t he pr ot oc ol.
3
Secti o ns 1. 4. 1. 1 ( St u d y D 6 0 7 0 C 0 0 0 0 1), 1. 4. 1. 2 (St u d y  D 6 0 7 0 C 0 0 0 0 5), a n d 1. 6. 2 
( P ote ntial Be nefits): U p date d cli nical e x perie nce per olecl u ma b I B e diti on 6. 0.
4
Secti o n 1. 4. 2 ( D ur val u ma b Cli nical E x perie nce): U p date d cli nical e x perie nce per 
d ur val u ma b I B e dit i on 1 5. 0.
5
Secti o n 1 0. 1 ( Si g nat ures): Re m o ve d si g nat ure a p pe n di x fr o m t he p r ot oc ol. Re n u m bere d 
s u bse q ue nt a p pe n dices acc or di n gl y.
9. 3
Pr ot oc ol A me n d me nt 1
Te xt re vi sio ns r es ul tin g fr o m t his a me n d me nt are i nc or p orate d i n t he b o d y of Pr ot oc ol 
A me n d me nt 1. T he pri nci pal reas o n f or t his a me n d me nt is t o re vise Part 2 of t he st u d y desi g n 
t o i ncl u de a n a d diti onal 3 0 s u bjects per treat me nt ar m i n C o h ort A a n d a d d a n i nteri m a nal ysis 
f or C o h ort A. T he reas o n f or t he c ha n ge i n st u d y desi g n f or Part 2 C o h ort A was base d o n 
i ncreasi n g t he p o wer of t he st u d y, t he hig her t ha n e x pecte d dr o p -o ut rate, a n d t he p osit i ve 
res ults of safety a n d efficac y of t he olecl u ma b a n d d ur va l u ma b c o m bi nati on see n i n t he F T I H 
St u d y  D 6 0 7 0 C 0 0 0 0 1. A d dit i onall y, t he sa m ple size f or Part 2 C o h ort B was i ncrease d t o 
3 5 s u bjects per treat me nt ar m ( pre vi o usl y 3 0 s u bjects) t o acc o u nt f or t he hi g her t ha n e x pecte d 
dr o p -o ut rate see n i n C o h ort A.
S u bsta nt ial c ha n ges t o t he pr ot oc o l are s u m marize d bel o w.
1
Secti o n 3. 1. 1 ( Over vie w), Fi g ure 2 ( 3. 1. 1-2) ( St u d y Fl o w Dia gra m [ Part 2: D ose 
E x pa nsi o n]) , Sectio n s 4. 1. 1 ( N u m ber of S u bjects), 4. 8. 2 ( Sa m ple Size) , a n d 4. 8. 7 (I nteri m 
A nal ysis) : Re vise d Part 2 of t he st u dy desi g n as detaile d bel o w.
(a) Part 2 C o h ort A: Re vise d n u m ber of s u bjects t o i ncl u de a n a d dit i onal 3 0 s u bjects per 
treat me nt ar m ( n o w u p t o 6 0 s u bjects per treat me nt ar m). Re vise d si g nifica nce le vel 
t o 0. 1 0 ( pre vi o usl y 0. 1 5) a n d i ncrease d p o wer t o 7 7 % ( pre vi o usl y 6 6 %) i n 
Secti o n 4. 8. 2. A d de d a n i nteri m a nal ysis i n Secti on 4. 8. 7 w he n a p pr o xi matel y 
3 0 e val ua ble s u bjects i n eac h treat me nt ar m ha ve bee n d ose d a n d reac h t he data 
c ut -off criteria.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
( b) Part 2 C o h ort B: Re vise d t he sa m ple size t o 3 5 s u bjects per treat me nt ar m. Re vise d 
sig nifica nce l e vel t o 0. 1 0 ( pre vi o usl y 0. 1 5), re vise d differe nce i n O R R t o 2 0 % 
( pre vi o usl y 1 5 %), a n d i ncrease d p o wer t o 7 2 % ( pre vi o usl y 6 3 %) i n Secti o n 4. 8. 2.
(c) U p date d t otal n u m ber of s u bjects i n t he st u d y  t o acc o u nt f or a d diti onal s u bjects i n 
Part 2 C o h orts A a n d B.
2
Secti o n 3. 1. 3. 4 ( Safety Re vie w C o m mit tee): A d de d S R C t o pr o vid e details re gar di n g 
o n g oi n g safety s ur veilla nce of s u bjects d uri n g t he ra n d omizat i on p hase o f t he st u d y.
C ha n ges t o t he pr ot oc ol c o nsi dere d t o be n o n-s u bsta n tial are s u m marize d bel o w.
1
Ti tle pa ge: U p date d me dical m o nit or.
2
S y n o psis: U p date d t o ali g n wit h c ha n ges t o t he b o d y  of t he pr ot oc ol.
3
Re n u m bere d ta bles a n d fi g ures se q ue nt iall y t o alig n wi t h Me dI m m u ne h o use st yle. 
Pre vi o us ta ble a n d fi g ure n u m bers are n ote d i n pare nt heses.
4
Secti o n 1. 4. 1 ( Ol ecl u ma b Cli nical E x perie nce): U p date d cli nical e x perie nce f or 
St u d y D 6 0 7 0 C 0 0 0 0 1 a n d a d de d cli nical e x perie nce f or St u d y  D 6 0 7 0 C 0 0 0 0 5 per 
ol ecl u ma b I B e ditio n 5. 1.
5
Secti o n 1. 4. 2 ( D ur val u ma b Cli nical E x perie nce): U p date d cli n ical e x perie nce per 
d ur val u ma b I B e dit i on 1 4. 0.
6
Secti o n 1. 6. 2 ( P ote ntial Be nefits): U p date d cli nical acti vit y o bser ve d i n t he P D A C c o h ort 
i n St u d y D 6 0 7 0 C 0 0 0 0 1 per olecl u ma b I B e dit i on 5. 1.
7
Secti o n 4. 1. 2 (I ncl usi o n  Crit eria): F or Criteri o n 8 , Ta ble 5 ( 4. 1. 2-1) ( Criteria f or A de q uate 
Or ga n a n d Marr o w F u ncti o n) , clarifie d t hat T B L ≤3 × U L N i n prese nce of d oc u me nte d 
Gil bert’s s y n dr o me or li ver metastases is all o we d o nl y f or s u bjects i n C o h ort B, as 
na b -pacli ta xel ca n n ot be gi ve n t o s u bjects i n C o h ort A u nless T B L ≤1. 5 × U L N.
8
Secti o n 4. 1. 3 ( E xcl usi o n  Crit eria): Re vise d as detaile d bel o w.
