Clinical trial NCT04993677
Conditions: Melanoma Carcinoma, Non-Small- Cell Lung
Keywords: Relapsed melanoma Refractory melanoma Metastatic uveal melanoma Metastatic PD-(L)1-naïve melanoma Non-squamous NSCLC NSCLC Non-small cell lung cancer Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2021-10-06; Completion date: 2024-11-25
Enrollment: 77 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is being done to see if an experimental drug (SEA-CD40) works when it's given with other cancer drugs to treat some types of cancer. It will also study side effects from the drug.

There are 2 parts in this trial. In one part, participants have melanoma that has come back after treatment or can't be removed by surgery. Participants in this part will get SEA-CD40 and pembrolizumab. In the other part, participants have non-small cell lung cancer (NSCLC) that has spread through their body. These participants will get SEA-CD40, pembrolizumab, carboplatin, and pemetrexed.

Detailed description:

Arms: arm 1: SEA-CD40 + pembrolizumab arm 2: SEA-CD40 + pembrolizumab + pemetrexed + carboplatin
Interventions: intervention 1: SEA-CD40 intervention 2: pembrolizumab (KEYTRUDA®) intervention 3: pemetrexed intervention 4: carboplatin
Intervention descriptions: intervention 1: Given into the vein (IV; intravenously); schedule is cohort-specific intervention 2: Given by IV; schedule is cohort-specific. intervention 3: Given by IV on Day 1 of each 21-day cycle. intervention 4: Given by IV on Day 1 of Cycles 1-4. Each cycle will be 21 days long.

Protocol documents:
Prot_000.pdf: 
This document contains information proprietary to Seagen Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Seagen Inc. You may disclose the contents of this document to study 
personnel under your supervision and to your Institutional Review Board (IRB) or Ethics Committee (EC) for the 
same purpose. You may not disclose the contents of this document to any other party, unless government regulations 
or laws require such disclosure, without prior written permission from Seagen Inc. Any supplemental information 
that may be added to this document is proprietary to Seagen Inc. and should be handled using the disclosure 
procedure described above.
Protocol Number:
SGNS40-002
Version:
Amendment 3; 05-Apr-2023
Protocol Title:
An Open-label, Phase 2 Basket Study of SEA-CD40 Combination 
Therapies in Advanced Malignancies
Investigational Product:
SEA-CD40
Brief Title:
A Study of SEA-CD40 Given with Other Drugs in Cancers
Phase:
2
IND Number:
156290
EudraCT Number:
2021‐002037‐42
Sponsor:
Seagen Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
Medical Monitor:
, MD
Seagen Inc.
Tel: 
Email: 
SAE Email or Fax:
See email or fax number specified on the SAE report form.
090177e1a1307203\Approved\Approved On: 05-Apr-2023 20:16 (GMT)
PPD
PPD
PPD


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2  of 1 3 5  
P R O T O C O L S Y N O P SI S  
Pr ot oc ol N u m ber  
S G N S 4 0 -0 0 2  
Versi o n  
A me n d me nt 3 ; 0 5 -A pr -2 0 2 3  
P h ase  
2  
Pr o d uct N a me  
S E A -C D 4 0  
S p o ns or  
Sea ge n  I nc. 
2 1 8 2 3 3 0t h Dri ve S E  
B ot hell, W A 9 8 0 2 1, U S A  
Pr ot oc ol Title  
A n O pe n -la bel, P hase 2 B as ket St u d y of S E A -C D 4 0 C o m bi nati o n T hera pies i n A d va nce d Mali g na ncies  
St u d y O bjecti ves  
Pri mar y O bj ecti ve  
C orres p o n di n g Pri mar y E n d p oi nt  
•  
T o e val uate t he a ntit u m or acti vit y of 
S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies  
•  
C o nfir me d O bj ecti ve Res p o ns e Rate ( O R R; 
c o nfir me d c o m plete res p o nse [ C R] or 
partial res p o nse [ P 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 Versi o n 1. 1 ( R E CI S T v 1. 1 ) per 
i n vesti gat or assess me nt  
Sec o n dar y O bj ecti ves  
C orres p o n di n g Sec o n dar y E n d p oi nts  
•  
T o e val uate t he safet y a n d t olera bilit y of 
S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies  
•  
T y pe, i nci de nce, se verit y, seri o us ness, a n d 
relate d ness of a d verse e ve nts ( A Es) 
•  
T y pe, i nci de nce, a n d se verit y of la b orat or y 
a b n or malities 
•  
Fre q ue nc y of treat me nt i nterr u pti o ns, d ose 
re d ucti o ns, a n d treat me nt disc o nti n uati o ns 
d ue t o A Es  
•  
T o e val uate c o ntr ol of disease  
•  
Disease c o ntr ol rate ( D C R; c o nfir me d C R , 
P R, a n d sta ble disease [ S D]) per 
i n vesti gat or assess me nt 
•  
T o e val uate d ura bilit y of res p o nse i n s u bj ects 
w h o res p o n d t o st u d y dr u g(s)  
•  
D urati o n of res p o nse ( D O R; d urati o n of 
c o nfir me d C R or P R) per i n vesti gat or 
assess me nt 
•  
T o e val uate pr o gressi o n -free s ur vi val (P F S ) 
a n d s ur vi val 
•  
P F S pe r i n vesti gat or assess me nt 
•  
O verall s ur vi val ( O S)  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3  of 1 3 5  
E x pl orat or y O bj ecti ves   
C orres p o n di n g E x pl orat or y E n d p oi nts  
•  
T o c haracterize t he p har mac o ki netics  ( P K) of 
S E A -C D 4 0 a n d i nci de nce of a nti dr u g 
a nti b o dies ( A D As ) w he n S E A -C D 4 0 is 
a d mi nistere d i n c o m bi nati o n wit h ot her 
t hera pies 
•  
Esti mates of selecte d P K para meters  
•  
I nci de nce of A D As 
C o h orts 1 , 2 , a n d 3 (Mel a n o m a ): 
•  
T o e val uate selecte d p har mac o d y na mic 
para meters of i nterest f or S E A -C D 4 0  
C o h orts 1, 2, a n d 3 ( Mel a n o m a):  
•  
E x pl orat or y c orrelati o ns bet wee n Q T c a n d 
plas ma c o nce ntrati o ns of S E A -C D 4 0  
•  
T o assess e x pl orat or y bi o mar kers of 
res p o nse, t o xicit y, a n d resista nce of 
S E A -C D 4 0 i n c o m bi nati o n wit h ot her 
t hera pies 
•  
Act ual a n d c ha n ge fr o m baseli ne val ues i n 
i m m u ne s u bsets a n d c yt o ki nes i n peri p heral 
bl o o d  
•  
T o e val uate t he a ntit u m or acti vit y of 
S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies 
per M o difie d R E CI S T  1. 1 f or I m m u ne -base d 
T hera p e utics (i R E CI S T)  
•  
C o nfir me d O R R ( i m m u ne c o m plete 
res p o nse [i C R] or i m m u ne partial res p o nse 
[i P R]) acc or di n g t o i R E CI S T 
•  
T o e val uate patie nt -re p orte d o utc o mes of 
disease/treat me nt -relate d s y m pt o ms, 
healt h -relate d q ualit y of life (H R Q o L ), a n d 
f u ncti o n  
All C o h orts : 
•  
Act ual a n d c ha n ge fr o m baseli ne sc ores o n 
t he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer q ualit y of life 
q ue sti o n naire ( E O R T C Q L Q-C 3 0)  
C o h orts 4 a n d 5 o nly  ( N S C L C):  
•  
Ti me -t o-deteri orati o n  (T T D)  i n eit her 
c o u g h, d ys p nea, or c hest pai n ( w hic he ver 
deteri orates first) as meas ure d b y t he 
N o n -S mall Cell L u n g Ca ncer S y m pt o m 
Assess me nt Q uesti o n naire ( N S C L C -S A Q)  
•  
Act ual a n d c ha n ge fr o m baseli ne val ues i n 
N S C L C -S A Q d o mai ns a n d t otal sc ores  
St u d y P o p ul ati o n  
Eli gi ble s u bj ects are at least 18  years of a ge wit h u nresecta ble metastatic ca ncer. T u m or t y pes e val uate d will i ncl u de 
rela pse d a n d/ or refract or y mel a n o ma , u veal mela n o ma, pr o gra m me d cell deat h pr otei n 1 ( P D -1) or P D -1 li ga n d  1 
( P D-L 1) ( P D -( L) 1-nai ve  mela n o ma, a n d n o n -s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C L C). S u bj ect s m ust ha ve a n 
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 sc ore of 0 or 1, meas ur a ble disease per 
R E CI S T  v 1. 1, a n d a d e q uate baseli ne la b orat or y data.  E xcl usi o n criteria i ncl u de, b ut are n ot li mite d t o,  h ist or y of 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4  of 1 3 5  
a n ot her mali g na nc y wit hi n 3  years, k n o w n acti ve ce ntral ner v o us s yste m ( C N S) metastases , a n d pre vi o us e x p os ure 
t o C D 4 0-tar gete d t hera p y. 
S u bj ect s wit h rela pse d a n d/ or refract or y mela n o ma ma y ha ve recei ve d u p t o 3  pri or li nes of t hera p y f or a d va nce d 
disease  a n d m ust ha ve pr o gresse d  o n treat me nt wit h a n a nti -P D -( L) 1 m o n ocl o nal a nti b o d y ( m A b ) a d mi nistere d 
eit her as m o n ot hera p y, or i n c o m bi nati o n wit h ot her c hec k p oi nt i n hi bit ors or ot her t hera pi es.  S u bj ects wit h 
n o n -u veal/ n o n -oc ular rela pse d a n d/ or refract or y mela n o ma wit h a tar geta ble B R A F m utati o n m ust ha ve bee n treate d 
wit h, bee n i nt olera nt of, or decli ne d treat me nt wit h B R A F/ M E K tar gete d t hera p y pri or t o st u d y e ntr y.   
S u bj ect s wit h u veal mela n o ma m ust n ot ha ve recei ve d pri or treat me nt f or a d va nce d or metastatic disease e xce pt 
a dj u va nt/ ne o a dj u va nt i m m u n ot hera p y s uc h as i nterfer o n, a nti -P D -( L) 1, or a ntic yt ot o xic T -l y m p h oc yte-ass ociate d 
pr otei n 4 ( C T L A -4 ) if rela pse di d n ot o cc ur d uri n g treat me nt or wit hi n 6 m o nt hs of treat me nt disc o nti n uati o n . 
S u bj ect s wit h u veal mela n o ma m ust ha ve ha d n o pri or re gi o nal, li ver -directe d t hera p y i ncl u di n g c he m ot hera p y, 
ra di ot hera p y, or e m b olizati o n. 
S u bj ect s wit h P D -( L) 1-nai ve  mela n o ma  m ust n ot ha ve recei ve d pri or treat me nt f or a d va nc e d or metastatic disease 
e xce pt a dj u va nt/ ne o a dj u va nt i m m u n ot hera p y s uc h as i nterfer o n, a nti -P D -( L) 1, or a nti-C T L A -4 if rela pse di d n ot 
occ ur d uri n g treat me nt or wit hi n 6  m o nt hs of treat me nt disc o nti n uati o n. S u bj ect s wit h P D -( L) 1-nai ve  mela n o ma a n d 
a tar geta ble B R A F m utati o n ma y ha ve recei ve d pri or B R A F/ M E K tar gete d t hera p y if c o m plete d 4  wee ks pri or t o 
first d ose of st u d y dr u g.  
S u bj ect s wit h n o n-s q ua m o us N S C L C m ust ha ve sta ge I V disease per A merica n J oi nt C o m mittee o n Ca ncer ( AJ C C ) 
8t h e diti o n, m ust ha ve n o k n o w n dri ver m utati o ns f or w hic h tar gete d t hera p y is a vaila ble, a n d m ust n ot ha ve 
recei ve d pri or t hera p y f or metastatic disease. A dj u va nt/ ne oa dj u va nt t hera p y is all o we d f or n o n -metastatic disease if 
f ull y c o m plete d at least 1 2  m o nt hs pri or t o dia g n osis of metastatic disease.  
F ull eli gi bilit y criteria are defi ne d i n Secti o n  4 .  
N u m ber of Pl a n ne d S u bject s 
U p t o a p pr o xi matel y 2 0 0  s u bjects ma y be e nr olle d i n t his st u d y. T his i ncl u des u p t o a p pr o xi matel y 4 0  s u bj ects 
e nr olle d i n eac h c o h ort.  
St u d y Desi g n  
T his p hase 2, gl o bal, o pe n -la bel, m ultice nter trial is desi g ne d t o assess t he acti vit y, safet y, a n d t olera bilit y of 
S E A -C D 4 0 i n c o m bi nati o n wit h sta n dar d of care t hera pies i n s u bj ects wit h selecte d s oli d t u m ors. 
S u bj ect s wit h t he f oll o wi n g s oli d t u m ors will be e nr olle d:  
 
T u m or t y pe  
St u d y dr u gs  
C o h ort 1  
Rela pse d/refract or y mela n o ma  
S E A -C D 4 0 a n d pe m br oliz u ma b  
C o h ort 2  
U veal mela n o ma  
C o h ort 3  
P D -(L) 1 -nai ve  mela n o ma  
C o h ort 4  
N o ns q ua m o us N S C L C; P D -L 1 1 % – 4 9 % T P S  
S E A -C D 4 0, car b o plati n, pe metre xe d, 
a n d pe m br oliz u ma b  
C o h ort 5  
N o ns q ua m o us N S C L C ; P D-L 1 < 1 % T P S  
A safet y m o nit ori n g c o m mitte e ( S M C) will m o nit or t he safet y of s u bj ects. 
F or C o h orts 1 , 2 , a n d 3 ( mel a n o m a), i nitiall y, u p t o 15  s u bj ects ma y e nr oll i n eac h c o h ort. I nteri m safet y a n d 
efficac y a nal yses will be perf or me d f or eac h c o h ort after 1 5  s u bj ects ha ve recei ve d st u d y dr u g a n d are res p o nse 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5  of 1 3 5  
e val ua ble. C o h orts ma y c o nti n ue t o e nr oll u p t o a n a d diti o nal 2 5  s u bj ects, f or a t otal of u p t o a p pr o xi matel y 
4 0  s u bj ects i n eac h c o h ort. D ue t o differe n ces i n sta n dar d of care, s u bj ects i n Fra nce will n ot be e nr olle d i n C o h ort  1.  
F or C o h orts 4 a n d 5 ( N S C L C), i nitiall y, 6  t otal s u bj ects will be e nr olle d acr oss t he 2 c o h orts; safet y will be 
assesse d after t he first treat me nt c ycle. If a p pr o ve d b y t he S M C, C o h orts 4  a n d 5  ma y c o nti n ue t o e nr oll u p t o 
1 5  s u bj ects per c o h ort, f oll o we d b y c o nti n uati o n t o u p t o 4 0  t otal s u bj ects per c o h ort if a p pr o priate.  
Res p o nse will  be assesse d e ver y 6  wee ks  ( Q 6 W) fr o m t he date of first d ose f or 24  wee ks  a n d e ver y 1 2  wee ks 
t hereafter u ntil c o nfir me d dise ase pr o gressi o n. Dia g n ostic-q ualit y c o m p ute d t o m o gra p h y ( C T) sca ns a n d/ or 
ma g netic res o na nce i ma gi n g ( M RI) will  be perf or me d o n t he c hes t a n d a b d o me n (a n d pel vis f or C o h orts 1, 2, 
a n d  3) . S u bj ect s’ cli nical d ata m ust b e a vaila ble f or case re p ort f or m ( C R F ) s o urce verificati o n. C o pies of all t u m or 
i ma ges m ust b e ma d e a vaila ble f or re vie w b y t he s p o ns or ( or its desi g nee) u p o n re q uest. T he s p o ns or ma y re q uest 
t hat i ma ges be se nt t o a ce ntral ve n d or t o be hel d f or later re vie w. 
T he deter mi nati o n of a ntit u m or acti vit y will be base d o n o bjecti ve res p o nse rate  (O R R ) assess me nts as defi ne d b y 
R E CI S T versi o n 1. 1 a n d b y i R E CI S T. Treat me nt deci si o ns b y t he i n vesti gat or will be base d o n i R E CI S T .  
S u bj ect s wit h u nc o nfir me d pr o gressi ve disease ( P D) per i R E CI S T (i U P D) ma y c o nti n ue st u d y treat me nt at t he 
discreti o n of t he i n vesti gat or, wit h a d diti o nal c o nse nt, if all of t he f oll o wi n g criteria are met : 
•  
E vi de nce of cli nical be nefit, defi ne d as t he sta bilizati o n or i m pr o ve me nt of disease relate d s y m pt o ms, as 
assesse d b y t he i n vesti gat or  
•  
N o s y m pt o ms or si g ns (i ncl u di n g w orse ni n g la b orat or y val ues) i n dicati n g u ne q ui v ocal disease 
pr o gressi o n  
•  
N o decli ne i n E C O G perf or ma nce stat us t hat ca n be attri b ute d t o disease pr o gressi o n  
•  
N o t u m or gr o wt h at critical a n at o mical sites (e g, le pt o me ni n geal disease) t hat ca n n ot be ma na ge d a n d 
sta bilize d b y pr ot oc ol--all o we d me dical i nter ve nti o ns pri or t o re peat d osi n g  
I n vesti g ati o n al Pr o d uct, D ose, a n d M o de of A d mi nistr ati o n 
C o h orts 1 , 2 , a n d 3 ( Mel a n o m a) 
S E A -C D 4 0 will be a d mi nister e d as a n i ntra ve n o us (I V) i nf usi o n at a d ose of 1 0 mc g/ k g o n Da y  1  a n d Da y  2 2  of 
eac h 4 2  -da y c ycle.  
P e m br oliz u ma b will be a d mi nistere d I V o n Da y  8 of eac h 4 2 -da y c ycle. T he d ose of pe m br oliz u ma b is t he sta n dar d 
a p pr o ve d d ose of 4 0 0  m g Q 6 W f or a p pr o ve d i n dicati o ns. 
C o h orts 4 a n d 5 ( N S C L C) 
S E A -C D 4 0 will be a d mi nister e d as a n I V i nf usi o n at a d ose of 1 0  mc g/ k g o n Da y  3 of eac h 2 1 -da y c ycle.  
P e m br oliz u ma b will be a d mi nistere d I V o n Da y 1 of eac h 2 1 -da y c ycle. T he d ose of pe m br oliz u ma b is t he sta n dar d 
a p pr o ve d d ose of 2 0 0  m g e ver y 3  wee ks ( Q 3 W) f or a p pr o ve d i n dicati o ns. 
P e metre xe d will be a d mi nister e d o n Da y 1 of eac h 2 1 -da y c ycle at a d ose of 5 0 0  m g/ m 2.  
Car b o plati n will be a d mi nister e d o n Da y 1 of C ycles 1  t o 4  at a d ose of area u n der t he c o nc e ntrati o n -ti me c ur ve 
( A U C) 5  m g per milliliter per mi n ute.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6  of 1 3 5  
D ur ati o n of Tre at me nt  
S u bj ect s w h o ac hie ve sta ble disease ( S D) or better ma y c o nti n ue st u d y treat me nt f or a p pr o xi matel y 2  years or u ntil 
u nacce pta ble t o xicit y, c o nfir me d disease pr o gressi o n, wit h dra wal of c o nse nt, or st u d y ter mi nati o n, w hic he ver occ urs 
first. 
P e m br oliz u ma b a d mi nistrati o n will be disc o nti n ue d o nce t he  s u bj ect has c o m plete d a p pr o xi matel y 2  years wit h 
pe m br oliz u ma b ( 3 5  a d mi nistr ati o ns  Q 3 W  or 1 8  a d mi nistrati o ns Q 6 W ). 
A ntit u m or Acti vit y  Assess me nts  
A ntit u m or acti vit y will be ass esse d b y ra di o gra p hic t u m or i ma gi n g at pr ot oc ol -s pecifie d ti me p oi nts. Res p o nse 
assess me nt f or pri mar y a n d sec o n dar y efficac y e n d p oi nts will be e val uate d b y t he i n vesti gat or usi n g R E CI S T  v 1. 1. 
S u bj ect s will be f oll o we d f or res p o nse assess me nts u ntil dise ase pr o gressi o n, s u bse q ue nt ca ncer t hera p y, st u d y 
ter mi nati o n b y t he s p o ns or, or deat h, w hic he ver c o mes first.  
P h ar m ac o ki netic a n d I m m u n o ge nicit y Assess me nts  
Bl o o d plas ma sa m ples f or p har mac o ki netics ( P K ) a n d ser u m sa m ples f or a nti dr u g a nti b o dies ( A D A) assess me nts of 
S E A -C D 4 0 will be c ollecte d at pr ot oc ol -defi ne d ti me p oi nts. P K para meters t o be esti mate d i ncl u de, b ut are n ot 
li mite d t o, A U C a n d ma xi m u m c o nce ntrati o n ( C ma x ). 
P h ar m ac o d y n a mic Assess me nts  
I n C o h orts 1, 2, a n d 3  o nl y, t he c orrelati o n bet wee n Q T c a n d plas ma c o nce ntrati o ns of S E A -C D 4 0 will be ass esse d.  
Bi o m ar ker Assess me nts  
P eri p heral bl o o d a n d t u m or tiss ue will b e c ollecte d at pr ot oc ol -s pecifie d ti me p oi nts. E x pl orat or y, pre dicti ve, a n d 
pr o g n ostic bi o mar kers ass ociate d  wit h res p o nse, resista nce, or safet y o bser vati o ns will be m o nit ore d bef ore a n d  
d uri n g treat me nt  wit h S E A -C D 4 0 . T hese c ollecti o ns ma y b e disc o nti n ue d at t he discreti o n of t he sp o ns or . 
T o c haracterize t he mali g na nc y a n d res p o nse t o st u d y treat me nt, bi o mar ker assess me nts i n t u m or bi os peci me ns ma y 
i ncl u de, b ut are n ot li mite d t o, c haracterizati o n of t he t u m or micr oe n vir o n me nt, P D -L 1 e x pressi o n,  dr u g tar get(s), 
t u m or s u bt y pi n g, pr ofili n g of s o matic m utati o ns a n d/ or ge ne e x pressi o n. Assa ys ma y i ncl u de, b ut are n ot li mite d t o, 
i m m u n o hist oc he mistr y (I H C) a n d ne xt ge nerati o n se q ue nci n g of R N A  a n d D N A.  
T o c haracterize t he mali g na nc y a n d i m m u ne res p o nse, bi o mar ker assess me nts i n peri p heral bl o o d ma y i ncl u de, b ut 
are n ot li mite d t o, meas ure me nt of baseli ne a n d dr u g -i n d uce d c ha n ges i n circ ulati n g bl o o d cell p o p ulati o ns, 
c yt o ki nes/c he m o ki nes , ge ne e x pressi o n, c yt o ge netics, ge neti c p ol y m or p his ms, s o matic m utati o ns ass ociate d wit h 
ca ncer, a n d circ ulati n g i m m u n e f u ncti o n a n d disease mar kers. Assa ys ma y i ncl u de, b ut are n ot li mite d t o, ne xt 
ge nerati o n se q ue nci n g of w h ole bl o o d, pr ote o mic met h o d ol o gies, i m m u n oassa ys as a mar ker of t u m or res p o nse or 
t hera p y resista nce, a n d mar kers of i m m u ne f u ncti o n, i ncl u di n g a b u n da nce of i m m u ne cell s u bsets a n d c yt o ki nes. 
Met h o ds of a nal ysis ma y i ncl u de, b ut are n ot li mite d t o, i m m u n oassa ys s uc h as fl o w c yt o metr y a n d e nz y me -li n ke d 
i m m u n os or be nt assa ys ( E LI S A). 
S afet y Assess me nts  
Safet y assess me nts will i ncl u d e t he s ur veilla nce a n d rec or di n g of a d verse e ve nts  ( A Es) i ncl u di n g seri o us a d verse 
e ve nts ( S A Es) , rec or di n g of c o nc o mita nt me dicati o n, a n d meas ure me nts of pr ot oc ol-s pecifie d p h ysical e xa mi nati o n 
fi n di n gs, vital si g ns, pr ot oc ol -s pecifie d la b orat or y tests, E C O G stat us, electr ocar di o gra ms ( E C Gs ), a n d pre g na nc y 
testi n g. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7  of 1 3 5  
P atie nt -Re p orte d O utc o me Assess me nts  
P atie nt -re p orte d o utc o me (P R O ) assess me nts will o nl y be a d mi nistere d t o s u bj ects e ntere d i n t he st u d y after 
c o m pleti o n of e nr oll me nt f or t he i nteri m a nal ysis i n eac h c o h ort.  
All C o h orts  
T o assess P R O s of dise ase/tr e at me nt -rel ate d s y m pt o ms, he alt h -rel ate d q u alit y of life ( H R Q o L ), a n d f u ncti o n, 
t he E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer q u alit y of life q uesti o n n aire ( E O R T C 
Q L Q -C 3 0 ) will  be a d mi niste re d t o s u bjects at b aseli ne, e ver y 21  d a ys ( Q 2 1 d) d uri n g tre at me nt c ycles , a n d at 
t he e n d of tre at me nt ( E O T) visit.  P R O c ollecti o ns m a y b e disc o nti n ue d at t he discreti o n of s p o ns or. C o h orts 4 
a n d 5 o nl y  ( N S C L C) 
T he N S C L C — S A Q will b e us e d t o assess se verit y of t he f oll o wi n g N S C L C s y m pt o ms: c o u g h, pai n, d ys p nea, 
fati g ue, a n d a p petite. T he N S C L C— S A Q will be a d mi nistere d a t baseli ne,  o n Da y  1 of ea c h treat me nt c ycle, a n d t he 
E O T  visit. T he P atie nt Gl o bal I m pressi o n scales of s y m pt o m se verit y ( P GI — S) a n d s y m pt o m c ha n ge ( P GI — C) will 
als o be i ncl u de d. T he P GI -S will be a d mi nistere d at baseli ne a n d at t he E O T  visit. T he P GI -C w ill be a d mi nistere d 
o n Da y  1  of C ycle  2 a n d be y o n d . 
Sc ores will be calc ulate d base d o n t he res pecti ve i nstr u me nts’ sc ori n g ma n uals.   
St atistic al M et h o ds  
T he pri mar y a nal ysis of t he st u d y will be perf or me d se parat el y f or eac h c o h ort w he n all treate d s u bj ects i n t he 
c o h ort ha ve bee n f oll o we d f or at least 6  m o nt hs or c o me off st u d y, w hic he ver c o mes first. T he pri mar y efficac y 
e n d p oi nt of c o nfir me d O R R p er R E CI S T v 1. 1  will be esti mate d f or eac h c o h ort base d o n t he res p o nse e val ua ble 
a nal ysis set , c o m prisi n g s u bj ects wit h meas ura ble  disease at baseli ne w h o recei ve d a n y a m o u nt of st u d y treat me nt 
a n d ha d at least 1 p ost baseli ne  disease assess me nt per R E CI S T or disc o nti n ue d st u d y treat me nt.  T he p oi nt esti mate 
of O R R a n d 9 5 % e xact c o nfi d e nce i nter vals ( C Is) usi n g t he Cl o p per -P ears o n met h o d will be pr o vi de d f or eac h 
c o h ort.  
I nteri m f utilit y a nal yses will b e perf or me d se p aratel y f or eac h c o h ort after a p pr o xi matel y 1 5  s u bj ects of a gi ve n 
c o h ort ha ve bee n treate d a n d are res p o nse e val ua ble. T he Ba yesia n pre dicti ve pr o ba bilit y of s uccess ( P p o S) 
a p pr oac h will be use d  t o i nf or m decisi o n-ma ki n g f or c o nti n ue d e nr oll me nt . A c o h ort is c o nsi dere d “s uccessf ul” if 
t he 9 0 % CI of t he res p o nse rat e at t he ma xi m u m sa m ple size e xcl u des t he bac k gr o u n d rate. At t he ti me of eac h 
i nteri m a nal ysis, t he Pp o S will be calc ulate d. A P p o S < 5 % i n dicates t hat it is u nli kel y t he O R R will be better t ha n 
t he res p o nse rate of c urre nt sta n dar d of care at t he e n d of t he c o h ort gi ve n t he i nteri m res ult. Base d o n efficac y a n d 
safet y data, t o get her with t he P p o S, a c o h ort ma y be st o p pe d earl y b y t he s p o ns or. A c o h ort ma y als o be 
disc o nti n ue d at a n y p oi nt at t he discreti o n of t he s p o ns or.  
Safet y meas ure me nts will be s u m marize d b y descri pti ve statistics base d o n t he safet y a nal ysis set. T he safet y 
a nal ysis set will i ncl u de all s u bj ects w h o recei ve d a n y a m o u nt of st u d y treat me nt.  
P R O o utc o mes e n d p oi nts will be s u m marize d usi n g descri pti ve statistics. Ti me -t o-deteri orati o n ( T T D ) a nal yses will 
als o be perf or me d f or t he N S C L C -S A Q q uesti o n naire.  
F or a sa m ple si ze of 4 0  s u bj ects per c o h ort, ass u mi n g c o nfir me d O R R is bet wee n 3 0 % a n d 8 0 %, t he 2 -si de d 9 5 % 
e xact CI are s u m marize d bel o w:  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8  of 1 3 5  
C o nfir me d O R R  
9 5 % E xact CI ( N = 4 0)  
3 0 %  
( 1 7 %, 4 7 %) 
4 0 %  
( 2 5 %, 5 7 %) 
5 0 %  
( 3 4 %, 6 6 %) 
6 0 %  
( 4 3 %, 7 5 %) 
7 0 %  
( 5 3 %, 8 3 %) 
8 0 %  
( 6 4 %, 9 1 %) 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9  of 1 3 5  
S C H E D U L E O F E V E N T S  
T a bl e  1 : 
S c h e d ul e of E v e nt s f or C o h ort s 1, 2, a n d 3 ( M el a n o m a)  
 
