Clinical trial NCT03611556
Conditions: Carcinoma Metastatic Pancreatic Adenocarcinoma
Keywords: MEDI9447 oleclumab immunotherapy pancreatic cancer durvalumab
Sponsor: MedImmune LLC
Start date: 2018-06-21; Completion date: 2022-07-22
Enrollment: 213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the safety, tolerability, and antitumor activity of oleclumab (MEDI9447) in combination with or without durvalumab plus chemotherapy in participants with metastatic pancreatic cancer.

Detailed description:
This is a Phase 1b/2, multicenter, open-label, dose-escalation, and dose-expansion study to assess the safety, preliminary antitumor activity, immunogenicity, and pharmacokinetics (PK) of oleclumab with or without durvalumab in combination with chemotherapy administered in participants with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants with previously untreated metastatic PDAC (first-line \[1L\] metastatic PDAC) will be enrolled in Cohort A. Participants with metastatic PDAC previously treated with gemcitabine-based chemotherapy (without exposure to 5-fluorouracil \[5-FU\], capecitabine, or oxaliplatin; second-line \[2L\] metastatic PDAC) will be enrolled in Cohort B. The study consists of 2 parts, dose escalation (Part 1) and dose expansion (Part 2).

Arms: arm 1: Participants with 1L metastatic disease will receive intravenous (IV) infusions of oleclumab 1500 mg every 2 weeks for 4 doses, then every 4 weeks (Q4W) in combination with durvalumab 1500 mg Q4W plus chemotherapy of gemcitabine 1000 mg/m\^2 and nab-paclitaxel 125 mg/m\^2, both on Days 1, 8, and 15 and then repeated on Q4W schedule until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 2: Participants with 1L metastatic disease will receive IV infusions of oleclumab 3000 mg every 2 weeks for 4 doses, then Q4W in combination with durvalumab 1500 mg Q4W plus chemotherapy of gemcitabine 1000 mg/m\^2 and nab-paclitaxel 125 mg/m\^2, both on Days 1, 8, and 15 and then repeated on Q4W schedule until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 3: Participants with 2L metastatic disease will receive IV infusions of oleclumab 1500 mg every 2 weeks for 4 doses, then Q4W in combination with durvalumab 1500 mg Q4W plus chemotherapy of mFOLFOX (oxaliplatin 85 mg/m\^2 IV; folinic acid 400 mg/m\^2 IV; 5-FU 400 mg/m\^2 IV bolus followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours) on Days 1 and 15 and then repeated on a Q4W schedule, until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 4: Participants with 2L metastatic disease will receive IV infusions of oleclumab 3000 mg every 2 weeks for 4 doses, then Q4W in combination with durvalumab 1500 mg Q4W plus chemotherapy of mFOLFOX (oxaliplatin 85 mg/m\^2 IV; folinic acid 400 mg/m\^2 IV; 5-FU 400 mg/m\^2 IV bolus followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours) on Days 1 and 15 and then repeated on a Q4W schedule, until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 5: Participants with 1L metastatic disease will receive IV infusions of chemotherapy of gemcitabine 1000 mg/m\^2 and nab-paclitaxel 125 mg/m\^2, both on Days 1, 8, and 15 and then repeated on Q4W schedule until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 6: Participants with 1L metastatic disease will receive IV infusions of oleclumab 3000 mg every 2 weeks for 4 doses, then Q4W in combination with chemotherapy of gemcitabine 1000 mg/m\^2 and nab-paclitaxel 125 mg/m\^2, both on Days 1, 8, and 15 and then repeated on Q4W schedule until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met. arm 7: Participants with 1L metastatic disease will receive IV infusions of oleclumab 3000 mg every 2 weeks for 4 doses, then Q4W in combination with durvalumab 1500 mg Q4W plus chemotherapy of gemcitabine 1000 mg/m\^2 and nab-paclitaxel 125 mg/m\^2, both on Days 1, 8, and 15 and then repeated on Q4W schedule until disease progression, intolerable toxicity, withdrawal of participant consent, or another discontinuation criterion is met.
Interventions: intervention 1: Oleclumab intervention 2: Durvalumab intervention 3: Gemcitabine intervention 4: Nab-paclitaxel intervention 5: Oxaliplatin intervention 6: Folinic acid intervention 7: 5-FU
Intervention descriptions: intervention 1: Participants will receive IV infusion of oleclumab as stated in arm description. intervention 2: Participants will receive IV infusion of durvalumab as stated in arm description. intervention 3: Participants will receive IV infusion of gemcitabine as stated in arm description. intervention 4: Participants will receive IV infusion of nab-paclitaxel as stated in arm description. intervention 5: Participants will receive IV infusion of oxaliplatin as stated in arm description. intervention 6: Participants will receive IV infusion of folinic acid as stated in arm description. intervention 7: Participants will receive IV infusion of 5-FU as stated in arm description.

Protocol documents:
Prot_000.pdf: 
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:
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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. 
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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.
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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
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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
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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
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C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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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.
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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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efficac y of M P D L 3 2 8 0 A (a nti-P D L 1) i n c o m bi nat i o n wit h be vaciz u ma b ( be v) a n d/ or 
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2 0 1 5; 3 3(s u p pl 3): 7 0 4.
B or g haei H, Paz -Ares L, H or n L, S pi gel D R, Stei ns M, Rea d y N E, et al. Ni v o l uma b vers us 
D oceta xel i n A d va nce d N o ns q ua m o us N o n -S m all-Cell L u n g Ca ncer. N E n gl J Me d. 
2 0 1 5; 3 7 3 ( 1 7): 1 6 2 7- 3 9.
C o nr o y  T, Desseig ne F, Yc h o u M, B o uc he O, G ui m ba u d R, Bec o uar n Y, et al. F O L FI RI N O X 
vers us ge mcita bi ne f or metastatic pa ncreat ic ca ncer. N E n gl J Me d. 2 0 1 1; 3 6 4( 1 9): 1 8 1 7- 2 5.
D ucre u x M, C u h na A S, Cara mella C, H olle bec q ue A, B urti n P, G oéré D, e t al. Ca ncer of t he 
pa ncreas: E S M O Cli nical Practice G ui deli nes f or dia g n osis, treat me nt a n d f o ll ow- u p. A n n 
O nc o l. 2 0 1 5; 2 6(s u p pl 5): v 5 6-v 6 8.
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e val uat i on cri t eria i n soli d t u m o urs: re vi se d R E CI S T g uideli ne ( versi o n 1. 1). E ur J Ca ncer. 
2 0 0 9; 4 5( 2): 2 2 8 - 4 7.
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of  a disease s pecific q uality of  life ( Q o L) q uesti o n naire m o d ule t o s u p ple me nt t he E O R T C 
c ore ca ncer Q o L q uesti o n naire, t he Q L Q -C 3 0 i n patie nts wit h pa ncreat ic ca ncer. E O R T C 
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a nal ysis of Res p o nse a n d Resect i on Perce nta ges. P L O S Me dici ne. 2 0 1 0; 7( 4):e 1 0 0 0 2 6 7.
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2 0 1 5; 1 5( 1): 8 - 1 8.
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. 
O nc otar get. 2 0 1 7; 8( 5): 8 7 3 8 -5 1.
La n ger CJ, Ga d geel S M, B or g haei H, Pa pa di mitra k o p o ul o u V A, Pat nai k A, P o well S F, et al. 
Car b o pl at i n a n d pe metre xe d with or wit h o ut pe m br oliz u ma b f or a d va nce d, n o n -s q ua m o us 
n o n- s mall-cell lu n g ca ncer: a ra n d o mise d, p has e 2 c o h ort of t he o pe n-label K E Y N O T E - 0 2 1 
st u d y. La ncet O nc ol. 2 0 1 6; 1 7( 1 1): 1 4 9 7- 5 0 8.
Lee JJ, Li u D D. A pre dict i ve pr o ba bility desi g n f or p hase II ca ncer cli nical trials. Cli n Trials. 
2 0 0 8; 5( 2): 9 3 - 1 0 6.
Li u N, Fa n g X D, Va di s Q. C D 7 3 as a n o vel pr o g n ostic bi o m ar ker f or h u ma n c ol orectal 
ca ncer. J S ur g O nc ol. 2 0 1 2; 1 0 6( 7): 9 1 8 -9; a ut h or re pl y 2 0.
L oi  S, P o m me y S, Hai be-Kai ns B, Bea vis P A, Darc y  P K, S m yt h MJ, et al. C D 7 3 pr o motes 
a nt hrac ycli ne resista nce a n d p o or pr o g n osis i n tri ple ne gat i ve breast ca ncer. Pr oc Natl Aca d 
S ci  U S A. 2 0 1 3; 1 1 0( 2 7): 1 1 0 9 1- 6.
L u X X, C he n Y T, Fe n g B, Ma o X B, Y u B, C h u X Y. E x pressi o n a n d cli nical si g nifica nce of 
C D 7 3 a n d h y p o xia -i n d uci ble fact or-1al p ha i n gastric carci n o ma. W orl d J Gastr oe nter ol. 
2 0 1 3; 1 9( 1 2): 1 9 1 2 - 8.
Merri mac k P har mace uticals
I. O NI V Y D E ™ (iri n oteca n li p os o me i njecti on) [ pac ka ge i nsert]. 
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 
i n vesti gati onal a nt i-i nterfer o n-alp ha m o n o cl o nal  a ntib o d y , i n s yste mic l u p us er yt he mat os us. 
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 
i n ca ncer patie nts base d o n p o p ulat i on p har mac o ki net ic a nal ysis. P har m Res. 
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 
N o. 2 1 7. 2 0 1 8.
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

SAP_001.pdf: 
Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
St atistic al A n al ysis Pl a n
A P h ase 1 b/ 2 St u d y  to E val uate t he Safet y , P h ar mac o ki net ics, a n d Cli nical Act i vity of 
Ol ecl u ma b ( M E DI 9 4 4 7) wit h or wit ho ut D ur val u ma b i n C o m bi nati on wi t h C he m ot h era p y i n 
S u bjects wit h Metastatic Pa ncreat ic D uctal A de n ocarci n oma
Pr ot oc ol N u m ber: D 6 0 7 0 C 0 0 0 0 5




Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 7. 4 A E SIs D uri n g W hic h S yste mic Ster oi ds, E n d ocri ne T hera p y , or Ot her 
I mm u n os u p pressa nts Were A d mi nistere d ...............................3 2
3. 7. 5 I mm u ne -me d iate d A d verse E ve nts (i m A E)..............................................3 2
3. 7. 6 Deat hs a n d Treat me nt Disc o nti n uat i ons d ue t o A d verse E ve nts ...............3 3
3. 7. 7 Cli nical La b orat or y  E val uati on ................................................................3 3
3. 7. 8 Ot her Safet y E val uat i ons .........................................................................3 4
3. 8
I mm u n o ge nicit y ..............................................................................................3 5
3. 9
P har mac o ki net ics............................................................................................3 5
4
I N T E RI M A N A L Y SI S..............................................................................................3 7
5
R E F E R E N C E S .........................................................................................................3 9
A P P E N DI C E S ....................................................................................................................4 1
A p pe n di x A: Deri vat i on of R E CI S T 1. 1 Disease Assess me nt O verall Res p o nse ........4 1
Tar get Lesi o n Res p o nse ..................................................................................4 1
N o n -Tar get Lesi o n Res p o nse ..........................................................................4 2
Di sease Assess me nt O verall Res p o nse per R E CI S T 1. 1 ..................................4 4
L oc ore gi o nal t hera p y ......................................................................................4 5
Assi g n me nt of Dates of Disease Pr o gressi o n or Disease Res p o nse ..................4 5
LI S T O F T A B L E S
Ta ble 2. 1 – 1
Pri mar y O bject i ve(s) a n d Ass ociate d E n d p oi nts............8
Ta ble 2. 1. 2 – 1
Sec o n dar y  O bjecti ves a n d Ass ociate d E n d p oi nts ..........9
Ta ble 3. 2 – 1
  A nal ysis P o p ulat i ons .................................................1 4
Ta ble 4. 4. 2 – 1 
S u m mar y o f Ce ns ori n g G ui deli nes f or P F S .................2 0
 
 
Ta ble A 1 
Assi g n me nt of res p o nses usi n g R E CI S T ......................4 4
Ta ble B 1 
Assi g n me nt of ti me -p oi nt res p o nse usi n g i R E CI S T ....4 8
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 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
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 ve nt
A E SI
A d verse e ve nt of s pecial i nterest
A L T
Ala ni ne a mi n o tra nsferase
A S T
As partate a mi n o tra nsferase
A T C
A nat o mical T hera pe utic C h e mical
A Z
Astra Ze neca
BI C R
Bli n de d i n de pe n de nt ce ntral re vie w
B L
Baseli ne
C D
Cl uster of differe ntiati o n
CI
C o nfi de nce i nter val
C R
C o m plete res p o nse
C R P
C- reacti ve pr otie n
C S P
Cli nical St u d y Pr ot oc ol
C S R
C li nical St u d y Re p ort
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 V
C oefficie nt of Varia nce
D A
Disease assess me nt
D C
Disease c o ntr ol
D C O
Data c ut -off
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 R F
electr o nic case re p ort f or m
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
 