(a) Cri t erio n 5: Clarifie d t hat s u bjects wit h t hr o m b osis d ue t o mec ha nical o bstr ucti o n b y 
t he t u m or t hat is f o u n d i nci de ntall y a n d is as y m pt o mat ic a n d d oes n ot re q uire t hera py 
ma y be e nr o lle d at t he i n vest i gat or’s discreti o n a n d s h o ul d be m o nit ore d cl osel y.
( b) Cri t erio n 2 1: A d de d e xcl usi o n  crit erio n f or s u bj ects wit h k n o w n aller g y or 
h y perse nsit i vity t o ge mcita bi ne, na b -pacli t a x el, o xali plati n, le uc o v ori n, or 5-F U.
9
Secti o n 4. 2. 2 ( Treat me nt Peri o d), Ta ble 7 ( 4. 2. 2-1) ( Sc he d ule o f Treat me nt Peri o d St u d y  
Pr oce d ures [ C o h ort A: Part 1 ( D ose Escalat i on) a n d Part 2 ( D ose E x pa nsi o n)]), a n d 
Ta ble 8 ( 4. 2. 2 -2) ( Sc he d ule of Treat me nt Peri o d St u d y Pr oce d ures [ C o h ort B: Part 1 
( D ose Escalati on) a n d Part 2 ( D ose E x pa nsi o n)]): Clarifie d ± 3 -d a y  tr e at me nt wi n d o w 
a p plies t o visits after C ycle 1 Da y 1.
1 0
Secti o n 4. 3. 4 ( Cli nical La b orat or y Tests): Re vise d s u b hea di n g f or “ Ser u m C he mistr y” t o 
“ Ser u m/ Plas ma C he mistr y” for clarificat i on.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 1
Secti o n 4. 3. 8 ( Bi o m ar ker E valu ati o n a n d Met h o ds): A d de d state me nt t o clarif y t hat C D 7 3 
e x pressi o n will be deter mi ne d i n a C A P/ C LI A la b orat or y  usi n g a vali date d, f ull y 
a ut o mate d, I H C assa y t o clarif y met h o d olo g y  for a nal ysis o f C D 7 3 e x pressi o n.
1 2
Secti o n 4. 5. 1 (I de ntit y of  I n vestigat i onal Pr o d ucts): Re vise d a p peara nce of d ur val u ma b t o 
“clear t o o palesce nt, c ol orless t o sli g ht l y yell o w li q ui d, f ree fr o m visi ble particles” 
( pre vi o usl y “free fr o m or practi call y free fr o m visi ble particles”) f or c o nsiste nc y wit h t he 
S u m mar y  of Pr o d uct C haracteristics. 
1 3
Secti o ns 4. 5. 1 (I de nti t y of I n vesti gati onal Pr o d ucts) a n d 4. 5. 4 ( St ora ge): Clarifie d t hat 
dr u g pr o d ucts s h o ul d be ke pt i n ori gi nal ( pre vi o usl y “sec o n dar y”) pac ka gi n g u ntil use t o 
pre ve nt pr ol o n ge d ( pre vi o usl y “e xcessi ve”) li g ht e x p os ure .
1 4
Secti o ns 4. 5. 1. 2 ( Olecl u ma b [ M E DI 9 4 4 7] I V Ba g Pre parati o n a n d A d mi nistrati o n) a n d 
4. 5. 1. 3 ( D ur val u ma b [ M E DI 4 7 3 6] I V Ba g Pre parati o n a n d A d mi nistrati o n): Re vise d as 
detaile d bel o w .
(a) Secti o n 4. 5. 1. 2: Re vise d olecl u ma b i nstr ucti o ns t o all o w a ne w olecl u ma b d ose t o be 
pre pare d if t he i nf usi o n ti me e xcee ds 4 h o urs si milar t o d ur val u ma b ( pre vi o usl y 
state d t hat t he olecl u ma b d ose ha d t o be a ba n d o ne d i n t his case).
( b) Secti o ns 4. 5. 1. 2 a n d 4. 5. 1 . 3: Re m o ve d re q ui re me nt t hat t he filter be i n-li ne f or 
ol ecl u ma b a n d d ur val u ma b t o all o w fle xi bilit y f or cli nical sites. A d de d a + 1 5- mi n ute 
wi n d o w t o t he 1 -h o ur olecl u ma b a n d d ur val u ma b i nf usi o n ti mes t o all o w fle xi bilit y 
f or t he cli nical sites a n d ti me to fl us h t he I V li ne .
1 5
Secti o n 4. 5. 1. 4 ( Treat m e nt A d mi nistrati o n): A d de d i nf usi o n t i mes f or c he m ot hera p y.
1 6
Secti o n 4. 7. 2 ( Pr o hi bite d C o nc o mita nt Me dicat i ons): Re vise d as detaile d bel o w.
(a) Cl arifie d t hat t he use of i m m u n os u p pressi ve me dicati o n as pre me dicat i on p rior t o 
c he m ot hera p y is all o we d.
( b) A d de d ca n na bi n o i ds as pr o hi bite d c o nc o mita nt me dicati on f or ole clu ma b treat m e nt 
ar ms d ue t o i nteractio n bet wee n ca n na bi n o i ds a n d a de n osi ne pat h wa y.
1 7
Secti o n 4. 8. 3. 1 ( Pri mar y Efficac y  A nal ysis): C o m paris o n of ar ms f or O R R will be 
o btai ne d fr o m C oc hra n -Ma ntel -Hae nszel test ( pre vi o usl y C hi s q uare or Fis her’s e xact 
test).
1 8
Secti o n 5. 3. 2. 3 (I m m u ne C o m ple x Disease): Delete d “a n d wit h c o nfir me d prese nce of 
A D As”. S u bjects w h o e x perie nce a n A E s us pecte d t o be i m m u ne c o m p le x-relate d will 
di sc o nti n ue treat me nt; c o nfir mat i on of t he prese nce of A D As is n ot re q uire d as A D A 
testi n g is n ot perf or me d i n real-ti me.
1 9
Secti o n 1 0. 1 ( Si g nat ures [ pre vi o usl y n u m bere d Secti o n 9. 1]): U p date d s p o ns or si g nat ure.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0  
A P P E N DI C E S
1 0. 1
C o ntr ace pti o n G ui d a nce
F or females o f c hil d beari n g p ote ntial:

Fe males of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are n ot s ur gicall y sterile (ie, 
s ur gical sterilizat i on i ncl u des bilateral t u bal li gati on, bilateral o o p h orect o m y, or 
h ysterect o m y) or t h ose w h o are n ot p ost me n o pa usal ( defi ne d as 1 2 m o nt hs wit h n o 
me nses wit h o ut a n alter nati ve me dical ca use).

A hi g hl y effect i ve met h o d of c o ntrace pti o n is defi ne d as o ne t hat res ults i n a l o w fail ure 
rate (ie, less t ha n 1 % per year) w he n use d c o nsiste nt l y a n d c orrectl y. T he acce pta ble 
met h o ds of c o ntrace pti o n are descri be d i n  Ta ble 1 4 (9. 2 - 1).

Fe male s u bjects m ust refrai n fr o m e g g cell d o nat i on a n d breastfee di n g w hile o n st u d y  a n d 
f or 1 80 da ys after t he fi nal d ose of i n vest i gati onal pr o d uct.
T a ble 1 4 (9. 2 - 1)
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n
B arrier Met h o ds
H or m o n al Met h o ds
•
I ntra uteri ne de vice
•
I ntra uteri ne h or m o ne-releasi n g s yste m ( UI S) a
•
Bilateral t u bal occl usi o n
•
Vasect o mize d part ner b
•
Se x ual a bsti ne nce c
C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g 
h or m o nal c o ntrace pti o n)

Oral (c o m bi ne d pill)

I njecta ble

Tra ns der mal ( patc h)
Pr o gest o ge n -o nl y  h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n d

I njecta ble

I m pla nta ble

I ntra va gi nal
a
T his is als o c o nsi dere d a h or m o nal met h o d.
b
Wit h a p pr o priate p ost -vasect o m y d oc u me ntati o n of s ur gical s uccess (a bse nce of s per m i n ejac ulate).
c
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual 
i nterc o urse d uri n g t he e ntire peri o d of t he st u d y a n d if it is t he preferre d a n d us ual lifest yle of t he s u bject.
d
Pr o gest o ge n -o nl y  h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he pri mar y m o de of acti o n 
(e g, mi ni pill), is n ot acce pte d as a hi g hl y effecti ve met h o d).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 2
A d diti o n al S afet y G ui d a nce
F urt her G ui d a nce o n t he Defi niti o n of a Seri o us A d verse E ve nt
Life -t hreate ni n g
‘ Life-t hreate ni n g’ mea ns t hat t he s u bject was at i m me diate ris k of deat h fr o m 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 ult i n t he 
s u bject’s deat h. ‘ Life-t hreate ni n g’ d oes n ot mea 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 patitis t hat res ol ve d with o ut he patic fail ure).
H os pitalizati 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 seri o us A E, alt h o 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 e de ma). H os pital a d missi o ns a n d/ or s ur gical 
o perati o ns pla n ne d bef ore or d uri n g a st u d y  are n ot c o nsi dere d A Es if t he ill ness or disease 
e xiste d bef ore t he s u bject was e nr olle d i n t he st u d y, pr o vi de 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 mp orta nt Me dical E ve nt or Me di cal I nter ve nti on
Me dical a n d scie ntific j u d g 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 m e 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 talizati on, disa bilit y or i nca paci t y but ma y je o par dize t he s u bject or ma y re q uire 
me dica l i nter ve ntio n t o pre ve nt o ne or m ore o utc o mes liste d i n t he defi nit i on of seri o 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 g me nt m ust be use d.
E xa m ples of  s uc h e ve nts are:

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 oo 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 ne mia re q uiri n g bl o o d tra nsf usi o n) or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitalizat 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
Assess me nt of Se verit y
Assess me nt of se verit y is o ne of t he res p o nsi bilities of t he i n vesti gat or i n t he e val uati o n of 
A Es a n d S A Es. Se verit y will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nst itut e C o m m o n 
Ter mi n o l og y Cri t eria for A d verse E ve nts versi o n 4. 0 3 as pr o vi de d i n bel o w. T he 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
deter mi nat i on o f se verity f or all ot her e ve nts n ot liste d i n t he C T C A E s h o ul d be ma de b y t he 
i n vesti gat or base d u p o n me dical j u d g me nt a n d t he se verity cate g ories o f Gra de 1 t o 5 as 
defi ne d bel o w.
Gra de 1
A n e ve nt of mil d i nte nsit y t hat is us uall y tra nsie nt a n d ma y 
re q uire o nl y mi ni mal treat me nt or t hera pe utic i nter ve nt i on. T he 
e ve nt d oes n ot ge nerall y i nterfere wit h us ual act i vities of dail y 
li vi n g.
Gra de 2
A n e ve nt of m o derate i nte nsit y t hat i s us uall y alle viate d wit h 
a d ditio nal  s pecific t hera pe utic i nter ve ntio n. T he e ve nt  i nterferes 
wi t h us ual a cti vities of dail y li vi n g, ca usi n g disc o mf ort b ut 
p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he s u bject.
Gra de 3
A se vere e ve nt t hat re q uires i nte nsi ve t hera pe utic i nter ve nt i on. 
T he e ve nt i nterr u pts us ual acti vit ies of dail y li vi n g, or 
sig nifica nt l y affects t he cli nical stat us of t he s u bject.
Gra de 4
A n e ve nt, a n d/ or its i m me diate se q uelae, t hat is ass ociate d wit h 
a n i m mi ne nt ris k of deat h.
Gra de 5
Deat h as a res ult of a n e ve nt.
It is i m p orta nt t o disti n g uis h bet wee n serio us cri teria a n d se verity of  a n A E. Se verity is a 
meas ure of i nte nsit y w hereas seri o us ness is defi ne d b y  t he crit eria i n Sect i on 5. 2 . A Gra de 3 
A E nee d n ot necessaril y be c o nsi dere d a n S A E. F or e xa m ple, a Gra de 3 hea dac he t hat persists 
f or se veral ho urs ma y  not m eet t he re g ulat or y defi nitio n  of a n S A E a n d w o uld be c o nsi dere d a 
n o nseri o us e ve nt, w hereas a Gra de 2 sei z ure res ultin g i n a h os pital a d m issi on w o ul d be 
c o nsi dere d a n S A E.
Assess me nt of Rel ati o ns hi p
A g ui de t o I nter preti n g t he Ca usalit y Q uesti o n
T he i n vest i gat or is re q uire d t o pr o vi de a n assess me nt of relati ons hi p of A Es a n d S A Es t o t he 
i n vesti gati onal pr o d uct. T he f o ll owi n g fact ors s h o ul d be c o nsi dere d 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 ma y ha ve bee n ca use d b y t he i n vesti gati o nal pr o d uct.

Ti me C o urse. E x p os ure t o s us pect i n vesti gat i onal pr o d uct. Has t he s u bject act uall y  
recei ve d t he s us pect i n vesti gati o nal pr o d uct? Di d t he A E occ ur i n a reas o na ble te m p oral 
r elat i ons hi p t o t he a d mi nistrati o n of t he s us pect i n vesti gati o nal pr o d uct?

C o nsiste nc y wit h k n o w n i n vest i gati onal pr o d uct pr ofile. Was t he A E c o nsiste nt wit h t he 
pre vi o us k n o wle d ge of t he s us pect i n vest i gati ona l pr o d uct ( p har mac o l og y  a n d t o xic o l og y ) 
or pr o d ucts of t he sa me p har mac o l ogi cal class? O R c o ul d t he A E be a nt ici pate d fr om it s 
p har mac o l ogi cal pr o perties? 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

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 i n vest i gati onal pr o d uct?

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 eti ol og y  s uc h as 
t he u n derl yi n g disease, ot her dr u gs, or ot her h ost or e n vir o n me ntal fact ors.

Re -c halle n ge e x perie nce. Di d t he A E re occ ur if t he s us pecte d i n vest i gati onal pr o d uct was 
rei ntr o d uce d after ha vi n g bee n st o p pe d? Me dI m m u ne 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, other fact ors c o ul d be c o nsi dere d s uc h as:

Is t his a rec o g nize d feat ure of o ver d ose of t he i n vesti gati onal pr o d uct?