 
Scree ni n g/ Baseli ne  
E nr oll me nt  
E ver y 4 2 -da y c ycle  
E O T  
F oll o w -u p  
S ur vi val 
f oll o w-u p  
 
Da y  
D – 2 8 
t o 1 
D – 7 t o 1 
( u nless 
ot her wise 
state d) 
Wit hi n 7 D 
of 1 st d ose  
D 1  
D 8  
D 2 2  
D 3 6  
Wit hi n  
3 0 – 3 7 D 
of last 
d ose A  
E ver y 1 2  w ks 
( u nless ot her wise 
state d) 
E ver y 1 2  w ks  
( u nless 
ot her wise 
state d) 
 
Visit wi n d o w  
 
 
 
± 2 d  
± 2 d  
± 2 d  
-2  d/ + 5  d  
 
± 1  w k  
± 1  w k  
Scree ni n g/ Baseli ne 
Ass ess me nts  
I ncl usi o n/ E xcl usi o n, me dical hist or y 
X  
 
S u b mit eli gi bilit y c o nfir mati o n t o  
S p o ns or pri or t o treat me nt  
C ycle  1 B  
 
 
 
 
 
 
I nf or m e d c o nse nt 
X  
 
 
 
 
 
 
 
 
M RI of brai n
C  
X  
 
 
 
 
 
 
 
 
 
Safet y Ass ess me nts  
Uri nal ysis, i ncl u di n g U P C rati o  
 
X  
X D  
 
 
 
 
 
 
Pre g na nc y test (s u bjects of 
c hil d beari n g p ote ntial) 
 
X E  
X F 
 
X G  
 
X  
X H  
 
P h ysical e xa mi nati o n  
 
X  
X I 
 
 
 
X  
X  
 
Wei g ht  
 
X  
X I 
 
 
 
X  
 
 
Hei g ht ( hei g ht meas ure d wit hi n t he 
pri or 1 2  m o nt hs ma y be utilize d)  
X  
 
 
 
 
 
 
 
 
C B C wit h differe ntial  
 
X  
X I 
X I,J 
X I 
 
X  
 
 
C he mistr y pa nel  
 
X  
X I 
X I,J 
X I 
 
X  
X (at first F U 
o nl y)  
 
T h yr oi d pa nel  
X  
 
X I 
 
 
 
X  
X (at first F U 
o nl y)  
 
H g b A 1c  
X  
 
 
 
 
 
X  
 
 
Vital si g ns  
 
X  
X  
X J 
X  
 
X  
 
 
P T/a P T T/I N R K  
 
X  
 
 
 
 
X  
 
 
E C O G perf or ma n ce stat us  
 
X  
X I 
 
 
 
X  
 
 
E C G  
X  
 
See  Ta ble  4  f or o n-treat me nt E C G 
ti me p oi nts (first 30  s u bjects o nl y) 
X  
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0  of 1 3 5  
 
 
Scree ni n g/ Baseli ne  
E nr oll me nt  
E ver y 4 2 -da y c ycle  
E O T  
F oll o w -u p  
S ur vi val 
f oll o w-u p  
 
Da y  
D – 2 8 
t o 1 
D – 7 t o 1 
( u nless 
ot her wise 
state d) 
Wit hi n 7 D 
of 1 st d ose  
D 1  
D 8  
D 2 2  
D 3 6  
Wit hi n  
3 0 – 3 7 D 
of last 
d ose A  
E ver y 1 2  w ks 
( u nless ot her wise 
state d) 
E ver y 1 2  w ks  
( u nless 
ot her wise 
state d) 
 
Visit wi n d o w  
 
 
 
± 2 d  
± 2 d  
± 2 d  
-2  d/ + 5  d  
 
± 1  w k  
± 1  w k  
C o nc o mita nt me dicati o ns  
Relate d t o st u d y pr oce d ures L 
C ollect fr o m Da y  1 pre d ose t hr o u g h safet y r e p orti n g 
peri o d of st u d y dr u g(s)  
 
 
A E c ollecti o n  
X M  
 
Tr eat me nt  
S E A -C D 4 0 a d mi nistrati o n  
 
 
 
X  
 
X  
 
 
 
 
Pe m br oliz u ma b a d mi nistrati o n  
 
 
 
X  
 
 
 
 
 
P K/I m m u n o ge nicit y
/ Bi o mar ker 
I nitiate retrie val of arc hi ve d t u m or 
s peci me n 
 
X  
 
 
 
 
 
 
 
T u m or bi o ps y ( F F P E) N  
X O  
 
 
 
 
C ycle  1 P 
 
 
 
Bl o o d sa m ple c ollecti o n  
See Ta ble  3  f or sa m ple c ollecti o n details. 
N ote sa m ple c ollecti o ns o n D a y  2 of C ycles 1 a n d 2.  
 
 
Res p o nse 
Ass ess me nt  
C T or M RI of c hest, a b d o me n, pel vis 
(a n d nec k a n d/ or brai n if 
d oc u me nte d or s us pecte d 
i n v ol ve me nt)Q  
X  
 
 
X R  
 
 
 
X S 
X T  
 
Disease a n d s ur vi val stat us U  
 
 
 
 
 
 
 
X  
X  
P R O Assess me nts  
E O R T C Q L Q -C 3 0  
 
X V  
X  
 
 
 
X  
 
 
A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C T =c o m p ute d t o m o gra p h y; D = da y; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E C G =elect r ocar di o gra m; E O R T C Q L Q -Q 3 0 = E ur o pea n 
Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer q ualit y of lif e q uesti o n naire; E O T =e n d of tr eat me nt; F F P E =f or mali n -fi xe d paraffi n e m be d de d; F U =f oll o w-u p; H g b = he m o gl o bi n; M RI = ma g netic 
res o na nce i ma gi n g; P K = p har mac o ki netic; P R O = patie nt-re p orte d o utc o me; P T/a P T T/I N R = pr ot hr o m bi n ti me/acti vate d partial t hr o m b o plasti n ti me/i nter nati o nal n or malize d rati o; U P C = uri ne pr otei n 
creati ni ne; w k = wee k  
A  E O T e val uati o ns m ust be o btai ne d bef ore t he i nitiati o n of n o n -pr ot oc ol a ntica ncer treat me nt. If E O T e val uati o ns are c o m plete d bef ore 3 0  da ys f oll o wi n g t he last st u d y treat me nt, c o n d uct a p h o ne 
scree n 3 0– 3 7  da ys f o ll o wi n g t he s u bject’s last st u d y treat me nt t o e ns ure t hat n o c ha n ges i n A E pr ofile ha ve occ urre d. 
B  C o nfir m eli gi bilit y pri or t o assess me nts a n d d osi n g o n C ycle  1 Da y  1.  
C  If a n M RI of t he brai n is me dicall y c o ntrai n dicate d, C T wit h c o ntrast is a n acce pta ble alter nati ve. 
D  Uri nal ysis s h o ul d be c o n d ucte d e ver y 3  c ycles starti n g i n C ycle 3. Ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g.  
E  C ollect o n St u d y Da y – 3 t o 1.  
F  I n C ycle 1, n ot re q uire d if perf or me d wit hi n 3  da ys pri or t o visit. I n all ot her c ycles, n ot re q uire d if perf or me d wit hi n 7  da ys pri or t o visit.  
G  N ot re q uire d if perf or me d wit hi n 7  da ys pri or t o d osi n g.  
H  After t he last d ose of st u d y dr u g, pre g na nc y tests will be perf or me d o nce a m o nt h f or 1 2 0  da ys or  per l ocal re g ulati o ns, w here a p plica ble. S u bjects ma y d o m o nt hl y h o me pre g na nc y tests a n d re p ort 
i nteri m res ults at t he f oll o w-u p visits.  
I Ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g.  
J C ollect pri or t o pe m br oliz u ma b a d mi nistrati o n.  
K  A n y s u bject rec ei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial as cli nicall y i n dicate d.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1  of 1 3 5  
L  Fr o m  ti me of i nf or me d c o nse nt. 
M  C ollect A E s if seri o us f or 90  da ys after t he last st u d y treat me nt a n d i m m u ne -relate d a d verse e ve nts (ir A Es) t hr o u g h t he first f oll o w -u p visit. If a s u bject starts a ne w a ntica ncer t hera p y, c ollecti o n of 
seri o us a d verse e ve nts ( S A Es) t hat are n ot relate d t o st u d y treat me nt a n d ir A Es ma y be st o p pe d 3 0  da ys after t he cessati o n of st u d y treat me nt (see  Secti o n 7. 7. 1. 3  f or details). St u d y treat me nt-relate d 
S A Es t hat occ ur after t he safet y re p orti n g peri o d s h o ul d als o be re p orte d t o t he s p o ns or.  
N  If a t u m or sa m ple is o btai ne d as part of sta n dar d of care d uri n g t he st u d y, a part of t hat sa m ple s h o ul d be s u b mitte d t o t he s p o ns or if a vaila ble.  
O  If arc hi ve d t u m or s peci me n is n ot a vaila ble, fres h t u m or bi o ps y is re q uire d. F or s u bjects w h o will ha ve a n on -treat me nt bi o ps y, a fres h baseli ne bi o ps y is re q uire d if arc hi val sa m ple c ollecte d wit hi n 
3 0  da ys pri or t o a ntici pate d first d ose of st u d y dr u g is n ot a vaila ble (see Secti o n 7. 4  f or details) 
P  Re q uire d f or s u bjects e nr olle d after c o m pleti o n of e nr oll me nt f or t he i nteri m a nal ysis i n C o h orts 1 a n d 2. O pti o nal f or all o t her s u bjects. T he sa me t u m or site s h o ul d be bi o psie d at baseli ne a n d o n 
treat me nt if p ossi ble (see S ecti o n 7. 4  f or details) 
Q  F or eac h assesse d lesi o n, t he sa me m o dalit y s h o ul d be use d t hr o u g h o ut t he d urati o n of t he st u d y.  
R  Res p o nse s h o ul d be assesse d b y C T or M RI e ver y 6  wee ks  ( ± 3 da ys) fr o m C ycle  1 Da y  1 re gar dless of d ose dela ys f or 2 4  wee ks a n d e ver y 1 2  wee ks ( ± 1  wee k) t hereafter.  
S  N ot re q uire d if c o n d ucte d 4  wee ks pri or t o E O T.  
T  Res p o nse assess me nts will c o nti n ue u ntil disease pr o gressi o n (i C P D per i R E CI S T), i nitiati o n o f ne w a ntica ncer t hera p y, st u d y ter mi nati o n b y t he s p o ns or, or deat h, w hic he ver c o mes first.  
U  After disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt, f oll o w -u p f or disease a n d s ur vi val stat us, a n d s u bse q ue nt a ntica ncer treat me nt i nf or mati o n u ntil deat h or st u d y cl os ure. Assess me nt 
of s ur vi val ca n be d o ne via p u blic or h os pital/ me dical rec or ds or a p h o ne call.  
V  Patie nt  re p orte d o utc o me ( P R O) assess me nts will o nl y be a d mi nistere d t o s u bjects e ntere d i n t he st u d y after c o m pleti o n of e nr oll me nt f or t he i nteri m a nal ysis i n eac h c o h ort. All P R O assess me nts 
s h o ul d be c o m plete d b y t he s u bject pri or t o disc ussi o n of t he s u bject’s healt h state, la b res ults, healt h rec or d, a n d pri or t o a n y st u d y dr u g a d mi nistrati o n or ot her st u d y assess me nt.   
N ote:  Eac h  ti me a s u bject disc o nti n ues a c o m p o ne nt of c o m bi nati o n t hera p y b ut is c o nti n ui n g wit h a n ot her c o m p o ne nt, cli nic visits a n d safet y assess me nts (i ncl u di n g pre g na nc y testi n g) ass ociate d wit h 
t he disc o nti n ue d treat me nt ma y be m o ve d or eli mi nate d (if c o nsi dered a p pr o priate after c o ns ultati o n wit h t he me dical m o nit or), if t here are n o ot her st u d y dr u gs a d mi nistere d o n t hat da y. If 
bi o mar ker/ P R O assess me nts fall o n a da y t hat n o l o n ger has a n y st u d y dr u g a d mi nistere d, t hese ma y be m o ve d t o t he ne xt sc he d u le d visit or eli mi nate d, if c o nsi dere d a p pr o priate after c o ns ultati o n wit h 
t he me dical m o nit or. P R O c ollecti o ns  ma y be disc o nti n ue d at t he discreti o n of s p o ns or.   
N ote: S u bjects i n Fra nce will n ot be e nr olle d i n C o h ort  1.  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2  of 1 3 5  
T a bl e  2 : 
S c h e d ul e of E v e nt s f or C o h ort s 4 a n d 5 ( N S C L C)  
 
 
Scree ni n g/ Baseli ne  
E nr oll me nt  
E ver y 2 1 -da y c ycle  
E O T  
F oll o w -u p  
S ur vi val 
f oll o w-u p  
 
Da y  
D – 2 8 
t o 1 
D – 7 t o 1 
( u nless 
ot her wise 
state d) 
Wit hi n 7 D 
of 1 st d ose  
D 1  
D 3  
D 1 5  
Wit hi n 3 0 – 3 7 D 
of last d ose A  
E ver y  1 2  w ks 
( u nless 
ot her wise 
state d) 
E ver y 
1 2  w ks  
( u nless 
ot her wise 
state d) 
 
Visit wi n d o w  
 
 
 
± 2 d  
 
-2 d/ + 5 d  
 
± 1  w k  
± 1  w k  
 
Scree ni n g/ Baseli ne 
Ass ess me nts  
I ncl usi o n/ E xcl usi o n, me dical hist or y 
X  
 
S u b mit eli gi bilit y c o nfir mati o n t o  
S p o ns or pri or t o treat me nt  
C ycle  1 B  
 
 
 
 
 
I nf or m e d c o nse nt 
X  
 
 
 
 
 
 
 
M RI of brai n
C  
X  
 
 
 
 
 
 
 
 
Safet y Ass ess me nts  
Uri nal ysis, i ncl u di n g U P C rati o  
 
X  
X D  
 
 
 
 
 
Pre g na nc y test (s u bjects of c hil d beari n g 
p ote ntial)  
 
X E  
X F 
 
 
X  
X G  
 
P h ysical e xa mi nati o n  
 
X  
X H  
 
 
X  
X  
 
Wei g ht  
 
X  
X H  
 
 
X  
 
 
Hei g ht ( hei g ht meas ure d wit hi n t he pri or 
1 2  m o nt hs ma y be utilize d)  
X  
 
 
 
 
 
 
 
C B C wit h differe ntial  
 
X  
X H  
X  
 
X  
 
 
C he mistr y pa nel  
 
X  
X H  
X  
 
X  
 
 
H g b A 1c  
X  
 
 
 
 
X  
 
 
T h yr oi d pa nel  
X  
 
X H,I  
 
 
X  
X (at first F U 
o nl y)  
 
Vital si g ns  
 
X  
X  
X  
 
X  
X (at first F U 
o nl y)  
 
P T/a P T T/I N R J 
 
X  
 
 
 
X  
 
 
E C O G perf or ma n ce stat us  
 
X  
X H  
 
 
X  
 
 
E C G  
X  
 
 
 
 
X  
 
 
C o nc o mita nt me dicati o ns  
Relate d t o st u d y pr oce d ures K  
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3  of 1 3 5  
 
 
Scree ni n g/ Baseli ne  
E nr oll me nt  
E ver y 2 1 -da y c ycle  
E O T  
F oll o w -u p  
S ur vi val 
f oll o w-u p  
 
Da y  
D – 2 8 
t o 1 
D – 7 t o 1 
( u nless 
ot her wise 
state d) 
Wit hi n 7 D 
of 1 st d ose  
D 1  
D 3  
D 1 5  
Wit hi n 3 0 – 3 7 D 
of last d ose A  
E ver y  1 2  w ks 
( u nless 
ot her wise 
state d) 
E ver y 
1 2  w ks  
( u nless 
ot her wise 
state d) 
 
Visit wi n d o w  
 
 
 
± 2 d  
 
-2 d/ + 5 d  
 
± 1  w k  
± 1  w k  
A E c ollecti o n  
C ollect fr o m Da y 1 pre d ose t hr o u g h safet y 
re p orti n g peri o d of st u d y dr u g(s) 
X L  
 
Tr eat me nt  
S E A -C D 4 0 a d mi nistrati o n  
 
 
 
 
X  
 
 
 
 
Pe m br oliz u ma b a d mi nistrati o n  
 
 
 
X  
 
 
 
 
 
Pe metre xe d a d mi nistrati o n  
 
 
 
X M  
 
 
 
 
 
Car b o plati n a d mi nistrati o n  
 
 
 
C ycles 1 –
4  
 
 
 
 
 
P K/I m m u n o ge nicit y
/ Bi o mar ker 
I nitiate retrie val of arc hi ve d t u m or 
s peci me n N  
 
X  
 
 
 
 
 
 
 
T u m or bi o ps y ( F F P E) O  
X N  
 
 
 
 
C ycle 
2 P 
 
 
 
Bl o o d sa m ple c ollecti o n  
See Ta ble  5  f or sa m ple c ollecti o n details. 
N ote sa m ple c ollecti o ns o n D a y 4 of C ycles 1 a n d 2.  
 
 
Res p o nse 
Ass ess me nt  
C T or M RI of c hest a n d a b d o me n, (a n d 
pel vis, nec k, a n d/ or brai n if d oc u me nte d 
or s us pe cte d i n v ol ve m e nt) Q  
X  
 
 
X R  
 
 
X S 
X T  
 
Disease a n d s ur vi val stat us U  
 
 
 
 
 
 
 
X  
X  
P R O Assess me nt  
E O R T C Q L Q -C 3 0  
 
X V  
 
X  
 
 
X  
 
 
N S C L C -S A Q  
 
X V  
 
X  
 
 
X  
 
 
P GI -S  
 
X V  
 
 
 
 
X  
 
 
P GI -C  
 
 
 
X W  
 
 
 
 
 