 
C CI
C CI
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
A b bre vi ati o n or 
S peci alize d Ter m
Defi niti o n
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
G C P
G o o d cli nical practice
I C F
I nf or me d c o nse nt f or m
I H C
I m m u n ohis t oc he mistr y
i m A E
I m m u ne-me diate d a d verse e ve nt
I P
I n vesti gati o nal pr o d uct
I T T
I nte nt-t o-treat
I V R S
I nteracti ve v oice res p o nse s yste ms
L L O Q
L o wer li mit of q ua ntificati o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
m R N A
Messe n ger R N A
MI D
Mi ni mall y i m p orta nt differe nce
M T D
Ma xi m u m t olerate d d ose
N A
N ot a p plica ble
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 E
N ot e val ua ble
N L R
Ne utr o p hil t o L y m p h oc yte rati o
N Q
N ot q ua ntifia ble
N R
N ot re p orta ble
N S
N o sa m ple
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 A C
Pa ncreatic d uctal a de n ocarci n o ma
P D -L 1
Pr o gra m me d cell deat h li ga n d - 1
P F S
Pr o gressi o n -free s ur vi val
P K
P har mac o ki netics
P R
Partial res p o nse
P R O
Patie nt re p orte d o utc o me
R E CI S T
Res p o nse e val uate d criteria i n s oli d t u m ors
S A E
Seri o us a d verse e ve nt
S A P
Statistical a nal ysis pla n
S D
Sta ble disease
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
A b bre vi ati o n or 
S peci alize d Ter m
Defi niti o n
S P P
Statistical pr o gra m mi n g pla n
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
T F L
Ta bles, Fi g ures a n d Listi n gs
T T F D
Ti me t o first deteri orati o n
T T R
Ti me t o res p o nse
T V
Tar get val ue
U L N
U p per li mit of n or mal ra n ge
v
versi o n
W H O
W orl d Healt h Or ga nizati o n




Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
1
I N T R O D U C TI O N
T his d oc u me nt has bee n writte n i n ali g n me nt wit h a me n d me nt 3 of t he Cli nical St u d y Pr ot oc ol 
( C S P) a p pr o ve d o n 2 4 t h J u ne 2 0 2 2 a n d descri bes t he statistical a nal ysis met h o d ol o g y  for 
pr ot oc ol  D6 0 7 0 C 0 0 0 0 5. T his is a P hase 1 b/ 2 m ult ice nter, o pe n -label, d ose -escalatio n a n d 
d ose -e x pa nsi o n st u d y  to assess t he s afet y,  preli mi nar y ant itu m or acti vit y,  i m m u n o ge nicity, a n d 
p har mac o ki net ic (P K) of  olecl u ma b wi t 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 m ot hera p y a d mi nistere d i n s u bjects wi t h metastatic pa ncreat ic d uctal  ade n ocarci n o ma  
( P D A C). As bac k gr o u n d i nf or mati on, a n o ver vie w of t he st u d y  desi g n is pr o vi de d. T he mai n 
p orti o n of  t his d o c u m e nt details t he statistical su m maries relati n g t o eac h st u d y  o bject i ve a n d 
descri bes t he ge neral c o n ve nt i ons a n d defi nit i ons t hat will be use d. I n a d dit i on, a s et of t a bl e 
t e mplates a n d s pecificati ons will be i ncl u de d i n a statistical pr o gra m mi n g pla n ( S P P) t o 
c o mple me nt t his d oc u me nt.
2
S T U D Y O V E R VI E W
2. 1   St u d y O bjecti ves
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 a ble 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 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 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 re s 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 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 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 

O R acc or di n g t o R E CI S T v 1. 1


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 of 4 9
S A P te m plate versi o n 3. 0
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.
1 L = first -li ne; 2 L = sec o nd- 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 ua ble Crite ria i n S oli d T u m ors; S A E = seri o 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.
2. 1. 2
  Sec o n d ar y O bjecti ve(s) a n d Ass oci ate d E n d p oi nts 
T a ble 2. 1. 2 – 1
Sec o n d ar y O bjecti ves 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 
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

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 
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 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 w it 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 w it 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

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


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 of 4 9
S A P te m plate versi o n 3. 0
P D A C.
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 w it 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 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.

De vel o p me nt 
of 
detecta ble 
A D As 
f oll o wi n g olecl u ma b a n d d ur val u ma b
P har mac o ki netics 
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 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 g i 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; 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 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.
2. 1. 3
  E x pl or at or y O bjecti ve(s) a n d Ass oci ate d E n d p oi nts 
 
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 of 4 9
S A P te m plate versi o n 3. 0
2. 2   St u d y Desi g n
T his is a P hase I b/ 2, m ult ice nter, o pe n la bel, d ose escalat i on a n d d ose e x pa nsi o n st u d y  to assess 
t he safety,  preli mi nar y a nt itu m or acti vit y,  im m u n o ge nicit y a n d P K of  ol ecl u ma b wi t h or 
wi t ho ut d ur val u ma b i n c h e mot h era p y ad mi nistere d i n s u bjects wi t h metastatic P D A C. S u bjects 
wi t h pr e vio usl y u ntreate d m etastatic 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 wi t h metastatic P D A C pre vi o usl y  treate d wit h ge mci ta bi ne-base d c he mot h era p y 
( wit ho ut e x p os ure t o 5 -F U, ca pecita bi ne , or o xali plat i 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 co nsists of  2 parts, d ose escalat i on ( Part 1) a n d d ose e x pa nsi o n ( Part 
2). All s u bjects i n b ot h c o h orts wil l be treate d u ntil disease pr o gressi o n, i ntol era ble t o xicit y, 
wi t hdra 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. Refer t o Secti o n 3. 1 
of  t he Cli nical St u d y  Pr ot oc ol (C S P ) f or a d ditio nal details. 
F or C o h ort A, a n i nteri m a nal ysis w ill 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 he d t he data c ut-off crit eria. Refer t o Sectio n 
4. 8. 7 of t he C S P f or a d diti o nal details. 
2. 3 Tre at m e nt Assi g n me nt a n d Bli n di n g
Tre at me nt Assi g n me nt
T his i s a n o pe n-la bel st u d y. S u bjects e nr olle d i n Part 1 w h o meet t he eli gi bility criteria will be 
assi g ne d o pe n-la bel i n vesti gati o nal pr o d uct.
I n Part 2 s u bjects i n C o h ort A will be ra n d omize d usi n g a 1: 1: 1 rati o t o recei ve eit her 
g e m cita bi ne a n d na b-pacli t a x el ( Ar m A1), ol e clu m a b + g e m cita bi ne a n d na b -pacli t a x el ( Ar m 
A 2) or ol e clu ma b + d ur val u ma b + ge mci ta bi ne a n d na b -pacli t a x el (Ar m A 3). S u bjects i n 
C o h ort B will be ra n d o mize d usi n g a 1: 1: 1 rati o t o recei ve eit her m F O L F O X ( Ar m B1), 
ol ecl 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). 
Ra n d o mizati o n will be stratifie d b y C D 7 3 e x pressio n  le vel. Refer t o Secti o n 4. 6 of  the C S P 
f or a d ditio nal  details.
Bli n di n g
T his st u d y  is n ot bli n de d.
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
2. 4 S a m ple Size
A t otal  of 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 
ex pa nsi o n (a p pr o xi matel y 21 0 s u bjects i n C o h ort A a n d a p pr o xi matel y 10 5 s u bjects i n 
C o h ort B). Refer t o Secti o n 4. 8. 2 of t he C S P f or a d dit i onal details.
3
S T A TI S TI C A L M E T H O D S
3. 1   Ge ner al C o nsi der ati o ns
Ta b ular s u m maries will be prese nte d f or t he d ose escalat i on a n d d ose e x pa nsi o n p hase 
se paratel y. U nl ess ot h er wise state d, i n t he d ose escalat i on p hase data will be s u m marize d b y 
c o h ort a n d d ose levels a n d, i n t he d ose e x pa nsi o n p hase data will be s u m marize d b y c o h ort, 
treat me nt ar ms a n d w here a p pr o priate b y C D 7 3. A t ot al col u m n will  be prese nte d f or ta bles 
r elate d t o st u d y s u bjects, e x p os ure, a d verse e ve nts, i m m u n o ge nicit y a n d p har mac o ki netics.
Cate g orical data will be s u m marize d b y fre q ue nc y distri b uti on ( n u m ber a n d perce nta ge of 
s u bjects falli n g wit hi 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 pt i ve 
statistics i ncl u di n g N, mea n, sta n dar d de viati on, me dia n, a n d ra n ge ( mi ni m u m a n d ma xi m u m). 
All a vaila ble data will be use d, a n d t hus missi n g data will n ot be i m p ute d, u nless ot h er wis e 
s pecifie d. I n ge neral, s u bjects wi t h missi n g data f or a para meter will be e xc l u de d fr o m t h e 
s u m mar y of this para meter. Ta bles will be s u p p orte d b y data list i n gs s h o wi n g t he ori gi nal data 
f or mi n g t he basis f or t he s u m maries. Data listi n gs will be s orte d b y treat me nt gr o u p, s u bject 
n u m ber a n d date c o llecte d w here a p plica ble. U nless state d ot her wise, t w o-side d c o nfi de nce 
i nter vals ( CIs) will be pr o d uce d at 9 5 %. 
Baseli ne val ues are defi ne d as t he last vali d assess me nt pri or t o t he first a d mi nistrati o n of 
i n vesti gati onal pr o d uct. F or efficac y data t his is t he last assess me nt pri or t o ran d o mizati o n. 
Baseli ne is deri ve d b y i de nt if yi n g rec or ds s uc h t hat date of c ollecti on is pri or t o treat me nt start 
date. I n t he sce nari o w here t he ti me part is missi n g, o nl y t he date parts will be c o m pare d. If n o  
baseli ne rec or d is prese nt w he n date of  colle ct i on is missi n g b ut treat me nt start date is n ot 
missi n g t he n t he data c ollecte d at scree ni n g will be use d as baseli ne. F or la b orat or y para meters 
w here t he cli nical safet y si g nal is a L o w A b n or malit y or Bi -di r e ctio nal , t he baseli ne val ues are 
i de ntifie d as t he mi ni m u m of  all pre -d osi n g val ues o n t hat partic ular date. F or lab orat or y 
para m eters w here t he safet y si g nal is a Hi g h A b n or malit y,  t he baseli ne val ues are i de ntifie d as 
t he ma xi m u m of all pre-d osi n g val ues o n t hat partic ular date.
Data a nal yses will b e c o n d ucte d usi n g t he S A S ® S yste m ( S A S I nstit ute, I nc., Car y, N C, U S A) 
Versi o n 9. 3 or a b o ve, u nless ot her wise s pecifie d. 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 2   A n al ysis P o p ul ati o ns
T he a nal ysis p o p ulat i ons are defi ne d i n Err or! Refere nce s o urce n ot f o u n d. . 
T a ble 3. 2 – 1
A n al ysis P o p ul ati o ns
P o p ul ati o n
Descri pti o n
All ra n d o mize d 
p o p ulati o n
T he all ra n d o mize d p o p ulati o n is defi ne d as all ra n d o mize d s u bjects.
I nte nt-t o-treat 
(I T T) p o p ulati o n
T he I T T p o p ulati o n 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 assi g n me nt. All 
a nal yses will be perf or me d o n t he I T T p o p ulati o n u nless ot her wise s pecifie d.
As -treate d 
p o p ulati o n
T he as -treate d p o p ulati o n is 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.
Res p o nse 
e val ua ble 
p o p ulati o n
T he res p o nse  e val ua ble p o p ulati o n i ncl u des s u bjects fr o m t he As -treate d P o p ulati o n w h o 
ha ve a baseli ne disease assess me nt ( D A), ha ve t he o p p ort u nit y t o be f oll o we d f or at least 
1 6 (f or c o h ort A) or 1 2 (f or c o h ort B) wee ks at t he ti me of t he data c ut off (i.e., d ose d at 
least 1 6 (f or c o h ort A) o r 1 2 (f or c o h ort B) wee ks pri o r t o t he ti me of t h e data c ut off), a n d 
eit her h as at least o ne p ost -baseli ne D A 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.
D L T e val ua ble 
p o p ulati o n
T he D L T -e val ua ble p o p ulati o n is defi ne d as all s u bjects e nr olle d i n Part 1 ( d ose escalati o n) 
w h o recei ve all pla n ne d d oses of olecl u ma b, d ur val u ma b, a n d c he m ot hera p y d uri n g t he 
D L T -e val uati on peri o d (fr o m t he first d ose of all st u d y tr eat me nts t hr o u g h Da y  28) a n d 
c o m plete t he safet y f oll o w-u p t hr o u g h t he D L T e val uati o n peri o d or e x perie nce a n y D L T .
P K e val ua ble 
p o p ulati o n
T he P K e val ua ble p o p ulati o n is defi ne d as all s u bjects w h o recei ve at least o ne d ose of I P 
wit h at least o ne re p orta ble P K c o nce ntrati o n. If necessar y t here ma y i nstea d be as ma n y as 
f o ur P K e val ua ble p o p ulati o ns ( o ne f or eac h of olecl u ma b, d ur val u ma b, ge mcita bi ne a n d 
na b -paclita xel).
A D A e val ua ble 
p o p ulati o n
T he A D A e val ua ble p o p ulati o n is defi ne d as all s u bjects i n t he safet y a nal ysis set w h o ha ve 
a n o n -missi n g baseli ne A D A res ult a n d at least o ne n o n -missi n g p ost -baseli ne A D A res ult. 
If necessar y t h ere m a y  ins tea d be t w o A D A e val ua ble p o p ulati o ns ( one f or eac h of 
olecl u ma b a n d d ur val u ma b).
A D A = a nti -dr u g a nti b o d y; D L T = d ose -li miti n g t o xicit y; I P = i n vesti gati o nal pr o d uct; P K = p har mac o ki netic
T he baseli ne a n d efficac y a nal yses of  ant itu m or acti vit y will be base d o n t he i nte nt -t o-treat 
p o p ul at i on. T he safety para meters will be s u m marize d base d o n t he as-treate d p o p ulat i on.  
D L T -e val ua ble p o p ulat i on will be use d f or t he M T D e val uati o n. T he efficac y para meters ma y 
be s u m marize d base d o n res p o nse -e val ua ble p o p ulatio n f or i nteri m  a nal ysis.  