Is t here a k n o w n mec ha nis m?
Ca usalit y of  ‘relate d’ is ma de if f o ll owi 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 bility’ o f 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’ o f a ca usal relati o 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.
T he ca usalit y asses s 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. Wit h li mite d or i ns ufficie nt i nf or mat i on i n t he 
case, it is li kel y t hat t he e ve nt(s) will be assesse d as ‘ n ot relate 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.
Relati o ns hi p t o Pr ot oc ol Pr oce d ures
T he i n vest i gat or is als o re q uire d t o pr o vi de a n assess me nt of relati ons hi p of S A Es t o pr ot oc ol 
pr oce d ures o n t he S A E Re p ort F or m. T his i ncl u des n o ntreat me nt -e mer ge nt S A Es (ie, S A Es 
t hat occ ur pri or t o t he a d mi nistrati o n o f i n vesti gati o nal pr o d uct) as well as treat me nt-e mer ge nt 
S A Es. A pr ot oc ol -relate d S A E ma y occ ur as a res ult of a pr oce d ure or i nter ve nt io n re q ui re d 
d uri n g t he st u d y  (e g, blo o d c ollect i on, was h o ut of a n e xist i n g me dicat i on). T he f o ll owi n g 
g ui deli nes s h o ul d be use d b y  in vesti gat ors t o assess t he relat i ons hi p of S A Es t o t he pr ot oc ol:
Pr ot oc ol  r elate d:
T he e ve nt occ urre d d ue t o a pr oce d ure/i nt er ve nti o n t hat was descri be d 
i n t he pr ot oc ol f or w hic h t here is n o alter nati ve eti ol o g y prese nt i n t he 
s u bject’s me dical rec or d.
N ot pr ot oc ol relate d:
T he e ve nt is relate d t o a n eti o l og y  ot her t ha n t he pr oce d ure/ 
i nter ve nt i on t hat was descri be d i n t he pr ot o c ol  (t h e alter nati ve eti ol og y  
m ust be d oc u me nte d i n t he st u d y  s u bject’s me dical rec or d).

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 3
N ati o n al I nstit ute of Aller g y a n d I nfecti o us Dise ase a n d F o o d 
Aller g y a n d A n a p h yl a xis Net w or k G ui d a nce f or A n a p h yl a xis 
Di a g n osis
Nati o nal I nst itut e of Aller g y a n d I nfecti o us Disease a n d F o o d Aller g y a n d A na p h yla xis 
Net w or k defi ne a na p h yla xis as a seri o us aller gic reacti o n t hat is ra pi d i n o nset a n d ma y ca use 
deat h. T he y  rec o g nize 3 cate g ories of a na p h yla xis, wit h criteria desi g nate d t o ca pt ure fr o m 
8 0 % of cases (cate g or y  1) t o > 9 5 % of all cases of a na p h yla xis (f or all 3 cate g ories). 
1
Ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v o l ve me nt of t he s ki n, m uc osal 
tiss ue, or b ot h (e g, ge neralize d hi ves, pr urit us or fl us hi n g, s w olle n li ps-t o n g ue-u v ula)
A N D A T L E A S T O N E O F T H E F O L L O WI N G
(a) Res pirat or y  c o mpr o mise (e g, d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d pea k 
e x pirat or y fl ow ( P E F), h y p o xe mia)
( b) Re d uce d bl o o d press ure ( B P) or ass ociate d s y m pt o ms of e n d -or ga n d ysf u nct i on (e g , 
h y p ot o ni a [c olla pse], s y nc o pe, i nc o nt i ne nce)
2
T w o or m ore of t he f o ll owi n g t hat occ ur ra pi dl y after e x p os ure t o a li kel y aller ge n f or t hat 
pati e nt ( mi n utes t o se veral h o urs):
(a) I n v ol ve me nt of t he s ki n-m uc osal t iss ue (e g, ge neralize d hi ves, itc h-fl us h, s w olle n 
li ps-t o ng ue- u v ula)
( b) Res pirat or y  c o mpr o mise (e g, d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d P E F, 
h y p o xe mia)
(c) Re d uce d B P or ass ociate d s y m pt o ms (e g, h y p ot o nia [c oll a pse], s y nc o pe, 
i nc o nti ne nce)
( d) Persi ste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o mit i n g)
3 
Re d uce d B P after e x p os ure t o k n o w n aller ge n f or t hat patie nt ( mi n utes t o se veral h o urs):
(a) A d ults: s yst olic B P of less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease fr o m t hat 
pers o n’s baseli ne
Refere nce:  S a m ps o n et al , 2 0 0 6

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 4
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
1 0. 4. 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 t o i de ntif y a n d a p pr o priatel y re p ort cases 
of  H y’s La w. 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. S pecific g ui da nce o n ma na gi n g li ver a b n or malities ca n be f o u n d i n 
Secti o n 3. 1. 4 of  t he pr ot oc ol.
D uri n g t he c o urse of t he st u d y , t he i n vest i 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 s u bject meets 
p ote nti al H y’s La w crit eria at a n y p oi nt d uri n g t he st u d y.
T he i n vest i gat or partici pates, t o get her wit h Me dI mm u ne cli nical pr o ject re prese ntati ves, i n 
re vie w a n d assess me nt of cases meeti n g p ote ntial H y’s La w criteria t o a gree w het her H y’s 
La w cri t eria are met. H y’s La w criteria are met if t here is n o alter nat i ve e x pla nati on f or t he 
ele vat i ons i n li ver bi oc he mist r y ot her t ha n dr u g-i n d uce d li ver i nj ur y ( DI LI) ca use d b y t he 
i n vesti gati onal pr o d uct. 
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 ote ntial H y’s La w/ H y’s La w 
cases a n d f or re p orti n g A Es a n d S 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 with sta n dar d safet y  re p orti n g pr ocesses.
1 0. 4. 2
Defi niti o ns
1 0. 4. 2. 1
P ote nti al H y’s L a w
A S T 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 o i nt d uri n g t he st u d y 
f oll owi n g t he start of i n vesti gati o nal pr o d uct irres pecti ve of a n i ncrease i n A L P.
1 0. 4. 2. 2
H y’s L a w
A S T 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 i n vest i gati onal pr o d uct, 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 dicat i n g c h olestasis, vir al he pat itis, or a n ot her dr u g. 
F or p ote ntial H y’s La w a n d H y’s La w, t he ele vati o n 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 vat i on i n T B L, b ut t here is n o s pecifie d ti mefra me 
wi t hi n w hic h t he ele vati ons i n tra nsa mi nases a n d T B L must occ ur.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 4. 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 ote ntial H y’s La w, 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 s u bject w h o meets a n y of t he f o ll owi n g i de nt ificati 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, wit h 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 cri teria are met will:

N otif y  t he s p o ns or st u d y re prese ntati ve

Deter mi ne w het her t he s u bject meets p ote ntial H y’s La w criteria (see Secti o n  1 0. 4. 2 ) b y 
re vie wi n g la b orat or y re p orts fr o m all pre vio us visits

Pr o m p tly e nter t he la b orat or y  data i nt o t he la b orat or y case re p ort f or m ( C R F )
1 0. 4. 4
F oll o w -u p
1 0. 4. 4. 1
P ote nti al H y’s L a w Criteri a N ot Met
If t he s u bject d oes n ot meet p ote ntial H y’s La w criteria t he i n vesti gat or will:

I nf or m t he st u d y re prese ntati ve t hat t he s u bject has n ot met  p ote ntial H y’s La w 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 t o t he g ui da nce pr o vi de d i n 
t he st u d y pr ot oc ol.
1 0. 4. 4. 2
P ote nti al H y’s L a w Criteri a Met
If t he s u bject d oes meet p ote ntial H y’s La w criteria t he i n vesti gat or will:

Deter mi ne w het her p ote ntial H y’s La w criteria were met at a n y  st u d y visit prior t o 
starti n g st u d y treat me nt (see Sectio n  1 0. 4. 6 )

N otif y t he s p o ns or st u d y re prese ntati ve w h o will t he n i nf or m t he st u d y t e a m
T he m e dical mo ni t or 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 s u bjects’ f ollo w -u p a n d t he c o nti n u o us re vie w of data. S u bse q ue nt t o 
t his c o ntact t he i n vesti gat or will:

M o ni t or t he s u bject 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.