A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C T =c o m p ute d t o m o gra p h y; D = da y; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E C G =electr ocar di o gra m; E O T =e n d of treat me nt; 
F F P E =f or mali n -fi xe d paraffi n e m be d de d; F U =f oll o w-u p; H g b = he m o gl o bi n; M RI = ma g netic res o na nce i ma gi n g; P K = p har mac o ki netic; P R O = patie nt -re p orte d o utc o me; P T/a P T T/I N R =pr ot hr o m bi n 
ti me/acti vate d partial t hr o m b o plasti n ti me/i nter nati o nal n or malize d rati o; U P C = uri ne pr otei n creati ni ne; w k = wee k  
A  E O T e val uati o ns s h o ul d be o btai ne d bef or e t he i nitiati o n of n o n -pr ot oc ol a ntica ncer treat me nt. If E O T e val uati o ns are c o m plete d bef ore 3 0  da ys f oll o wi n g t he last st u d y treat me nt, c o n d uct a p h o ne 
scree n 3 0– 3 7  da ys f oll o wi n g t he s u bject’s last st u d y treat me nt t o e ns ure t hat n o c ha n ges i n A E pr ofile ha ve occ urre d.  
B  C o nfir m eli gi bilit y pri or t o assess me nts a n d d osi n g o n C ycle  1 Da y  1.  
C  If a n M RI or t he brai n is n ot me dicall y f easi ble, C T ma y be use d. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 4  of 1 3 5  
D  Uri nal ysis s h o ul d be c o n d ucte d e ver y 6  c ycles starti n g i n C ycle 6. Ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g.  
E  C ollect o n St u d y Da y – 3 t o 1.  
F  I n C ycle 1, n ot re q uire d if perf or me d wit hi n 3  da ys pri or t o visit. I n all ot her c ycles, n ot re q uire d if perf or me d wit hi n 7  da ys pri or t o visit.  
G  After t he last d ose of st u d y treat me nt, pre g na nc y tests will be perf or m e d o nce a m o nt h f or 6  m o nt hs, or per l ocal re g ulati o ns, w here a p plica ble. S u bjects ma y d o m o nt hl y h o me pre g na nc y tests a n d 
re p ort i nteri m res ults at t he f oll o w-u p visits.  
H  Ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g.  
I C ycle  1 a n d e ver y sec o n d c ycle t hereafter  
J A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ul ati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial as cli nicall y i n dicate d.  
K  Fr o m ti me of i nf or me d c o nse nt.  
L  C ollect A es if seri o us f or 90  da ys after t he last st u d y treat me nt a n d i m m u ne -relate d a d verse e ve nts (ir A Es) t hr o u g h t he first f oll o w-u p visit. If a s u bject starts a ne w a ntica ncer t hera p y, c ollecti o n of 
seri o us a d verse e ve nts ( S A Es) t hat are n ot relate d t o st u d y treat me nt a n d ir A Es ma y be st o p pe d 3 0  da ys after t he cessati o n of st u d y treat me nt (see Secti o n 7. 7. 1. 3  f or details). St u d y treat me nt-relate d 
S A Es t hat occ ur after t he safet y re p orti n g peri o d s h o ul d als o be re p orte d t o t he s p o ns or.  
M  See S ecti o n 5. 3  re gar di n g c ortic oster oi d a n d a nti-e metic pr o p h yla xis. 
N  If arc hi ve d t u m or s peci me n is n ot a vaila ble, fres h t u m or bi o ps y is re q uire d (see S ecti on 7. 4  f or details). C ollecti o n of fres h bi o psies ma y be st o p pe d at t he discreti o n of t he s p o ns or . 
O  If a t u m or sa m ple is o btai ne d as part of sta n dar d of care d uri n g t he st u d y, a part of t hat sa m ple s h o ul d be s u b mitte d t o t he s p o ns or if a vaila ble. 
P  O n -treat me nt bi o ps y is o pti o nal. 
Q  F or eac h assesse d lesi o n, t he sa me m o dalit y s h o ul d be use d t hr o u g h o ut t he d urati o n of t he st u d y.  
R  Res p o nse s h o ul d be assesse d b y C T e ver y 6  wee ks ( ± 3  da ys) fr o m  C ycle  1 Da y  1 re gar dless of d ose dela ys f or 2 4  wee ks a n d e ver y 1 2  wee ks ( ± 1  wee k) t hereafter.  
S  N ot re q uire d if c o n d ucte d 4  wee ks pri or t o E O T.  
T  Res p o nse assess me nts will c o nti n ue u ntil disease pr o gressi o n (i C P D per i R E CI S T), i nitiati o n of ne w a ntica ncer  t hera p y, st u d y ter mi nati o n b y t he s p o ns or, or deat h, w hic he ver c o mes first. 
U  After disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt, f oll o w -u p f or disease a n d s ur vi val stat us, a n d s u bse q ue nt a ntica ncer treat me nt i nf or mati o n u ntil deat h or st u d y cl os ure. Assess me nt 
of s ur vi val ca n be d o ne via p u blic or h os pital/ me dical rec or ds or a p h o ne call.  
V   Patie nt -re p orte d o utc o me ( P R O) assess me nts will o nl y be a d mi nistere d t o s u bjects e ntere d i n t he st u d y after c o m pleti o n of e nr oll me nt f or t he i nteri m a nal ysis i n eac h c o h ort . All P R O assess me nts 
s h o ul d be c o m plete d b y t he s u bject pri or t o disc ussi o n of t he s u bject’s healt h state, la b res ults, healt h rec or d, a n d pri or t o a n y st u d y dr u g a d mi nistrati o n or ot her st u d y assess me nt.  P R O c ollecti o ns  ma y 
be disc o nti n ue d at t he discreti o n of s p o ns or.  
W   N ot re q uire d i n C ycle  1. P GI -C s h o ul d be a d mi nistere d fr o m C ycle  2 o n war d.  
N ote: Eac h ti me a s u bject disc o nti n ues a c o m p o ne nt of c o m bi nati o n t hera p y b ut is c o nti n ui n g wit h a n ot her c o m p o ne nt, cli nic vi sits a n d safet y assess me nts (i ncl u di n g pre g na nc y testi n g) ass ociate d wit h 
t he disc o nti n ue d treat me nt ma y be m o ve d or eli mi nate d (if c o nsi dere d a p pr o priate after c o ns ultati o n wit h t he me dical m o nit or), if t here are n o ot her st u d y dr u gs a d mi nistere d o n t hat da y. If 
b i o mar ker/ P R O assess me nts fall o n a da y t hat n o l o n ger has a n y st u d y dr u g a d mi nistere d, t hese ma y be m o ve d t o t he ne xt sc he d ule d visit or eli mi nate d, if c o nsi dere d a p pr o priate after c o ns ultati o n 
wit h t he me dical m o nit or.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 5  of 1 3 5  
BI O M A R K E R A N D E C G C O L L E C TI O N S  
T a bl e  3 : 
Bi o m ar k er C oll e cti o n s f or C o h ort s 1, 2, a n d 3 ( M el a n o m a)  
C ycle  
St u d y 
Da y  
Ti me  
C ollecti o n 
Wi n d o w  
Relati ve Ti me  
S E A -C D 4 0 
P K  
S E A -C D 4 0 
A D A  
Ser u m  
P B M C  
Plas ma  
cf D N A 
P D 
Fl o w A  
Ge n ot y pi n g  
Da y  – 7  t o – 1   
 
 
X  
X  
X  
 
X  
X  
C ycle  1 
a n d 2 
Da y  1  
Pre d ose S E A -C D 4 0 B  
w it hi n 4    hrs 
pri or t o  
Start of S E A -C D 4 0 i nf usi o n  
X C  
X  
X  
X  
X  
X  
X  
 
1  h r i ntra-d ose  B ,D ,E  
± 1 5  mi n  
1  h o ur after start of S E A -C D 4 0 
i nf usi o n 
X  
 
 
 
 
 
 
 
2  h rs i ntra-d ose  B ,D ,F 
± 1 5  mi n  
2  h o urs after start of S E A -C D 4 0 
i nf usi o n 
X  
 
 
 
 
 
 
 
E n d of S E A -C D 4 0 
i nf usi o n 
wit hi n 3 0    mi n  
E n d of S E A -C D 4 0 i nf usi o n  
X C  
 
 
 
X  
 
 
 
2  hr s 
± 1 5  mi n  
X  
 
 
 
X  
 
 
 
Da y  2  
2 4  hr sB  
± 4  hr  
Start of S E A -C D 4 0 i nf usi o n  
X C  
 
 
 
X  
 
C ycle 1  
 
Da y  2 2  
Pre d ose S E A -C D 4 0 B  
w it hi n 4  hr s 
pri or t o  
Start of S E A -C D 4 0 i nf usi o n  
X  
X  
 
 
X  
 
 
 
E n d of S E A -C D 4 0 
i nf usi o n 
wit hi n 1 5    mi n 
E n d of S E A -C D 4 0 i nf usi o n  
X  
 
 
 
 
 
 
 
All ot her 
c ycles  
Da y  1  
Pre d ose S E A -C D 4 0 B  
wit hi n 2 4  hr s 
Start of S E A -C D 4 0 i nf usi o n  
X  
X  
C ycles 
3 – 4  
C ycles 3 –
4  
X  
 
C ycles 
3 – 6  
 
E O T  
3 0 – 3 7  da ys after last  st u d y dr u gG  
X  
X  
X  
X  
X  
X  
 
 
A D A =a nti dr u g a nti b o d y; cf D N A =cell -free D N A; E O T =e n d of treat me nt; E C G =electr ocar di o gra m; hr(s) = h o ur(s); mi n(s) = mi n utes(s); P B M C = peri p heral bl o o d m o n o n uclear cell; 
P D = p har mac o d y na mic; P K = p har mac o ki netic ; P R O =patie nt re p orte d o utc o mes  
A  Bl o o d sa m ples f or P D fl o w s h o ul d be c ollecte d i n C o h orts 1 a n d 2 fr o m s u bjects e nr olli n g bef ore t he first i nteri m a nal ysis at  U S sites o nl y.  
B  T he ti me n ote d is relati ve t o t he start of t he S E A -C D 4 0 i nf usi o n.  
C  F or t he first 3 0  s u bjects acr oss C o h orts 1, 2, a n d 3, E C Gs s h o ul d be perf or me d wit hi n 3 0  mi n utes pri or t o P K sa m ple c ollecti o n at t hese ti me p oi nts. (see Ta ble  4 ) 
D  Bl o o d sa m ples c ollecte d d uri n g t he S E A -C D 4 0 i nf usi o n s h o ul d be o btai ne d fr o m t he c o ntralateral ar m, or a n ot her site ot her t ha n t he i nf usi o n li ne.  
E  C ollect 1  hr i ntra -d ose sa m ple if S E A -C D 4 0 i nf usi o n ti me e xcee ds 1  h o ur if c ollecti o n wi n d o w d oes n ot o verla p wit h e n d of i nf usi o n.  
F  C ollect 2  hr i ntra -d ose sa m ple if S E A -C D 4 0 i nf usi o n ti me e xcee ds 2  h o urs if c ollecti o n wi n d o w d oes n ot o verla p wit h e n d of i nf usi o n.  
G  E O T sa m ples m ust be c ollect e d bef or e i nitiati o n of a ne w a ntica ncer treat me nt (see  Secti o n  6. 4 ). 
N ote: If c ollecti o n kits are u na vaila ble o n t he i nte n de d c ollecti o n da y, t he sa m ple c ollecti o n ma y be o mitte d i n c o ns ultati o n wit h t he s p o ns or.  
N ote: S u bjects i n Fra nce will n ot be e nr olle d i n C o h ort 1.   
N ote: A n y sa m ples a n d data c ollecti o n f or e x pl orat or y o bjecti ves w hic h are n ot necessar y t o e val uate a n y pri mar y a n d sec o n dar y o bjecti ve ca n  be disc o nti n ue d at t he discreti o n of t he s p o ns or  (f or 
e xa m ple, b ut n ot li mite d t o: P R Os, S E A -C D 4 0 P K, C D 4 0 A D A, Plas ma, P D fl o w, T u m or b i ops y , Ge n ot y pi n g, Ser u m, P B M C, cf D N A).
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 6  of 1 3 5  
T a bl e  4 : 
E C G C oll e c ti o n s f or C o h ort s 1, 2, a n d 3 –  U p t o 3 0 S u bj e ct s i n T ot al ( U S sit e s o nl y)  
C ycle  
St u d y Da y  
Ti me  
Relati ve Ti me  
E C G  
C ycles  1 a n d 2  
Da y  1  
Pre d ose  
S T A R T of S E A -C D 4 0 i nf usi o n  
X  
3 0  mi n utes  p ost e n d of i nf usi o n  
E N D of S E A -C D 4 0 i nf usi o n, wit hi n 3 0  mi n utes pri or t o p ost d ose P K bl o o d dra w  
X  
2  h o urs  
E N D of S E A -C D 4 0 i nf usi o n, pri or t o 2 -h o ur P K bl o o d dra w  
X  
Da y  2  
2 4  h o ur s 
S T A R T of i nf usi o n, wit hi n 3 0  mi n utes  pri or t o 2 4 -h o ur P K bl o o d dra w  
X  
E C G =electr ocar di o gra m ; P K = p har mac o ki netic  
N ote: E C Gs s h o ul d be perf or me d wit hi n 3 0  mi n utes pri or t o P K sa m ple c ollecti o n at c orres p o n di n g ti me p oi nts . O n -treat me nt E C Gs s h o ul d be perf or me d f or u p t o a p pr o xi matel y 3 0 s u bjects at U S sites 
acr oss C o h orts 1, 2, a n d 3 .
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 7  of 1 3 5  
T a bl e  5 : 
Bi o m ar k er C oll e cti o n s f or C o h ort s 4 a n d 5 ( N S C L C)  
C ycle  
St u d y 
Da y  
Ti me  
C ollecti o n 
Wi n d o w  
Relati ve Ti me  
S E A -C D 4 0 
P K  
S E A -C D 4 0 
A D A  
Ser u m  
P B M C  
Plas ma  
cf D N A 
P D 
Fl o w A  
Ge n ot y pi n g  
Da y  – 7  t o – 1  
 
 
X  
X  
X  
 
X  
X  
C ycles  1 
a n d 2 
Da y  1  
Pre d ose c he m o a n d 
pe m br oliz u ma b (-4 8  hr) B ,C  
wit hi n 4  hr s 
pri or t o  
Start of pe m br oliz u ma b 
i nf usi o n 
 
 
X  
X  
X  
X  
X  
 
Da y  3  
Pre d ose S E A -C D 4 0 ( 0  hr)  
w it hi n 4  hrs 
pri or t o  
Start of S E A -C D 4 0 i nf usi o n  
X  
X  
 
 
X  
 
C ycle  1  
 
1  h r i ntra-d ose B, D ,E  
± 1 5  mi n  
1  h o ur after start of 
S E A -C D 4 0 i nf usi o n  
X  
 
 
 
 
 
 
 
2  h rs i ntra-d ose B ,D ,F  
± 1 5  mi n  
2  h o urs after start of 
S E A -C D 4 0 i nf usi o n  
X  
 
 
 
 
 
 
 
E n d of S E A -C D 4 0 i nf usi o n  
wit hi n 1 5  m i n 
E n d of S E A -C D 4 0 i nf usi o n  
X  
 
 
 
X  
 
 
 
2  hr s 
± 1 5  mi n  
2  h o urs after e n d of 
S E A -C D 4 0 i nf usi o n 
X  
 
 
 
X  
 
 
 
Da y  4  
2 4  hr sB  
wit hi n 4  hr s 
pri or t o  
Start of S E A -C D 4 0 i nf usi o n  
X  
 
 
 
X  
 
C ycle  1  
 
C ycles 3, 
4, 6, a n d 
8  
Da y  1  
Pre d ose c he m o a n d 
pe m br oliz u ma b (– 4 8  hr) B  
wit hi n 4  hr s 
pri or t o  
Start of pe m br oliz u ma b 
i nf usi o n 
X  
X  
C ycles 
3 – 4  
C ycles 
3 – 4  
X  
 
X  
 
E O T  
3 0 – 3 7  da ys after last st u d y dr u g G  
X  
X  
X  
X  
X  
X  
 
 
A D A =a nti dr u g a nti b o d y; E O T =e n d of treat me nt; E C G =electr ocar di o gra m; hr(s) = h o ur(s); mi n(s) = mi n utes(s); P B M C = peri p heral bl o o d m o n o n uclear cell; P D = p har mac o d y na mic ; P K = p har mac o ki netic ; 
P R O = patie nt re p orte d o utc o mes 
A  Bl o o d sa m ples f or P D fl o w s h o ul d be c ollecte d fr o m s u bjects e nr olli n g bef ore t he first i nteri m a nal ysis at U S sites o nl y.  
B  T he ti me n ote d is relati ve t o t he start of t he S E A -C D 4 0 i nf usi o n.  
C  C ollect pre -d ose sa m ples pri or t o  a d mi nisteri n g pre-me dicati o n.  
D  Bl o o d sa m ples c ollecte d d uri n g t he S E A -C D 4 0 i nf usi o n s h o ul d be o btai ne d fr o m t he c o ntralateral ar m, or a n ot her site ot her t ha n t he i nf usi o n li ne.  
E  C ollect 1  hr i ntra -d ose sa m ple if S E A -C D 4 0 i nf usi o n ti me e xcee ds 1  h o ur  if c ollecti o n wi n d o w d oes n ot o verla p wit h e n d of i nf usi o n. 
F  C ollect 2  -hr i ntra -d ose sa m ple if S E A -C D 4 0 i nf usi o n ti me e xcee ds 2  h o urs  if c ollecti o n wi n d o w d oes n ot o verla p wit h e n d of i nf usi o n. 
G  E O T sa m ples m ust be c ollecte d bef or e i nitiati o n of a ne w a ntica ncer treat me nt (see  Secti o n  6. 4 ). 
N ote: If c ollecti o n kits are u na vaila ble o n t he i nte n de d c ollecti o n da y, t he sa m ple c ollecti o n ma y be o mitte d i n c o ns ultati o n wit h t he sp o ns or   
N ote: A n y sa m ples a n d data c ollecti o n f or e x pl orat or y o bjecti ves w hic h are n ot necessar y t o e val uate a n y pri mar y a n d sec o n dar y o bjecti ve  ca n  be disc o nti n ue d at t he discreti o n of t he s p o ns or (f or 
e xa m ple, b ut n ot li mite d t o: P R Os, S E A -C D 4 0 P K, C D 4 0 A D A, Plas ma, P D fl o w, T u m or bi o ps y , Ge n ot y pi n g, Ser u m, P B M C, cf D N A).
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 8  of 1 3 5  
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  
S C H E D U L E O F E V E N T S  ............................................................................................................................................ 9  
BI O M A R K E R A N D E C G C O L L E C TI O N S ............................................................................................................... 1 5  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  .............................................................................. 2 3  
1.  
I N T R O D U C TI O N ................................................................................................................................ 2 7  
1. 1.  
C D 4 0  ..................................................................................................................................................... 2 7  
1. 2.  
R ole of C D 4 0 i n Ca ncer ........................................................................................................................ 2 7  
1. 3.  
T u m or I m m u n ol o g y: I m m u ne E vasi o n Vers us Acti vati o n  ................................................................... 2 7  
1. 4.  
Descri pti o n of S E A -C D 4 0  .................................................................................................................... 2 8  
1. 5.  
S E A -C D 4 0 Mec ha nis m of Acti o n  ........................................................................................................ 2 8  
1. 6.  
S u m mar y of N o ncli nical T o xicit y  ........................................................................................................ 2 8  
1. 7.  
P e m br oliz u ma b  ..................................................................................................................................... 2 9  
1. 7. 1.  
P har mace utical a n d T hera pe utic Bac k gr o u n d  ..................................................................... 3 0  
1. 7. 2.  
Precli nical a n d Cli nical Trials wit h P e m br oliz u ma b  ........................................................... 3 0  
1. 7. 3.  
J ustificati o n f or Q 3 W P e m br oliz u ma b D ose  ....................................................................... 3 1  
1. 7. 4.  
J ustificati o n f or Q 6 W P e m br oliz u ma b D ose  ....................................................................... 3 2  
1. 8.  
C he m ot hera p y i n N S C L C  ..................................................................................................................... 3 2  
1. 9.  
Car b o plati n, P e metre xe d, a n d P e m br oliz u ma b i n N S C L C  ................................................................... 3 3  
1. 1 0.  
P e m br oliz u ma b C o m bi nati o n T hera p y  ................................................................................................. 3 3  
1. 1 1.  
C he m ot hera p y C o m bi nati o n T hera p y  ................................................................................................... 3 4  
1. 1 2.  
S u m mar y of Cli nical St u d y S G N S 4 0 -0 0 1  ............................................................................................ 3 4  
1. 1 3.  
Rati o nale f or St u d y  ............................................................................................................................... 3 5  
1. 1 4.  
Assess me nt of B e nefit -Ris k  .................................................................................................................. 3 5  
2.  
O BJ E C TI V E S  ....................................................................................................................................... 3 6  
3.  
I N V E S TI G A TI O N A L P L A N ............................................................................................................... 3 7  
3. 1.  
S u m mar y of St u d y Desi g n  .................................................................................................................... 3 7  
3. 1. 1.  
C o h orts 1, 2, a n d 3 ( Mela n o ma)  .......................................................................................... 3 8  
3. 1. 2.  
C o h orts 4 a n d 5 ( N S C L C)  ................................................................................................... 3 9  
3. 1. 3.  
D urati o n of Treat me nt  ......................................................................................................... 3 9  
3. 1. 4.  
St o p pi n g Criteria .................................................................................................................. 4 0  
3. 1. 4. 1.  
E nr oll me nt P a use at t he C o h ort Le vel  ...................................................................... 4 0  
3. 1. 4. 2.  
E nr oll me nt Halt f or t he E ntire St u d y  ....................................................................... 4 0  
3. 1. 5.  
E n d of St u d y  ........................................................................................................................ 4 0  
3. 1. 6.  
Retreat me nt  .......................................................................................................................... 4 0  
3. 1. 7.  
Safet y M o nit ori n g C o m mittee  ............................................................................................. 4 0  
3. 1. 8.  
Trial O perati o ns a n d Data C ollecti o n after S E A -C D 4 0 E x pir y  ........................................... 4 1  
3. 2.  
Disc ussi o n a n d Rati o nale f or St u d y Desi g n  .......................................................................................... 4 1  
3. 2. 1.  
Rati o nale f or St u d y Desi g n  .................................................................................................. 4 1  
3. 2. 2.  
Met h o d of Assi g ni n g S u bj ects t o Treat me nt Gr o u ps  ........................................................... 4 2  
3. 2. 3.  
Rati o nale f or Selecti o n of S E A -C D 4 0 D ose a n d Sc he d ule  ................................................. 4 2  
3. 2. 4.  
Bli n di n g a n d U n bli n di n g  ..................................................................................................... 4 2  
4.  
S T U D Y P O P U L A TI O N  ....................................................................................................................... 4 2  
4. 1.  
I ncl usi o n Criteria .................................................................................................................................. 4 2  
4. 2.  
E xcl usi o n Criteria  ................................................................................................................................. 4 7  
4. 3.  
Re pr o d ucti ve P ote ntial  .......................................................................................................................... 4 8  
4. 4.  
Re m o val of S u bj ects fr o m St u d y Treat me nt or Assess me nts  ............................................................... 4 9  
4. 4. 1.  
Disc o nti n uati o n of St u d y Treat me nt  .................................................................................... 4 9  
4. 4. 2.  
S u bj ect Wit h dra wal fr o m St u d y  .......................................................................................... 4 9  
5.  
T R E A T M E N T S  .................................................................................................................................... 5 0  
5. 1.  
Treat me nts A d mi nistere d  ...................................................................................................................... 5 0  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 9  of 1 3 5  
5. 1. 1.  
S E A -C D 4 0  ........................................................................................................................... 5 0  
5. 1. 1. 1.  
Descri pti o n  ............................................................................................................... 5 0  
5. 1. 1. 2.  
D ose a n d A d mi nistrati o n  .......................................................................................... 5 1  
5. 1. 1. 3.  
St ora ge a n d Ha n dli n g  ............................................................................................... 5 1  
5. 1. 1. 4.  
P ac ka gi n g a n d La beli n g  ........................................................................................... 5 1  
5. 1. 1. 5.  
Pre p arati o n  ............................................................................................................... 5 2  
5. 1. 2.  
P e m br oliz u ma b  .................................................................................................................... 5 2  
5. 1. 2. 1.  
Descri pti o n  ............................................................................................................... 5 2  
5. 1. 2. 2.  
Met h o d of Pr oc ure me nt  ............................................................................................ 5 2  
5. 1. 2. 3.  
D ose a n d A d mi nistrati o n  .......................................................................................... 5 2  
5. 1. 2. 4.  
St ora ge a n d Ha n dli n g  ............................................................................................... 5 2  
5. 1. 2. 5.  
Pre p arati o n  ............................................................................................................... 5 3  
5. 1. 3.  
P e metre xe d a n d Car b o plati n  ................................................................................................ 5 3  
5. 1. 3. 1.  
Descri pti o n  ............................................................................................................... 5 3  
5. 1. 3. 2.  
Met h o d of Pr oc ure me nt  ............................................................................................ 5 3  
5. 1. 3. 3.  
D ose a n d A d mi nistrati o n  .......................................................................................... 5 3  
5. 1. 3. 4.  
St ora ge a n d Ha n dli n g  ............................................................................................... 5 3  
5. 1. 3. 5.  
P ac ka gi n g a n d La beli n g  ........................................................................................... 5 4  
5. 1. 3. 6.  
Pre p arati o n  ............................................................................................................... 5 4  
5. 2.  
D ose M o dificati o ns  ............................................................................................................................... 5 4  
5. 2. 1.  
D ose M o dificati o ns a n d T o xicit y Ma na ge me nt f or I m m u ne -Relate d A Es 
Ass ociate d wit h P e m br oliz u ma b a n d/ or S E A -C D 4 0  ........................................................... 5 4  
5. 2. 2.  
D ose M o dificati o ns S E A -C D 4 0  .......................................................................................... 5 8  
5. 2. 3.  
D ose M o dificati o ns P e m br oliz u ma b  ................................................................................... 5 8  
5. 2. 3. 1.  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt of I nf usi o n -re acti o ns Relate d t o 
P e m br oliz u ma b  ........................................................................................................ 5 8  
5. 2. 3. 2.  
Ot her All o we d D ose I nterr u pti o ns a n d M o dificati o ns f or P e m br oliz u ma b  ............. 6 0  
5. 2. 4.  
D ose M o dificati o ns P e metre xe d/ Car b o plati n  ...................................................................... 6 0  
5. 3.  
Re q uire d Pre me dicati o n a n d P ost me dicati o n  ....................................................................................... 6 2  
5. 4.  
C o nc o mita nt T hera p y  ........................................................................................................................... 6 3  
5. 4. 1.  
Re q uire d C o nc o mita nt T hera p y  ........................................................................................... 6 3  
5. 4. 2.  
All o we d C o nc o mita nt T hera p y  ............................................................................................ 6 3  
5. 4. 3.  
Pr o hi bite d C o nc o mita nt T hera p y  ......................................................................................... 6 4  
5. 5.  
Ma na ge me nt of Treat me nt -E mer ge nt A d verse E ve nts  ......................................................................... 6 4  
5. 5. 1.  
Ma na ge me nt of I nf usi o n/I nj ecti o n or H y perse nsiti vit y Reac ti o ns ...................................... 6 4  
5. 5. 1. 1.  
S E A -C D 4 0  ............................................................................................................... 6 4  
5. 5. 2.  
Aller gic/ H y perse nsiti vit y Rea cti o n  ..................................................................................... 6 5  
5. 5. 2. 1.  
A na p h yla xis  ............................................................................................................. 6 6  
5. 5. 3.  
Ma na ge me nt of O ver d ose  .................................................................................................... 6 6  
5. 5. 4.  
Ma na ge me nt of Oc ular E ve nts  ............................................................................................ 6 7  
5. 6.  
Treat me nt C o m plia nce  .......................................................................................................................... 6 7  
5. 7.  
C o nti n ue d Access t o S E A -C D 4 0 After t he E n d of t he St u d y  ............................................................... 6 7  
5. 8.  
Visit Sc he d uli n g f or Si n gle Treat me nt Disc o nti n uati o n  ....................................................................... 6 7  
6.  
S T U D Y A C TI VI TI E S  .......................................................................................................................... 6 7  
6. 1.  
Sc he d ule of E ve nts  ............................................................................................................................... 6 7  
6. 2.  
C o h orts 1, 2, a n d 3 ( Mela n o ma)  ........................................................................................................... 6 8  
6. 2. 1.  
Scree ni n g Visit ( Da ys – 2 8 t o 1)  ........................................................................................... 6 8  
6. 2. 2.  
B aseli ne Visit  ....................................................................................................................... 6 9  
6. 2. 3.  
Treat me nt P eri o d ( Da y 1 t o Da y 4 2)  ................................................................................... 6 9  
6. 2. 3. 1.  
Da y 1 ( ± 2 da ys)  ........................................................................................................ 6 9  
6. 2. 3. 2.  
Da y 2 ( C ycles 1 a n d 2 o nl y)  ..................................................................................... 7 0  
6. 2. 3. 3.  
Da y  8 ( ± 2  da ys)  ........................................................................................................ 7 0  
6. 2. 3. 4.  
Da y  2 2 ( ± 2  da ys)  ...................................................................................................... 7 1  
6. 2. 3. 5.  
Da y  3 6 ( – 2/ + 5  da ys; C ycle  1 o nl y)  .......................................................................... 7 1  
6. 2. 4.  
Res p o nse Assess me nts  ........................................................................................................ 7 1  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 0  of 1 3 5  
6. 3.  
C o h orts 4 a n d 5 ( N S C L C)  .................................................................................................................... 7 2  
6. 3. 1.  
Scree ni n g Visit ( Da ys – 2 8 t o 1)  ........................................................................................... 7 2  
6. 3. 2.  
B aseli ne Visit  ....................................................................................................................... 7 2  
6. 3. 3.  
Treat me nt P eri o d ( Da y  1 t o Da y  2 1)  ................................................................................... 7 3  
6. 3. 3. 1.  
Da y  1 ( ± 2 da ys)  ........................................................................................................ 7 3  
6. 3. 3. 2.  
Da y  3  ........................................................................................................................ 7 4  
6. 3. 3. 3.  
Da y 4 ( C ycles 1 a n d 2 o nl y)  ..................................................................................... 7 4  
6. 3. 3. 4.  
Da y 1 5 ( – 2/ + 5 da ys; C ycle 2 o nl y)  .......................................................................... 7 4  
6. 3. 4.  
Res p o nse Assess me nts  ........................................................................................................ 7 4  
6. 4.  
E n d of Treat me nt Visit ( 3 0 t o 3 7  da ys after last d ose of st u d y dr u g; all c o h ort s) ................................. 7 5  
6. 5.  
F oll o w -u p (all c o h orts)  ......................................................................................................................... 7 6  
6. 6.  
S ur vi val F oll o w -u p (all c o h orts)  ........................................................................................................... 7 7  
6. 7.  
E n d of F oll o w -u p (all c o h orts)  .............................................................................................................. 7 7  
7.  
S T U D Y A S S E S S M E N T S  .................................................................................................................... 7 7  
7. 1.  
Scree ni n g/ Baseli ne Assess me nts  .......................................................................................................... 7 7  
7. 2.  
Res p o nse/ A ntit u m or Acti vit y Assess me nts  .......................................................................................... 7 8  
7. 3.  
P har mac o ki netic a n d I m m u n o ge nicit y Assess me nts  ............................................................................ 7 8  
7. 4.  
P har mac o d y na mic a n d Bi o mar ker Assess me nts  ................................................................................... 7 8  
7. 5.  
Bi os peci me n Re p osit or y  ....................................................................................................................... 8 0  
7. 6.  
P atie nt -Re p orte d O utc o mes Assess me nts  ............................................................................................. 8 0  
7. 7.  
Safet y Assess me nts  ............................................................................................................................... 8 1  
7. 7. 1.  
A d verse E ve nts  .................................................................................................................... 8 1  
7. 7. 1. 1.  
Defi niti o ns  ................................................................................................................ 8 1  
7. 7. 1. 2.  
Pr oce d ures f or Eliciti n g a n d Rec or di n g A d verse E ve nts  ......................................... 8 3  
7. 7. 1. 3.  
Re p orti n g P eri o ds f or A d verse E ve nts a n d Seri o us A d verse E ve nts  ....................... 8 6  
7. 7. 1. 4.  
Seri o us A d verse E ve nts Re q uire I m me diate Re p orti n g  ........................................... 8 6  
7. 7. 1. 5.  
E ve nts of Cli nical I nterest  ........................................................................................ 8 7  
7. 7. 1. 6.  
S p o ns or Safet y Re p orti n g t o Re g ulat or y A ut h orities  ............................................... 8 7  
7. 7. 2.  
Vital Si g ns  ........................................................................................................................... 8 7  
7. 7. 3.  
Cli nical La b orat or y T ests  .................................................................................................... 8 8  
7. 7. 4.  
P h ysical E xa mi nati o n  .......................................................................................................... 8 8  
7. 7. 5.  
Electr ocar di o gra ms  .............................................................................................................. 8 8  
7. 7. 6.  
Pre g na nc y T esti n g  ............................................................................................................... 8 9  
7. 7. 7.  
E C O G P erf or ma nce Stat us  .................................................................................................. 8 9  
7. 8.  
A p pr o priate ness of Meas ure me nts  ........................................................................................................ 8 9  
8.  
D A T A Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E  ........................................................ 8 9  
8. 1.  
Site Trai ni n g a n d M o nit ori n g Pr oce d ures  ............................................................................................. 8 9  
8. 2.  
Data Ma na ge me nt Pr oce d ures  .............................................................................................................. 9 0  
8. 3.  
Access t o S o urce Data  .......................................................................................................................... 9 0  
8. 4.  
Acc urac y a n d Relia bilit y of D ata  .......................................................................................................... 9 0  
8. 5.  
Q ualit y Ass ura nce Pr oce d ures  .............................................................................................................. 9 1  
8. 6.  
Data Ha n dli n g a n d Rec or d Kee pi n g  ..................................................................................................... 9 1  
8. 6. 1.  
Data Ha n dli n g  ...................................................................................................................... 9 1  
8. 6. 2.  
In vesti gat or Rec or d Rete nti o n  ............................................................................................. 9 1  
9.  
D A T A A N A L Y SI S M E T H O D S  .......................................................................................................... 9 1  
9. 1.  
Deter mi nati o n of Sa m ple Size  .............................................................................................................. 9 1  
9. 2.  
St u d y E n d p oi nt Defi niti o ns  .................................................................................................................. 9 2  
9. 2. 1.  
C o nfir me d O R R  ................................................................................................................... 9 2  
9. 2. 2.  
Disease C o ntr ol Rate  ........................................................................................................... 9 2  
9. 2. 3.  
D urati o n of Res p o nse  .......................................................................................................... 9 2  
9. 2. 4.  
Pr o gressi o n -Free S ur vi val  ................................................................................................... 9 3  
9. 2. 5.  
O verall S ur vi val  ................................................................................................................... 9 3  
9. 2. 6.  
P R O E n d p oi nts  .................................................................................................................... 9 3  
9. 3.  
Sta tistical a n d A nal ytical Pla ns ............................................................................................................. 9 3  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 1  of 1 3 5  
9. 3. 1.  
Ge neral C o nsi derati o ns  ........................................................................................................ 9 3  
9. 3. 1. 1.  
Ra n d o mizati o n a n d Bli n di n g  .................................................................................... 9 3  
9. 3. 1. 2.  
A dj ust me nts f or C o variates  ...................................................................................... 9 3  
9. 3. 1. 3.  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  .................................................................. 9 4  
9. 3. 1. 4.  
M ultice nter St u dies  .................................................................................................. 9 4  
9. 3. 1. 5.  
M ulti ple C o m paris o ns a n d M ulti plicit y  ................................................................... 9 4  
9. 3. 1. 6.  
Data Tra nsf or mati o ns a n d Deri vati o ns  ..................................................................... 9 4  
9. 3. 1. 7.  
A nal ysis Sets  ............................................................................................................ 9 4  
9. 3. 1. 8.  
E xa mi nati o n of S u b gr o u ps  ....................................................................................... 9 4  
9. 3. 1. 9.  
Ti mi n g of A nal ys es  .................................................................................................. 9 5  
9. 3. 2.  
S u bj ect Dis p ositi o n  .............................................................................................................. 9 5  
9. 3. 3.  
S u bj ect C haracteristics  ........................................................................................................ 9 5  
9. 3. 4.  
Treat me nt A d mi nistrati o n  .................................................................................................... 9 5  
9. 3. 5.  
Efficac y A nal yses  ................................................................................................................ 9 5  
9. 3. 5. 1.  
Pri mar y Efficac y A nal yses  ....................................................................................... 9 5  
9. 3. 5. 2.  
Sec o n dar y Efficac y A nal yses  ................................................................................... 9 5  
9. 3. 6.  
P har mac o ki netic a n d I m m u n o ge nicit y A nal yses  ................................................................. 9 5  
9. 3. 7.  
Bi o mar ker A nal yses  ............................................................................................................ 9 6  
9. 3. 8.  
P atie nt -Re p orte d O utc o mes A nal yses  ................................................................................. 9 6  
9. 3. 9.  
Safet y A nal yses  ................................................................................................................... 9 6  
9. 3. 9. 1.  
E xte nt of E x p os ure  ................................................................................................... 9 6  
9. 3. 9. 2.  
A d verse E ve nts ......................................................................................................... 9 6  
9. 3. 9. 3.  
Deat hs a n d Seri o us A d verse E ve nts  ......................................................................... 9 7  
9. 3. 9. 4.  
Cli nical La b orat or y Res ults  ...................................................................................... 9 7  
9. 3. 9. 5.  
Ot her Safet y A nal yses  .............................................................................................. 9 7  
9. 3. 1 0.  
I nteri m A nal yses .................................................................................................................. 9 7  
1 0.  
I N F O R M E D C O N S E N T, E THI C A L R E VI E W, A N D R E G U L A T O R Y 
C O N SI D E R A TI O N S  ............................................................................................................................ 9 8  
1 0. 1.  
I nf or me d C o nse nt ................................................................................................................................. 9 8  
1 0. 2.  
Et hical Re vie w  ...................................................................................................................................... 9 8  
1 0. 3.  
Re g ulat or y C o nsi derati o ns  .................................................................................................................... 9 8  
1 0. 3. 1.  
I n vesti gat or I nf or mati o n ...................................................................................................... 9 9  
1 0. 3. 2.  
Pr ot oc ol A me n d me nts a n d St u d y T er mi nati o n  .................................................................... 9 9  
1 0. 4.  
St u d y D oc u me ntati o n, Pri vac y a n d Rec or ds Rete nti o n  ........................................................................ 9 9  
1 0. 5.  
Cli nical Trial A gree me nt  ...................................................................................................................... 9 9  
1 1.  
R E F E R E N C E S  ................................................................................................................................... 1 0 0  
A P P E N DI X  A.  
P E R F O R M A N C E S T A T U S S C A L E S C O N V E R SI O N  ................................................... 1 0 5  
A P P E N DI X  B.  
C O N T R A C E P TI V E A N D B A R RI E R G UI D A N C E  ......................................................... 1 0 7  
A P P E N DI X  C.  
N E W Y O R K H E A R T A S S O C I A TI O N F U N C TI O N A L C LA S SI FI C A TI O N O F 
H E A R T F AI L U R E  ............................................................................................................................. 1 0 9  
A P P E N DI X  D.  
I M M U N E-B A S E D R E S P O N S E E V A L U A TI O N C RI T E RI A F O R S O LI D 
T U M O R S A N D R E CI S T V E R SI O N 1. 1  ........................................................................................... 1 1 0  
A P P E N DI X  E.  
I N T E RI M A N A L Y SI S U SIN G P R E DI C TI V E P R O B A B I LI T Y O F S U C C E S S ............. 1 1 3  
A P P E N DI X  F.  
E U R O P E A N O R G A NI S A TI O N F O R R E S E A R C H A N D T R E A T M E N T O F 
C A N C E R ( E O R T C) Q U A LI T Y -O F -LI F E Q U E S TI O N N AI R E F O R C A N C E R  .............................. 1 1 6  
A P P E N DI X  G.  
N O N -S M A L L C E L L L U N G C A N C E R S Y M P T O M A S S E S S M E N T 
Q U E S TI O N N AI R E ( N S C L C -S A Q) V 1. 0  .......................................................................................... 1 1 9  
A P P E N DI X  H.  
P A TI E N T G L O B A L I M P R E S SI O N O F S E V E RI T Y ( P GI S) S C A L E  ............................. 1 2 1  
A P P E N DI X  I. 
P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E ( P GI C) S C A L E  ............................... 1 2 2  
A P P E N DI X  J. 
I N V E S TI G A T O R SI GN A T U R E P A G E  ........................................................................... 1 2 3  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 2  of 1 3 5  
A P P E N DI X  K.  
D O C U M E N T HI S T O R Y  .................................................................................................. 1 2 4  
 