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 3   St u d y S u bjects
3. 3. 1
  S u bject Dis p ositi o n a n d C o m pleti o n St at us
S u bject dis p osit i on a n d c o mplet i on stat us will be liste d per s u bject. Dis p osit i on of  su bjects 
t hr o u g ho ut t he stu d y a n d wi t h res pect t o disc o nt i n uati on of  treat me nt a n d e n d of  st u d y an d 
c o mplet i on stat us will be s u m marize d b y t he n u m ber a n d perce nta ge of  su bjects f or t he I T T 
p o p ul at i on. 
Ti me o n st u d y fr o m ti me of  first d ose/ra n d o mi zatio n  will be prese nte d usi n g s wi m mer pl ots 
f or t he I T T p o p ulatio n a n d w here a p pr o pri ate t hese ma y be prese nte d b y C D 7 3 le vels.  
3. 3. 2
  De m o gr a p hics a n d B aseli ne C h ar acteristics
D e m o gra p hics a n d baseli ne disease c haracterist ics will be s u m marize d f or t he I T T p o p ulat i on 
a n d s u m maries will 
i ncl u de a t otal col u m n . De m o gra p hic a n d baseli ne c haracteristic 
i nf or mat i on relate d t o a ge, se x, race, et h nicit y, wei g ht, hei g ht, Easter n C o o perati ve O nc ol o g y 
Gr o u p ( E C O G) stat us will be s u m marize d wi t h su m mar y  st atistics a n d ma y be liste d wi t h 
f urt her i nf or mat i on. I nf or m at i on relati n g t o pri or a nt ica ncer treat me nt, pri or s yste mic t hera p y, 
pri or r a di at i on t hera p y a n d pri or s ur gi cal a n d me dical pr oce d ures will als o be liste d f or eac h 
s u bject. 
T u m or hist or y  incl u di n g hist ol o g y , sta ge, a n d perti ne nt bi omar ker res ults at t he ti me of i nit ial 
di a g n osis a n d at stu d y e ntr y will be s u m marize d a n d w here a p pr o priate t his ma y als o b e 
s u m marize d b y C D 7 3 le vels. T he baseli ne disease c haracterist ics  su m mar y  will i ncl u de 
descri pt i ve statistics of ti me fr om pr i mary d ia g n osis t o st u d y e ntr y ( m o nt hs), baseli ne C R P a n d 
baseli ne car b o h y drate a nt i ge n 1 9 - 9 ( C A 1 9-9 ). It will als o i ncl u de fre q ue nc y distri b ut i ons f or 
di sease sta ge at i nitial dia g n osis (I, II, III, I Va, I V b, I Vc, u n k n o w n), t u m or sta ge at st u d y e ntr y 
( T 0, Ti s, T 1, T 2, T 3, T 4, T X, u n k n o w n), n o de sta ge at st u d y ent r y (N 0, N 1, N 2, N 3, N X, 
u n k n o w n), m etastasis sta ge at st u d y e ntr y ( M 0, M 1, M X, u n k n o w n).
Pri or a nt ica ncer treat me nt will be s u m marize d a n d w here a p pr o priate ma y als o be s u m mari z e d 
b y C D 7 3 le vels a n d recrui t me nt wa ve. T he s u m mar y will i ncl u de t he n u m ber a n d perce nt of 
s u bjects per treat me nt cate g or y (s yste mic t hera p y, ra diati on, ca ncer r elate d s ur ger y, ot her), 
n u m ber of  pr e vio us s yste mic re gi me ns f or me tastatic disease , best res p o nse ( c o mplete 
res p o nse, pa rtial res p o nse, sta ble disease, pr o gressi ve disease, n ot e val ua ble, n ot a p plica ble) 
t o t he most rece nt li ne of t hera p y , li n e of t hera p y, ti me o n prior s yste mic t hera p y ( ≤6 m o n t hs, 
> 6 m o nt hs) a n d t i me o n pri or ra diati on ( ≤6 m o nt hs, > 6 m o nt hs).
Baseli ne t u mo r c haracterist ics i ncl u di n g n u m ber a n d sites of  tar get a n d n o n- tar get t u mor 
lesio ns as well as s u m of  t ar g et lesio n s dia meter will be s u m marize d.  N u m ber of  metastatic 
sites at baseli ne, defi ne d as t he n u m ber of or ga ns t hat ha ve baseli ne tar get or n o ntar get lesio n s 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
n ot at t he pri mar y site, will als o be liste d. Ot her baseli ne t u m or c haracterist ics, i ncl u di n g, P D-
L 1 t u m or cells , P D-L 1 i m m u ne cells a n d s mo ki n g hist or y , will be s u m marize d. I n a d ditio n, a 
listi n g detaili n g si g nifica nt me dical hist or y fi n di n gs will be pr o vi de d. 
3. 3. 3
  St u d y Dr u g E x p os ure
Treat me nt e x p os ure will be s u m marize d f or t he as-treate d p o p ulati on . D uratio n of e x p os ure t o 
t he I Ps i n wee ks, n u m ber of  doses a n d r elat i ve d ose i nte nsity will  be s um marize d b y descri pti ve 
statistics a n d b y fre q ue nc y. 
D urati o n of e x p os ure i n wee ks is defi ne d b y last date of act ual d osi n g (i.e., a d ose was act uall y 
gi ve n) i n t he last c ycle pl us t he n u m ber of  da ys i n t he d osi n g i nter val mi n us t he d at e of  first 
treat me nt wit h I P. F or s u bjects w h o die or if a D C O occ urs prior t o t he last d ose date pl us t he 
n u m ber of  da ys i n t he d osi n g i nter val, d urat i on of e x p os ure i n wee ks is defi ne d as date of 
deat h/ D C O ( w hic he ver occ urs first) mi n us t he date of first treat me n t plus 1 da y .
Relati ve d ose i nte nsit y is a perce nt of  total  act u al dose t hat a s u bject recei ve d d uri n g 
c orres p o n di n g st u d y treat me nt peri o d vers us t he t otal int e n de d d ose f or t he sa me st u d y 
treat me nt p erio d acc or di n g t o t he st u d y  pr ot o c ol. T h e d et ails of the d ose i nte nsit y calc ulat i on 
will be pr o vi de d i n t he S P P as part of t he e x p os ure T F L te m plates.
D osi n g de viat i ons f or I P(s) will be liste d wi t h reas o ns f or de viat i ons f or t he f oll owi n g 
cate g ories: dela ys, o m issi ons, re d uctio ns, a n d i nterr u pti o ns.  Dosi n g dela ys will be deri ve d 
base d o n t he sc he d ule d d osi n g dates usi n g t he pre vi o us d ose gi ve n as r efere nce. T he n u m ber 
of  s u bjects wit h d osi n g dela ys a n d t otal d ose dela ys will be s u m marize d. 
3. 3. 4
  C o nc o mit a nt Me dic ati o ns
T he n u m ber a n d perce nta ge of  s u bjects w h o t o o k c o nc o mita nt me dicati ons will be s u m mari ze d 
f or t he I T T p o p ulati o n b y t he ge neric na me, c o de d b y W H O 
Dr u g Dict i onar y . A listi n g 
pr o vi di n g i nf or mati on a b o ut t he r o ute, i n dicati on, d ose a n d fre q ue nc y will als o be pr o vi de d.  
C o nc o mita nt me d icati ons will  incl u de all c o nc o mita nt me d icati ons ta ke n o n or af t er t h e date 
of  first d ose of  IP or a n y c o nc o mita nt me dicat i o n starte d pri or t o t he first d ose of  st u d y 
treat me nt t hat c o nti n ue d be yo n d t he date of first d ose of I P.
T he use of s u bse q ue nt a nt ica ncer treat me nt after t he disc o nti n uati on of st u d y treat me nt will be 
s u m marize d a n d w here a p pr o priate ma y als o be s u m marize d b y C D 7 3 levels b y t he t ype of 
s u bse q ue nt a ntica ncer treat me nt f or t he as-treate d p o p ulat i on.
3. 3. 5
  Pr ot oc ol De vi ati o ns
I nci de nce of  im p orta nt pr ot oc ol de viati o ns will be s u m marize d b y de viati o n cate g ories. A 
pr ot oc ol  de viati on is deter mi ne d t o be i m p orta nt if it meets a n y o ne of t he f oll owi n g cri t eria:


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0

S u bject e ntere d i nt o t he stu d y b ut d oes n ot satisf y i ncl usi on crit eria n u m ber 5, 6, 8, 9, 1 0 
o r e xcl usi on cri t eria 2, 3, 5, 6, 1 5, 1 8.

I nc orrect i nf or me d c o nse nt pr oce d ure (i nclu di n g rec o nse nt) f or m ai n I C F s uc h as n o I C F, 
c o nse nt n ot si g ne d, wr o n g c o nse nt versi o n si g ne d, u na p pr o ve d c o nse nt use d.

S eri o us breac h of G C P.

S u bject recei ve d t he i nc orrec t treat me nt, o ver d ose or e x pire d treat me nt.

A de viat i on t hat affects t he a bilit y t o i nter pret data wi t h res pect t o t he pri mar y o bject i ve 
f or e xa m ple, missi n g or i nc orrectl y c ollecte d disease assess me nts or a n y err or t hat i m pacts 
t he a bilit y t o pr o perl y  mea s ure t he disease res p o nse.

Cri teria met  duri n g t he st u d y but t he s u bject was n ot wit h dra w n as per pr ot oc o l 
re q uire me nts.

S u bject n ot ra n d o mize d per pr ot oc ol  or per I V R S pr oce d ure (t his d oes n ot i ncl u de 
di s pe nsi n g or a d mi nisteri n g st u d y tr e at me nt). I n so m e cases u nre p orte d S A E s detecte d i n 
t he s o urce data ma y be defi ne d as i m p orta nt pr ot oc ol de viati o ns.
I nci de nce of  C O VI D - 1 9 i m p orta nt pr ot oc ol de viati o ns will  als o be s u m marize d b y de viat i on 
cate g ories.
F urt her i nf or mati on f or i m p orta nt pr ot oc ol de viati o ns ca n be f ou n d i n t he Pr ot oc ol D e vi atio n 
Cri teria F or m.
A listi n g will be pr o vi de d wi t h pr ot oc ol de viat i on details. N o ne of  t he de viat i ons will l ea d t o 
s u bjects bei n g e xcl u de d fr o m a n y anal ysis p o p ulat i ons descri be d i n 3. 2 , u nless ot her wi s e 
s pecifie d. If a de viatio n is serio us e n o u g h t o ha ve a p ote ntial i m pact o n t he pri mar y a nal ysis, 
se nsiti vity a nal yses ma y b e p erfor m e d. 
3. 4   Effic ac y A n al yses
F or eac h of t he a nal yses t here will be n o f or m al statistical c o mparis o n bet wee n d ose l e vels i n 
Part 1.
3. 4. 1
  Pri m ar y Effic ac y E n d p oi nt a n d A n al yses
T he pri mar y  efficac y e n d p o i nt is o bject i ve res p o nse ( O R). O R is defi ne d as best o verall 
res p o nse of  co nfir me d res p o nse ( C R) or partial res p o nse ( P R) acc or di n g t o R E CI S T versi o 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 mo n g all o verall res p o nses rec or de d fr o m t he start of  treat me nt wit h 
i n vesti gati onal pr o d uct u ntil o bjecti ve d oc u me ntati o n of  PD, or t he last e val ua ble disease 
assess me nt i n t he a bse nce o f P D pri or t o t he i nitiati o n of s u bse q ue nt a ntica ncer t hera p y or e n d 
of  the st u d y, w hic h e 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 rec or de d at a visit a n d c o nfir me d b y re peat i ma gi n g n ot 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
less t ha n 2 8 d a y s ( 4 wee ks) aft er t he visit w he n t he res p o nse was first o bser ve d wi t h no 
e vi de nce of pr o gressi o n bet wee n t he i nit ial a n d C R/ P R c o nfir mati on visit. 
T he o bject i ve res p o nse rate ( O R R) will be esti mate d b y t he pr o p orti o n 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 o mial distri b ut i on. S u bjects t hat ha ve missi n g o vera ll 
res p o nse assess me nts will be c o nsi dere d as n o n -res p o n ders, a n d will t heref ore be c o u nte d i n 
t he de n o mi nat or, b ut n ot i n t he n u merat or of O R R. T he pri mar y a nal ysis of O R R will be base d 
o n t he I T T p o p ulat i on a n d will be re p orte d b y treat me nt ar m. A n est i mate of t he rate differe nce 
a n d its CI ( 8 0 % a n d 9 5 %) of  the O R R bet wee n t he c o ntr ol ar m an d e x peri me ntal treat me nt 
ar ms will  be re p orte d. C o m par is o n of  ar ms f or O R R will be o btai ne d fr om C oc hra n -Ma ntel -
Hae nszel test, stratifie d b y C D 7 3 le vel.
I n a d ditio n, f urt her i nf or mati o n descri bi n g t he res p o nse ( per pr o gra m mat ic deri vat i on 
perf or m e d b y t he S p o ns or base d u p o n t he i n vesti gat or assesse d data) f or eac h of  t ar g et, n o n-
tar get a n d ne w lesio n s a n d t he s u bjects o verall res p o nse, a n d a d ditio nall y a n i n vesti gat or 
assess me nt of o verall res p o nse b y R E CI S T versio n 1. 1 will be liste d f or eac h s u bject b y  visit. 
3. 4. 2
  Sec o n d ar y Effic ac y E n d p oi nt(s) a n d A n al yses
T he sec o n dar y efficac y en d p o i nts i ncl u de d urati o n of  res p o nse ( D o R), disease c o ntr ol (D C), 
pr o gressi o n -free s ur viv al  (P F S) a n d o verall s ur vi val ( O S). T he efficac y e n d p o i nts will be 
s u m marize d base d o n t he I T T P o p ulat i on. T he efficac y e n d p o i nts will als o be liste d f or eac h 
s u bject.
Efficac y a nal yses, e xce pt f or O S, will be base d o n a n a p plicat i on of  RE CI S T versi o n 1. 1
(Eise n ha uer et al, 2 0 0 9 ) t o i n vesti gat or assesse d t u mor meas ure me nts .  
Pr o gra m mat ic deri vati o n g ui da nce use d f or t he a p plicat i on o f R E CI S T versi o n 1. 1 are pr o vi de d 
i n A p pe n di x A: Deri vat i on of  RE CI S T 1. 1 Disease Assess me nt O verall Res p o n s e. R E CI S T 
versi o n 1. 1 g ui deli nes will be use d t o deter mi ne disease res p o nse.
3. 4. 2. 1
D ur ati o n of Res p o nse
A nal ysis of d urati o n of res p o nse is f or Part 2 o nl y.
D urati o n of res p o nse ( D o R) is defi ne d as t he ti m e fr o m t he first d oc u me ntati o n of a n o bjecti ve 
res p o nse u nt il t he first d oc u m e nt atio n of  a 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 . O nl y s u bjects w h o ha ve ac hie ve d o bjecti ve res p o nse (c o nfir me d C R or 
c o nfir me d P R) will be e valu at e d f or D o R. D o R is defi ne d i n m o nt hs as f o ll ows:  
D O R ( m o nt hs) = ( Date of P D/ deat h or ce ns ori n g – Date of first c o nfir me d disease res p o nse + 
1) / ( 3 6 5. 2 5/ 1 2)