I n vesti gate t he eti ol og y  of t he e ve nt a n d perf or m dia g n ostic i n vestigat i ons as disc usse d 
wi t h t h e me dical mo ni t or.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

If at a n y time (i n c o ns ultat i on wi t h t h e me dical mo ni t or) t he p ote ntial H y’s La w case 
meets seri o us criteria, re p ort it as a n S A E usi n g sta n dar d re p orti n g pr oce d ures .
1 0. 4. 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 sect i on s h o ul d be f o ll owe d f or all  cases w here p ote ntial H y’s La w 
criteria are met.
N o l ater t ha n 3 wee ks after t he bi oc he mistr y a b n or mality was i ni tiall y detecte d, t he me dical 
m o nit or will  c o ntact t he i n vesti 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 ote ntial H y’s La w cri t eria ot her t ha n DI LI 
ca use d b y t he i n vesti gati onal pr o d uct. T he me dical m o nit or 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.
If t here is a n a gree 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 ntl y 
w het her t he A E meets t he criteria f or a 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 C R F

If t he alter nati ve e x pla nati on is a n A E/ S A E, rec or d t he A E / S A E i n t he C R F acc or di n gl y 
a n d f o ll ow t he s p o ns or’s 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 L T or A S T a n d T B L 
ele vat i ons ot her t ha n t he i n vest i gati onal pr o d uct:

Re p ort a n S A E (re p ort ter m ‘ H y’s La w’) acc or di n g t o t he s p o ns or’s 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 y’s La w case, a ca usalit y 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 3 wee ks i n o btai ni n g t he i nf or mati o n necessar y t o 
assess w het her or n ot t he case meets t he criteria f or H y’s La w, t he n it is ass u me d t hat t here is 
n o al ter native e x pla nat i on u ntil s uc h t i me as a n i nf or me d decisi on ca n be ma de:

Re p ort a n S A E (re p ort ter m ‘ P ote ntial H y’s La w’) a p pl yi n g seri o us criteria a n d ca usalit y 
assess me nt as per a b o ve

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

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 y’s La w criteria are met. U p date t he S A E re p ort acc or di n g t o t he o utc o me of 
t he re vie w
1 0. 4. 6
Acti o ns Re q uire d W he n P ote nti al H y’s L a w Criteri a Are Met Bef ore 
a n d After St arti n g St u d y Tre at me nt 
T his sect i on is a p plica ble t o s u bjects wit h li ver metastases w h o meet p ote ntial H y’s La w 
criteria o n st u d y treat me nt ha vi n g pre vi o usl y met p ote ntial H y’s La w criteria at a st u d y  visit 
pri or t o starti n g st u d y  treat me nt.
At  t he first o n st u d y treat me nt occ urre nce of p ote ntial H y’s La w criteria bei n g met , t he 
in vesti gat or will:

Deter mi ne if t here has bee n a si g nifica nt c ha n ge i n t he s u bjects’ c o n dit i on c o m pare d wit h 
t he last visit w here p ote ntial H y’s La w criteria were 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 n otif y t he st u d y re prese ntati ve, w h o will i nf or m t he 
ce ntral st u d y tea 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  1 0. 4. 4. 2
A ‘si g nifica nt’ c ha n ge i n t he s u bject’s c o n dit i on 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 L T, 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 on 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 me dical mo ni t or if t here is a n y u ncertaint y.
1 0. 4. 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 s u bject meets p ote ntial H y’s La w criteria o n st u d y tr e at me nt 
a n d has alrea d y met p ote ntial H y’s La w criteria at a pre vi o us o n st u d y  treat me nt 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 ote nti al H y’s La w 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 ote ntial H y’s La w 
criteria bei n g met a n d a ns wer t he f oll owi n g q uest i o n:

Was t he alter nat i ve ca use f or t he pre vi o us occ urre nce of p ote nti al H y’s La w crit eria 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 s u bject meet p ote ntial H y’s La w criteria pri or 
t o startin g st u d y  treat me nt a n d at t heir first o n st u d y tr e at me nt visit as descri be d i n 
Secti o n  1 0. 4. 6 ? 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
If N o : fol l ow t he pr ocess descri be d i n Sect i on  1 0. 4. 4. 2 .
If Y es :
Deter mi ne if t here has bee n a si g nifica nt c ha n ge i n t he s u bject’s c o n dit i on c o m pare d wit h 
w he n p ote ntial H y’s La w criteria were pre vi o usl y met:

If t here is n o si g nifica nt c ha n ge n o actio n is re q ui re 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  1 0. 4. 4. 2
A ‘si g nifica nt’ c ha n ge i n t he s u bject’s c o n dit i on 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 L T, 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 on 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 me dical mo ni t or if t here is a n y u ncertai nty.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 5
Ge netic Rese arc h
I ncl usi o n criteri a
F or i ncl usi o n i n this ge net ic researc h, s u bjects m ust f ulfill all of t he i ncl usi on cri t eria 
descri be d i n t he mai n b o d y  of t he Cli nical St u d y Pr ot oc ol a n d :

Pr o vi de i nf or m e d c o nse nt f or t he ge netic sa m pli n g a n d a nal yses.
E xcl usi o n criteri a
E xcl usi o n fr om t his ge netic researc h ma y be f or a n y of t he e xclusi o n  crit eria s pecifie d i n t he 
mai n st u d y  or a n y of t he f oll owi n g:

N o n -le u k oc yte de plete d w h ole bl o o d tra nsf usi on i n 1 2 0 da ys of ge netic sa m ple c ollecti o n
Disc o nti n u ati o n of s u bjects fr o m t his ge netic rese arc h
S pecific reas o ns f or disc o nti n ui n g a s u bject fr o m t his ge netic researc h are:
Wit h dra wal o f c o nse nt f or ge net ic researc h: S u bjects ma y wit h dra w fr om t his ge netic researc h 
at a n y ti me, i n de pe n de nt of a n y decisi on c o ncer ni n g partici pat i on i n ot her as pects of t he mai n 
st u d y. Vol u nt ar y  disc o nti n uati on will n ot prej u dice f urt her treat me nt. Pr oce d ures f or 
di sc o nti n uati on are o utli ne d i n Sect i on 4. 1. 9 of  t he pr ot oc ol.
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 6
1 0. 6. 1
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0

Pr o gressi ve Dise ase ( P D) - At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get 
lesio ns, ta ki n g as refere nce t he s mallest s u m o n st u d y  (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 ditio n t o t he relati ve i ncrease o f 2 0 %, t he s u m  must 
als o de m o nstrate a n a bs o l ute i ncrease o f at least 5 m m. ( N ote: t he a p peara nce of o ne or 
m o re ne w lesio ns is als o c o nsi dere d P D.)