LI S T O F I N -T E X T T A B L E S  
T a ble  1:  
Sc he d ule of E ve nts f or C o h orts 1, 2, a n d 3 ( Mela n o ma)  ........................................................................ 9  
T a ble  2:  
Sc he d ule of E ve nts f or C o h orts 4 a n d 5 ( N S C L C)  ............................................................................... 1 2  
T a ble  3:  
Bi o mar ker C ollecti o ns f or C o h orts 1, 2, a n d 3 ( Mela n o ma)  ................................................................. 1 5  
T a ble  4:  
E C G C ollecti o ns f or C o h orts 1, 2, a n d 3 –  U p t o 3 0 S u bj ects i n T otal ( U S sites o nl y)  ........................ 1 6  
T a ble  5:  
Bi o mar ker C ollecti o ns f or C o h orts 4 a n d 5 ( N S C L C)  .......................................................................... 1 7  
T a ble  6:  
St u d y Treat me nts  .................................................................................................................................. 5 0  
T a ble 7:  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne -relate d A Es 
Ass ociate d wit h P e m br oliz u ma b a n d/ or S E A -C D 4 0  ............................................................................ 5 5  
T a ble 8:  
P e m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d Treat me nt G ui deli nes  ............................... 5 9  
T a ble 9:  
Rec o m me n de d D ose M o dificati o ns f or C he m ot hera p y He mat ol o gical T o xicit y  ................................. 6 1  
T a ble 1 0:  
Rec o m me n de d D ose M o dificati o ns f or C he m ot hera p y N o n -He mat ol o gical T o xicit y  ......................... 6 2  
T a ble 1 1:  
Treat me nt Rec o m me n dati o ns a n d D ose M o dificati o ns f or S E A -C D 4 0 I nf usi o n/I nj ecti o n or 
H y perse nsiti vit y Reacti o ns  ................................................................................................................... 6 5  
 