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
T he date of P D/ deat h or ce ns ori n g is t he sa me as defi ne d f or P F S i n 3. 4. 2. 3 . T he me dia n D o R 
a n d its 9 5 % CI will be esti mate d usi n g t he Ka pla n -Meier m et h o d. 
3. 4. 2. 2
Dise ase C o ntr ol 
Di sease c o ntr ol ( D C) is defi ne d as C R, P R, or S D ( mai ntai ne d f or ≥ 8 wee ks [ ± 3 da ys]). D C R 
will be est i mate d b y t he pr o p orti o n of  su bjects wi t h DC a n d its 2- si de d 9 5 % CIs will be 
esti mate d usi n g a n e xact pr o ba bilit y met h o d. A n esti mate of  the differe nce i n D C R bet wee n 
t he c o ntr ol ar m a n d e x peri me ntal treat me nt ar m will be re p ort e d. 
3. 4. 2. 3
Pr o gressi o n -free S ur vi v al 
A nal ysis of pr o gressi o n -free s ur vi val is f or Part 2 o nl y.
Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr om ra n d omizat i on u nt il t he first 
d oc u m e nt atio n of  a 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, 
re gar dless of  whet her t he s u bject recei ves s u bse q ue nt a ntica ncer treat me nt pri or t o pr o gressi o n. 
S u bjects w h o ha ve n o d oc u me nte d pr o gressi o n a n d are still ali ve at t he ti me of  anal ysis will 
be ce ns ore d at t he ti me of  t he latest date of assess me nt fr o m t heir last e val ua ble R E CI S T 1. 1 
assess me nt. P F S i n m o nt hs is defi ne d i n m o nt hs as f o ll ows:  
P F S ( m o nt hs ) = ( Date of P D/ deat h or ce ns ori n g – ra n d omizat i on + 1) / ( 3 6 5. 2 5/ 1 2),
T he ce ns ori n g g ui da nce a n d t he date of P D/ deat h or ce ns ori n g are gi ve n i n Ta ble 3. 4. 2 -1. T he 
n u m ber a n d perce nta ge of  su bjects e x perie nci n g a P F S e ve nt a n d Ka pla n -Meier pl ots  of PF S 
will be prese nte d b y tr e at me nt ar m. T he me dia n P F S a nd its 9 5 % CI will be est i mate d usi n g 
t he Ka pla n-Meier met h o d. T he pr o p orti o n of s u bjects pr o gressi o n free a n d ali ve at 4, 6, 8, 1 2, 
1 5, 1 8 m o nt hs ( P F S -4, P F S -6, P F S -8, P F S -1 2, P F S -1 5, P F S -1 8)  a n d ass ociate d 9 5 % CIs will 
be est i mate d usi n g t he Ka pla n-Meier
met h o d.
T he differe nce i n P F S bet wee n eac h treat me nt ar m a n d c o ntr ol ar m will be teste d f or 
sig nifica nce b y  usi n g a stratifie d l og- ra n k test at  t he o verall 2-si de d α = 0. 0 5 sig nifica nce level 
a djusti n g f or C D 7 3 le vel ( C D 7 3 Hi g h vs L o w). T he stratifie d l og-r a n k test will be carrie d o ut 
wi t h t he Breslo w met h o d f or ha n dli n g ti es. T h e hazar d rati o b et wee n eac h treat me nt ar m a nd 
t he c o ntr ol ar m wit h t w o-si de d 9 5 % CI will be esti mate d b y stratifie d C o x re gressi on m o del 
wi t h ties ha n dle d b y t he Efr o n met h o d (Ef r o n et al, 1 9 7 7). 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
T a ble 4. 4. 2 – 1 
S u m m ar y of Ce ns ori n g G ui deli nes f or P F S 
Sit u ati o n
D ate of P D/ De at h or Ce ns ori n g
P F S O utc o me
D oc u me nte d c o nfir me d Pr o gr essi ve Disease ( P D) 
or  deat h
Date of earliest si g n of P D or deat h, 
w h ic he ver c o mes first
E ve nt ( u nless t he 
ce ns ori n g r ule 
s pecifie d bel o w)
Deat h or P D i m me diatel y after ≥ 2 c o nsec uti ve 
misse d or n o n -e val ua ble disease assess me nts as 
per t he pr ot oc ol s pecifie d assess me nt sc he d ule
Date of t he last pr o gressi o n -free 
disease assess me nt pri or t o misse d or 
n o n- e val ua ble assess me nts, or t he 
ra n d o mizati o n (first d ose date f or 
Part 1), w h ic he ver occ urre d last
Ce ns ore d
N o P D or deat h at ti me of a nal ysis or l ost t o 
f oll o w- u p
Date of last a deq uate pr o gr essi o n -
free disease assess me nt
Ce ns ore d
N o t u m or assess me nt at baseli ne a n d n o e vi de nce 
of P D at first p ost -baseli ne disease assess me nt
O R
N o t u m or assess me nt p ost -first d ose, a n d n o deat h 
pri or t o sec o n d sc he d ule d p ost -baseli ne disease 
assess me nt
Date of ra n d o mizati o n (first d ose 
date f or Part 1)
Ce ns ore d
P D = pr o gressi ve disease; P F S = pr o gressi o n -free s ur vi val
S u bjects ha vi n g missi n g lesi on data at baseli ne or n o disease assess me nts p ost -first d ose of 
i n vesti gati onal pr o d uct will ha ve P F S ce ns ore d at t he date of ra n d o mizati on (first d ose date f or 
Part 1) u nless t he s u bject di es prior t o t he sec o n d sc he d ule d p ost -baseli ne disease assess me nt 
i n w hic h case t he deat h date will q ualif y as a P F S e ve nt. 
If a s u bject has t w o or m ore c o nsec uti ve misse d or n o n -e valua ble assess me nts f oll o we d b y  a n 
assess me nt s h o wi n g n o ra di ol ogi c disease pr o gressi o n, t he n t he ass u m pti o n wi ll be t hat t he 
s u bject di d n ot pr o gress d uri n g t he misse d or n o n- e val ua ble assess me nts. T w o or m o re 
c o nsec ut i ve assess me nts is defi ne d as f oll ows: f or c o h ort A, ≥ 1 6 + 1 wee ks f or t he first 4 8 
wee ks or ≥ 2 4 + 1 wee ks t hereafter; f or c o h ort B, ≥ 1 2 + 1 wee ks f or t he fir st 2 4 wee ks or ≥ 1 6 + 1 
wee ks t hereafter (t w o disease assess me nts as per pr ot oc ol pl us a 1 wee k visit wi n d o w t o all o w 
f or a late assess me nt) after t he last e val ua ble p ost-baseli ne disease assess me nt.
3. 4. 2. 4
O ver all S ur vi v al
A nal ysis of o verall s ur vi val is f o r Part 2 o nl y.
O verall s ur vi val ( O S) is defi ne d as t he ti me fr om t he ra n d omizat i on u nt il deat h d ue t o a n y 
ca use. A s u bject ali ve at t he e n d of  st u d y or l ost t o f oll ow- u p will be ce ns ore d f or O S at t he 
last date w he n t he s u bject was k n o w n t o be ali ve o btai n e d fr om d ate of  last c o ntact, wit h dra wal 
c o nse nt, ref use t o be f oll owe d u p, or last k n o w n ali ve o n e n d of  tr e at me nt, e n d of  st u d y, a n d
s ur vi val stat us/f oll ow - u p C R Fs. 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
F or i nc om p lete O S data (e. g. f or O S a nal ysis at i nteri m a nal ysis), t he last date f or each 
i n di vi d ual s u bject is defi ne d as t he latest a m o n g t he f oll owi n g dates rec or de d o n t he case re p ort 
f or ms ( C R Fs):
•
A E start, st o p, a n d c ha n ge dates, date A E met  the crit eria f or S A E, date A E met  an d n o  
l on ger m et crit eria for A E SI
•
A d missi o n a n d disc har ge da tes of h os pitalizati on
•
St u d y  treat me nt d at e
•
D at e of  last c o ntact, wit hdra wal c o nse nt, ref use t o be f oll ow e d u p, or l ast k n o w n ali ve o n 
e n d of treat me nt, e n d of st u d y, a n d s ur vi val stat us/f oll ow - u p C R Fs
•
La b orat or y  test dates i ncl u di n g ( b ut n ot li mite d t o) h e mat olo g y , c he mistr y, uri nal ysis, 
c oa g ulat i on, 
t u mor 
bi o ps y, 
i m m u n o gl o bi n, p har mac o ki net ics, 
 
.
•
Di sease assess me nt dates o n R E CI S T C R F
•
Date of visit, vital si g ns, E C O G, E C G, brai n sca n a n d p h ysical e xa mi nat i on
•
Start a n d st o p dates of  prior or s u bse q ue nt a ntica ncer treat me nt
•
Dates o n 
•
Start a n d e n d date of c o nc o mita nt me dicat i on a n d s ur gical/ me dical pr oce d ure
•
F or w o me n, date of l ast me nstr ual p erio d 
•
O nset a n d res ol ut i on date of i nf usi o n rel ate d reacti o ns
•
Di a g n osis date of pa ncreat ic ca ncer 
•
Date of scree n fail ure 
•
Date of c ollect i on of data c ollecte d e xter nall y 
O S is defi ne d i n m o nt hs as f o ll ows:  
O S ( m o nt hs) = ( Date of deat h or ce ns ori n g – Date of ra n d o mizat i on + 1) / ( 3 6 5. 2 5/ 1 2).
T he n u m ber an d perce nta ge of  su bjects e x perie nci n g a n O S e ve nt a n d Ka pla n -Meier pl ots  of 
O S will be prese nte d b y treat me nt ar m. T he me dia n O S a n d its 9 5 % CI will be est i mate d usi n g 
t he Ka pla n -Meier met h o d. T he pr o p orti o n of  su bjects ali ve at 4, 6, 8, 1 2, 1 5 a n d 1 8 m o n t hs 
( O S-4, O S -6, O S -8, O S -1 2, O S -1 5, O S -1 8) a n d ass ociate d 9 5 % CI will be esti mate d usi n g t he 
Ka pla n -M ei er m et h o d. 
T he differe nce i n O S bet wee n gr o u ps will be teste d f or sig nifica nce b y usi n g a stratifie d l og -
ra n k test at  the o verall 2- si de d α = 0. 0 5 si g nifica nce le vel, wi t h CD 7 3 le vel ( C D 7 3 Hi g h vs L o w) 
as t he stratificat i on varia ble.  T he stratifie d l og- ra n k test will be carrie d o ut wit h t he Breslo w 
met h o d f or ha n dli n g ties. T he hazar d rati o wit h t wo -si de d 9 5 % CI will be esti mate d b y 
stratifie d C o x re gressi on m o d el  wit h ties ha n dle d b y t h e Efr o n met h o d (Ef r o n et al, 1 9 7 7). 
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 4. 3
  H a n dli n g of Dr o p o uts a n d Missi n g D at a
I n ge neral, missi n g data are n ot i m p ute d f or statistical anal ysis. G ui da nce re gar di n g t he 
ha n dli n g of  dr o p o uts a n d m issi n g data a n d ce ns ori n g will a p pl y u nif or m l y to all efficac y 
a nal yses res ultin g fr o m a n a p plicat i on of  R E CI S T 1. 1 t o i n vesti gat or assesse d t u mor 
meas ure me nts ( details are s pecifie d i n t he c orres p o n di n g e n d p o i nt sectio n a n d A p pe n di x A:  
Deri vat i on of  RE CI S T 1. 1 Disease Assess me nt O verall Res p o n se). F or i n vesti gat or re p orte d 
o utc o m es, a nal yses will prese nt o utc o m es re p orte d b y t he i n vesti gat or wit h o ut c o nsi derat i on 
of  missi n g data or ce ns ori n g r ules. 
3. 4. 4
  S u b gr o u p A n a l yses
S u b gr o u p a nal yses ( w here e x pl ore d) are a p plica ble t o Part 2 o nl y.
3. 4. 4. 1
A n al ysis b y C D 7 3 Le vels
W he n a p pr o pri ate (e. g. s ufficie nt sa m ple size i n eac h s u b gr o u p) , a nal ysis of O R, P F S a n d O S  
b y C D 7 3 e x pressi o n le vel at baseli ne ( hi g h vs l ow) as meas ure d b y I H C i n arc hi val a n d/ or 
fres h t u mor bi o psies will  be c o n d ucte d f or Part 2. F or t he O R a nal ysis wi t hi n eac h s u b gr o u p 
cate g or y Fis hers e xact test will be use d a n d f or P F S a n d O S C o x Pr o p orti o nal Hazar ds will be 
use d. A d dit i on al  efficac y e nd p oi nts m a y als o be e x plore d.
3. 4. 4. 2
U ni v ari ate A n al yses 
U ni variate a nal ysis ma y be perf or me d f or t he I T T p o p ulat i on i n Part 2 t o c o m pare t he efficac y 
effect of t he c o nt r ol ar m agai nst t he e x peri me ntal treat me nt ar ms. F or t he u ni variate a nal ysis 
t he f o ll owi n g s u b gr o u p fact ors ma y  be c o nsi dere d:

Se x ( Male, Fe male)

A ge gr o u p ( < 6 5 y ears, ≥ 6 5 y ears)

T u m or sta ge at st u d y  e ntr y ( T 1 or T 2, T 3 or T 4)

E C O G at baseli ne ( 0, 1)

C R P at baseli ne ( < 4. 5 m g/ L, ≥4. 5 m g/ L)

S u m  of tar get lesio n s at baseli ne (≤1 0 0 m m , > 1 0 0 m m)

Li ver m etastasis prese nt at baseli ne ( Yes, N o)

N L R at baseli ne ( ≤5, > 5)
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
F or eac h treat m e nt ar m o verall a n d wit hi n eac h s u b gr o u p le vel t he n u mber a n d perce nta ge of 
s u bjects wit h a c o nfir me d res p o nse will be re p orte d. I n a d dit i on t he rate differe nce a n d 
c orres p o n di n g 9 5 % CI f or t he c o m paris o n of treat me nt ar ms will be pr o vi de d.   
F or eac h treat m e nt ar m o verall a n d wit hi n eac h s u b gr o u p le vel t he n u m ber a n d perce nta ge of 
pati e nts wit h a n e ve nt will be re p orte d. Me dia n P F S ( base d o n a p plicati on of R E CI S T versi o n 
1. 1 t o i n vest i gat or assess me nts) a n d O S will be assesse d via Ka pla n-Meier m et h o ds.
Hazar d rati os f or P F S a n d O S will be calc ulate d usi n g a C o x pr o p orti o nal hazar ds m o del wit h 
treat me nt as t he o nl y  ter m an d t he 9 5 % CI will be calc ulate d usi n g a pr ofile li keli h o o d 
a p pr oac h, a n d ties bei n g ha n dle d usi n g Ef r o n met h o d. A hazar d r atio of  <1 will fa v or t he 
e x peri me ntal treat me nt ar m. A ‘ b y’ state me nt will be use d t o o btai n t he H R a n d 9 5 % CI f or 
eac h s u b gr o u p level se paratel y. F or a s u b gr o u p fact or wit h less t ha n 2 0 e ve nts acr oss b ot h 
treat me nt ar ms, hazar d ratios a n d CI will n ot be prese nte d. 
3. 4. 5
  
3. 4. 5. 1
 
 
 
 
3. 4. 5. 2
C CI
C CI
C CI
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 4. 6
Ot her Effic ac y A n al yses
3. 4. 6. 1
Ti me t o Res p o nse 
Ti me t o res p o nse ( T T R) is defi ne d as t he time fr o m r a n d o mi zat i on u nt il the first d oc u m e ntatio n 
of  a n o bjecti ve res po nse. O nl y s u bjects w h o ha ve ac hie ve d o bject i ve res p o nse (c o nfir me d C R 
or c o nfir me d P R) will be e val uate d f or T T R. T T R is defi ne d i n m o nt hs as f o ll ows:
T T R ( m o nt hs) = ( date of first c o nfir me d o bjecti ve res p o nse – date of first d ose/ra n d o mi zat i on 
+ 1) / ( 3 6 5 . 3 5/ 1 2)
T he me dia n T T R a n d its 9 5 % CI will be est i mate d usi n g t he Ka pla n -Meier met h o d ( wit ho ut 
ce ns ori n g beca use all s u bjects ha ve e ve nts) f or t he I T T p o p ulat i on. 
3. 4. 6. 2
C h a n ge fr o m B aseli ne i n T u m or Sizes
T he perce nt c ha n ge fr om baseli ne i n tar get lesio n s u m of dia meters (lo n gest f or n o n -n o dal 
lesio ns, s h ort a xi s f or n o d al lesio n s) will be calc ulate d at eac h a de q uate p ost -baseli ne disease 
assess me nt (see A p pe n di x A: Deri vat i on of  RE CI S T 1. 1 Disease Assess me nt O verall 
Res p o n s e) a n d prese nte d as s u m mar y statist ics f or t he I T T p o p ulati on. It ma y als o be prese nte d 
b y usi n g s pi der pl ots. T he perce nt c ha n ge fr o m baseli ne i n tar get lesi on s u m of  dia meters is 
defi ne d as f o ll ows:
1 0 0 * ( Σ Dia meters at D A X - Σ Dia meters at B L) / ( Σ Dia meters at B L).
T he best perce nt c ha n ge fr o m ba seli ne i n tar get lesi o n s u m of dia meters is defi ne d as t he lar gest 
re d uctio n or s mallest i ncrease (in t he case w here a re d uctio n d oes n ot occ ur) fr o m baseli ne 
o bser ve d o ver all p ost -baseli ne di sease asses s me nts p rior t o t he i nitiati on of  su bse q ue nt 
a nt ica ncer treat me nt. T his will be prese nte d as s u m mar y statist ics a n d t he best perce nt c ha n ge 
fr om baseli ne ma y als o be prese nte d al o n gsi de d urati o n of  tr e at me nt (as bars) usi n g waterfall 
pl ots f or t he I T T p o p u lati on a n d w here a p pr o priate t hese ma y  be prese nte d b y C D 7 3 le vels. 
Tar get lesi on meas ure me nts a n d s u m of di a meters will be liste d b y disease assess me nt a n d 
s u bject.
3. 4. 6. 3
Se nsiti vit y A n al ysis
S o m e a nal ysis of efficac y e n d p o i nts ma y be re peate d usi n g t he all ran d o mi ze d p o p ulat i on as a 
se nsiti vity a nal ysis.
3. 4. 6. 4
Bli n de d I n de pe n de nt Ce ntr al Re vie w ( BI C R) A n al ysis
A n y a nal ysis of t he BI C R is f or Part 2 o nl y a n d ma y be re p orte d se paratel y. T he i n de pe n de nt 
data re vie w will  pr o vi de a R E CI S T v 1. 1 res p o nse f or eac h visi t f or eac h s u bject. F or eac h 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
pati e nt, t he i n de pe n de nt re vie wer will pr o vi de t he first a n d last dates of i ma gi n g data f or eac h 
ti me p oi nt (i.e. f or visits w here pr o gressi o n is/is n ot i de ntifie d). T he i n de pe n de nt re vie w 
R E CI S T res p o nse f or eac h visit will n ot i ncl u de a n y i m p utatio n f or missi n g data or scali n g 
r ules f or t otal tu m or size. T he data fr o m t he i n de pe n de nt re vie w of  sca ns will  be 
pr o gra m mat icall y c o m bi ne d wi t h deat h i nf or mati on b y A Z or d esi g nee f or t he calc ulat i on of  
pr o gressi o n a n d res p o nse. F urt her i n f or matio n ca n be f o u n d i n t he I n de pe n de nt Re vie w Master 
C harter.
T he deri vat i on a n d a nal yses of t he BI C R best o verall res p o nse a n d O R R a n d P F S is i de ntical 
t o t hat gi ve n i n Sect i ons  3. 4. 1 a n d 3. 4. 2 . Anal yses of di sa gree me nts bet wee n res p o nse a n d/ or 
pr o gressi o n stat us betwee n t he s p o ns or ( base d u p o n t he i n vesti gat or data) a n d t he BI C R ma y 
als o be perf or m e d. A listi n g of  co nc or da nce bet wee n BI C R a n d i n vesti gat or data i n t er ms of  
visit res p o nses ma y  als o be pr o vide d. 
3. 4. 6. 5
A n al ysis b y Recr uit me nt W a ve 
S o m e efficac y en d p o i nts i n Part 2 f or C o h ort A ma y be re peate d f or a nal ysis b y recr uit me nt 
wa ve. 
Recr ui t me nt wa ve 1 is defi ne d as s u bjects recr uite d u p t o a n d i ncl u di n g 1 5 N o v 2 0 1 9. 
Recr ui t me nt wa ve 2 is defi ne d as s u bjects recr uite d fr o m 0 8 Dec 2 0 2 0.
3. 5   
3. 5. 1
  
C CI
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 5. 3
  C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 6   
.
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 7   S afet y A n al yses
All safety a nal yses will be p erf or m e d base d o n t he as-treate d p o p ulat i on, u nless ot her wise 
s pecifie d. 
3. 7. 1
  M a xi m u m T oler ate d D ose E v al u ati o n 
T he Ma xi m u m 
T ol erate d D o se ( M T D) e val uat i o n will be base d o n t he D L T E val ua ble 
P o p ul at i on. T he n u m ber a n d perce nta ge of  su bjects wit h D L Ts d uri n g t he d ose escalat i on 
p hase will be prese nte d b y  d os e le vel. 
3. 7. 2
  A d verse E ve nts a n d Seri o us A d verse E ve nts
T he Me di c al Dicti onar y  for Re g ulat or y Act i vities ( Me d D R A) versi o n 2 2 or a m o re rece nt 
versi o n will be use d t o c o de t he a d v erse e ve nts ( A Es).
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as e ve nts prese nt at  baseli ne t hat 
w orse n i n i nte nsit y aft er a d mi nistrati o n of  IP or e ve nts a bse nt at baseli ne t hat e mer ge aft er 
a d mi nistrati o n of  IP. T E A Es will be prese nte d b y s ystem or ga n class a n d pr ef erre d t er m a nd 
re p orte d as fre q ue ncies. T he y  ma y be s orte d acc or di n g t o fre q ue nc y i n a n e x peri me ntal 
treat me nt ar m or t ot al s u bjects acr oss all d ose levels/treat me nt ar m s per c o h ort or, b y hi g hest 
se verity.  I nci de nce, se verit y a nd r el at i ons hi p t o I P will  als o be liste d. S pecific T E A Es will be 
c o u nte d o nce f or eac h s u bject f or calc ulat i n g perce nta ges. I n a d ditio n, if t he sa me T E A E occ urs 
m ult i ple ti mes wi t hi n a partic ular s u bject, t he hi g hest se verity a n d level of  relat i ons hi p 
o bser ve d will be re p orte d. A n o verall s u m mar y of T E A Es, treat me nt relate d T E A Es t o at least 
o ne st u d y dr u g, ol ecl u ma b relate d T E A Es hi g h gra de ( Gra de > = 3) T E A Es, treat m e nt relate d 
hi g h gra de T E A Es t o at least o ne st u d y dr u g a n d ol ecl u ma b relate d hi g h gra de T E A Es  will 
als o be prese nte d a n d, if a n y ass ociat i ons of i nterest bet wee n T E A Es a n d baseli ne 
c haracterist ics are o bser ve d, a d diti onal stratifie d res ults ma y be prese nte d. 
Treat me nt e mer ge nt serio us a d verse e ve nts ( S A Es) will be prese nte d b y s yste m or ga n class 
a nd preferre d t er m an d re p orte d as fre q ue ncies. Treat me nt relate d treat me nt e mer ge nt S A Es 
a n d o lecl u ma b relate d treat me nt e mer ge nt S A Es will be prese nte d i n t he sa me wa y. 
A Es a n d S A Es c o nsi dere d t o be n o n- treat me nt e mer ge nt mea ni n g t he y occ urre d aft er t he 
si gni n g of t he i nf or me d c o nse nt a n d pri or t o t he i nitiat i on of I P will be liste d. 
3. 7. 3
  A d verse E ve nts of S peci al I nterest
A n a d verse e ve nt of s pecial i nterest ( A E SI) is o ne of scie nt ific a n d me dical i nterest s pecific t o 
u n dersta n di n g of  the i n vesti gati onal pr o d uct a n d ma y re q uir e close m o nit ori n g a n d ra pi d 
c o m m u nicat i on b y t he i n vest i gat or t o t he s p o ns or.