St a ble Dise ase ( S D) - N ei t her s ufficie nt s hri n ka ge 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, ta ki n g as refere nce t he s mallest s u m of  dia meters w hile o n 
st u d y.
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 peara nce of all n o n -tar get lesio ns a n d n or m alizat i on of 
t u mor m ar ker le vel. All l y m p h n o des m ust be n o n -pat h ol o gi cal i n size ( < 1 0 m m s h ort 
a xis). 

N o n -c o m plete res p o nse/ N o n -pr o gressi ve dise ase ( N o n -C R/ N o n -P D) - Persiste nce of 
1 or m ore n o n -tar get lesio n (s) a n d/ or mai nte na nce of t u m or mar ker le vel a b o ve t he 
n or m al li mits.

Pr o gressi ve Dise ase ( P D) - U ne q ui v ocal pr o gressi o n of e xist i n g n o n-tar get lesio n s will 
be defi ne d as t he o verall le vel of s u bsta nt ial 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 disease, t he o verall t u m or b ur de n has i ncrease d 
s ufficie ntl y t o merit disc o nti n uati on of t hera p y  (see Sectio ns 4. 1. 6 a n d 4. 1. 7 ). I n t he 
a bse nce of meas ura ble disease, c ha n ge i n n o n meas ura ble disease c o m para ble i n 
ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble disease. 
E xa m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge,’ a n i ncrease i n 
l y m p ha n gitic disease fr o m l ocalize d t o wi des prea d.
A p pe ar a nce of Ne w L esi o ns
T he a p peara nce of ne w lesi o ns is c o nsi dere d P D acc or di n g t o R E CI S T versi on 1. 1. 
C o nsi deri n g t he u ni q ue res p o nse ki netics t hat ha ve bee n o bser ve d wit h i m m u n ot hera p y, ne w 
lesio ns ca n n o net heless deri ve cli nical be nefit (B or g haei et al, 2 0 1 5 ). I n t he a bse nce of ra pi d 
cli nical deteri orati o n, s u bjects ma y c o nti n ue t o recei ve st u d y t hera p y if i n vesti gat ors c o nsi der 
t hat s u bjects c o nti n ue t o be nefit fr o m treat me nt (see Sectio n 4. 1. 7 ). 
E v al u ati o n of O ver all Res p o nse
 
 
 If a s u bject 
di sc o nti n ues t he st u d y d ue t o P D a n d be gi ns a n ot her treat me nt, a c onfir mat or y  sca n is n ot 
re q uire d. Treat me nt of s u bjects ma y c o nt i n ue bet wee n t he i nitial assess me nt of P D a n d 
c o nfir mat i on of P D ( w hic h is n ot re q uire d b y R E CI S T versio n 1. 1) . T hese s u bjects ma y 
c o nti n ue t o recei ve st u d y t hera p y be yo n d c o nfir me d P D i n acc or da nce wit h Sect i on 4. 1. 7 a n d 
if i n vesti gat ors c o nsi der t hat s u bjects c o nti n ue t o recei ve be nefit fr om treat me nt. I n t he 
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
a bse nce of cli nical deteri orati o n, s uc h m o dificati o ns t o t he R E CI S T ma y disc o ura ge t he earl y 
di sc o nti n uati on of treat m e nt a n d pr o vi de a m ore c o m plete e val uat i on of  st u d y t hera p y 
a nt itu m or acti vit y t ha n w o uld be see n wi t h c o n ve ntio nal  res p o nse crit eria.
Ta ble 1 5 ( 9. 8 - 1) pr o vi des o verall res p o nses f or all p ossi ble c o m bi nat i ons of  t u mor res p o nses 
i n tar get a n d n o n-tar get lesi ons wit h or wit h o ut t he a p peara nce of ne w lesi o ns.
T a ble 1 5 ( 9. 8 - 1)
E v al u ati o n of O ver all Res p o nse usi n g R E CI S T v 1. 1
T ar get Lesi o ns
N o n -t ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C o m plete res p o nse
C o m plete res p o nse ( or n o n o n -
tar get lesi o n)
N o
C o m plete res p o nse
N o tar get lesi o n
a 
C o m plete res p o nse
N o
C o m plete res p o nse
C o m plete res p o nse
N ot e val ua ble
b
N o
Partial res p o nse
C o m plete res p o nse
N o n -c o m plete res p o nse /
n o n- pr o gressi ve disease
N o
Partial res p o nse
Partial res p o nse
N o n -pr o gressi ve disease a n d
n ot e val ua ble ( or n o n o n -tar get 
lesi o n) b
N o
Partial res p o nse
Sta ble disease
N o n -pr o gressi ve disease a n d
n ot e val ua ble ( or n o n o n -tar get 
lesi o n) b
N o
Sta ble disease
N ot all e val uate d
N o n -pr o gressi ve disease
N o
N ot e val ua ble
N o tar get lesi o n a
N ot all e val uate d
N o
N ot e val ua ble
N o tar get lesi o n a
N o n -c o m plete res p o nse /
n o n- pr o gressi ve disease
N o
N o n -c o m plete res p o nse /
n o n- pr o gressi ve disease
Pr o gressi ve disease
A n y
Yes/ N o
Pr o gressi ve disease
A n y
Pr o gressi ve disease
Yes/ N o
Pr o gressi ve disease
A n y
A n y
Yes
Pr o gressi ve disease
N o tar get lesi o n a
U n e q ui v ocal pr o gressi ve disease
Yes/ N o
Pr o gressi ve disease
N o tar get lesi o n a
A n y
Yes
Pr o gressi ve disease
R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; v = versi o n.
a
Defi ne d as n o tar get lesi o n at baseli ne.
b
N ot e val ua ble is defi ne d as eit her w he n n o or o nl y a s u bset of lesi o n meas ure me nts are ma de at a n 
assess me nt.
Refere nce:  Eise n ha uer et al, 2 0 0 9

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
 
 
 
 
T a ble 1 6 ( 9. 9 - 1)
C CI
C CI
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 6 ( 9. 9 - 1)
C CI
C CI
C CI

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
1 0. 9
Olecl u m a b D osi n g M o dific ati o n f or T o xicit y M a n a ge me nt
Ta ble 1 7 ( 9 . 1 0-1) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes f or 
I mm u ne -me d iate d Reacti ons – Ge neral C o nsi derati o ns
Ta ble 1 8 ( 9 . 1 0-3) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes f or 
I nf usi on -r elate d Reactio ns
Ta ble 1 9 ( 9 . 1 0-4) Ol ecl u ma b D osi n g M o dificat i on a n d T o xicit y Ma na ge m e nt G uideli nes f or 
N o n -i m m u ne-me d iate d Reacti ons

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 7 ( 9 . 1 0-1)
Olecl u m a b D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes f or I m m u ne- me di ate d 
Re acti o ns – Ge ner al C o nsi der ati o ns
Ge ner al C o nsi der ati o ns
D ose M o dific ati o ns
T o xicit y M a n a ge me nt
Dr u g a d mi nistrati o n m o dificati o ns of st u d y dr u g/st u d y re gi me n will be ma de t o 
ma na ge p ote ntial i m m u ne -relate d A Es base d o n se verit y of treat me nt-e mer ge nt 
t o xicities gra de d per N CI C T C A E v 4. 0 3 ( u nless ot her wise i n dicate d).
I n a d diti o n t o t he criteria f or per ma ne nt disc o nti n uati o n of st u d y dr u g/st u d y 
re gi me n base d o n C T C gra de/se verit y (see bel o w), per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n f or t he f oll o wi n g c o n diti o ns:

I na bilit y t o re d uce c ortic oster oi d t o a d ose of ≤1 0 m g of pre d nis o ne per 
da y ( or e q ui vale nt) wit hi n 1 2 wee ks of t he start of t he i m A E.