LI S T O F I N -T E X T FI G U R E S  
Fi g ure  1:  
St u d y Desi g n  ......................................................................................................................................... 3 8  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 3  of 1 3 5  
LI S T O F A B B R E VI A TI O N S A N D D E FI N ITI O N S O F T E R M S  
A D A  
a nti dr u g a nti b o d y  
A E  
a d verse e ve nt  
AJ C C  
A merica n J oi nt C o m mittee o n  Ca ncer  
A L K  
a na plastic lar ge -cell l y m p h o ma ki nase  
A L T  
ala ni ne a mi n otra nsferase  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A S T  
as partate a mi n otra nsferase  
A U C  
area u n der t he c o nce ntrati o n -ti me c ur ve  
β -h C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
C ma x  
ma xi m u m c o nce ntrati o n  
C tr o u g h 
tr o u g h c o nce ntrati o n 
C B C  
c o m plete bl o o d c o u nt  
cf D N A 
cell-free D N A 
CI  
c o nfi de nce i nter val  
C N S  
ce ntral ner v o us s yste m  
C R  
c o m plete res p o nse  
Cr Cl  
creati ni ne cleara nce  
C R F  
case re p ort f or m 
C T  
c o m p ute d t o m o gra p h y  
C T L A -4  
c yt ot o xic T -l y m p h oc yte-ass ociate d pr otei n 4  
D C  
de n dritic cells  
D C R  
disease c o ntr ol rate  
DI LI  
dr u g -i n d uce d li ver i nj ur y 
D O R  
d urati o n of res p o nse  
E C G  
electr ocar di o gra m  
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 G R F  
e pi der mal gr o wt h fact or rece pt or  
E O R T C  Q L Q -C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca nc er q ualit y of life q uesti o n naire  
E O T  
e n d of treat me nt  
e P R O 
electr o nic patie nt -rep orte d o utc o me  
F A S  
f ull a nal ysis set  
F F P E  
f or mali n-fi xe d paraffi n-e m be d de d  
F U  
f oll o w-u p  
H N S C C  
hea d a n d nec k s q ua m o us cell carci n o ma  
H N S T D  
hi g hest n o n -se verel y t o xic d os e 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 4  of 1 3 5  
H R Q o L  
healt h -relate d q ualit y of life 
H g b  
he m o gl o bi n  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I B 
I n vesti gat or’s Br oc h ure  
I C D 
i m m u n o ge nic cell deat h 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
i C P D 
c o nfir me d pr o gressi ve disease per i R E CI S T  
i C R 
i m m u ne c o m plete res p o nse 
I E C 
i n de p e n de nt et hics c o m mittee 
I g 
i m m u n o gl o b uli n 
I g G 1 
i m m u n o gl o b uli n G 1 
I g G 4 
i m m u n o gl o b uli n G 4 
I g V 
i m m u n o gl o b uli n V 
I H C 
i m m u n o hist oc he mistr y 
I H R 
i nf usi o n or h y perse nsiti vit y re acti o n 
I N D 
i n vesti gati o nal ne w dr u g 
i P R 
i m m u ne partial res p o nse 
I R B 
i nstit uti o nal re vie w b oar d 
ir A E 
i m m u ne-relate d A Es  
i R E CI S T 
I m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors  
I R R 
i nf usi o n-relate d reacti o n 
i U P D 
i m m u ne u nc o nfir me d pr o gressi ve disease 
I V 
i ntra ve n o us(l y) 
L D H  
lactate de h y dr o ge nase 
m A b  
m o n ocl o nal a nti b o d y  
M A S C C  
M ulti nati o nal Ass ociati o n of S u p p orti ve Care i n Ca ncer  
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
M H C  
maj or hist oc o m pati bilit y c o m ple x  
M O A  
mec ha nis m of acti o n  
M RI  
ma g netic res o na nce i ma gi n g  
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 T er mi n ol o g y Criteria f or A d verse E ve nts  
N K  
nat ural killer [cells]  
N O A E L  
n o o bser ve d a d verse effects le vel  
N S AI D S  
n o n -ster oi d a nti-i nfla m mat or y dr u gs 
N S C L C  
n o n -s mall cell l u n g ca ncer 
N S C L C -S A Q  
N o n -S mall Cell L u n g Ca ncer S y m pt o m Assess me nt Q uesti o n naire  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 5  of 1 3 5  
O R R  
o bj ecti ve res p o nse rate  
O S  
o verall s ur vi val  
P B M C  
peri p heral bl o o d m o n o n uclear cells  
P B P K  
p h ysi ol o gicall y -base d P K  
P C R  
p ol y merase c hai n reacti o n  
P D  
pr o gressi ve disease  
P D  
p har mac o d y na mics  
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 -( L) 1 
pr o gra m me d cell deat h pr otei n 1 ( P D -1) or P D -1 li ga n d 1 ( P D -L 1)  
P D -L 2  
pr o gra m me d cell deat h li ga n d 2  
P F S  
pr o gressi o n -free s ur vi val 
P GI -C  
P atie nt Gl o bal I m pressi o n of S y m pt o m C ha n ge  
P GI -S  
P atie nt Gl o bal I m pressi o n of S y m pt o m Se verit y  
P K  
p har mac o ki netics  
P p o S  
pre dicti ve pr o ba bilit y of s uccess  
P R  
partial res p o nse  
P R O  
patie nt -re p orte d o utc o mes 
P T/a P T T/I N R  
pr ot hr o m bi n ti me/acti vate d partial t hr o m b o plasti n ti me/i nter nati o nal n or malize d rati o 
Q 2 W  
e ver y 2  wee ks  
Q 3 W  
e ver y 3  wee ks  
Q 3 W x 5  
e ver y 3  wee ks  fi ve ti mes 
Q 6 W  
e ver y 6  wee ks  
Q 2 1 d  
e ver y 2 1  da ys  
Q 4 2 d  
e ver y 4 2  da ys  
R E  
res p o nse e val ua ble a nal ysis set 
R E CI S T v 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S C  
s u bc uta ne o us(l y) 
S D  
sta ble disease  
S M C  
Safet y M o nit ori n g C o m mittee  
S o C  
sta n dar d of care 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T N F  
t u m or necr osis fact or 
T P S  
t u m or pr o p orti o n sc ore 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 6  of 1 3 5  
T T D  
ti me-t o-deteri orati o n  
U L N  
u p per li mit of  n or mal  
U P C  
u ri ne pr otei n creati ni ne rati o 
U S P  
U nite d States P har mac o peia  
U S PI  
U nite d States Prescri bi n g I nf or mati o n  
w k  
wee k  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 7  of 1 3 5  
1.  
I N T R O D U C TI O N 
A c o m plete s u m mar y of t he cli nical a n d n o ncli nical data rel e va nt t o t he i n v esti gati o nal pr o d u ct 
a n d its st u d y i n h u ma n s u bjects is pr o vi de d i n t he S E A -C D 4 0 I n v esti gat or’s Br oc h ure (I B). 
1. 1.  
C D 4 0  
O ne wi del y e x presse d sti m ulat or y rece pt or, C D 4 0, is a me m ber of t he t u m or necr osis fact or 
( T N F) rece pt or s u perfa mil y a n d is n or mall y e x presse d a n d utilize d b y t he i m m u ne s yste m. C D 4 0 
is e x presse d b y a nti ge n -prese nti n g cells ( A P Cs ), i ncl u di n g de n dritic cells ( D Cs), B cells, 
macr o p ha ges a n d m o n oc yt es (Gr uss 1 9 9 7 ; va n K o ote n 1 9 9 7 ). It is als o e x presse d o n se veral 
t y pes of B-cell ne o plas ms, i ncl u di n g n o n -H o d g ki n l y m p h o ma, m ulti ple m yel o ma, c hr o nic 
l y m p h oc ytic l y m p h o ma, Wal de nstr ö m’s  macr o gl o b uli ne mia, a n d H o d g ki n l y m p h o ma, as well as 
o n a si g nifica nt perce nta ge of s oli d t u m ors, i ncl u di n g  mela n o ma a n d ot her carci n o mas (ie, 
pa ncreatic, l u n g, o vari a n, bla d der, breast, c ol o n, a n d pr ostatic) (Car b o ne 1 9 9 6 ; Wi n gett 1 9 9 8 ; 
C o o ke 1 9 9 9 ; Ottaia n o 2 0 0 2 ; Ki m 2 0 0 3 ; T o n g 2 0 0 3 ). 
1. 2.  
R ol e of C D 4 0  i n C a n c er 
C D 4 0 bi n ds t o C D 4 0 li ga n d ( C D 4 0 L, C D 1 5 4), w hic h is tra nsie ntl y e x press e d o n acti vate d 
T  cells, a n d at varia ble le vels o n m o n oc ytes, acti v ate d B  cells, e pit helial a n d vasc ular e n d ot helial 
cells, s m o ot h m uscle cells, a n d D Cs. S uc h i nteracti o ns lea d t o c o g n ate, a nti ge n -dri ve n B - a n d 
T -cell acti vati o n a n d differe ntiati o n (va n  K o ote n 2 0 0 0 ; El g ueta 2 0 0 9 ). C D 4 0 acti vati o n has bee n 
s pecificall y de m o nstr ate d t o e v o ke t u m or-s pecific c yt ot o xic T-cell res p o nses, li kel y i n part b y 
i n d uci n g a n d/ or e n ha n ci n g a d h esi o n pr otei ns li ke C D 5 4, c o-sti m ulat or y m olec ules li ke C D 8 6 
a n d maj or hist oc o m pati bilit y c o m ple x ( M H C) a nti ge ns o n A P Cs, i ncl u di n g D Cs, s u g gesti n g its 
val ue as a n o n c ol o g y t h era pe utic tar get (Fre nc h 1 9 9 9 ; K urts 2 0 1 0 ; Gaje ws ki 2 0 1 3 ). 
A n u m ber of C D 4 0 -dir ecte d a nti b o dies ha ve bee n de vel o pe d, all of w hi c h h a ve elicite d s o me 
cli nical acti vit y i n b ot h h e mat ol o gic a n d s oli d mali g na n cies (Hassa n 2 0 1 4 ). C D 4 0-directe d 
a nti b o dies t hat ha ve bee n st u die d i n t he cli nic i ncl u de C hi  L o b 7/ 4 (J o h ns o n 2 0 1 3), l ucat u m u ma b 
(Be nsi n ger 2 0 1 2 ; B yr d 2 0 1 2 ; Fa nale 2 0 1 4 ), C P-8 7 0, 8 9 3 (R uter 2 0 1 0 ; Beatt y 2 0 1 3 ; 
V o n der hei de 2 0 1 3 b ), a n d i n partic ular, dacet uz u ma b (A d va ni 2 0 0 9 ; F ur m a n 2 0 1 0 ; H ussei n 2 0 1 0 ; 
B uri n gt o n 2 0 1 1 ; F orer o -T orres 2 0 1 3 ; de V os 2 0 1 4 ).  
1. 3.  
T u m or I m m u n ol o g y: I m m u n e E v a si o n V er s u s A cti v ati o n  
M uc h atte nti o n has f oc us e d o n mec ha nis ms of i m m u ne s yste m e v asi o n b y t u m ors, s uc h as t he 
e x pl oitati o n of t he c yt ot o xic T -l y m p h o c yt e-ass o ciate d pr otei n 4 ( C T L A 4 )-C D 8 0/ C D 8 6 a n d 
pr o gra m me d cell deat h 1 ( P D -1 ) or  pr o gra m me d cell deat h li ga n d  1 ( P D -L 1 ) (t o get her referre d t o 
as P D -( L) 1 hereafter) i n hi bit or y s yste ms. As de m o nstrate d i n cli nical st u dies of m o n ocl o nal 
a nti b o dies a gai nst C T L A 4 or P D -1 (calle d c hec k p oi nt i n hi bit ors), d ysre g ul ati o n of i n hi bit or y 
rece pt ors b y t u m ors a n d/ or t heir e n vir o n me nts r es ults i n relati ve i m m u ne s u p pressi o n or 
i n hi biti o n (H o di 2 0 1 0 ; T o palia n 2 0 1 2 ; Ha mi d 2 0 1 3 ). H o we v er, defecti ve i m m u ne sti m ulati o n or 
acti vati o n has als o be e n c o nsi dere d t o c o ntri b ute t o t u m or pat h o ge n esis, lea di n g t o t he a d v e nt of 
i m m u n osti m ulat or y a p pr oac hes t o c a ncer treat me nt, s uc h as c hi meric a nti ge n rece pt or ( C A R) 
T  cells (Kers ha w 2 0 1 3 ) or t he ca n cer vacci ne si p ule ucel -T f or pr ostat e ca n cer (Ka nt off 2 0 1 0 ). I n 
t his re gar d, se v eral ot her i m m u ne pat h wa ys m a y pr o vi de tar gets f or i m m u n osti m ulat or y 
t hera pe utic i nter ve nti o n, i ncl u di n g acti vati o n of A P Cs, t o pr o m ote t u m or a nti ge n-s p ecific T-cell 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 8  of 1 3 5  
res p o nses. Ma n y n o v el i n vesti gati o nal t hera pies f or ca ncer ha ve t heref ore p urs ue d se veral 
m o n ocl o nal a nti b o d y ( m A b) tar gets i n c o -sti m ulat or y a n d i n hi bit or y s yste ms, s uc h as n o vel B 7 
li ga n ds, C D 2 7, 4-I B B ( C D 1 3 7), L A G 3 ( C D 2 2 3), 2 B 4 ( C D 2 4 4), TI M 3, or B T L A ( C D 2 7 2) 
(Mell ma n 2 0 1 1 ; Par d oll 2 0 1 2 ). 
1. 4.  
D e s cri pti o n of S E A -C D 4 0  
T o i m pr o ve u p o n t he bi ol o gic acti vit y of dacet uz u ma b, S E A -C D 4 0 has bee n ge n er at e d as a 
n o nf uc os yl ate d deri vati ve. It h as t he sa me a mi n o aci d se q ue n ce a n d is pr o d uce d b y a d di n g t he 
f uc os yl ati o n i n hi bit or 2-fl u or of uc ose d uri n g ma n ufact ur e of dacet uz u ma b. S E A-C D 4 0 
de m o nstrates si g nifi ca ntl y s u peri or bi n di n g t o b ot h hi g h - a n d l o w-affi nit y allelic varia nts of 
Fcγ RIIIa, res ulti n g i n m ore p ote nt a nti b o d y-de p e n de nt cell ular c yt ot o xicit y  (A D C C ) acti vit y 
a gai nst b ot h a C D 4 0 -p ositi ve l y m p h o ma B -cell li ne a n d n or mal B cells. A d diti o nall y, t his 
i ncreas e d Fcγ RIIIa bi n di n g res ults i n e n ha nce d a g o nistic si g nali n g t o A P Cs as de m o nstrate d b y 
pr o -i nfla m mat or y c yt o ki ne secreti o n a n d i n d ucti o n of i m m u ne c o-sti m ulat or y rece pt ors s uc h as 
C D 8 0, C D 8 6, a n d M H C Class I a n d II a nti ge ns ( M H CI a n d M H CII). I n t his wa y, S E A -C D 4 0 is 
e x pecte d t o acce nt uate i m m u ne acti vati o n m ore p ote ntl y b y pri mi n g n ai v e C D 4 + a n d C D 8 + T 
cells t o differe ntiate i nt o hel per a n d c yt ot o xic T cells, res pecti vel y, a n d f urt her m ore t o pr o m ote 
t he secreti o n of pr o-i nfla m mat or y c yt o ki nes, l ea di n g t o t he acti vati o n of nat ural killer ( N K ) cells 
as well as f urt h er acti vati o n of A P Cs. Direct e n ga ge m e nt of C D 4 0 o n t u m or cells ma y pr o m ote 
l ocal i m m u ne acti vati o n a n d e x ert direct a nti-pr oliferati ve effects. S E A -C D 4 0 ma y t heref ore 
c o nfer m ulti ple be n eficial a nti -t u m or mec ha nis ms s u peri or t o ot her C D 4 0-directe d t hera pies, 
i ncl u di n g dacet uz u ma b (Hassa n 2 0 1 4 ).  
1. 5.  
S E A -C D 4 0 M e c h a ni s m of  A cti o n  
C D 4 0 is a wi del y e x presse d me m ber of t h e T N F rece pt or s u perfa mil y f o u n d o n t he s urface of 
m yel oi d cells. As a T N F fa mil y me m ber, C D 4 0 acti vati o n re q uires cl usteri n g of t he rece pt or o n 
t he cell s urface i n a pr ocess k n o w n as a g o nis m. C D 4 0 a g o nis m results i n i n d ucti o n of c yt o ki n es 
a n d c he m o ki nes a n d u p -re g ul ates c o-sti m ulat or y rece pt ors o n i n nat e cells i n a wa y t hat pr o m otes 
t he tra nsf or mati o n of n ai ve  C D 8 +  T cells i nt o a nti ge n e x perie nce d m e m or y C D 8 +  T cells.  
S E A -C D 4 0 is a n o nf uc os yl ate d a nti b o d y t h a t bi n ds wit h hi g h affi nit y t o C D 4 0 a n d Fcγ RIIIa 
w hile a v oi di n g bi n di n g t o t he i n hi bit or y Fcγ RII b rece pt or. A g o nis m of C D 4 0 is facilitate d b y 
I g G 1 a nti b o dies c o nc o mita nt bi n di n g t o C D 4 0 o n m yel oi d cells a n d Fc rece pt ors e x presse d o n 
i m m u ne effect or cells, eg, N K a n d m yel oi d cells. T here are 2  t y pes of Fc rece pt ors, t h ose t hat 
t hat acti vate ( FcγRIIIa, Fc γRIIa, Fc γRI) or t h ose t hat s u p press ( Fc γRII b) m yel oi d cell 
f u ncti o nalit y. S E A-C D 4 0 i n d uces i n nate cell acti v ati o n i n 2  c o m pli me ntar y wa ys; o ne b y 
facilitati ng t he cl usteri n g a n d a g o nis m of C D 4 0 a n d t he ot her b y dri vi n g a p ositi ve acti vati n g 
si g nal t hr o u g h FcγRIIIa. S E A -C D 4 0 c o nfers a nti -t u m or acti vit y b y acti vati n g i n nate cells i n a 
s pecific w a y, w hic h dri v es a nti ge n s pecifi c me m or y C D 8 + T -cell res p o nses.  
1. 6.  
S u m m ar y of N o n cli ni c al T o xi cit y  
T he t o xicit y of S E A -C D 4 0 has bee n e val uate d i n e x pl orat or y a n d G o o d La b orat or y 
Practice -c o m plia nt st u dies i n c y n o m ol g us m o n ke ys at d ose le vels 0. 0 3  t o 3 0  m g/ k g a d mi nistere d 
i ntra ve n o usl y (I V) as eit her si n gl e or re peat d oses  ( Q 3 W x 5). S E A-C D 4 0 -relate d fi n di n gs were 
li mite d t o c ha n ges i n cli nical o bser va ti o ns, he mat ol o g y, cli nical c he mistr y, o p ht hal m ol o g y, fl o w 
c yt o metr y, c yt o ki nes, or ga n wei g hts, hist o pat h ol o g y,  i m m u n o hist oc he mistr y (I H C), 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 2 9  of 1 3 5  
t o xic o ki netics, a n d i m m u n o ge ni cit y. No tr eat me nt -relate d fi n di n gs w ere o bser ve d i n b o d y 
wei g hts, f o o d c o ns u m pti o n, c oa g ulati o n, uri nal ysis, res pirat or y rate, heart rate, bl o o d press ur e, 
b o d y te m perat ur e, electr ocar di o gra ms ( E C Gs), ne ur ol o gical e xa ms, me nstr ual c ycles, male 
re pr o d ucti ve e n d p oints, or T -l y m p h o c yt e pr oliferati o n f oll o wi n g a d mi nistrati o n of S E A-C D 4 0 at 
u p t o 3 0  m g/ k g. O verall, t he m ost pr o mi ne nt effects o bser ve d were i nf usi o n-relate d reacti o ns, 
i ncreas e d c yt o ki ne pr o d u cti o n, decreases i n l y m p h oc yt es  i n t he peri p her y a n d s plee n, t hy m us a n d 
l y m p h n o des, t hr o m b oc yt o pe nia, tra nsie nt li ver e n z y m e (ala ni n e a mi n otra nsferas e [ A L T]) 
ele vati o n, a n d vas c ular/ p eri vasc ular i nfiltrates i n m ulti ple tiss ues . I n a d diti o n, 1 a ni mal treate d 
wit h a si n gle d ose of 3 0  m g/ k g S E A -C D 4 0 ha d tr a nsie nt bilate ral oc ular i nfla m mati o n 
( pa n u veitis) n ote d 1-w ee k p ost d ose t hat rec o vere d wit hi n 3  wee ks p ost d ose. A n ot her a ni mal 
treate d wit h re peat d oses of 3 0  m g/ k g  S E A -C D 4 0 was e ut ha nize d earl y ( Da y 5 6, a p pr o xi matel y 
2  wee ks p ost t he 3r d d os e) d ue t o m ori b u n dit y ca use d b y a pr o gressi o n of a pre -e xisti n g i nfecti o n 
wit h Pl as m o di u m s p p . T he i nfecti o n was n ot c o nsi dere d S E A-C D 4 0 relate d, b ut t he relati o ns hi p 
of t he pr o gressi o n of t h e i nfecti o n was u ncertai n . T he si n gle d os e n o o bser ve d a d verse effect 
le vel ( N O A E L) a n d hi g h est n o n -se verel y t o xic d ose le vel ( H N S T D) f or S E A-C D 4 0 i n m o n ke ys 
were 3  a n d 3 0 m g/ k g,  res pecti vel y. T he re peat -d os e ( Q 3 W x 5)  H N S T D f or S E A -C D 4 0 i n 
m o n ke ys w as 3 0  m g/ k g.  
A n e x pl orat or y si n gle -d ose st u d y i n h u ma n C D 4 0 tra ns ge nic mice was perf or me d t o c o m pare t he 
p har mac o d y n a mic effects, p har mac o ki netics ( P K), a n d i njecti o n site t o xicit y of 1  mc g/ k g 
S E A -C D 4 0 w he n gi ve n via I V or s u bc ut a ne o us ( S C) a d mi nistrati o n. S E A -C D 4 0 was well 
t olerate d wit h  b ot h r o utes of a d mi nistrati o n . N o i njecti o n site irritati o n or a d verse 
hist o pat h ol o gical fi n di n gs were o bs er ve d i n t he tail, s ki n, or s u bc utis wit h eit her r o ute of 
a d mi nistrati o n. Ser u m c o nce ntrati o n of S E A -C D 4 0 pea ke d b et wee n 2  t o 8  h o urs p ost d ose 
f oll o wi n g I V a d mi nistrati o n, a n d at 2 4 h o urs p ost d ose f oll o wi n g S C a d mi nistrati o n. S E A -C D 4 0 
bi oa vaila bilit y aft er S C a d mi nistrati o n was a p pr o xi matel y 1 5 %, relati ve t o I V a d mi nistrati o n. 
H o we ver, differe nces i n area u n d er t he c o nce ntrati o n -ti me c ur ve ( A U C) e x p os ure di d n ot see m 
t o i m pact a ntit u m or acti vit y i n precli nical m odels. C o nsiste nt wit h pre vi o us st u dies, I V 
a d mi nistrati o n of S E A -C D 4 0 i n t his m o use m o del le d t o i ncreas es i n c yt o ki ne pr o d ucti o n a n d 
B -cell acti vati o n a n d re d ucti o ns i n circ ulati n g B  cells. W hile t he sa me p har mac o d y na mics 
c ha n ges occ urre d wit h S C treat me n t, t he res p o nses were atte n uate d. 
A c o m plete s u m mar y of  t he n o ncli nical data rele va nt t o t he S E A-C D 4 0 i n vesti gati o nal pr o d u ct 
a n d its st u d y i n h u ma n s u bjects is pr o vi de d i n t he S E A-C D 4 0 I B.  
1. 7.  
P e m br oli z u m a b  
Pe m br oliz u ma b is a p ote nt h u ma nize d I g G 4 m A b wit h hi g h s pecifi cit y of bi n di n g t o t he P D -1 
rece pt or, t h us i n hi biti n g its i nteracti o n wit h P D-L 1 a n d pr o gra m me d cell deat h li ga n d  2 ( P D -L 2). 
Base d o n precli nic al i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or bl o c ki n g 
acti vit y f or P D -1. Pe m br oliz u ma b has a n acce pt a ble precli nical safet y pr ofile a n d is i n cli nical 
de vel o p me nt as a n I V i m m u n ot hera p y f or a d va nce d mali g na n cies. Ke ytr u d a ® ( pe m br oliz u ma b) 
is i n dicate d f or t he tr eat me nt of patie nts acr oss a n u m ber of i n dicati o ns. F or m ore details on 
s pecific i n dicati o ns r efer t o t he I B. 
Refer t o t he I B/a p pr o ve d la beli n g f or detaile d bac k gr o u n d i nf or mati o n o n M K -3 4 7 5.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 0  of 1 3 5  
1. 7. 1.  
P h ar m a c e uti c al a n d T h er a p e uti c B a c k gr o u n d  
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic  
tra nsf or mati o ns has bee n k n o w n f or deca des (Disis 2 0 1 0 ). Acc um ulati n g e vi de nce s h o ws a 
c orrel ati o n bet wee n t u m or -i nfiltrati n g l y m p h oc ytes i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n 
vari o us mali g n a ncies. I n partic ular, t he prese n ce of C D 8 + T -cells a n d t he rati o of C D 8 +  effect or 
T -cells/ F o x P 3 + re g ulat or y T -cells ( T-re gs) c orrelates wit h i m pr o ve d pr o g n osis a n d l o n g -ter m 
s ur vi val i n s oli d mali g na ncies, s uc h as o v aria n, c ol orectal, a n d p a ncreatic ca ncer; h e pat ocell ular 
carci n o ma; mali g na nt mela n o ma; a n d re n al cell carci n o ma. T u m or -i nfiltrati n g l y m p h oc ytes ca n 
be e x pa n de d  e x vi v o a n d rei nf use d, i n d uci n g d ura ble o bjecti ve t u m or res p o nses i n ca ncers s uc h 
as mela n o ma (D u dl e y 2 0 0 5 ; H u n der 2 0 0 8 ). 
T he P D -1 rece pt or -li ga n d i nteracti o n is a maj or p at h wa y hijac k e d b y t u m ors t o s u p press i m m u ne 
c o ntr ol. T he n or mal f u n cti o n of P D -1, e x presse d o n t he cell s urface of acti v ate d T -cells u n der 
healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or e x cessi ve i m m u ne res p o nses, i ncl u di n g 
a ut oi m m u ne reacti o ns. P D -1 (e n c o de d b y t he ge n e P dc d 1) is a n I g s u perfa mil y m e m ber relate d 
t o cl uster of differe ntiati o n 2 8 ( C D 2 8) a n d C T L A -4 t hat has bee n s h o w n t o ne gati vel y re g ulat e 
a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds ( P D -L 1 a n d/ or P D -L 2) (O kaza ki 2 0 0 1 ; 
Gree n wal d 2 0 0 5 ). 
T he str uct ure of m uri ne P D -1 has bee n res ol ve d (Z ha n g 2 0 0 4 ). P D-1 a n d its fa mil y me m bers are 
t y pe I tra ns me m br a ne gl yc o pr otei ns c o ntai ni n g a n I g-vari a bl e– t y p e (I g V-t y p e) d o mai n 
res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic tail res p o nsi ble f or t he bi n di n g of si g nali n g 
m olec ules. T he c yt o plas mic tail of P D -1 c o ntai ns 2  t yr osi ne-base d si g nali n g m otifs, a n 
i m m u n orece pt or t yr osi ne-base d i n hi biti o n m otif , a n d a n i m m u n orece pt or t yr osi ne-base d s witc h 
m otif. F oll o wi n g T -cell sti m ulati o n, P D -1 recr uits t he t yr osi ne p h os p h atases, S H P -1  a n d S H P -2, 
t o t he i m m u n orece pt or t yr osi ne-base d s witc h m otif wit hi n its c yt o plas mic tail, lea di n g t o t he 
de p h os p h or yl ati o n of effect or m olec ules s u c h as C D 3 zeta ( C D 3ζ), pr otei n ki nase C -t heta 
( P K C θ), a n d zeta-c hai n -ass ociate d pr otei n ki nase ( Z A P 7 0),  w hi c h are i n v ol ve d i n t he C D 3 T -cell 
si g nali n g cas ca d e (O kaza ki 2 0 0 1 ; C he m nitz 2 0 0 4 ; S he p par d 2 0 0 4 ; Rile y 2 0 0 9 ). T he mec h a nis m 
b y w hic h P D -1 d o w n -m o d ulates T -cell res p o nses is si milar t o, b ut disti nct fr o m, t hat of C T L A -4, 
beca use b ot h m ole c ules re g ul ate a n o v erla p pi n g set of si g nali n g pr otei ns (P arr y 2 0 0 5 ; 
Fra n cisc o  2 0 1 0 ). As a c o nse q ue nce, t h e P D-1/ P D -L 1 pat h w a y is a n attracti ve tar get f or 
t hera pe utic i nter ve nti o n i n s oli d t u m ors. 
1. 7. 2.  
Pr e cli ni c al a n d Cli ni c al Tri al s  wit h P e m br oli z u m a b  
T hera p e utic st u dies i n m o use m o dels ha ve s h o w n t hat a d mi nistrati o n of a nti b o dies bl oc ki n g 
P D -1/ P D -L 1 i nteracti o n e n ha nces i nfiltrati o n of t u m or -s pecific C D 8 + T cells a n d ulti matel y 
lea ds t o t u m or rejecti o n, eit her as a m o n ot hera p y or i n c o m bi nati o n wit h ot her treat me nt 
m o dalities (Str o me 2 0 0 3 ; Bla n k 2 0 0 4 ; Hira n o 2 0 0 5 ; C urra n 2 0 1 0 ; Pil o n -T h o mas 2 0 1 0 ; 
We ber  2 0 1 0 ; S pra n ger  2 0 1 4 ). A nti-m o use P D -1 or a nti -m o use P D -L 1 a nti b o dies ha ve 
de m o nstrate d a ntit u m or res p o nses i n m o dels of s q ua m o us cell carci n o ma, p a ncreatic carci n o ma, 
mela n o ma, ac ute m yel oi d le u ke mia a n d c ol or ectal carci n o ma (Str o me 2 0 0 3 ; Z ha n g 2 0 0 4 ; 
N o mi  2 0 0 7 ; C urra n 2 0 1 0 ; Pil o n -T h o mas 2 0 1 0 ). I n s uc h st u dies, t u m or i nfiltrati o n b y C D 8 + T 
cells a n d i ncrease d I F N -γ, gra nz y me B a n d p erf ori n e x pressi o n were o bser ve d, i n dicati n g t h at 
t he mec ha nis m u n derl yin g t he a ntit u m or acti vit y of P D -1 c hec k p oi nt i n hi biti o n i n v ol ve d l ocal 
i nfiltrati o n a n d acti vati o n of effect or T cell f u ncti o n i n vi v o (C urra n 2 0 1 0 ). E x peri me nts ha ve 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 1  of 1 3 5  
c o nfir me d t he i n vi v o efficac y of a nti -m o use P D -1 a nti b o d y as a m o n ot hera p y, as well as i n 
c o m bi nati o n wit h c he m ot hera p y, i n s y n ge n eic m o use t u m or m o dels (see t h e I B).  
1. 7. 3.  
J u stifi c ati o n f or Q 3 W P e m br oli z u m a b D o s e  
T he pla n ne d d ose of pe m br oliz u ma b f or C o h orts 4 a n d 5 is 2 0 0 m g e v er y 3  wee ks ( Q 3 W). Bas e d 
o n t he t otalit y of data ge nerate d i n t he Ke ytr u da d e vel o p me nt pr o gra m, 2 0 0  m g Q 3 W is a n 
a p pr opriate d os e of pe m br oliz u ma b f or a d ults acr oss all i n dicati o ns a n d re gar dless of t u m or t y pe. 
As o utli ne d bel o w, t his d ose is j ustifie d b y:  
•  Cli nical data fr o m 8  ra n d o mize d st u dies i n mela n o ma a n d n o n -s mall cell l u n g ca ncer 
(N S C L C ) i n dicati o ns de m o nstrati n g flat d ose- a n d e x p os ure-efficac y relati o ns hi ps 
fr o m 2  m g/ k g Q 3 W t o 1 0  m g/ k g e ver y 2  wee ks ( Q 2 W)  re prese nti n g a n a p pr o xi mate 
5  t o 7. 5  f ol d e x p os ure ra n ge (refer t o t he I B) 
•  P o p ulati o n P K a nal ysis s h o wi n g t hat b ot h fi x e d d osi n g a n d wei g ht -base d d osi n g 
pr o vi des si milar c o ntr ol of P K varia bilit y wit h c o nsi dera ble o verla p i n t he distri b uti o ns 