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
Per pr ot oc ol Secti o n 5. 3, A d verse E ve nts of  Speci al I nterest Gr o u p t er ms f or Olecl u ma b 
i ncl u de b ut are n ot li mite d t o t he f o ll owi n g: 

Car di ac C hest Pai n, Transie nt Isc he mic Attac k, a n d T hr o m b oe m b o lis m

E d e m a

I mm u ne C o m ple x Disease
Per pr ot oc ol Secti o n 5. 3, A d verse E ve nts of  Speci al Int erest Gr o u p t er ms f or D ur val u ma b 
i ncl u de b ut are n ot li mite d t o t he f o ll owi n g:

Di arr hea/c olitis a n d i ntesti nal perf orati o ns

P ne u m o nit is

He pati tis

E n d ocri n o pat h y  (i.e. e ve nts of h y p o p h ysitis/ h y p o pit uitaris m, T y pe 1 dia betes mellit us, 
a dre nal i ns ufficie nc y, a n d h y per- a n d h y p ot h yr oidis m , t h yr oidi tis)

Ras h/ der mat itis

Ne p hrit is 

Pa ncreat itis 

M y o c ar di tis

M y osi tis/ p ol y m y ositis

Ne ur o pat h y / ne ur o m usc ular t o xicity (e. g., G uillai n -Barre s y n dr o me 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 nti al i m m u ne-
me diate d etiol o g y  incl u de, b ut are n ot li mite d t o, p ericar ditis, sarc oi d osis, u veit is a n d 
ot her e ve nts i n v ol vi n g t he e ye, s ki n, he mat ol o gical a n d r he u mat olo gi cal eve nts , 
vasc ulit is, 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.
M ore i nf or mati on re gar di n g A E SIs ca n be f ou n d i n pr ot oc ol . Ot h er cate g ories ma y be a d de d 
or e xist i n g t erms ma y be m o difie d as necessar y. A n A Z
me dicall y q ualifie d e x pert aft er 
c o ns ultati o n wi t h the Gl o bal Pat ient  Safet y P h ysicia n has re vie we d t he A Es of  int erest a n d 
i de ntifie d w hic h hi g her -level a n d w hic h pr ef erre d ter ms c o ntri b ute t o eac h A E SI gr o u p. 
F urt he r re vie ws ma y ta ke place pri or t o D B L t o e ns ure a n y f urt her ter ms n ot alrea d y incl u de d 
are ca pt ure d wit hi n t he cate g ories. Preferre d ter ms use d t o i de ntif y eac h A E SI gr o u p will be 
liste d bef ore D B L.
T he A E SIs f or ol ecl u ma b a n d d ur val u ma b will be liste d b y gr o u p a n d preferre d ter m  for eac h 
s u bject. S u m maries will i ncl u de T E A Es of  speci al int erest f or eac h of  olecl u ma b a n d 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
d ur val u ma b a n d treat me nt r elat e d T E A Es of special i nterest, b ot h of w hic h will be prese nte d 
b y gr o u p a n d preferre d ter m a n d ma y be or dere d b y hi g hest se verit y.
3. 7. 4
A E SIs 
D uri n g 
W hic h 
S yste mic Ster oi ds, E n d ocri ne 
T her a p y, 
or Ot her
I m m u n os u p press a nts Were A d mi nistere d
A E SIs d uri n g w hic h s yste mic ster oi ds, e n d ocri ne t hera p y, or ot her i m m u n os u p pressa nts were 
a d mi nistere d will be pr o gra m mat icall y i dent ifie d b y searc hi n g f or d at es of  init iati on of  t hes e 
a ge nts a n d c o m pari n g t o t he o nset dates a n d res ol uti o n dates of A E SIs f or i n di vi d ual s u bjects. 
T he c o nc o mita nt me d icati ons a d mi nistere d t o s u bjects will be i de ntifie d b y searc hi n g t he 
cli nical data base f or sele ct A T C c o des t o i de ntif y s yste mic ster oids, e n d ocri ne t hera p y a n d 
ot her i m m u n os u p pressa nts. See a list of  select A T C c o des i n t he d ur val u ma b i m A E c harter. 
T he last versi o n of  the d ur val u ma b i m A E c harter bef ore t he D C O ( Data C ut Off) date f or 
a nal ys is will be use d.  
S u m maries of  AE SIs d uri n g w hic h s yste mic ster oids or ot her i m m u n os u p pressa nts were 
a d mi nistere d as liste d i n t he d ur val u ma b i m A E c harter will be pr o vi de d.
3. 7. 5
  I m m u ne-me di ate d A d verse E ve nts (i m A E)
T o f ull y c haracterize t he A E SI (e xcl u di n g A E SI gr o u p I nf usi on relate d/ H y perse nsi tivit y/  
A na p h ylactic 
reactio ns) d uri n g w hic h 
s yste mic ster oids, e n d ocri ne t hera p y, or ot her 
i m m u n os u p pressa nts were a d mi nistere d ( See Secti o n 3. 7. 4 ), t he S p o ns or will perf or m me dical 
re vie w of  th ose A E SIs a n d classif y the m as i m m u ne-me diate d A Es (im A E s) or n ot i m A Es. 
See f urt her details i n t he d ur val u ma b i m A E C harter. 
I mm u ne -me d iate d A Es will be defi ne d as a n y A E SIs t hat ( 1) d urin g w hic h t he use of s yste mic 
ster oids, e n d ocri ne t hera p y , or ot her i m m u n os u p pressa nts were a d mi nistere d, ( 2) is c o nsiste nt 
wi t h an i m m u ne me d iate d mec ha nis m of  actio n, a n d ( 3) f or w hic h, t here is n o clear alter nate 
etiol o g y . 
i m A Es will be deri ve d b y first pr o gra m mat icall y i de ntif yi n g A E SIs d uri n g w hic h s yste mic 
ster oids, e n d ocri ne t hera p y, or ot her i m m u n os u p pressa nts were a d mi nistere d as o utli ne d a b o ve 
i n S e cti o n 3. 7. 3 . A furt her cli nical e val uat i on of  all suc h e ve nts will be ma de t o e ns ure t here 
was n o clear alter nate etiol o g y  befor e classif yi n g t he m as i m A Es f or t he p ur p ose of  anal ysis 
a n d re p orti n g. 
I mm u ne- me d iate d a d verse e ve nts will be liste d b y preferre d te r m for eac h s u bject a n d s orte d 
b y treat me nt ar m. S u m maries will  incl u de treat me nt e mer ge nt i m A Es w hic h ma y als o be 
or dere d b y  hi g hest se verity a n d treat me nt relate d treat me nt e mer ge nt i m A Es.


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
3. 7. 6
  De at hs a n d Tre at me nt Disc o nti n u ati o ns d ue t o A d verse E ve nts
T he m o rtality s u m mar y will s u m marize  s u bjects w h ose e n d of st u d y stat us is deat h, as well as 
ca use of  deat h (t o xicit y relate d t o i n vesti gati onal pr o d uct or disease u n der i n vesti gati on, or 
ot her). F or t h ose s u bjects w h o die d d ue t o a n A E, t he A E c o nt ri b uti n g t o deat h a n d t he A E’s 
r elat i ons hi p t o I P will be s u m marize d.
S u m maries will be pr o vi de d f or T E A Es a n d treat me nt relate d T E A Es res ulti n g i n per ma ne nt 
di sc o nti n uati on of  treat me nt S u p p orti n g listi n gs will be pr o vi de d f or A Es res ultin g t o deat h 
a n d A Es res ul ti n g i n p er m a ne nt disc o nt i n uati on of treat m e nt. A d ditio nall y  s u m maries will be 
pr o vi de d f or T E A Es a n d olecl u ma b relate d T E A Es res ultin g i n per ma ne nt disc o nti n uati on of  
ol ecl u ma b.
3. 7. 7
  Cli nic al L a b or at or y E v al u ati o n
La b orat or y  tests will be gr o u pe d acc or di n g t o c he mistr y, c oa g ulat i on, he mat ol o g y, t h yr oi d 
f u ncti on a n d ur i nal ysis. List i n gs will be pr o vi de d f or all la b orat or y res ults, i ncl u di n g uri nal ysis. 
Descri pt i ve st atistics ma y be pr o vi de d f or t he cli nical lab orat or y  res ults, i ncl u di n g t he val ues 
at baseli ne a n d e n d of  treat me nt visit as well  as 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  para meters will be assesse d at baseli ne as well as t hr o u g h o ut t he stu d y. F or 
c he mistr y a n d he mat ol o g y para meters, la b orat or y a b n or malities wit h t o xicity gra des acc or di n g 
t o t he N CI C T C A E versi o n 4. 0 3 will be deri ve d. La b orat or y a b n or malities occ urri n g fr om t he 
start of  IP a d mi nistrati o n t o t he last assess me nt o n st u d y will be prese nte d. W o rst t o xicit y 
gra de,  gra de s hifts of 2 or m ore fr o m baseli ne t o t he ma xi m u m gra de a n d c ha n ge fr o m baseli ne 
will be prese nte d. S u m maries i n dicati n g h y per - a n d h y p o - direct i onalit y of  cha n ge ma y be 
pr o d uce d w here a p pr o priate. La b orat or y para meters t hat ca n n ot be gra de d via N CI C T C A E 
will be s u m marize d wit h fre q ue ncies of p ost -basel i ne la b orat or y val ues cate g orize d as l o w ( L), 
n or m al ( N), or hig h ( H) usi n g la b orat or y  nor m al ra n ges c o mpare d t o baseli ne.
Li ver F u ncti o n P ar a meters
S u bjects wi t h ele vate d p ost -baseli ne A L T, A S T or T otal  Bilir u bi n t hat fall i nto t he f oll owi n g 
cate g ories w ill b e i de nt ifie d. N u m ber a n d perce nta ge of t hese s u bjects will be ta b ulate d.
Li ver F u ncti o n P ar a meters
Cate g or y
A L T
•
> = 3 × – < = 5 × U L N
•
> 5 × – < = 8 × U L N
•
> 8 × – < = 1 0 × U L N
•
> 1 0 × – < = 2 0 × U L N   
•
> 2 0 × U L N


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
Li ver F u ncti o n P ar a meters
Cate g or y
A S T
•
> = 3 × – < = 5 × U L N
•
> 5 × – < = 8 × U L N
•
> 8 × – < = 1 0 × U L N,
•
> 1 0 × – < = 2 0 × U L N   
•
> 2 0 × U L N
T ot al  bilir u bi n
•
> = 2 × – < = 3 × U L N
•
> 3 ×  – < = 5 × U L N
•
> 5 × U L N 
A L T or A S T
•
> = 3 × – < = 5 × U L N
•
> 5 × – < = 8 × U L N
•
> 8 × – < = 1 0 × U L N,
•
> 1 0 × – < = 2 0 × U L N   
•
> 2 0 × U L N
P ote nti al H y’s la w
•
( A S T > = 3 × U L N or  AL T > = 3 × U L N) a n d ( T otal 
Bilir u bi n > = 2 × U L N) a
U L N: u p per li mit of n or mal ra n ge.
a: T otal Bilir u bi n > = 2 × U L N is defi ne d as at least o ne case of p ost -d ose T B L > = 2 x U L N 
occ urre d at t he sa me da y  or after t he first i nci de nce date of A L T or  AS T > = 3 x U L N p ost 
treat me nt.
I n di vi d ual s u bject data s h o wi n g ele vate d A L T or A S T pl us t otal bilir u bi n fall i nto t he 
“ P ote ntial H y’s la w” will be liste d.
3. 7. 8
  Ot her S afet y E v al u ati o ns
3. 7. 8. 1
Vit al Si g ns
Vi t al si g ns will be assesse d at baseli ne a n d t hr o u g h o ut t he st u d y. Vit al si g n data will be liste d 
b y s u bject a n d ma y be s u m marize d b y st u d y visit w hic h will incl u de descri pti ve stati stics f or 
t he v al u e of t he para meters a n d t he c ha n ges fr om baseli ne f or t h e as-treate d p o p ulat i on. Data 
will be s u m marize d o nl y  w he n t he visit has at least 1 0 % s u bjects wit h no n -missi n g val ues.
3. 7. 8. 2
Electr oc ar di o gr a m
Electr ocar di o gra m ( E C G) res ults will be assesse d at baseli ne as well as t hr o u g h o ut t he st u d y. 
E C G para m eters i ncl u de: E C G mea n heart rate, P R, R R, Q R S, Q T, Q Tc B, a n d Q Tc F. F or 
triplicates, a vera ges will be ta ken at eac h ti me p oi nt pri or t o t he calc ulat i on of  descri pt i ve 
statistics. Cli nicall y si g nifica nt E C G res ults will be re p orte d as A Es. E C G para meter data a n d 
res ults ( n or mal vs. a b n or mal) will be liste d b y s u bject. E C G para meter data will be s u m mari ze d 
b y st u d y  visit w hic h will i ncl u de descript i ve st atistics f or t he val ue of t he para meters a n d t he 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
c ha n ges fr om baseli ne f or t he as-treate d p o p ulat i on. Data will be s u m marize d o nl y w he n t he 
visit has at least 1 0 % s u bjects wit h n o n -missi n g val ues. 
A d dit i onall y , a s u m mar y will  be pr o d uce d t hat s h o ws t he n u m ber a n d perce nta ge of s u bjects 
meet i n g t he crit eria f or a n ota ble Q Tc i nter val. T his will be pr o d uce d f or Q Tc F o nl y; t h e 
cate g ories for o bser ve d val ues are > 4 5 0, > 4 8 0, a n d > 5 0 0 a n d t he cate g ories f or c ha n ge fr o m 
baseli ne val ues are > 3 0 a n d > 6 0.
3. 7. 8. 3
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us
Easter n C o o perati ve O nc o l og y  Gr o u p ( E C O G) perf or ma nce stat us will be assesse d at baseli ne 
as well as t hr o u g h o ut t he st u d y. E C O G will be s u m marize d f or t he s hift fr om baseli ne t o t h e 
“ w orst” perf or ma nce p ost -baseli ne o n treat me nt peri o d.
3. 8   I m m u n o ge nicit y
A s u m mar y of  im m u n o ge nicit y res ults will be pr o vi de d s h o wi 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 nti dr u g a nti b o dies ( A D As) t o ol ecl u ma b a n d d ur val u ma b, 
base d o n t he s u bjects i n t he A D A e val ua ble p o p ulat i on. S u bjects a n d/ or data e xcl u de d fr om 
t he A D A e val ua ble p o p ulat i on ma y be prese nte d i n se parate o ut p uts.
T he f o ll owi n g cate g ori es will be i ncl u de d i n t he s u m mar y ta ble:

A D A p osit i ve at baseli ne a n d/ or p ost -baseli ne visit s

A D A i nci de nce, defi ne d as perce nta ge of s u bjects wit h treat me nt e mer ge nt A D A