Gra de 3 r ec urre nce of a pre vi o usl y e x perie nce d treat me nt -relate d 
i mA E f oll o wi n g res u m pti o n of d osi n g .
Gra de 1
N o d ose m o dificati o n
Gra de 2
H ol d st u d y dr u g/st u d y re gi me n d ose u ntil res ol uti o n t o Gra de ≤1.
If t o xicit y w orse ns, t he n treat as Gra de 3 or Gra de 4.
St u d y  dr u g/st u d y re gi me n ca n be res u me d o nce e ve nt i m pr o ves t o 
Gra de ≤1 after c o m pleti o n of ster oi d ta per t o pre d nis o ne d ose 
e q ui vale nt of ≤1 0 m g/ da y .
Gra de 3
H ol d st u d y dr u g/st u d y re gi me n d ose u ntil res ol uti o n t o Gra de ≤1.
If t o xicit y w orse ns, t he n treat as Gra de 4.
St u d y  dr u g/st u d y re gi me n ca n be res u me d o nce e ve nt i m pr o ves t o 
Gra de ≤1 after c o m pleti o n of ster oi d ta per t o pre d nis o ne d ose 
e q ui vale nt of ≤1 0 m g/ da y.
Gra de 4
Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y re gi me n.
N ote: F or Gra de ≥2 as ym pt o matic a m y lase or li pase le vels, st u d y dr u g/st u d y 
re gi me n ma y be c o nti n ue d , a n d c o nti n ue t o m o nit or patie nt cl osel y f or s y m pt o ms 
or si g ns of pa ncreatitis .
N ote: St u d y dr u g/st u d y re gi me n s h o ul d be per ma ne ntl y disc o nti n ue d i n Gra de 3 
e ve nts wit h hi g h li keli h o o d f or m or bi dit y a n d/ or m ortalit y – e g, m y ocar ditis, or 
ot her si milar e ve nts. Si milarl y, c o nsi der w het her st u d y dr u g/st u d y re gi me n s h o ul d 
be per ma ne ntl y disc o nti n ue d i n Gra de 2 e ve nts wit h hi g h li keli h o o d f or m or bi dit y 
a n d/ or m ortalit y – e g, m y ocar ditis, or ot her si milar e ve nts – w he n t he y d o n ot 
It is rec o mme n de d t hat ma na ge me nt of i m A Es f oll o ws t he g ui deli nes prese nte d i n t his 
ta ble:

It is p ossi ble t hat e ve nts wit h a n i nfla m mat or y or i m m u ne-me diate d 
mec ha nis m c o ul d occ ur i n nearl y all or ga ns.

Patie nts s h o ul d be t h or o u g hl y e val uate d t o r ule o ut a n y alter nati ve eti ol o g y 
(e g, disease pr o gressi o n, c o nc o mita nt me dicati o ns, a n d i nfecti o ns) t o a 
p ossi ble i m m u ne -me diate d e ve nt. I n t he a bse nce of a clear alter nati ve 
eti ol o g y, all s uc h e ve nts s h o ul d be ma na ge d as if t he y were i m m u ne 
relate d. 
Ge neral rec o m me n dati o ns f oll o w.

S y m pt o matic a n d t o pical t hera p y s h o ul d be c o nsi dere d f or l o w -gra de 
( Gra de 1 or 2) e ve nts. 

F or se vere ( Gra de ≥3) or persiste nt ( > 3 t o 5 da ys) l o w -gra de ( Gra de 2) 
e ve nts, pr o m ptl y start pre d nis o ne 1 t o 2 m g/ k g/ da y P O or I V e q ui vale nt.

S o me e ve nts wi t h hi g h li keli h o o d f or m or bi dit y a n d/ or m ortalit y – e g, 
m y ocar ditis , or ot her si milar e ve nts – s h o ul d pr o gress ra pi dl y t o hi g h d ose 
I V c ortic oster oi ds ( met h yl pre d nis ol o ne at 2 t o 4 m g/ k g/ da y) e ve n if t he 
e ve nt is Gra de 2, a n d if cli nical s us pici o n is hi g h a n d/ or t here has bee n 
cli nical c o nfir mati o n. C o nsi der, as necessar y, disc ussi n g wit h t he st u d y 
me dical m o nit or , a n d pr o m ptl y p urs ue s pecialist c o ns ultati o n.

If s ym pt o ms rec ur or w orse n d uri n g c ortic oster oi d ta peri n g ( 2 8 da ys of 
ta per), i ncrease t he c ortic oster oi d d ose ( pre d nis o ne d ose 2 t o 4 m g/ k g/ da y 
P O or I V e q ui vale nt) u ntil sta bilizati o n or i m pr o ve me nt of s y m pt o ms, t he n 
res u me c ortic oster oi d ta peri n g at a sl o wer rate ( > 2 8 da ys of ta per).

M ore p ote nt i m m u n os u p pressi ves s uc h as T N F i n hi bit ors ( e g, i nfli xima b) 
s h o ul d be c o nsi dere d f or e ve nts n ot res p o n di n g t o s yste mic ster oi ds, wit h 
t he e xce pti o n of i m m u ne-me diate d he patitis ( w herei n, alter nates s uc h as 
m yc o p he n olate m ofetil s h o ul d be c o nsi dere d) . Pr o gressi o n t o use of m ore 
p ote nt i m m u n os u p pressi ves s h o ul d pr ocee d m ore ra pi dl y i n e ve nts wit h 

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 7 ( 9 . 1 0-1)
Olecl u m a b D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes f or I m m u ne- me di ate d 
Re acti o ns – Ge ner al C o nsi der ati o ns
Ge ner al C o nsi der ati o ns
D ose M o dific ati o ns
T o xicit y M a n a ge me nt
ra pi dl y i m pr o ve t o Gra de < 1 u p o n treat me nt wit h s yste mic ster oi ds a n d f oll o wi n g 
f ull ta per.
N ote: T here are s o me e xce pti o ns t o per ma ne nt disc o nti n uati o n of st u d y dr u g f or 
Gra de 4 e ve nts ( i e, h y pert h yr oi dis m, h y p ot h yr oi dis m, T y pe 1 dia betes mellit us , 
a dre nal i ns ufficie nc y, h y p o p h ysitis ) t hat ha ve bee n c o ntr olle d wit h 
h or m o ne -re place me nt or ot her a p pr o priate t hera p y a n d t he patie nt is cli nicall y 
sta ble as per i n vesti gat or or treati n g p h ysicia n’s cli nical j u d g me nt. 
hi g h li keli h o o d f or m or bi dit y a n d/ or m ortalit y – e g, m y ocar ditis, or ot her 
si milar e ve nts – w he n t hese e ve nts are n ot res p o n di n g t o s yste mic ster oi ds.