of e x p os ures, s u p p orti n g s uita bilit y of 2 0 0  m g Q 3 W   
•  Cli nical data s h o wi n g me a ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g o v erall 
s ur vi val at 2 0 0 m g Q 3 W acr oss m ulti ple i n dicati o ns, a n d  
•  P har mac ol o g y data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic cir c ulati o n (i nferre d 
fr o m P K data) a n d t u m or (i nferre d fr o m p h ysi ol o gicall y-b ase d P K [ P B P K] a nal ysis) at 
2 0 0  m g Q 3 W.  
A m o n g t he 8  ra n d o mize d d ose-c o m paris o n st u dies, a t otal of 2 2 6 2  partici pa nts were e nr olle d 
wit h mela n o ma a n d N S C L C, c o v eri n g differe nt disease setti n gs (treat me nt nai ve , pre vi o usl y 
treate d, P D-L 1 e nric h e d, a n d all -c o mers) a n d differe nt treat me nt setti n gs ( m o n ot hera p y a n d i n 
c o m bi nati o n wit h c he m ot hera p y). Fi ve st u dies c o m pare d 2  m g/ k g Q 3 W vers us 1 0  m g/ k g Q 2 W 
( K N 0 0 1 C o h ort B 2, K N 0 0 1 C o h ort D, K N 0 0 2, K N 0 1 0, a n d K N 0 2 1), a n d 3 st u dies c o m pare d 
1 0  m g/ k g Q 3 W vers us 1 0  m g/ k g Q 2 W ( K N 0 0 1 C o h ort B 3, K N 0 0 1 C o h ort F 2 a n d K N 0 0 6). All 
of t hese st u dies de m o nstr ate d flat d ose - a n d e x p os ure -res p o nse relati o ns hi ps acr oss t he d oses 
st u die d re pres e nti n g a n a p pr o xi mate 5- t o 7. 5-f ol d differe n ce i n e x p os ure. T he 2 m g/ k g ( or 
2 0 0  m g fi x e d -d ose) Q 3 W pr o vi de d si milar res p o nses t o t he hi g hest d oses st u die d. S u bse q ue ntl y, 
flat d ose-e x pos ure -res p o nse relati o ns hi ps were als o o bser ve d i n ot her t u m or t y pes i n cl u di n g h ea d 
a n d nec k ca ncer, bla d d er ca ncer, gastric ca n cer, a n d classical H o d g ki n L y m p h o ma, c o nfir mi n g 
2 0 0  m g Q 3 W as t he a p pr o priate d ose i n de pe n de nt of t he t u m or t y p e. T hese fi n di n gs  are 
c o nsiste nt wit h t he mec h a nis m of acti o n  ( M O A) of pe m br oliz u ma b, w hic h acts b y i nteracti o n 
wit h i m m u ne cells, a n d n ot via direct bi n di n g t o ca ncer cells.  
A d diti o nall y, p har mac ol o g y dat a cle arl y s h o w tar get sat urati o n at 2 0 0  m g Q 3 W. First, P K data i n 
K N 0 0 1 e val uati n g tar get -me diate d dr u g dis p ositi o n ( T M D D) c o n cl usi vel y de m o nstrate d 
sat urati o n of P D-1 i n s yst e mic circ ulati o n at d oses m uc h l o wer t ha n 2 0 0  m g Q 3 W. Sec o n d, a 
P B P K a nal ysis was c o n d ucte d t o pre dict t u m or P D -1 sat urati o n o ver a wi d e ra n ge of t u m or 
pe netrati o n a n d P D -1 e x pressi o n. T his e val uati o n c o ncl u de d t hat pe m br oli z u ma b at 2 0 0  m g 
Q 3 W ac hie ves f ull P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.  
Fi nall y, p o p ul ati o n P K a nal ysis of pe m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of b o d y 
wei g ht a n d ot her partici p a nt c o variat es o n e x p os ure, has s h o w n t hat t he fi x e d -d osi n g pr o vi d es 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 2  of 1 3 5  
si milar c o ntr ol of P K varia bilit y as wei g ht-b ase d d osi n g, wit h c o nsi dera ble o verla p i n t he 
distri b uti o n of e x p os ures fr o m t he 2 0 0  m g Q 3 W fi x e d d ose a n d 2  m g/ k g Q 3 W d ose. S u p p orte d 
b y t hese P K c haracteristics a n d gi ve n t hat fi x e d -d ose has a d va nt a ges of re d uce d d osi n g 
c o m ple xit y a n d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0  m g Q 3 W fi x e d -d ose was selecte d f or 
e val uati o n acr oss all pe m br oliz u ma b pr ot oc ols.  
1. 7. 4.  
J u stifi c ati o n f or Q 6 W  P e m br oli z u m a b D o s e  
T he pla n ne d d ose of pe m br oliz u ma b f or C o h orts 1, 2, a n d 3 is 4 0 0  m g e v er y 6  wee ks ( Q 6 W).  
A 4 0 0  m g Q 6 W d osi n g re gi me n of pe m br oliz u ma b is e x pecte d t o ha ve a si milar be nefit -ris k 
pr ofile as 2 0 0  m g Q 3 W, i n all treat me nt setti n gs i n w hic h 2 0 0  m g Q 3 W pe m br oliz u ma b is 
c urre ntl y a p pr o priate  (Lala 2 0 1 8 ). S pecificall y, t h e d osi n g re gi me n of 4 0 0  m g Q 6 W f or 
pe m br oliz u ma b is c o nsi dere d a d e q uate base d o n m o deli n g a n d si m ulati o n ( M & S) a n al ys es, 
gi ve n t he f oll o wi n g rati o nale: 
•  P K si m ulati o ns de m o nstrati n g t hat i n ter ms of p e m br oliz u ma b e x p os ures : 
o  A vera ge c o nce ntrati o n o ver t he d osi n g i nter val ( C a v g) ( or area u n der t h e c ur ve 
[ A U C]) at 4 0 0 m g Q 6 W is si milar t o t hat at t he a p pr o ve d 2 0 0  m g Q 3 W d ose, 
t h us bri d gi n g efficac y bet wee n d osi n g re gi me ns.  
o  Tr o u g h c o nce ntrati o ns ( C mi n ) at 4 0 0 m g Q 6 W are ge n erall y wit hi n t he ra n ge 
of t h ose ac hie v e d wit h 2  m g/ k g or 2 0 0  m g Q 3 W i n t he maj orit y ( > 9 9 %) of 
patie nts.  
o  Pea k c o nce ntrati o ns ( C ma x ) at 4 0 0 m g Q 6 W are well bel o w t he C ma x  f or t he 
hi g hest cli nicall y teste d d ose of 1 0  m g/ k g Q 2 W, s u p p orti n g t hat t he safet y 
pr ofile f or 4 0 0  m g Q 6 W s h o ul d be c o m para bl e t o t he esta blis he d safet y 
pr ofile of pe m br oliz u ma b.  
o  E x p os ure -res p o nse ( E-R) f or pe m br oliz u ma b has bee n de m o nstrat e d t o be flat 
acr oss i n dicati o ns, a n d O S pre dicti o ns i n mela n o ma a n d N S C L C de m o nstrate 
t hat effic ac y at 4 0 0 m g Q 6 W is e x pecte d t o be si milar t o t hat at 2 0 0  m g or 
2  m g/ k g Q 3 W, gi ve n t h e si milar e x p os ures; t h us 4 0 0  m g Q 6 W is e x pecte d t o 
be effi caci o us a cr oss  i n di cati o ns.  
1. 8.  
C h e m ot h er a p y i n N S C L C  
Pri or t o t he i ntr o d ucti o n of i m m u n ot hera p y, c he m ot hera p y f or m e d t he bac k b o ne of treat me nt 
strate gies i n N S C L C. W hile si n gle-a ge nt acti vit y wit h cis plati n was n ote d, t he be nefit o v er 
s u p p orti ve care was mar gi nal wit h o ne year s ur vi val rates o n t he or der of 1 0 %  t o 1 5 % 
(N o n -s mall Cell L u n g Ca ncer C olla b orati ve Gr o u p 1 9 9 5). Gra d u all y, plati n u m d o u blet 
c o m bi nati o ns were i ntr o d uce d wit h si g nifi ca nt i m pr o ve me nts i n o ne year s ur vi val t o 3 3 % 
(Sc hiller 2 0 0 2 ). Gi ve n its effic ac y a n d t olera bilit y, plati n u m d o u blet t hera p y wit h pe metr e x e d 
beca me a sta n dar d of care i n n o n-s q ua m o us N S C L C u ntil t he i ntr o d ucti o n of i m m u n ot hera p y 
(Sca gli otti 2 0 0 8 ).  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 3  of 1 3 5  
1. 9.  
C ar b o pl ati n, P e m etr e x e d, a n d P e m br oli z u m a b i n N S C L C  
Car b o plati n a n d p e metre x e d precli nical  data s u g gest  t hat, i n a d diti o n t o t heir c yt ot o xic f u ncti o n, 
t he y p ossess i m m u ne m o d ulat or y f u ncti o ns, s uc h as i ncreasi n g T -cell i nfiltrati o n a n d a nti ge n 
prese ntati o n  i n t ur n lea di n g t o i ncrease d T-cell rec o g niti o n of t u m or cells , t hat ha ve t he p ote ntial 
t o s y ner giz e wit h im m u n ot hera pies li k e pe m br oliz u ma b i n N S C L C (Le o netti 2 0 1 9 ). 
K E Y N O T E -1 8 9 was a gl o bal, d o u ble -bli n d, place b o -c o ntr olle d p hase 3 trial c o m pari n g 
plati n u m -base d c he m ot h era p y c o m bi ne d wit h pe metre x e d pl us eit her pe m br oliz u ma b or place b o 
i n n o ns q ua m o us N S C L C wit h o ut se nsitizi n g E G F R/ A L K  a n a plastic lar ge -cell l y m p h o ma ki nas e  
(A L K ) m utati o ns  t hat s o u g ht t o e x a mi ne t he a d diti o nal be nefit of pe m br oli z u ma b w he n a d de d t o  
plati n u m d o u blet c he m ot hera p y . I n t his trial, t here was a si g nifica nt i m pr o v e me nt i n O S a n d 
pr o gressi o n -free s ur vi val (P F S ) i n t he pe m br oliz u ma b c o h ort rel ati ve t o c he m ot hera p y al o n e 
(me dia n O S /P F S of 2 2  m o nt hs /9  m o nt hs vs 1 0. 7  m o nt hs /4. 9  m o nt hs , res pecti vel y); i m p orta ntl y, 
t his relati ve i m pr o ve me nt was n ote d i n all gr o u ps re gar dl ess of brai n or li ver metastasis. 
H o we ver, w hile  all le vels of t u m or pr o p orti o n sc ore (T P S ) ha d rel ati ve be nefit, t he a bs ol ute 
be nefit was n ot distri b ute d e ve nl y a m o n g patie nts, as patie nts wit h T P S  ≥5 0 % ha d a me dia n P F S 
of 1 1. 1  m o nt hs  c o m pare d wit h  9. 2  m o nt hs  a n d 6. 2  m o nt hs  i n T P S  1 % t o 4 9 % a n d < 1 % 
res pecti vel y (Ga d geel 2 0 2 0 ). Gi ve n t hese differe ntial o utc o mes  de pe n de nt o n T P S , t here is a 
nee d t o i m pr o ve o utc o mes i n patie nts wit h N S C L C, partic ularl y t h ose wit h T P S < 5 0 % . 
1. 1 0.  
P e m br oli z u m a b C o m bi n ati o n T h er a p y  
Pe m br oliz u ma b is a hi g hl y sele cti ve a nti -P D -1 h u ma nize d m A b t hat i n hi bits P D -1 acti vit y b y 
bi n di n g t o t he P D -1 rece pt or o n T cells t o bl oc k bi n di n g t o P D -1 li ga n ds ( P D -L 1 a n d P D -L 2). 
Bl oc ki n g t he P D -1 pat h w a y i n hi bits t he ne gati ve i m m u ne re g ulati o n ca us e d b y P D -1 rece pt or 
si g nali n g (H a mi d 2 0 1 3 ). A nti-P D -( L)1 a nti b o dies, i ncl u di n g pe m br oliz u ma b, re verse T -cell 
s u p pressi o n a n d i n d uce a ntit u m or res p o nses (R o bert 2 0 1 4 ). Refer t o t he c urre nt pe m br oliz u ma b 
U nite d States prescri bi n g  i nf or mati o n f or a p pr o ve d treat me nt i n dicati o ns. 
S E A -C D 4 0 a n d pe m br oli z u ma b act t hr o u g h disti n ct a n d c o m ple me ntar y mec ha nis ms of acti o n. 
Bi n di n g of S E A -C D 4 0 t o C D 4 0 o n A P Cs a n d e n ha nce d cr ossli n ki n g via Fcγ RIIIa lea ds t o A P C 
acti vati o n a n d e n h a nce d a nti ge n  prese nt ati o n t o t u m or s pecific T cells. It is h y p ot hesize d t hat t he 
acti vate d c yt ot o xic T cells will mi grate i nt o t u m or sites, a n d i n hi bit or y m olec ules will be bl oc ke d 
b y P D -( L)1 m A bs. I n precli nical m o dels, S E A -C D 4 0 a n d t he c hec k p oi nt i n hi bit ors i pili m u m a b 
(a nti-C T L A 4) or pe m br oliz u ma b (a nti -P D 1) c o m bi ne t o sti m ulate a T -cell res p o nse t o c o m m o n 
t u m or a nti ge n p e pti des fr o m peri p heral bl o o d m o n o n uclear cells ( P B M Cs) is olate d fr o m d o n ors 
wit h mela n o ma ( n = 3), breast ca n cer ( n = 3), or pa n creatic ca n cer ( n = 3) (Gar dai 2 0 1 5 ). 
T he i m m u ne c hec k p oi nt i n hi bit ors s uc h as pe m br oliz u ma b ha ve si g nifica nt a d de d be nefit t o 
patie nt gr o u ps wit h hi g h u n met nee d, h o we v er, o nl y a s u bset of patie nts res p o n d t o c hec k p oi nt 
i n hi bit ors, a n d ma n y pati e nts w h o i nitiall y b e nefit fr o m c hec k p oint i n hi bit ors e ve nt uall y 
pr o gress. It is h y p ot hesize d t hat b y c o m bi ni n g c hec k p oi nt i n hi bit ors wit h i m m u ne c o -sti m ulat or y 
a ge nts s uc h as S E A -C D 4 0, t he a ntit u m or i m m u ne res p o nse will be m ore r o b ust, a n d d ura ble 
res p o nse rates will mea ni n gf ull y i ncrease. Gi ve n t hat S E A -C D 4 0 is s h o w n t o be a bi ol o gicall y 
a n d cli nicall y acti ve m ol ec ule i n hea vil y pre -tr eat e d patie nts wit h a d va nce d s oli d t u m ors, a n d 
pe m br oliz u ma b has d oc u me nte d si n gle  a ge nt acti vit y i n patie nts wit h metastatic mela n o ma a n d 
N S C L C, it is h y p ot hesiz e d t hat pe m br oliz u ma b c o m bi nati o n t hera p y c o ul d p ote ntiall y be m or e 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 4  of 1 3 5  
effecti ve t ha n a d mi nistrati o n of eit her a ge nt al o ne. M ore o ver, b ot h a ge nts are reas o n a bl y well 
t olerate d, ha v e fe w o verl a p pi n g t o xicities, a n d ca n be a d mi nistere d i n t he o ut patie nt setti n g. 
1. 1 1.  
C h e m ot h er a p y C o m bi n ati o n T h er a p y  
Alt h o u g h u pfr o nt  c he m oi m m u n ot hera p y h as i m pr o ve d o utc o mes si g nifi ca ntl y i n metastatic 
N S C L C, t here is a si g nifi ca nt u n met nee d f or i m pr o ved  res p o nse rates i n patie nts wit h 
T P S  < 5 0 % , es peciall y i n li g ht of t he fact t hat u p t o half of all N S C L C patie nts will q uic kl y 
pr o gress  des pite tr eat me nt a n d n ot ha ve t he o p p ort u nit y t o recei ve sec o n d-li ne t hera p y 
(Da vies  2 0 1 7 ). As s uc h, im pr o ve me nt i n fr o nt -li ne t hera pies i n patie nts less res p o nsi ve t o 
c he m oi m m u n ot hera p y re prese nts a n o p p ort u nit y t o  i m pr o ve s ur vi val i n t hese patie nts b y virt u e 
of t he a bilit y f or t he m t o utilize sec o n d-li ne t hera pies u p o n fail ure. Gi ve n t h at S E A -C D 4 0 
a p pears t o h a ve its effi cac y e n ha n ce d b y a nti ge n release fr o m  c o nc urre nt  c he m o i m m u n ot hera p y 
a d mi nistrati o n  a n d t hat t here is a n a p pr o ve d c he m o i m m u n ot hera p y re gi me n i n fr o nt-li ne N S C L C 
wit h  i nferi or o utc o mes i n patie nts wit h T P S < 5 0 % , it is h y p ot hesize d t hat t he a d diti o n of 
S E A -C D 4 0 t o c he m oi m m u n ot hera p y i n t his s u bset of patie nts will res ult i n i m pr o ve d o utc o mes 
wit h a ma na gea ble  safet y pr ofile. 
T here is si g nifica nt pr ecli nical data i n s u p p ort of c o m bi ni n g S E A -C D 4 0 wit h c he m ot hera p y . D ue 
t o its af uc os ylat e d Fc bac k b o ne , S E A-C D 4 0 a p pears t o e n ga ge acti vati n g Fc -γ rece pt ors m or e 
effecti vel y t ha n ot her C D 4 0 a g o nist a nti b o dies  (Ze n g 2 0 2 0 ). D ue t o t his prefere ntial e n ga ge me nt, 
t here is si g nifi ca nt a u g m e ntati o n i n vitr o of i m m u ne -acti vati n g c yt o ki nes, s uc h as C X C L 1 0 a n d 
I F N-γ, wit h o ut c o m me ns urate i ncreases i n i m m u n os u p pressi ve c yt o ki nes, s uc h as I L-1 0 a n d 
M D C , w he n S E A-C D 4 0 is c o m bi ne d wit h na b -p aclita xel c he m ot hera p y. F urt her m ore, w he n 
peri p heral c yt o ki nes are e x a mi ne d i n x e n o graft m o dels, t here is a n i ncreas e i n c yt o ki n es, as well 
as t u m or-i nfiltrati n g C D 1 1 b + macr o p ha ges, C D 3 + T -cells, a n d o verall T -cells w he n S E A-C D 4 0 
is c o m bi ne d wit h na b -paclita x el  relati ve t o eit her t hera p y al o ne, i n dicati n g t hat t here is s y n er g y 
bet wee n S E A -C D 4 0 a n d c he m ot hera p y. C o m pare d t o ot her i n vesti gati o nal C D 4 0 a g o nists, t here 
are si g nifica ntl y hi g her le vels of I F N -γ a n d C X C L 1 0 a n d l o wer le v els of t he i m m u ne i n hi b it or y 
c yt o ki ne I L-1 0 f or treate d l u n g ca ncer cells w he n S E A -C D 4 0 is c o m bi ne d i n vitr o wit h 
o x ali plati n, a c he m ot hera p y k n o w n t o i n d uce i m m u n o ge ni c cell deat h (I C D), i n dicati n g 
i m m u n ol o gic s y n er g y (S u n 2 0 1 9 ). N ota bl y, S E A -C D 4 0 a n d o x ali plati n c o m bi ne d i n d uce d 
si g nifica nt i ncreas es i n I L-1 2 p 4 0  a n d C X C L 1 0 i n mice beari n g s oli d t u m ors, i n dicati n g t hat t his 
s y ner g y bet wee n I C D-i n d uci n g c he m ot hera p y a n d S E A-C D 4 0 h ol ds i n vi v o. Gi ve n t hat 
car b o plati n a n d p e metre x e d are b ot h c he m ot hera pi es k n o w n t o i n d uce I C D  w he n utilize d al o ne 
or i n c o m bi nati o n wit h ot her c he m ot hera pies  a n d t hat S E A -C D 4 0 a p pears t o s y ner gize 
s pecificall y wit h I C D-i n d uci n g c he m ot hera p y, it is belie ve d t hat t he c o m bi n ati o n of 
sta n dar d-of -care c he m ot hera p y wit h S E A -C D 4 0 will p r o vi de si gnifica nt t hera pe utic b e nefit i n 
fr o nt-li ne metastatic N S C L C (N o v osia dl y 2 0 1 8 ; Sc haer 2 0 1 9 ; Flies wasser 2 0 2 0 ). 
1. 1 2.  
S u m m ar y of Cli ni c al St u d y S G N S 4 0 -0 0 1  
A n o n g oi n g p has e 1 d ose -re gi me n fi n di n g st u d y, S G N S 4 0-0 0 1, is e val uati n g t he safet y, 
t olera bilit y, a n d a ntit u m or acti vit y of S E A-C D 4 0 as m o n ot hera p y i n s u bjects wit h a d va nce d 
s oli d a n d he mat ol o gic m ali g na n cies. S G N S 4 0-0 0 1 is als o e val uat i n g S E A -C D 4 0 i n c o m bi nati o n 
wit h c he m ot hera pies a n d/ or pe m br oliz u ma b i n s u bjects wit h a d va nce d s oli d t u m ors 
(e g, mela n o ma, N S C L C, hea d a n d n ec k s q ua m o us cell carci n o ma [ H N S C C ], a n d pa ncreatic 
ca ncer). 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 5  of 1 3 5  
I n m o n ot hera p y, S E A-C D 4 0 was a d mi nistere d eit her I V or S C o n Da y  1 of eac h 3 -wee k c ycle at 
d oses ra n gi n g fr o m 0. 6  mc g/ k g t o 3  m g/ k g . I n c o m bi nati o n t hera p y, S E A -C D 4 0 was 
a d mi nistere d I V o n Da y 1 a n d pe m br oliz u ma b 2 0 0  m g is a d mi nistere d o n Da y  2 of eac h 2 1 -d a y 
c ycle. S u bject s wit h pa ncreatic ca ncer were a d mi nistere d ge mcita bi ne a n d na b -paclita xel o n 
Da ys  1, 8 , a n d 1 5 of eac h 2 8 -da y c ycl e; S E A -C D 4 0 o n Da y  3 of eac h 2 8 -d a y c ycle; a n d 
pe m br oliz u ma b 4 0 0  m g Q 6 W . S u bject s c o nti n ue d o n st u d y treat me nt u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y.  
T he ma xi m u m t olerate d d ose ( M T D) f or S E A -C D 4 0 m o n ot hera p y was n ot e x cee de d f or s u bjects 
wit h s ol i d t u m ors or l y m p h o mas. As detaile d i n t he S E A -C D 4 0 I B, i nf usi o n or h y p erse nsiti vit y 
reacti o ns (I H Rs) are a n i de ntifie d ris k f or S E A-C D 4 0 a n d ha ve b ee n o bs er ve d i n s u bjects 
a d mi nistere d S E A -C D 4 0  i n St u d y S G N S 4 0 -0 0 1 . T he c o m bi nati o n of S E A -C D 4 0 a n d 
pe m br oliz u ma b was deter mi ne d t o be t olera ble  i n St u d y S G N S 4 0-0 0 1 .  
A s u m mar y of cli nical safet y d ata fr o m St u d y S G N S 4 0 -0 0 1 is pr o vi de d i n t he S E A -C D 4 0 I B.  
1. 1 3.  
R ati o n al e f or St u d y  
Base d o n pri or e x perie nce wit h dacet uz u ma b a n d S E A -C D 4 0 (Secti o n  1. 1 2 ) a n d t he p ote ntial 
r ole of C D 4 0 i n a ntit u m or i m m u nit y, S E A-C D 4 0 ma y h a ve br oa d t hera pe utic p ote ntial i n ma n y 
t y pes of m ali g n a ncies. B y c o m p ari n g o utc o mes i n s u bjects recei vi n g S E A-C D 4 0 c o m bi nati o n 
t hera p y t o t h ose of hist orical c o ntr ols, we will det er mi ne t he p ote ntial  f or S E A -C D 4 0 w he n 
c o m bi ne d wit h  a p pr o ve d t hera pies. Efficac y data ac q uire d t hr o u g h t his trial will i nf or m decisi o ns 
t o p urs ue lar ger ra n d o mi ze d trials f or i n di vi d ual i n dicati o ns. I nitiall y, t he trial will f oc us o n 
p o p ulati o ns t hat are m ost li kel y t o ha ve a meas ura ble be nefit wit hi n t he c o nfi nes of a s maller 
sa m ple siz e, s pecificall y mela n o ma a n d N S C L C wit h T P S < 5 0 %.  
1. 1 4.  
A s s e s s m e nt of B e n efit -Ri s k  
T his bas ket st u d y will e nr oll s u bjects wit h m ulti ple t u m or t y pes t o e val uate  w het her t he  a d diti o n 
of S E A -C D 4 0 t o sta n dar d of care treat me nts ca n i m pr o ve res p o nse rates a n d/ or s ur vi val . 
Preli mi nar y safet y dat a fr o m t he o n g oi n g p hase 1 st u d y ( S G N S 4 0 -0 0 1 ; s u m marize d i n 
Secti o n  1. 1 2 ) s u g gest t hat S E A -C D 4 0 c o m bi ne d wit h pe m br oliz u ma b a n d/ or c he m ot hera p y  is 
t olera ble. A s u m mar y of cli nical safet y dat a fr o m St u d y S G N S 4 0 -0 0 1 is pr o vi de d i n t he 
S E A -C D 4 0 I B.  
I nitiall y, e nr oll me nt i n t his  st u d y will be li mite d t o s u bjects wit h N S C L C a n d mela n o ma ; t he 
hist ol o gies i ncl u de d ma y  be e x pa n de d via pr ot oc ol a me n d me nt. S E A -C D 4 0 is belie ve d t o ha ve 
t he p ote ntial t o s y ner giz e wit h c urre nt c he m oi m m u n ot hera p y strate gi es a n d c o ul d pr o vi de 
cli nical be nefit wit hi n patie nt p o p ulati o ns i n w hic h i m m u n ot hera p y is sta n dar d of care, 
es peciall y t h ose wit h  s u b o pti mal res p o nses t o t hera p y. Gi ve n t hat S E A-C D 4 0 c o m bi ne d wit h 
c he m ot hera p y a n d i m m u n ot hera p y has d e m o nstrate d t olera bilit y i n t he p hase 1 st u d y 
( S G N S 4 0-0 0 1)  a n d t hat precli nical dat a s u p p ort  t hese c o m bi nati o ns, t he c h ose n patie nt 
p o p ulati o ns are c o nsi dere d a p pr o priate f or i ncl usi o n i n t his trial. 
T he s p o ns or has c o n d u ct e d a ris k assess me nt f or t he c o nc o mita nt use of C O VI D -1 9 v acci n es. It 
has deter mi ne d t hat t he a d mi nistrati o n of a C O VI D -1 9 vacci ne d uri n g t his trial is c o nsi dere d a 
c o nc o mita nt me dicati o n t hat d oes n ot re q uire a d vi ce or ti mi n g of t he vacci ne be y o n d t he 
g ui da n ce alr ea d y o utli ne d i n t his st u d y pr ot oc ol ( s ee S ecti o n 5. 4. 2 ). T his patie nt p o p ulati o n is at 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 6  of 1 3 5  
ris k f or se vere C O VI D-1 9 disease a n d t heref ore will be nefit fr o m a d mi nistrati o n of a vacci ne 
t hat pre ve nts se vere dise ase. 
2.  
O B J E C TI V E S  
T his st u d y will e val uate t he a ntit u m or acti vit y, safet y, a n d t olera bilit y of S E A -C D 4 0  i n s u bjects 
wit h a d va nce d or metastatic s oli d mali g na ncies . S pecific o bjecti ves a n d c orres p o n di n g e n d p oi nts 
f or t he st u d y are s u m mariz e d bel o w: 
Pri mar y O bj ecti ve  
C orres p o n di n g Pri mar y E n d p oi nt  
•  
T o e val uate t he a ntit u m or acti vit y of 
S E A -C D 4 0 c o m bi ne d wit h ot her 
t hera pies  
•  
C o nfir me d O bj ecti ve Res p o ns e Rate ( O R R; 
c o nfir me d c o m plete 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 v 1. 1 per 
i n vesti gat or assess me nt (Eise n ha uer 2 0 0 9 ) 
Sec o n da r y O bj ecti ves 
C orres p o n di n g Sec o n dar y E n d p oi nts  
•  
T o e val uate t he safet y a n d 
t olera bilit y of S E A-C D 4 0 c o m bi ne d 
wit h ot her t hera pies  
•  
T y pe, i nci de nce, se verit y, seri o us ness, a n d 
relate d ness of a d verse e ve nts (A Es ) 
•  
T y pe, i nci de nce, a n d se verit y of la b orat or y 
a b n or malities 
•  
Fre q ue nc y of treat me nt i nterr u pti o ns, d ose 
re d ucti o ns, a n d treat me nt disc o nti n uati o ns d ue t o 
A Es  
•  
T o e val uate c o ntr ol of disease  
•  
Disease c o ntr ol rate ( D C R; c o nfir me d C R , P R, a n d 
sta ble disease [ S D]) per i n vesti gat or assess me nt 
•  
T o e val uate d u ra bilit y of res p o nse i n 
s u bj ects w h o res p o n d t o st u d y 
dr u g(s)  
•  
D urati o n of res p o nse ( D O R; d urati o n of c o nfir me d 
C R or P R) per i n vesti gat or assess me nt  
•  
T o e val uate P F S a n d s ur vi val  
•  
Pr o gressi o n -free s ur vi val ( P F S) per i n vesti gat or 
assess me nt 
•  
O verall s ur vi val ( O S) 
E x pl orat or y O bj ecti ves  
C orres p o n di n g E x pl orat or y E n d p oi nts  
•  
T o c haracterize t he 
p har mac o ki netics ( P K) of 
S E A -C D 4 0 a n d i nci de nce of 
a nti dr u g a nti b o dies ( A D As ) w he n 
S E A -C D 4 0 is a d mi nistere d i n 
c o m bi nati o n wit h ot her t hera pies  
•  
Esti mates of selecte d P K para meters  
•  
I nci de nce of A D As 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 7  of 1 3 5  
C o h orts 1 , 2, a n d 3 ( Mel a n o m a): 
•  
T o e val uate selecte d 
p har mac o d y na mic para meters of 
i nterest f or S E A-C D 4 0.  
C o h orts 1 , 2, a n d 3  ( Mel a n o m a): 
•  
E x pl orat or y c orrelati o ns bet wee n Q T c a n d plas ma 
c o nce ntrati o ns of S E A -C D 4 0  
T o assess e x pl orat or y bi o mar kers of res p o nse, 
t o xicit y, a n d resista nce of S E A-C D 4 0 i n 
c o m bi nati o n wit h ot her t hera pies  
Act ual a n d c ha n ge fr o m baseli ne val ues i n i m m u ne s u bsets a n d 
c yt o ki nes i n peri p heral bl o o d  
•  
T o e val uate t he a ntit u m or acti vit y of 
S E A -C D 4 0 c o m bi ne d  wit h ot her 
t hera pies per M o difie d R E CI S T 1. 1 
f or I m m u ne-base d T hera p e utics 
(i R E CI S T) 
•  
C o nfir me d O R R ( i m m u ne c o m plete res p o nse [i C R] 
or i m m u ne partial res p o nse [i P R]) acc or di n g t o 
i R E CI S T 
•  
T o e val uate patie nt -re p orte d 
o utc o mes of 
disease /treat me nt-relate d s y m pt o ms, 
healt h -relate d q ualit y of life 
(H R Q o L ), a n d f u ncti o n  
All C o h orts:  
•  
Act ual a n d c ha n ge fr o m baseli ne sc ores o n t he 
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt 
of Ca ncer q ualit y of life q uesti o n naire 
( E O R T C Q L Q -C 3 0)  
C o h orts 4 a n d 5 o nly ( N S C L C):  
•  
Ti me -t o-deteri orati o n  ( T T D) i n eit her c o u g h, 
d ys p nea, or c hest pai n ( w hic he ver deteri orates first) 
as meas ure d b y t he N o n -S mall Cell L u n g Ca ncer 
S y m pt o m Assess me nt Q uesti o n naire 
( N S C L C-S A Q)  
•  
Act ual a n d c ha n ge fr o m baseli ne val ues i n 
N S C L C -S A Q  d o mai ns a n d t otal sc ores  
3.  
IN V E S TI G A TI O N A L P L A N  
3. 1.  
S u m m ar y of St u d y D e si g n  
T his is a p hase 2 , gl o bal , o pe n -la bel, m ultice nter trial desi g ne d t o assess t he acti vit y, safet y, a n d 
t olera bilit y of S E A-C D 4 0 i n c o m bi nati o n wit h sta n dar d-of -care t hera pies i n a d ults wit h selecte d 
s oli d t u m ors. T he st u d y will i ncl u de m ulti ple i n dicati o n-s pecifi c c o h orts. U p t o a p pr o xi matel y 
2 0 0  s u bjects ma y b e e nr olle d i n t his st u d y. Fi g ure  1  prese nts t he o verall st u d y desi g n.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