Persi ste nt p osit i ve, defi ne d as p osi tive at ≥2 p ost -baseli ne assess me nts ( wit h ≥1 6
wee ks bet wee n first a n d last p osit i ve) or p ositi ve at last p ost-ba seli ne assess me nt

Tra nsie nt p osit i ve, defi ne d as ne gat i ve at last p ost -baseli ne assess me nt a n d p osi ti ve
at o nl y  one p ost -baseli ne assess me nt or at ≥2 p ost -baseli ne assess me nts ( wit h <1 6
wee ks bet wee n first a n d last p osit i ve)

Treat me nt -b o oste d, defi ne d as b aseli ne A D A p osi tive t hat was b o oste d t o a 4 -f ol d
or hi g h er l e v el fol l owi n g dr u g a d mi nistrati o n
S u bjects wit h p ositi ve A D A res ults will als o be liste d.
3. 9   P h ar m ac o ki netics
S er u m  co nce ntrati o ns of  olecl u ma b a n d d ur val u ma b, a n d plas ma c o nce ntrati o ns of  
g e m cita bi ne a n d n a b -paclit a xel f or eac h sc he d ule d ti me-p oi nt will be s u m marize d f or eac h 
visit/t i me p oi nt an d d ose level or tr e at m e nt ar m (as a p pr o priate) usi n g a p pr o priate descri pt i ve 
statistics. All ser u m a n d plas ma c o nce ntrati o n data will be liste d f or eac h su bj e ct, b y  a n al yt e. 
T he f o ll owi n g descri pt i ve statistics are prese nte d f or ser u m a n d plas ma c o nce ntrati o ns:


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0

n

n bel o w L L O Q

ge o m etric me a n ( g mea n)

ge o m etric c oefficie nt of varia nce ( %) ( g C V)

arit h metic me a n of n o n lo g -tra nsf or me d data ( mea n)

sta n dar d de viatio n of  no n l o g -tra nsf or me d data ( St d De v)

c oefficie nt of varia nce ( %) ( C V)

me dia n

mi ni m u m ( mi n)

ma xi m u m ( ma x)
T he g m ea n is calc ulate d as e x p( μ), w here μ is t he mea n of t he data o n t he nat ural l o g scale.
T he g C V is calc ulate d as 1 0 0 x s qrt[e x p(s 2) -1], w here s is t he St d De v of t he data o n t he 
nat ural  lo g scale.
H a n dli n g of N o n -Q u a ntifi a ble C o nce ntr ati o ns
I n di vi d ual c o nce ntrati o ns bel o w t he L L O Q of t he bi oa nal ytical assa y are re p orte d as N Q i n 
t he list i n gs wit h t he L L O Q defi ne d i n t he f o ot n otes of t he rele va nt T F Ls. I n di vi d ual plas ma 
c o nce ntrati o ns t hat are N ot Re p orta ble are re p orte d as N R a n d t h ose t hat are missi n g are 
re p orte d as N S ( N o Sa m ple) i n t he listi n gs. Plas ma c o nce ntrati o ns t hat are N Q, N R or N S are 
ha n dle d as f o ll ows f or t he pr o visi o n of des cri pti ve statist ics:

A n y val ues re p orte d as N R or N S are e xcl u de d fr om t he s u m mar y ta bles a n d 
c orres p o n di n g fi g ures.

At  a ti me p oi nt w here less t ha n or e q ual t o 5 0 % of t he c o nce ntrati o n val ues are N Q, all 
N Q val ues are set t o t he L L O Q, a n d all descri pt i ve statistics are calc ulate d acc or di n gl y.

At  a time p oi nt w here m o re t ha n 5 0 % ( b ut n ot all) of  the val ues are N Q, t he g m ea n, 
g S D a n d g C V % are set t o N C. T he ma xi m u m val ue is re p orte d fr o m t he i n di vi d ual 
data, a n d t he mi ni m u m a n d me dia n are set t o N Q.

If all co nce ntrati o ns are N Q at a ti me p oi nt, n o descri pt i ve st atistics ar e c alc ulate d f or 
t hat ti me p oi nt. T he g mea n, mi ni m u m, me d ia n a n d ma xi m u m are re p orte d as N Q a n d 
t he g C V % a n d g mea n ± g S D as N C.

T he n u m ber of  values bel o w L L O Q ( n < L L O Q) are re p orte d f or eac h ti me p oi nt 
t o get her wit h t he t otal n u m ber of c ollecte d val ues ( n).
T hree o bser vat i ons > L L O Q are re q uir e d as a mi ni m u m f or a plas ma c o nce ntratio n t o be 
s u m marize d. 
T w o o bser vati o ns > L L O Q are prese nte d as mi ni m u m a n d ma xi m u m wit h t he ot her s u m mar y  
statistics as N C.


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
Precisi o n a n d R o u n di n g R ules f or P K c o nce ntr ati o n d at a
P K c o nce ntrati o n data list i n gs prese nt t o t he sa me n u m ber of si g nifica nt fi g ures as t he data 
recei ve d fr om t he bi oa nal ytical la b orat or y ( us uall y b ut n ot al wa ys t o 3 si g nifica nt fi g ures)
a n d a gai nst t he sa me u nits as recei ve d.
P K c o nce ntrati o n descri pt i ve statistics prese nt 4 si g nifica nt fi g ures wit h t he e xce pti on of t he 
mi n a n d ma x w hic h prese nt 3 si g nifica nt fi g ures a n d n a n d n < L L O Q w hic h prese nt as 
i nte gers.
4
I N T E RI M A N A L Y SI S
I nteri m a nal yses c o m par i n g t he e x peri me ntal treat me nt ar m to t he c o ntr ol ar m will be 
perf or m e d i n Part 2 C o h ort A usi n g a j o i nt Ba yesia n pre dicti ve pr o ba bilit y.  Ba yesia n pre dict i ve 
pr o ba bilit y allo ws f or c o ntin u o us assess me nts f or earl y Go/ N o -G o  decisi o n ma ki n g i n si n gle 
ar m trials (Lee a n d Li u, 2 0 0 8 ). A j oi nt Ba yesia n pre di ct i ve pr o ba bilit y a p pr oac h allo ws f or 
c o nti n u o us assess me nts of t he delt a (δ ), or differe nce, of t he O R Rs bet wee n t he e x peri me ntal 
treat me nt ar m a n d c o ntr ol ar m (P ul kste nis et al ., 2 0 1 7). 
F ut ility i nteri m a nal ysis will be p erf or m e d aft er 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 crit eria. T he data c ut off 
crit erio n is defi ne d as t he o p p ort u nit y t o be f oll owe d f or at least 1 6 wee ks at t he ti me of  the 
data c ut off a n d ha ve at least o ne 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. T he i nteri m a nal ysis will be base d o n t he s u bset 
of  the I T T P o p ulat i on t hat ha ve satisfie d t he data c ut off crit eria. E nr oll me nt 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




Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 9 of 4 9
S A P te m plate versi o n 3. 0
5
R E F E R E N C E S
 
 
Ef r o n B. T he efficie nc y of  Co x’s li keli h o o d f uncti o n f or ce ns ore d data. J A m Stat Ass oc. 
1 9 7 7: 7 2( 3 5 9): 5 5 7 -6 5.
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R et al . Ne w res p o nse 
e val uat i on crit eria i n s oli d t u mo urs: re vise d R E CI S T g ui deli ne ( versio n 1. 1). E ur J Ca ncer. 
2 0 0 9; 4 5( 2): 2 2 8 -4 7.
 
 
 
Klei n J P, L o ga n B, Har h off M, A n d ers o n P K. A nal yzi n g s ur vi val c ur ves at a fi xe d p oi nt i n 
ti me. Statistics i n Me dici ne. 2 0 0 7; 2 6: 4 5 0 5 - 1 9.
Lee JJ, Li u D D. A pre di ct i ve pr o ba bilit y desi g n f or p hase II ca ncer cli nical tri als. Cli n Tri als. 
2 0 0 8; 5: 9 3 - 1 0 6.
 
.
 
 
 
 
 
 
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 ncreat ic ca ncer wit h na b-pacli t a x el plus g e m cita bi ne. N E n gl J Me d. 2 0 1 3; 3 69( 1 8): 1 6 9 1 -
7 0 3.
C CI
C CI
C CI
C CI
C CI
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
W hite hea d A, W hite hea d J.  A ge neral para metri c a p pr oac h t o t he met a-a nal ysis of  ra n d o mize d 
cli nical trials.  Statist ics i n Me dici ne. 1 9 9 1; 1 0: 1 6 6 5- 7 7.
 
 
Y o o C, H wa n g J Y, Ki m  JE, 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 dy 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 in pat ient s wi t 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.
C CI


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 1 of 4 9
S A P te m plate versi o n 3. 0
A P P E N DI C E S
A p pe n di x A: Deri v ati o n of R E CI S T 1. 1 Dise ase Assess m e nt O ver all Res p o n se
G ui da nce re gar di n g t he ha n dli n g of  dr o p o uts a n d missi n g data will a p pl y unif or ml y t o all 
efficac y a nal yses res ult i n g fr om a n a p plicat i on of  R E CI S T 1. 1 t o i n vestigat or assesse d t u m or 
meas ure me nts. F or i n vesti gat or re p orte d o utc o mes, a nal yses will  prese nt o utc o m es re p orte d 
b y t he i n vesti gat or wit h o ut c o nsi derati o n of missi n g data or ce ns ori n g r ules. 
T ar get Lesi o n Res p o nse
Tar get lesi o n res p o nse will be pr o gra m mat icall y deri ve d o n t he data c ollect i on i nstr u me nt o nce 
R E CI S T 1. 1 criteria are a p plie d t o t he site pers o n nel rec or de d tar get lesi o n meas ure me nts. 
P ossi ble val ues i ncl u de:

C R – C o m plete Res p o nse

P R – Parti al Res p o nse

S D – Sta ble Disease

P D – Pr o gressi ve Disease

N E – N o n -e val ua ble

N A – N ot A p plica ble (set v al ue f or all p ost -b aseli ne dise ase assess me nts o nly if n o 
t ar get lesi o ns are i de ntifie d at b aseli ne)
T he deri vat i on f or t ar g et lesio n  res p o nse is as f oll o ws ( ple ase n ote t he or der of t he al g orit h m 
bel o w  is i m p ort a nt):
1.
If “ A n y Tar get Lesi o ns Prese nt” e q uals “ N o” o n t he T ar get Lesi o ns – B aseli ne C R F, 
t he n all p ost -baseli ne “ Tar get Lesi o n Res p o nse” e q uals “ N A”. 
2.
Else, if “ Perce nt C ha n ge fr o m Na dir S u m o f Dia meters” is greater t ha n or e q ual t o 2 0 % 
a n d t he a bs olute i ncrease fr o m t he na dir ( defi ne d as t he “ T otal” for eac h p ost -baseli ne 
di sease assess me nt mi n us t he “ Na dir S u m of Dia meters”) is greater t ha n or e q ual  t o 5 
m m, t he n “ Tar get Lesi o n Res p o nse” e q uals “ P D”.
3.
Else, if “ N ot D o ne” is selecte d, or “ Meas ure me nt” is left bla n k, or “ Lesi o n n o l on ger 
Meas ura ble” i s selecte d a n d e q ual t o “ N E”, or “ Lesi o n I nter ve nt i on” is selecte d f or a n y
Tar get Lesi o n i de ntifie d at Baseli ne, t he n “ Tar get Lesi o n Res p o nse” e q uals “ N E”.
4.
Else, if “ T otal No n -L y m p h N o de” e q uals “ 0” a n d all L y m p h N o de Tar get Lesi o n 
“ Meas ure me nts” are less t ha n “ 1 0” i n di vi d uall y, t he n “ Tar get Lesi o n Res p o nse” e q uals 
“ C R”. 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
N ote:  This ste p re q uires e xa mi ni n g “ Meas ure me nts” se paratel y f or Tar get Lesi o ns 
wi t h “L y m p h N o de” e q ual t o “ Yes” a n d “ N o”.
5.
Else, if “ Perce nt C ha n ge fr o m Baseli ne S u m  of Dia meters” is less t ha n or e q ual t o -
3 0 %, t he n “ Tar get Lesi o n Res p o nse” e q uals “ P R”.
6.
Else, “ Tar get Lesi o n Res p o nse” e q uals “ S D”.
If a s u bject has a missi n g t u mor meas ure me nt at a di sease assess me nt f or 1 or m o re tar get 
lesio ns, t he s u m  of dia meters (lo n gest f or n o n -n o dal  le sio n s, s h ort a xis f or n o dal lesio n s) will 
be re p orte d f or t he re mai ni n g t ar get lesi ons. T hese data will be use d t o i n dicate ra di ol ogic 
di sease pr o gressi o n if t he s u m of di a meters f or t he o bser ve d lesi ons i ncreases at least 2 0 % 
fr om t he na dir s u m o f diamete rs of all tar get lesi ons a n d de m o nstrates at least a 5 m m a bs o l ute 
i ncrease fr om t he na dir s u m o f dia meters of all tar get lesi ons, i n s pite of t he missi n g data ( or if 
ot her cri t eria for P D are m et).
N o n -T ar get Lesi o n Res p o nse
N o n -t ar get lesio n  res p o nse will be assi g ne d b y sit e pers o n nel f oll owi n g a q ualitat i ve o verall 
assess me nt of all n o n-tar get lesio n s. 
P ossi ble val ues i ncl u de:

C R – C o m plete Res p o nse
o
Di sa p peara nce of  all n o n- tar get lesi ons a n d n or malizat i on of  tu m or mar ker 
le vel. All l y m p h n o des m ust be n o n -pat h o l ogi cal i n size ( < 1 0 m m s h ort a xis)

N o n -C R/ N o n -P D – N o n- C o m plete Res p o nse / N o n -Pr o gressi ve Disease
o
Persi ste nce of  one or m o re n o n- tar get lesio n (s) a n d/ or ma i nte na nce of  tu m or 
mar ker l e vel a b o ve t he n or mal li mits

P D – Pr o gressi ve Disease
o
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. 