Wit h l o n g- ter m ster oi d a n d ot her i m m u n os u p pressi ve use, c o nsi der nee d 
f or P ne u m ocystis jir ovecii p ne u m o nia ( PJ P, f or merl y k n o w n as 
P ne u m ocystis c ari nii p ne u m o nia) pr o p h yla xis, gastr oi ntesti nal pr otecti o n, 
a n d gl uc ose m o nit ori n g.

Disc o nti n uati o n of st u d y dr u g/st u d y re gi me n is n ot ma n date d f or Gra de 
3/ Gra de 4 i nfla m mat or y reacti o ns attri b ute d t o l ocal t u m or res p o nse 
(e g, i nfla m mat or y reacti o n at sites of metastatic disease a n d l y m p h n o des). 
C o nti n uati o n of st u d y dr u g/st u d y re gi me n i n t his sit uati o n s h o ul d be base d 
u p o n a be nefit -ris k a nal ysis f or t hat patie nt.
A E = a d verse e ve nt; C T C = C o m m o n T o xicit y Criteria; 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; i m A E = i m m u ne -me diate d a d verse e ve nt; I V = i ntra ve n o us; 
N CI = Nati o nal Ca ncer I nstit ute; PJ P = P ne u m o cystis jir ovecii p ne u m o nia (f or merl y k n o w n as P ne u m ocystis c ari nii p ne u m o nia); P O = b y m o ut h; T N F = t u m or necr osis fact or .

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 8 ( 9 . 1 0-3)  
Olecl u m a b D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt 
G ui deli nes f or I nf usi o n -rel ate d Re acti o ns
Se verit y Gr a de 
of t he E ve nt 
( N CI C T C A E 
versi o n 4. 0 3)
D ose M o dific ati o ns
T o xicit y M a n a ge me nt
A n y Gra de
Ge neral G ui da nce
F or A n y Gra de:

Ma na ge per i nstit uti o nal sta n dar d at t he 
discreti o n of i n vesti gat or.

M o nit or patie nts f or si g ns a n d s y m pt o ms 
of i nf usi o n -relate d reacti o ns (e g, fe ver 
a n d/ or s ha ki n g c hills, fl us hi n g a n d/ or 
itc hi n g, alterati o ns i n heart rate a n d bl o o d 
press ure, d ys p nea or c hest disc o m f ort, or 
s ki n ras hes) a n d a na p h yla xis 
(e g, ge neralize d urticaria, a n gi oe de ma, 
w heezi n g, h y p ote nsi o n, or tac h ycar dia).
Gra de 1 or 2
F or Gra de 1:
T he i nf usi o n rate of st u d y dr u g/st u d y 
re gi me n ma y be decrease d b y 5 0 % or 
te m p oraril y i nterr u pte d u ntil res ol utio n of 
t he e ve nt.
F or Gra de 2:
T he i nf usi o n rate of st u d y dr u g/st u d y 
re gi me n ma y be decrease d 5 0 % or 
te m p oraril y i nterr u pte d u ntil res ol uti o n of 
t he e ve nt.
S u bse q ue nt i nf usi o ns ma y be gi ve n at 5 0 % 
of t he i nitial i nf usi o n rate.
F or Gra de 1 or 2:

Aceta mi n o p he n a n d/ or a nti hista mi nes 
m a y  be a d mi nistere d per i nstit uti o nal 
sta n dar d at t he discreti o n of t he 
i n vesti gat or.

C o nsi der pre me dicati o n per i nstit uti o nal 
sta n dar d pri or t o s u bse q ue nt d oses.

Ster oi ds s h o ul d n ot be use d f or r o uti ne 
pre me dicati o n of Gra de ≤2 i nf usi o n 
reacti o ns.
Gra de 3 or 4
F or Gra de 3 or 4:
Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y 
re gi me n.
F or Gra de 3 or 4:

Ma na ge se vere i nf usi o n -relate d reacti o ns 
per i nstit uti o nal sta n dar ds ( e g, I M 
e pi ne p hri ne, f oll o we d b y I V 
di p he n h y dra mi ne a n d ra niti di ne, a n d I V 
gl uc oc ortic oi d).
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; I M = i ntra m usc ular; I V = i ntra ve n o us; N CI = Nati o nal Ca ncer 
I nstit ute.

Me dI m m u ne
Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5 A me n d me nt 3
Olecl u ma b ( M E DI 9 4 4 7)
2 4J u n 2 0 2 2 ; Fi nal
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 4 4
Te m plate 1 8. 0
T a ble 1 9 ( 9 . 1 0-4 )  
Olecl u m a b D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt 
G ui deli nes f or N o n -i m m u ne-me di ate d Re acti o ns
Se verit y Gr a de of 
t he E ve nt ( N CI 
C T C A E 
versi o n 4. 0 3)
D ose M o dific ati o ns
T o xicit y M a n a ge me nt
A n y Gra de
N ote: D ose m o dificati o ns are n ot re q uire d f or 
A Es n ot dee me d t o be relate d t o st u d y 
treat me nt (ie, e ve nts d ue t o u n derl yi n g 
disease) or f or la b orat or y a b n or malities n ot 
dee me d t o be cli nicall y si g nifica nt.
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.
Gra de 1
N o d ose m o dificati o ns.
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.
Gra de 2
H ol d st u d y dr u g/st u d y re gi me n u ntil 
res ol uti o n t o ≤Gra de 1 or baseli ne.
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.
Gra de 3
H ol d st u d y dr u g/st u d y re gi me n u ntil 
res ol uti o n t o ≤Gra de 1 or baseli ne.
F or A Es t hat d o w n gra de t o ≤Gra de 2 wit hi n 7 
da ys or res olve t o ≤Gra de 1 or baseli ne wit hi n 
1 4 da ys, res u me st u d y dr u g/st u d y re gi me n 
a d mi nistrati o n. Ot her wise, disc o nti n ue st u d y 
dr u g/st u d y re gi me n.
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.
Gra de 4
Disc o nti n ue st u d y dr u g/st u d y re gi me n ( N ote: 
F or Gra de 4 la bs, decisi o n t o disc o nti n ue 
s h o ul d be base d o n acc o m pa n yi n g cli nical 
si g ns/s y m pt o ms, t he in vesti gat or’s cli nical 
j u d g me nt, a n d c o ns ultati o n wit h t he 
s p o ns or.).
Treat acc or di n gl y, as per i nstit uti o na l sta n dar d.
A E = a d verse e ve nt; 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; N CI = Nati o nal Ca ncer I nstit ute.

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 6 0 7 0c 0 0 0 0 5-cs p-a me n d me nt- 3
D oc u me nt Title:
D 6 0 7 0 C 0 0 0 0 5 Cli nical St u d y Pr ot oc ol A me n d me nt 3
D oc u me nt I D:
D oc I D- 0 0 4 1 8 3 2 8 9
Versi o n L a bel:
2. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
3 0-J u n- 2 0 2 2 0 1: 0 8 U T C
C o nte nt A p pr o val
2 9-J u n- 2 0 2 2 1 2: 5 5 U T C
C o nte nt A p pr o val
3 0-J u n- 2 0 2 2 1 8: 5 1 U T C
A ut h or A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D
P P D