Study SGNS40-002
Clinical Protocol
Amendment 3: 05-Apr-2023
SEA-CD40
Seagen Inc. – Confidential
Page 38 of 135
Figure 1:
Study Design
For the NSCLC cohorts (Cohorts 4 and 5), the safety monitoring committee (SMC) will assess 
safety after the first 6 subjects have completed at least 1 treatment cycle. For all cohorts, an
interim analysis will be performed after at least 15 subjects have received the study drugs and are 
response evaluable in each cohort. While the interim analysis is performed, enrollment in the 
cohort may continue. The Bayesian predictive probability approach will be used to inform 
decision-making for continued enrollment (Lee 2008b). At the time of the interim analysis, the 
predictive probability of success (PpoS) will be calculated. Based on the totality of activity and 
safety data, together with the PpoS, the cohort may continue or be stopped early by the sponsor. 
A cohort may also be discontinued at any point at the discretion of the sponsor.
On a periodic basis, an SMC will monitor the safety of subjects in the study (Section 3.1.7). 
Ongoing, real-time review of subject safety will also be conducted by the sponsor’s drug safety 
department throughout the study. 
Response will be assessed by computed tomography (CT) or magnetic resonance imaging (MRI)
scans Q6W from the first dose of study drug for 24 weeks and every 12 weeks thereafter until 
disease progression, initiation of new anticancer treatment, study termination by the sponsor, or 
death, whichever occurs first. The determination of antitumor activity will be based on objective 
response rate (ORR) assessments as defined by RECIST v1.1 and by immune-related Response 
Evaluation Criteria in Solid Tumors (iRECIST). Treatment decisions will be determined by the 
investigator.
3.1.1.
Cohorts 1, 2, and 3 (Melanoma)
Cohorts 1, 2, and 3 will evaluate SEA-CD40 in combination with pembrolizumab in subjects 
with unresectable melanoma. Cohort 1 will enroll subjects with relapsed and/or refractory 
melanoma who have received up to 3 prior lines of systemic therapy and have progressed on 
treatment with an anti-PD-(L)1 mAb as the most recent therapy. Cohort 2 will enroll subjects 
with metastatic uveal melanoma. Cohort 3 will enroll subjects with metastatic PD-(L)1-naive
melanoma. Full eligibility criteria are detailed in Section 4. Due to differences in standard of 
care, subjects in France will not be enrolled in Cohort 1.
090177e1a1307203\Approved\Approved On: 05-Apr-2023 20:16 (GMT)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 3 9  of 1 3 5  
I nitiall y, u p t o 1 5 s u bjects ma y e nr oll i n eac h c o h ort. I nt eri m safet y a n d efficac y a nal yses  will be 
perf or me d f or eac h c o h ort after 1 5  s u bjects h a ve recei ve d st u d y dr u g a n d are res p o ns e e val u a ble. 
C o h orts ma y c o nti n ue t o e nr oll u p t o a n a d diti o nal  2 5  s u bjects, f or a t otal of u p t o a p pr o xi matel y 
4 0  s u bjects i n eac h c o h ort. 
3. 1. 2.  
C o h ort s 4 a n d 5 ( N S C L C) 
C o h ort s 4 a n d 5 will e val uate S E A -C D 4 0 i n c o m bi nati o n wit h car b o plati n , pe metre x e d, a n d 
pe m br oliz u ma b i n s u bjects wit h sta ge I V n o n -s q ua m o us N S C LC . C o h ort 4 will e nr oll s u bjects 
wit h P D -L 1  T P S  e x pressi o n of 1 % – 4 9 % . C o h ort 5 will e nr oll s u bjects wit h P D-L 1 T P S 
e x pressi o n  < 1 %.  
I nitiall y, 6 t otal s u bjects will be e nr olle d acr oss C o h orts 4  a n d 5 ; safet y will be assesse d after t he 
first treat me nt c ycl e. If a p pr o ve d b y t he S M C, C o h orts 4  a n d 5  ma y c o nti n ue t o e nr oll u p t o 
1 5  s u bjects per c o h ort. I nteri m safet y a n d efficac y a nal ys es will be perf or m e d f or eac h c o h ort 
after 1 5 s u bjects ha ve recei ve d st u d y dr u g a n d are res p o nse e v al ua ble. C o h orts ma y c o nti n ue t o 
e nr oll u p t o a n a d diti o nal 2 5  s u bjects, f or a t otal of u p t o a p pr o xi matel y 4 0 s u bjects i n eac h 
c o h ort. 
3. 1. 3.  
D ur ati o n of Tr e at m e nt  
S u bject s w h o ac hie ve st a ble disease ( S D) or better ma y c o nti n ue st u d y tr eat me nt f or 
a p pr o xi matel y 2  years or u ntil u nacce pta ble t o xicit y, c o nfir me d diseas e pr o gressi o n, wit h dra wal 
of c o nse nt, or st u d y ter mi nati o n, w hic he ver occ urs first.  
Pe m br oliz u ma b a d mi nistrati o n will be disc o nti n ue d o nce t he  s u bject h as c o m plete d 
a p pr o xi matel y 2  years wit h pe m br oliz u ma b ( 3 5  a d mi nistrati o ns f or Q 3 W d osi n g  or 
1 8  a d mi nistrati o ns f or Q 6 W d osi n g ). 
S u bject s wit h pr o gressi ve disease  ( P D) per R E CI S T v 1. 1 s h o ul d ha ve f oll o w -u p i ma gi n g n o lat er 
t ha n 6 t o 8 wee ks be y o n d  t he i nitial dia g n osis of ra di o gra p hi c disease pr o gressi o n t o c o nfir m 
pr o gressi ve dise ase per i R E CI S T . 
S u bject s wit h u n c o nfir me d pr o gressi ve dis ease  (i U P D) per i R E CI S T m a y c o nti n ue st u d y 
treat me nt at t he discreti o n of t he i n vesti gat or, wit h a d diti o nal c o nse nt, if all of t he f oll o wi n g 
criteria are met:  
•  E vi de nce of cli nical be nefit, defi ne d as t he sta bilizati o n or i m pr o ve me nt of disease 
relate d s y m pt o ms, as ass esse d b y t he i n vesti gat or 
•  N o s y m pt o ms or si g ns (i ncl u di n g w orse ni n g la b orat or y v al ues) i n dicati n g u n e q ui v ocal 
disease pr o gressi o n  
•  N o decli ne i n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma n ce stat us t hat 
ca n be attri b ute d t o disease pr o gressi o n  
•  N o t u m or gr o wt h at critic al a nat o mical sites ( e g, l e pt o me ni n geal disease) t h at ca n n ot 
be ma na ge d a n d sta b iliz e d b y pr ot o c ol-all o we d m e dical i nter ve nti o ns pri or t o re peat 
d osi n g  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 0  of 1 3 5  
3. 1. 4.  
St o p pi n g Crit eri a  
3. 1. 4. 1.  
E nr oll m e nt P a u s e at t h e C o h ort L e v el  
If a deat h is c o nsi dere d t o be relate d t o S E A -C D 4 0  b y t he sp o ns or, e nr oll me nt will be pa use d 
u ntil:  
1.  T he cas e is re vie we d b y t he i n vesti gat or, t he sp o ns or, a n d t he S M C , a n d 
2.  T he sp o ns or has n otifie d a p plica ble re g ulat or y aut h orities of t he o utc o me of t he safet y 
assess me nt a n d j ustificati o n f or restarti n g e nr oll me nt i n t he affecte d c o h orts , a n d has 
recei v e d a p pr o val t o res u me, if re q uire d b y l o cal r e g ul ati o ns. 
3. 1. 4. 2.  
E nr oll m e nt H alt f or t h e E ntir e S t u d y 
E nr oll me nt i n t he e ntire st u d y will be halte d b y t he sp o ns or if t he o verall be nefit -ris k bala nce is 
c o nsi dere d n e gati ve.  
Safet y will be c o nti n u o usl y m o nit ore d t hr o u g h o ut t he st u d y b y t he s p o ns or a n d t he S M C, wit h 
c o nsi derati o n f or e nr oll me nt halt if t he i nci de nce a n d/ or t he se verit y of t o xicit y lea ds t o a 
ris k-be nefit ass ess me nt t hat is u nacce pt a ble t o t he st u d y p o p ulati o n. T he s p o ns or will c o ns ult 
wit h t he S M C t o c o nsi der w het her t o all o w s u bjects alrea d y recei vi n g treat me nt t o c o nti n ue, t o 
c o nsi der m o dificati o ns t o t he pr ot oc ol t o c o nti n ue e nr oll me nt, or t o ter mi nate t he st u d y.  
If e nr oll me nt is halte d d u e t o safet y c o n cer ns, e nr oll me nt ca n o nl y b e restarte d after a p pr o priate 
a me n d me nts a n d  n otificati o ns t o Re g ulat or y A ut h orities, wit h a p pr o val t o res u me, if re q uir e d b y 
l ocal re g ulati o ns. 
3. 1. 5.  
E n d of St u d y  
T he st u d y will be cl ose d 3  years  after t he l ast s u bject recei ves t he last d os e, or w he n n o s u bjects 
re mai n i n f oll o w-u p, w hi c he ver occ urs first. I n a d diti o n, t he s p o ns or ma y t er mi nate t he st u d y at 
a n y ti me (s ee Secti o n  1 0. 3. 2 ).  
If t he sp o ns or ter mi nat es t he st u d y earl y, i n vesti gat ors are i nstr ucte d t o c o nti n ue disease 
assess me nts per pr ot o c ol , u nless ot her wise i n dicat e d b y t h e s p o ns or, u ntil t he st u d y ter mi nati o n 
date . S u bject s disc o nti n ui n g  treat me nt will be f oll o we d f or 3 0  d a ys p ost -treat me nt f or 
S E A -C D 4 0  a n d/ or c he m ot hera p y a n d 9 0  d a ys p ost -treat me nt f or p e m br oliz u ma b, u nless safet y 
c o ncer ns warra nt f urt h er f oll o w -u p. Patie nts i n s ur vi val f oll o w -u p at t he ti me of earl y st u d y 
ter mi nati o n will be c o nta cte d o ne last ti me, re gar dless of t he date of t h e pri or assess me nt, f or 
fi nal s ur vi val assess me nt.  T he i n vesti gat or will be e x pecte d t o m o nit or f or a n d re p ort a n y seri o us 
a d verse e v e nts (S A Es ) a n d pre g na nci es, as detail e d i n  S ecti o n 7. 7. 1. 3  a n d Secti o n  7. 7 . 6. 
Tr u ncate d  d ata ma y  be c ollecte d  at t he discreti o n of t he s p o ns or .  
3. 1. 6.  
R etr e at m e nt  
Retreat me nt is n ot per mitte d  o n t his st u d y . 
3. 1. 7.  
S af et y M o nit ori n g C o m mitt e e  
T he S M C will m o nit or safet y t hr o u g h o ut t he st u d y a n d will ma ke rec o m me n dati o ns t o t he 
s p o ns or. T he S M C is c o m p ose d of site i n vesti gat ors a n d re prese ntati ves fr o m t he s p o ns or 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 1  of 1 3 5  
(i ncl u di n g t he st u d y me dical m o nit or, dr u g s afet y re pres e ntati ve, a n d bi ostatisticia n). T he S M C 
will re vie w cli nical dat a fr o m e nr olle d s u bjects f or safet y assess me nt. T h e c o m mittee will 
m o nit or t he safet y of s u bjects i n t his st u d y t hr o u g h re g ular a n d/ or a d h oc meeti n gs t hat i ncl u de 
re vie w of data pertai ni n g t o treat me nt-e mer ge nt t o xicities. F urt her details will be d oc u me nte d i n 
a n S M C c harter.  
3. 1. 8.  
Tri al O p er ati o n s a n d D at a C oll e c ti o n aft er S E A-C D 4 0 E x pir y   
If at least 6 m o nt hs ha ve  ela pse d si nce t h e last s u bject was e nr olle d i n t he st u d y, a n d if t here are 
n o m ore t ha n 1 5  s u bjects still o n st u d y recei vi n g o nl y dr u g(s) wit h a k n o w n safet y pr ofile  (s uc h 
as pe m br oliz u ma b/ pe metre x e d c o m bi nati o n t hera p y or pe m br oliz u ma b m o n ot hera p y ), a data base 
l oc k of t he st u d y m a y occ ur t o all o w t he a n al ysis of t he S E A-C D 4 0 -relate d st u d y data.  
A n y re mai ni n g s u bjects ma y c o nti n ue t o recei ve st u d y treat me nts ot her t ha n S E A -C D 4 0  
(pe m br oliz u ma b wit h or wit h o ut car b o plati n a n d pe metre x e d)  per pr ot oc ol a n d be see n b y t h e 
i n vesti gat or p er us ual sta n dar d of care. C h e m ot hera pies ma y be s u p plie d per  Secti o n  5. 1. 3. 2 . T he 
i n vesti gat or will be e x pecte d t o m o nit or f or pr o gressi o n  a n d re p ort a n y S A Es a n d pre g na ncies, as 
o utli ne d i n Secti o n  7. 7. 1. 3  a n d Sec ti o n 7. 7. 6 . N o ot her data will be c ollecte d. T he re mai ni n g 
s u bjects are c o nsi dere d t o be o n st u d y u ntil a disc o nti n uati o n criteri o n is met , or t he st u d y is 
ter mi nate d b y t he s p o ns or.  
3. 2.  
Di s c u s si o n a n d R ati o n al e f or St u d y D e si g n  
T his st u d y will e val uate S E A -C D 4 0 i n c o m bi nati o n wit h sta n dar d of care treat me nts f or 
a d va nce d s oli d t u m or ca ncers.  
3. 2. 1.  
R ati o n al e f or St u d y D e si g n  
T his is a p hase 2 st u d y d esi g ne d t o assess t he effi cac y a n d safet y of S E A -C D 4 0 c o m bi nati o n 
t hera p y. B y c o m pari n g s u bjects o n st u d y t o rel e va nt hist orical c o ntr ols, we h o pe t o de m o nstrate 
t he utilit y of S E A-C D 4 0 i n treati n g s oli d t u m ors. Gi ve n its i m m u n ol o gic mec ha nis ms of acti o n, 
S E A -C D 4 0 has p ote ntial effic ac y acr oss a br oa d ra n ge of t u m or t y p es w he n a d mi nistere d i n 
c o m bi nati o n wit h a ge nts tar geti n g P D -( L) 1 i n hi biti o n a n d/ or c he m ot hera p y. Efficac y will be 
assesse d b y O R R  as t he pri mar y e n d p oi nt. A d diti o nal c o h orts of i nterest ma y b e a d d e d t o t his 
st u d y via a pr ot oc ol a me n d me nt. 
C o h orts 1 , 2 , a n d 3 will assess S E A -C D 4 0 i n c o m bi nati o n wit h pe m br oliz u ma b. T his 
c o m bi nati o n was pre vi o usl y deter mi ne d t o be t olera ble i n St u d y S G N S 4 0 -0 0 1 (see Secti o n 1. 1 2 , 
a n d t he S E A-C D 4 0 I B ). C o h orts 4 a n d 5 will assess S E A -C D 4 0 i n c o m bi nati o n wit h car b o plati n , 
pe metre x e d, a n d pe m br oliz u ma b. Safet y of t his c o m bi nati o n will be re vie we d b y t h e S M C after  
6  s u bjects acr oss C o h orts 4 a n d 5 ha ve recei ve d  at least  1  c ycle of treat me nt. If after t his safet y 
re vie w t he c o m bi nati o n is dee me d t olera ble, e nr oll me nt i n C o h orts 4  a n d/ or 5  ma y c o nti n ue.  
I n all C o h orts, a n i nteri m a nal ysis of safet y a n d efficac y will be p erf or me d after 1 5  s u bjects are 
res p o nse e v al ua ble. Base d o n t he t otalit y of data,  a n a d diti o nal 2 5  s u bjects (f or a t otal of 
4 0  s u bjects per c o h ort) ma y b e e nr olle d t o all o w f or a p pr o priat e p o wer t o detect  a differe nce 
bet wee n t he treat me nt gr o u p a n d rele v a nt hist orical c o ntr ols.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 2  of 1 3 5  
3. 2. 2.  
M et h o d of A s si g ni n g S u bj e ct s t o Tr e at m e nt Gr o u p s  
S u bject s will be e nr olle d i n c o h orts base d o n t u m or t y pe a n d acc or di n g t o t he eli gi bilit y criteria 
detaile d i n Secti o n 4 . F or C o h orts 4 a n d 5 , s u bjects wit h N S C L C will be e nr olle d base d u p o n 
le vel of P D-L 1 e x pressi o n  b y l oc al assess me nt . 
3. 2. 3.  
R ati o n al e f or S el e cti o n of S E A -C D 4 0 D o s e  a n d S c h e d ul e  
S E A -C D 4 0 will be a d mi nistere d at a d ose of 1 0  mc g/ k g e v er y 2 1  da ys  ( Q 2 1 d). 
I n t he p h ase 1 st u d y, S G N S 4 0 -0 0 1, t his d ose a n d sc he d ule, a d mi nistere d as m o n ot hera p y a n d i n 
c o m bi nati o n wit h pe m br oliz u ma b  a n d/ or c he m ot hera p y ( ge mcita bi ne a n d n a b -pa clita xel ) was 
a de q uatel y t olerate d a n d de m o nstrate d a n acce pta ble safet y pr ofile , p ote nt p har mac o d y n a mic 
acti vit y, a n d preli mi nar y e vi de nce of  cli nical acti vit y. M ore i nf or mati o n is pr o vi de d i n t he 
S E A -C D 4 0 I B.  
I n precli nic al m o dels, o pti mal s y ner g y h as bee n re p orte d w he n C D 4 0 a g o nists are a d mi nistere d 
a p pr o xi matel y 2  da ys after c he m ot hera p y (N o wa k 2 0 0 3 ; Wi n o gra d 2 0 1 5 ; B yr n e 2 0 1 6a ; 
B yr ne  2 0 1 6 b ; M orris o n 2 0 2 0 ). T his ti mi n g is h y p ot hesize d t o c oi nci de wit h a nti ge n release fr o m 
c he m ot hera p y, w hic h ma y facilitate a s y ner gistic i m m u ne res p o nse. C o m para ble ti mi n g has b ee n 
utilize d i n pri or cli nical trials of C D 4 0 a g o nists (Beatt y 2 0 1 3 ; V o n der hei d e 2 0 1 3a ; 
V o n der hei de  2 0 1 3 b ; C o veler 2 0 2 0 ; O ’Hara  2 0 2 1 ). 
S y ner g y b et wee n S E A -C D 4 0 a n d P D -( L) 1 t ar geti n g t hera p y is e n ha n ce d w he n t hese a ge nts are 
a d mi nistere d o n se parate da ys (Gar dai 2 0 1 7 ) (Sea ge n, d ata o n file). T h us , S E A -C D 4 0 a n d 
pe m br oliz u ma b will be d ose d o n se parate da ys.   
3. 2. 4.  
Bli n di n g a n d U n bli n di n g  
T his is a n o pe n -la bel st u d y. 
4.  
S T U D Y P O P U L A TI O N  
S u bject s m ust meet all of t he e nr oll me nt criteri a t o be eli gi ble f or t his st u d y . Eli gi bilit y criteria 
ma y n ot be wai ve d b y t h e i n vesti gat or a n d s u bjects are t o be  re vie we d i n t he e ve nt of a g o o d 
cli nical practice a u dit a n d/ or healt h re g ulat or y a ut h orit y i ns pecti o n.  
4. 1.  
I n cl u si o n Crit eri a 
1.  Hist ol o gicall y or c yt ol o gicall y c o nfir me d dia g n osis of u nresecta ble mali g na nc y of o ne of 
t he f oll o wi n g t y pes: 
a. C o h ort 1: Rela pse d a n d/ or refract or y m etastatic  m ela n o ma  
i. 
U veal/ oc ular m ela n o ma is e x cl u de d . 
ii. 
S u bject s ma y ha v e recei v e d u p t o 3  pri or li nes of s yst e mic t hera p y f or 
a d va nce d disease  ( pri or a dj u va nt/ ne oa dj u va nt i m m u n ot hera p y s uc h as 
i nterfer o n, a nti-P D -( L)-1 , or a nti -C T L A -4  will  n ot c o u nt as a li ne of t hera p y 
as l o n g as rela ps e di d n ot occ ur d uri n g tr eat me nt or wit hi n 6  m o nt hs of 
treat me nt disc o nti n uati o n). 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 3  of 1 3 5  
iii. 
S u bject s m ust ha ve pr o gresse d o n treat me nt wit h a n a nti-P D -( L) 1 m A b 
a d mi nistere d eit her as m o n ot hera p y, or i n c o m bi n ati o n wit h ot her c hec k p oi nt 
i n hi bit ors or ot her t hera pies. P D-( L)1 treat me nt pr o gressi o n is defi ne d  as 
meeti n g  all of t he f oll o wi n g criteria: 
•  Has recei ve d at least 2  d oses of a n a p pr o ve d a nti -P D -( L) 1 m A b . 
•  Has de m o nstrate d diseas e pr o gressi o n after P D -(L )1  as defi n e d b y 
R E CI S T  v 1. 1. T he i nitial e vi de nce of P D is t o be c o nfir me d b y a s ec o n d 
assess me nt n o less t ha n 4  wee ks fr o m t he date o f t he first d oc u me nte d P D, 
i n t he a bse nce of ra pi d cli nical pr o gressi o n. 
•  Pr o gressi ve disease  h as b ee n d oc u me nt e d wit hi n 1 2  wee ks fr o m t he last 
d ose of a nti -P D -( L) 1 m A b . 
o  Pr o gressi ve disease is d eter mi ne d acc or di n g t o i R E CI S T . 
o  T his deter mi nati o n is ma de b y t h e i n vesti gat or. O nce P D is 
c o nfir me d, t he i nitial dat e of P D d oc u me ntati o n will be 
c o nsi dere d t he date of dis ease pr o gressi o n . 
•  Last d ose of a nti-P D -( L)1 m ust ha ve bee n wit hi n 9 0  da ys pri or t o 
e nr oll me nt ; m ost rece nt a nti-P D -( L) 1 t hera p y m ust n ot ha ve bee n 
disc o nti n ue d d ue t o Gra d e 3 or hi g her  i m m u ne-rel ate d a d verse e v e nt 
(ir A E). 
i v. 
S u bject s e ntere d i n t he st u d y after c o m pleti o n of e nr oll me nt f or t he i nteri m 
a nal ysis (s ee Secti o n  9. 3. 1 0 ) s h o ul d ha ve a t u m or site accessi ble f or bi o ps y 
a n d a gree t o ha ve fres h  b aseli ne a n d o n-tr eat me nt bi o ps ies, if a p pr o priate i n 
t he o pi ni o n of t he i n vesti gat or. A n arc hi val sa m pl e c ollecte d wit hi n 3 0  da ys 
pri or t o t he first d ose of st u d y dr u g ma y s u bstit ute f or t he baseli ne bi o ps y.  
v.  
S u bjects  wit h a tar geta bl e B R A F m utati o n m ust ha ve bee n treat e d wit h, bee n 
i nt olera nt of, or decli ne d treat me nt wit h B R A F/ M E K tar gete d t h era p y pri or t o 
st u d y e ntr y.  
vi.  
D ue t o differe nces i n sta n dar d of care, s u bj ects i n Fra n ce will n ot be e nr olle d 
i n C o h ort 1. 
b.  C o h ort 2: Metastatic u veal  mela n o ma  
i. 
S u bject s m ust n ot ha ve  recei ve d pri or treat me nt f or a d va nce d or met astatic 
disease e x ce pt as f oll o ws : 
•  Pri or a dj u va nt / ne oa dj u va nt i m m u n ot hera p y s uc h as i nterfer o n, 
a nti -P D -( L)1, or a nti -C T L A -4 if rel a pse di d n ot occ ur d uri n g tr eat me nt or 