N E – N o n- e val ua ble

N A – N ot A p plica ble (set v al ue f or all p ost -b aseli ne dise ase assess me nts o nly if n o 
n o n- t ar get lesi o ns are i de ntifie d at b aseli ne)
T h o u g h n o n -tar get lesi on res po nses are a s u bjecti ve decisi o n  ma de b y t he sit e pers o n nel , 
certai n res p o nses ma y be li mite d de pe n di n g o n t he n o n- tar get lesi on stat uses rec or de d. A n 


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
alg ori t h m is pr o vi de d b el o w hi g hli g hti n g a p pr o priate p ossi ble n o n -tar get lesio n  res p o nses 
base d o n rec or ded data. Reac hi n g a re d b o x (■) si g nifies ha vi n g reac he d t he o nl y allo wa ble 
n o n- tar get lesio n  res p o nses base d o n n o n- tar get lesi on stat uses. Reac hi n g a gree n b o x (■) 
sig nifies ha vi n g reac he d t he e n d of t he al g orit h m a n d m ore t ha n o ne p ossi ble n o n -tar get lesi on 
res p o nse is p ossi ble fr om w hic h t he I n vest i gat or ma y c h o ose.
1.
a) If n o n o n -t ar get lesio ns are i de nt ifie d at baseli ne, all p ost-baseli ne n o n -tar get 
lesio n res p o nses s h o ul d e q ual  N A. ■
b) Else, if a n y n o n -tar get lesio n s are ide nt ifie d at baseli ne, res p o nses ma y be li mite d 
t o C R, N o n-C R/ N o n -P D, P D, N E (i .e., res p o nses of N A are n ot per mitte d). 
G o t o R ule 2.
2.
a) If all n o n-tar get lesio ns ha ve a stat us are “ A bse nt”, t he res p o nses ma y  be li mite d 
t o C R. ■
b) Else, if at least o ne n o n -tar get lesio n stat us is N O T “ A bse nt”, t he res p o nses ma y  
be li mite d t o N o n-C R/ N o n -P D, P D, N E ( i.e. , res p o nses of C R, N A are n ot per mitte d). 
G o t o R ule 3 . 
3.
a) If all n o n-tar get lesio ns ha ve a stat us of “ U ne q ui v ocal Pr o gressi o n”, res p o nses 
ma y be li mite d t o P D. ■
b) Else, if n o n o n -tar get lesi ons ha ve a stat us of “ U ne q ui v ocal Pr o gressi o n”, 
res p o nses ma y be li mite d t o N o n-C R/ N o n -P D, N E ( i.e. , res p o nses of C R, P D, N A are 
n ot per mitte d).
G o t o R ule 4.
c) Else, if at least o ne ( b ut n ot all) n o n-tar get lesio n  has a stat us of “ U ne q ui v ocal 
Pr o gressi o n”, t he res p o nses ma y  be li mite d t o N o n-C R/ N o n -P D, P D, N E ( i.e. , 
res p o nses of C R, N A are n ot per mitte d). ( N ote:  N o res p o nse h as bee n eli mi n ate d as 
a n o pti o n here. )
G o t o R ule 5. 
4.
a) If all n o n-tar get lesio ns ha ve a stat us of “ N o n -e val ua ble” a n d/ or “ N ot D o ne” is 
selecte d, res p o nses ma y be li mite d t o N E. ■
b) Else, if n o n o n -tar get lesi ons ha ve a stat us of “ N o n -e val ua ble” a n d “ N ot D o ne” is 
n ot sel ecte d, res p o nses ma y be li mite d t o N o n-C R/ N o n -P D ( i.e. , res p o nses of C R, 
P D, N E, N A are n ot per mitte d). ■ 
c) Else, if at least o ne ( b ut n ot all) n o n- tar get lesio n  has a stat us of “ N o n-e val ua ble” 
a n d/ or “ N ot D o ne” is selecte d, t he res p o nses ma y be li mite d t o N o n -C R/ N o n -P D, N E 
(i.e. , res p o nses of C R, P D, N A are n ot per mitte d). ■
(N ote:  N o res p o nse h as bee n eli mi n ate d as a n o pti o n here. ) 
5.
a) If all n o n-tar get lesio ns ha ve a stat us of “ N o n -e val ua ble” a n d/ or “ N ot D o ne” is 
selecte d, res p o nses ma y be li mite d t o N E. ■
b) Else, if n o n o n -tar get lesi ons ha ve a stat us of “ N o n -e val ua ble” a n d “ N ot D o ne” is 
n ot sel ecte d, res p o nses ma y be li mite d t o N o n-C R/ N o n -P D, P D ( i.e. , res p o nses of 
C R, N E, N A are n ot per mitte d). ■


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
c) Else, if at least o ne ( b ut n ot all) n o n -tar get lesio n  has a stat us of “ N o n-e val ua ble” 
a n d/ or “ N ot D o ne” is selecte d, t he res p o nses ma y be li mite d t o N o n -C R/ N o n -P D, P D, 
N E ( i.e. , res p o nses of C R, N A are n ot per mitte d). ■
(N ote:  N o res p o nse h as bee n eli mi n ate d as a n o pti o n here. ) 
If a s u bject has a missi n g t u m or stat us at a disease assess me nt f or 1 or m ore n o n -tar get lesi ons,  
r a diol o gic disease pr o gressi o n will 
be deter mi ne d if t he r e mai ni n g n o n- tar get lesi ons 
q ualitat i vel y de m o nstrate u ne q ui v ocal pr o gressi o n ( or if ot her criteria f or P D are met).
Dise ase Assess me nt O ver all Res p o nse per R E CI S T 1. 1
I n vesti gat or visit disease res p o nse will be pr o gra m mat icall y deri ve d o n t he data c ollect i on 
i nstr u me nt usi n g R E CI S T 1. 1 criteria base d u p o n tar get lesio n  res p o nse, n o n- tar get lesi on 
res p o nse, a n d ne w lesio n  data. Missi n g val ues i n an y of  tar get lesio n  res p o nse, n o n- tar get 
lesio n res p o nse, a n d ne w lesi o n data will res ult i n t he disease res p o nse n ot bei n g deri ve d.
P ossi ble val ues i ncl u de:

C R – C o m plete Res p o nse

P R – Parti al Res p o nse

S D – Sta ble Disease

P D – Pr o gressi ve Disease

N E – N o n- e val ua ble
T a ble A 1 
Assi g n me nt of res p o nses usi n g R E CI S T
T ar get 
Lesi o n 
Res p o nse
N o n -T ar get Lesi o n Res p o nse
Ne w Lesi o n
Deri ve d 
R E CI S T 
Dise ase 
Res p o nse
C R
C R or N A
N o
C R
C R
N o n -C R/ N o n -P D or N E
N o (or  N E)
P R
P R
C R or N o n -C R/ N o n -P D or N E or N A
N o (or  N E)
P R
S D
C R or N o n -C R/ N o n -P D or N E or N A
N o (or  N E)
S D
P D
A n y
A n y
P D
A n y
P D
A n y
P D
A n y
A n y
Yes
P D
N E
C R or N o n -C R/ N o n -P D or N E or N A
N o
N E
N A
C R
N o
C R
N A
N o n -C R/ N o n -P D
N o
S D ( N o n -C R/ N o n -P D) a
N A
N E or N A
N o (or  N E)
N E
N A
C R or N o n -C R/ N o n -P D
N E
S D ( N o n-C R/ N o n -P D) a
a Per R E CI S T 1. 1, “ S D ( N o n -C R/ N o n -P D)” is preferre d o ver “ S D” f or n o n -tar get disease si nce S D is i ncreasi n gl y 
use d as e n d p oi nt f or assess me nt of efﬁcac y  in s o me trials s o t o assi g n t his cate g or y w h e n n o lesi o ns ca n be 
meas ure d is n ot a d vi se d.


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
(N ote: “( or N E) ” v al ues u n der Ne w  Lesi o n will o nly be i ncl u de d i n c o nfir m ati o n of  
pr o gressi o n or c o nfir m ati o n of ne w  lesi o ns are re q uire d per pr ot oc ol. T he l ast 4 r o ws m ay be 
eli mi n ate d fr o m a ny st u dy t h at re q uires i de ntific ati o n of  at le ast o ne me as ur a ble lesi o n at 
B aseli ne. O ne m ay c h o ose t o all o w  suc h cells t o re m ai n if a n i n de pe n de nt ce ntr al revie w is 
i ncl u de d i n t he tri al.)
If a s ubject has a missi n g t u m or meas ure me nt at s o me assess me nt(s) f or 1 or m o re tar get lesio n s 
a n d crit eria f or P D are n ot ot her wise met, a n o verall res p o nse of  NE will be assi g ne d f or t h e 
assess me nt(s).
L oc ore gi o n al t her a p y
A n y s u bject recei vi n g l oc ore gio nal  thera p y , i ncl u di n g s ur ger y, w hile o n st u d y that direct l y 
affects o ne or mor e of  t he t ar g et lesio n s selecte d at baseli ne will be i de ntifie d. A s u bject wit h 
a s u bse q ue nt res p o nse or S D will be c o nsi dere d t o be n o n -e val ua ble at all disease assess me nts 
t hat occ ur o n or after t he date of l oc ore gi o nal t hera p y. Ot her wise, t he s u bject will be assesse d 
i g n ori n g t he l oc ore gi o nal t hera p y.
Assi g n me nt of D ates of Dise ase Pr o gressi o n or Dise ase Res p o nse
F or all a nal yses of  en d p o i nts res ultin g fr om a n a p plicat i on of  RE CI S T 1. 1 t o i n vesti gat or 
assesse d t u mor m eas ure me nts, t here ma y be cases i n w hic h disease assess me nts s pa n a series 
of dates. F or esta blis hi n g t he start date of  a su bse q ue nt l y c o nfir me d res p o nse i n w hic h t h e 
di sease assess me nt s pa ns m ulti ple da ys, t he date of res p o nse assi g ne d will be t he latest date of 
e val uat i ons c orres p o n di n g t o t he disease assess me nt. T he date of late st e valu ati o n will als o be 
assi g ne d f or a mi d -st u d y assess me nt s h o wi n g S D as t he date assi g ne d f or t he p ur p oses of 
ce ns ori n g d urati o n o f res p o nse, T T P a n d P F S. 
T he date of  PD will be t he first date at  whic h a n y o bject i ve dia g n osti c t est pr o vi des data 
i n dicat i n g P D. S pecificall y, f or R E CI S T 1. 1 t he date of P D will be t he earliest of t he f oll owi n g 
3 e val uat i on dates:

Date of  PD as i n dicate d b y tar get lesio n s:  If P D is trig gere d b y a c ha n ge i n s u m of 
di a meters of tar get lesi o ns, a n d t he dates of e val uati o n o f the tar get lesi o ns var y  for t he 
sa me assess me nt, assi g n t he first e val uat i on date a m o n g tar get l esio ns.

Date of  PD as i n dicate d b y n o n- tar get lesi ons:  If t he dates of  eval uat i on of  the n o n-
tar get lesio n s var y  for t h e sa me assess me nt, assi g n t he first e valuat i on date f or w hic h 
a n y n o n-tar get lesio n  e x hi bits a stat us of U ne q ui v ocal Pr o gressio n.


Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0

Date of P D as i n dicate d b y ne w lesi o ns:  If m ult i ple ne w lesi ons are i de nt ifie d a n d t he 
dates of  eval uat i on f or t he ne w lesi ons v ar y  for t he sa me assess me nt, assi g n t he first 
e val uat i on date f or w hic h a n y ne w lesi o n is detecte d.
I n sce nari os w here t he I n vesti gat or disease res p o nse is eit her a res p o nse or P D, a n d differs 
fr om t hat of  the a p plicat i on of  RE CI S T 1. 1 t o i n vesti gat or assesse d t u mor meas ure me nts 
se parate res p o nse a n d/ or pr o gressi o n dates will be re q uire d. Deter mi nat i on of t he start date of 
a s u bse q ue ntl y c o nfir me d res p o nse i n w hic h t he disease assess me nt s pa ns m u lti ple da ys 
r e mai ns t he sa me as descri be d pre vi o usl y. S pecificall y, t he date of  res p o nse assi g ne d will be 
t he latest date of e val uatio ns c orres p o n di n g t o t he di sease assess me nt. T he date of P D will be 
t he earliest date of e val uat i ons c orres p o n di n g t o t he disease assess me nt. 




Me dI m m u ne
Statistical A nal ysis Pla n f or Pr ot oc ol D 6 0 7 0 C 0 0 0 0 5
M E DI 9 4 4 7
0 1 A u g 2 0 2 2 ; Versi o n 3. 0 , 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 4 9
S A P te m plate versi o n 3. 0
O ver all Res p o nse at Si n gle Ti me P oi nt
Ta ble B 1 s h o ws h o w t he disease res p o nse will be deter mi ne d base d o n t he 
 criteria.
T a ble B 1 
Assi g n me nt of ti me -p oi nt res p o nse usi n g 
C CI
C CI
C CI




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-sa p-e d- 3
D oc u me nt Title:
d 6 0 7 0c 0 0 0 0 5-sa p-e d- 3
D oc u me nt I D:
D oc I D- 0 0 4 9 4 2 3 8 2
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
0 2- A u g- 2 0 2 2 0 8: 4 1 U T C
A ut h or A p pr o val
0 2- A u g- 2 0 2 2 0 8: 4 4 U T C
C o nte nt 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