wit hi n 6  m o nt hs of treat me nt disc o nti n uati o n  
ii. 
N o pri or re gi o n al, li ver -directe d t hera p y i ncl u di n g c he m ot hera p y, ra di ot hera p y, 
or e m b oliz ati o n   
iii. 
S u bjec ts e ntere d i n t he st u d y after c o m pleti o n of e nr oll me nt f or t he i nteri m 
a nal ysis (s ee Secti o n  9. 3. 1 0 ) s h o ul d ha ve a t u m or site accessi ble f or bi o ps y a n d 
a gree t o h a ve fres h bas eli ne a n d o n -tr eat me nt bi o psies, if a p pr o priate i n t he 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 4  of 1 3 5  
o pi ni o n of t he i n vesti gat or. A n arc hi val sa m ple c ollecte d wit h i n 30  da ys pri or 
t o t he first d ose of st u d y dr u g ma y s u bstit ute f or t he baseli ne bi o ps y.  
c. C o h ort 3: Metastatic P D -( L)1 -nai v e  mela n o ma  
i. 
U veal/ oc ular m ela n o ma is e x cl u de d  
ii. 
S u bject s m ust n ot ha ve recei ve d pri or treat me nt f or a d va nce d or met astatic 
disease e x ce pt  as f oll o ws:  
•  Pri or a dj u va nt/ ne oa dj u va nt i m m u n ot hera p y s uc h as i nterfer o n, 
a nti -P D -( L)1, or a nti -C T L A -4 if rel a pse di d n ot occ ur d uri n g tr eat me nt or 
wit hi n 6  m o nt hs of treat me nt disc o nti n uati o n  
•  F or s u bjects wit h a tar get a ble B R A F m utati o n, pri or B R A F/ M E K tar get e d 
t hera p y is all o we d if c o m plete d 4 wee ks pri or t o first d ose of st u d y 
treat me nt 
•  S u bjects wit h a tar geta bl e B R A F m utati o n w h o are ra pi dl y pr o gressi n g 
s h o ul d be treate d wit h B R A F/ M E K tar get e d t hera p y t o sta bilize disease 
pri or t o e nr oll me nt, u nless c o ntrai n dicate d  
d.  C o h orts 4  a n d 5 : N o n-s q ua m o us N S C L C 
i. 
S u bject s m ust ha ve sta ge I V disease p er A merica n J oi nt C o m mittee o n Ca ncer 
(AJ C C ) 8 t h e diti o n 
ii. 
N o k n o w n dri ver m utati o ns/alterati o ns m utati o n f or w hic h tar gete d t hera p y is 
a vaila ble (e g, E G F R, A L K, etc.)   
iii. 
M ust ha ve n o n -s q ua m o us hist ol o g y. Mi x e d t u m ors will be cate g orize d b y t he 
pre d o mi na nt cell t y pe; if s mall cell ele me nts are prese nt, t he s u bject is 
i neli gi ble 
i v. 
N o pri or t hera p y f or met astatic disease. A dj u v a nt/ ne oa dj u va nt t hera p y is 
all o we d f or n o n -metastatic disease if f ull y c o m plete d at least 1 2  m o nt hs pri or 
t o dia g n osis of metastatic disease. 
v.  
N o pri or treat me nt wit h a nti -P D -( L)1  or P D -L 2 a ge nt or a n a nti b o d y tar geti n g 
ot her i m m u n o -re g ulat or y rece pt ors or mec h a nis ms 
vi.  
A ble a n d willi n g t o ta k e f olic a ci d or vita mi n B 1 2 s u p ple me ntati o n  
vii.  
D oes n ot ha ve s y m pt o matic ascites or ple ural eff usi o n. S u bject s w h o are 
cli nicall y sta ble f oll o wi n g treat me nt f or t hes e c o n diti o ns (i ncl u di n g t hera p e utic 
t h orac o- or parace nt esis) are eli gi ble  
viii.  
Has n ot recei ve d ra diati o n t hera p y t o t he l u n g > 3 0  G y wit hi n 6  m o nt hs pri or t o 
first d ose of st u d y dr u g 
i x. 
C o h ort 4 : P D -L 1 1 % – 4 9 % T P S b y l ocal  ass ess me nt  
x.  
C o h orts 5 : P D-L 1 < 1 %  T P S b y l ocal assess me nt  
2.  Ha ve pr o vi de d arc hi val t u m or tiss ue fr o m l ocati o ns n ot ra diate d pri or t o bi o ps y; f or m ali n  
fi x e d s peci me ns after t he s u bject has bee n di a g n ose d wit h metastatic diseas e will be 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 5  of 1 3 5  
preferre d. Bi o psies o btai ne d pri or t o recei pt of a dj u va nt/ ne oa dj u va nt c h e m ot hera p y will 
be per mitte d if rece nt bi o ps y is n ot feasi ble. If arc hi val t u m or sa m ple is n ot a va ila ble, a 
fres h bas eli ne bi o ps y is r e q uire d. 
3.  A ge 1 8  years or ol der.  
4.  A n 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 sc ore of 0 or 1 
(see A p p e n di x  A  f or c o n versi o n of perf or ma nce stat us usi n g Kar n ofs k y scale, if 
a p plica ble).  
5.  Meas ura ble dis ease p er R E CI S T v 1. 1 at baseli ne.  
•  Lesi o ns t hat ha v e ha d pri or i ntralesi o nal t hera pies i ncl u di n g T -V E C are n ot  c o nsi dere d 
meas ura ble  
•  Lesi o ns sit uate d i n a pre vi o usl y irra diat e d area are c o nsi dere d meas ura bl e if 
pr o gressi o n has bee n de m o nstrate d i n s uc h lesi o ns  
6.  T he f oll o wi n g b aseli ne la b orat or y data:  
•  C o h orts 1, 2 , a n d 3:  a bs ol ute ne utr o p hil c o u nt ( A N C) ≥1 5 0 0/ µ L  
C o h orts 4 a n d 5:  A N C ≥2 0 0 0  µ L.  
•  H e m o gl o bi n ( H g b) ≥9  g/ d L  wit h o ut pac k e d re d bl o o d cell ( p R B C) tra nsf usi o n 
wit hi n t he pri or 2  wee ks. S u bject s ca n be o n sta ble d ose of er yt hr o p oi eti n (≥ 
a p pr o xi matel y 3  m o nt hs).  
•  P latelet c o u nt ≥1 0 0, 0 0 0/ μ L  
•  S er u m bilir u bi n ≤1. 5  x u p per li mit of n or mal ( U L N) or ≤3  x U L N f or s u bj ects wit h 
Gil bert’s disease or d oc u me nte d he patic t u m or i n v ol ve me nt  
•  C reati ni ne cleara n ce ( Cr Cl) ≥4 5  m L/ mi n calc ulat e d per i nstit uti o nal sta n dar d  
•  A L T a n d as partate a mi n otra nsferase ( A S T) ≤2. 5  x U L N ( ≤5  x  U L N if t h ere is 
e vi de nce of he patic i n v ol ve me nt b y m ali g n a nt disease)  
7.  S u bject s of c hil d beari n g p ote ntial, as defi ne d i n S ecti o n  4. 3 , u n der t he f oll o wi n g 
c o n diti o ns: 
a. M ust ha ve a ne gati ve ser u m or uri ne pre g n a nc y test ( mi ni m u m se nsiti vit y 2 5  mI U/ m L 
or e q ui vale nt u nits of bet a h u ma n c h ori o nic g o n a d otr o pi n [ β -h C G]) res ult wit h i n 
3  da ys pri or t o t he first d ose of a n y st u d y dr u g. S u bject s wit h false p ositi ve res ults 
a n d d oc u me nte d v erific ati o n t hat t he s u bject is n ot pre g na nt are eli gi ble f or 
partici pati o n  
b.  C o h orts  1, 2, a n d 3 : 
i. 
M ust a gree n ot t o tr y t o b ec o me pre g na nt d uri n g t he s t u d y a n d f or at least 
1 2 0  da ys  after t he fi nal d ose of st u d y dr u g  
ii. 
M ust a gree n ot t o breastf ee d or d o nat e o va, starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h 1 2 0  d a ys  aft er t he fi nal d ose of st u d y dr u g  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 6  of 1 3 5  
iii. 
If se x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g n a nc y, m ust c o nsiste ntl y use 
t he acce pta ble c o m bi nati o ns of c o ntrace pti ve met h o ds (as defi ne d i n 
A p pe n di x  B ) starti n g at ti me of i nf or me d c o ns e nt a n d c o nti n ui n g t hr o u g h o ut 
t he st u d y a n d f or at least 1 2 0  da ys  after t he fi nal d ose of st u d y dr u g  
c. C o h orts  4 a n d 5:  
i. 
M ust a gree n ot t o tr y t o b ec o me pre g na nt d uri n g t he st u d y a n d f or at least 
6  m o nt hs  after t he fi nal d ose of st u d y dr u g  
ii. 
M ust a gree n ot t o breastf ee d or d o nat e o va, starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h 6 m o nt hs after t h e fi nal d ose of st u d y dr u g  
iii. 
If se x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g n a nc y, m ust c o nsiste ntl y use 
t he acce pta ble c o m bi nati o ns of c o ntrace pti ve met h o ds (as defi ne d i n 
A p pe n di x  B ) starti n g at ti me of i nf or me d c o ns e nt a n d c o nti n ui n g t hr o u g h o ut 
t he st u d y a n d f or at least 6  m o nt hs  after t he fi nal d ose of st u d y dr u g  
8.  S u bjects b or n male , u n der t he f oll o wi n g c o n diti o ns:  
a. C o h orts 1, 2, a n d 3: 
i. 
M ust a gree n ot t o d o nate s per m starti n g at ti me  of i nf or me d c o nse nt a n d 
c o nti n ui n g u ntil  t he fi nal d ose of st u d y dr u g. 
ii. 
If se x uall y acti ve wit h a pers o n of c hil d beari n g p ote ntial i n a wa y t hat c o ul d 
lea d t o pre g na n c y, m ust c o nsiste ntl y use t he acce pta ble c o m bi nati o ns of 
c o ntrace pti ve met h o ds  (as defi ne d i n A p pe n di x  B ) starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g u ntil t he fi nal d ose of st u d y dr u g.  
iii. 
If se x uall y acti ve wit h a pers o n w h o is pre g n a nt or breastf ee di n g, m ust 
c o nsiste ntl y use a c o n d o m  (as defi ne d i n A p pe n di x  B ) starti n g at ti me of 
i nf or me d c o nse nt a n d c o nti n ui n g u ntil  t he fi nal d ose of st u d y dr u g. 
b.  C o h orts 4 a n d 5:  
i. 
M ust a gree n ot t o d o nate s per m starti n g at ti me of i nf or me d c o nse nt a n d 
c o nti n ui n g t hr o u g h o ut t he st u d y p eri o d a n d f or at least 6  m o nt hs  after t he fi nal 
d ose of st u d y dr u g.  
ii. 
If se x uall y acti ve wit h a pers o n of c hil d beari n g p ote ntial i n a wa y t hat c o ul d 
lea d t o pre g na n c y, m ust c o nsiste ntl y use t he acce pta ble c o m bi nati o ns of 
c o ntrace pti ve met h o ds (as defi ne d i n A p pe n di x  B ) starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u d y a n d f or at least 6  m o nt hs  after t he 
fi nal d ose of st u d y dr u g 
iii. 
If se x uall y acti ve wit h a pers o n w h o is pre g n a nt or breastf ee di n g, m ust 
c o nsiste ntl y use a c o n d o m  (as defi ne d i n A p pe n di x  B ) starti n g at ti me of 
i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u d y a n d f or at least 6  m o nt hs  
after t he fi nal d ose of st u d y dr u g.  
9.  T he s u bject m ust pr o vi de writte n i nf or me d c o ns e nt.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 7  of 1 3 5  
4. 2.  
E x cl u si o n Crit eri a  
1.  Hist or y of a n ot her mali g na nc y wit hi n 3  years bef ore t he first d ose of st u d y dr u g, or a n y 
e vi de nce of resi d ual disease fr o m a pre vi o usl y dia g n ose d m ali g na n c y. E x ce pti o ns are 
mali g na n cies wit h a ne gli gi ble ris k of metast asis or deat h ( e g, 5-year O S  ≥9 0 %), s uc h as 
a de q uatel y tr eate d carci n o ma i n sit u of t he cer vi x, n o n -mela n o ma s ki n carci n o ma, 
l ocalize d pr ostate ca n cer, d uctal carci n o ma i n sit u, or Sta ge I uteri ne ca n cer.  
2.  Has k n o w n acti ve ce ntr al ner v o us s yst e m ( C N S) metastases a n d/ or carci n o mat o us 
me ni n gitis. S u bject s wit h pre vi o usl y tr eate d brai n metastases ma y partici pate pr o vi de d 
t he y are ra di ol o gicall y sta ble, ie, wit h o ut e vi de nce of pr o gressi o n f or at least 4  wee ks b y 
re peat i ma gi n g ( n ot e t hat t he re peat i ma gi n g s h o ul d be perf or me d d uri n g st u d y 
scree ni n g), cli nicall y sta ble a n d wit h o ut re q uire m e nt of ster oi d treat me nt f or at least 
1 4  da ys pri or t o first d os e of st u d y treat me nt.   
3.  Pre vi o us e x p os ure t o C D 4 0 -tar gete d t h era py . 
4.  C urre ntl y o n c hr o nic s yst e mic ster oi ds. P h ysi ol o gic c ortic oster oi d re place m e nt t hera p y 
(e g, p re d nis o n e 10  m g e q ui vale nt or less per da y)  or i nter mitte nt use of br o nc h o dilat ors, 
i n hale d ster oi ds, t o pical ster oi ds, or l ocal ster oi d i njecti o ns is all o we d.  
5.  Has ha d a n all o ge neic tiss ue/s oli d or ga n tr a ns pla nt.  
6.  A n y u n c o ntr olle d  Gra de 3 or hi g h er ( p er t he  Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts [ N CI C T C A E ], v 5. 0 ) viral, bacterial, or f u n gal 
i nfecti o n wit hi n 2  wee ks pri or t o t he first d ose of st u d y dr u g. R o uti ne a nti micr o bial 
pr o p h yla xis is per mitte d.  
7.  K n o w n t o be p ositi ve f or he patitis B b y s urface a nti ge n e x pressi o n. K n o w n t o ha ve acti ve 
he patitis C i nfecti o n ( p ositi ve b y p ol y m eras e c h ai n reacti o n [ P C R]  or o n a nti viral t hera p y 
f or he patitis C wit hi n t he last 6  m o nt hs). S u bject s w h o ha ve bee n treate d f or he patitis C 
i nfecti o n are per mitte d if t he y h a ve d oc u m e nte d s ustai ne d vir ol o gic res p o ns e of 
1 2  wee ks . 
8.  N ote: N o testi n g f or h e patitis B a n d h e patitis C is re q uire d u nless ma n dat e d b y a l o cal 
healt h a ut h orit y.  
9.  K n o w n t o be p ositi ve f or h u ma n i m m u n o deficie nc y vir us ( HI V). N ote: N o HI V testi n g is 
re q uire d u nless ma n d ate d b y l ocal healt h a ut h orit y. 
1 0.  D oc u me nte d hist or y of a cere bral vas c ular e ve nt (str o ke or tra nsie nt isc h e mic attac k), 
u nsta ble a n gi na, m y ocar dial i nfa rcti o n, or car diac s y m pt o ms c o nsiste nt wit h Ne w Y or k 
Heart Ass o ciati o n Class III -I V (see A p pe n di x  C ) wit hi n 6  m o nt hs pri or t o t heir first d ose 
of st ud y dr u g . 
1 1.  C o n gesti ve heart fail ure, Class III or I V, b y t h e Ne w Y or k Heart Ass ociati o n criteria.  
1 2.  C urre nt t hera p y wit h ot her s yste mic a nti -ne o pl astic or i n vesti gati o nal a ge nts.  
1 3.  Ra di ot hera p y wit hi n 2  w ee ks pri or t o first d ose of st u d y dr u g . S u bject s m ust ha ve 
rec o vere d fr o m all ra diati o n-relate d t o xicities, n ot re q uire c ortic oster oi ds, a n d n ot ha ve 
ha d ra diati o n p ne u m o nitis. A 1 -wee k was h o ut is per mitte d f or palliati ve ra diati o n 
(≤2  wee ks of ra di ot hera p y) t o n o n -C N S diseas e.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 8  of 1 3 5  
1 4.  M aj or s ur ger y a n d/ or a n y c o m plicati o ns fr o m t he s ur ger y fr o m w hic h t he s u bject has n ot 
rec o vere d a de q uat el y. 
1 5.  T his criteri o n h as bee n re m ove d  (see I ncl usi o n Criterio n  7).   
1 6.  K n o w n h y p erse nsiti vit y t o a n y e x ci pie nt c o ntai ne d i n t he dr u g f or m ulati o n of S E A -C D 4 0 
or ot her st u d y dr u gs.  
1 7.  Has a n acti v e a ut oi m m u ne disease t hat h as re q uir e d s yste mic treat me nt i n past 2  years 
(ie, wit h use of diseas e m o dif yi n g a ge nts, c ortic ost er oi ds,  or i m m u n os u p pressi ve dr u gs). 
Re place me nt t hera p y (e g, t h yr o xi ne , i ns uli n, or p h ysi ol o gic c ortic oster oi d re place m e nt 
t hera p y f or a dre nal or pit uitar y i ns ufficie nc y) is n ot c o nsi dere d a f or m of s yste mic 
treat me nt a n d is all o we d. 
1 8.  Has a dia g n osis of cli nic all y si g nifica nt i m m u n o deficie nc y . 
1 9.  Has a hist or y of ( n o n -i nf ecti o us) p ne u m o nitis/i nterstitial l u n g disease t hat re q uire d 
ster oi ds or has c urre nt p n e u m o nitis/i nterstitial l u n g diseas e. L y m p ha n gitic s prea d of 
mali g na n c y is n ot e x cl usi o nar y.  
2 0.  Has recei ve d a li ve or li ve -atte n uat e d vacci ne wit hi n 3 0  da ys pri or t o t he first d ose of 
st u d y i nter ve nti o n. N ote: A d mi nistrati o n of kille d vacci nes are all o we d.  
2 1.  Esti mate d life e x pecta nc y < 1 2  wee ks.  
2 2.  Ot her seri o us u n derl yi n g me dical c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d 
i m pair t he s u bject’s a bilit y t o recei ve or t olerat e t he pla n ne d treat me nt a n d f oll o w-u p . 
2 3.  Has a k n o w n ps yc hi atric or s u bsta nce a b use dis or der t hat w o ul d i nterfere wit h t he 
s u bject’s a bilit y t o c o o p erate wit h t he re q uire me nts of t he st u d y. 
2 4.  Has recei ve d pri or s yst e mic a nti -ca ncer t hera p y i ncl u di n g i n vesti gati o nal a ge nts wit hi n 
4  wee ks pri or t o tr eat me nt. 
2 5.  Is c urre ntl y p artici pati n g i n or has partici pate d i n a st u d y of a n i n v esti gati o n al a ge nt or 
has use d a n i n vesti gati o n al de vice wit hi n 4  wee ks pri or t o t he first d ose of st u d y 
treat me nt. 
N ote: S u bject s w h o ha ve e ntere d t he f oll o w-u p p h ase of a n i n v esti gati o nal st u d y ma y 
partici pate as l o n g as it has bee n 4  wee ks after t he last d ose of t he pre vi o us 
i n vesti gati o nal a ge nt. 
2 6.  C o h orts 4 a n d 5 : S u bjects wit h Cr Cl < 8 0  m L/ mi n w h o ha ve ha d treat me nt wit h 
i b u pr ofe n or ot her n o nster oi dal a nti-infla m mat or y dr u gs ( N S AI Ds) d uri n g t he 2  da ys 
bef ore p e metre x e d a d mi nistrati o n.  
2 7.  C o h orts 4 a n d 5 : S u bjects w h o ha ve recei ve d l o n g acti n g N S AI Ds (s uc h as pir o xica m or 
r ofec o xi b) d uri n g t he 5  d a ys pri or t o pe metr e x e d a d mi nistrati o n.  
4. 3.  
R e pr o d u cti v e P ot e nti al  
A pe rs o n of c hil d beari n g p ote ntial is a n y o ne w h o has e x perie nce d m e narc h e a n d w h o has n ot 
u n der g o ne per ma ne nt  steriliz ati o n (e g, h ysterect o m y, bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y) or h as n ot c o m plete d me n o pa use. Me n o pa use is defi n e d cli nicall y as 1 2  m o nt hs 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 4 9  of 1 3 5  
of a me n orr hea i n a p ers o n o ver 4 5  years ol d i n t he a bse nce of ot her bi ol o gi cal, p h ysi ol o gical, or 
p har mac ol o gic al ca uses.  
A s u bject w h o ca n get s o me o ne pre g n a nt is a n y o n e w h o has testes a n d w h o has n ot u n der g o ne 
per ma ne nt steriliz ati o n ( defi ne d as bilateral orc hi dect o m y) . 
4. 4.  
R e m o v al of S u bj e ct s fr o m St u d y Tr e at m e nt or A s s e s s m e nt s  
Sea ge n  or t heir d esi g n ee m ust be n otifie d if a s u bject is wit h dra w n fr o m st u d y treat me nt or fr o m 
t he st u d y. T he reas o n(s) f or wit h dra wal m ust be d o c u me nte d i n t he s u bject’s me dical rec or ds a n d 
case re p ort f or m ( C R F).  
4. 4. 1.  
Di s c o nti n u ati o n of St u d y Tr e at m e nt  
A s u bject’s st u d y treat me nt ma y be disc o nti n ue d f or a n y of t he f oll o wi n g reas o ns: 
•  P D  
•  A d verse e ve nt ( A E)  
•  Pre g n a nc y  
•  I n v esti gat or decisi o n 
•  S u bject  decisi o n, n o n -A E  
•  St u d y t er mi nati o n b y s p o ns or 
•  Ot her, n o n -A E  
S u bject s w h o disc o nti n ue fr o m st u d y tr eat me nt will re mai n o n st u d y f or f oll o w-u p u nless t he y 
wit h dra w c o nse nt.  
St u d y treat me nt will be c o nsi dere d t o be o n g oi n g if a s u bject is recei vi n g a n y st u d y dr u g. If a 
st u d y dr u g is disc o nti n ue d, st u d y treat me nt ma y c o nti n ue wit h t he re mai ni n g dr u g(s). 
S u bject s m ust disc o nti n ue pe m br oliz u ma b after c o m pleti o n of 1 8  a d mi nistrati o ns f or Q 6 W 
d osi n g  or 3 5  a d mi nistrati o ns f or Q 3 W d osi n g (a p pr o xi matel y 2  years). N ote: T he n u m ber of 
a d mi nistrati o ns is calc ulate d starti n g wit h t he first d ose of pe m br oliz u ma b.  
4. 4. 2.  
S u bj e ct  Wit h dr a w al fr o m St u d y  
A n y s u bject ma y be disc o nti n ue d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
•  S u bject  wit h dra wal of c o nse nt  
•  St u d y t er mi nati o n b y s p o ns or  
•  L ost t o f oll o w -u p  
•  Deat h  
•  Ot her  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 0  of 1 3 5  
5.  
T R E A T M E N T S  
5. 1.  
Tr e at m e nt s A d mi ni st er e d  
All s u bjects will recei ve S E A -C D 4 0 , t he i n vesti gati o nal a ge nt u n der st u d y i n t his pr ot oc ol. 
All st u d y treat me nts a re o utli ne d i n Ta ble  6  a n d i n Secti o ns  5. 1. 1 , 5. 1. 2 , a n d 5. 1. 3 . 
T a bl e  6 : 
St u d y Tr e at m e nt s  
St u d y Dr u g  
R o ute of 
A d mi nistrati o n  
D ose/ P ote nc y  
Fre q ue nc y  
Sc he d ule  
S E A -C D 4 0 (all 
c o h orts)  
I V i nf usi o n 
1 0  mc g/ k g  
Q 2 1 d  
C o h orts 1, 2, a n d 3:  
Da y  1 a n d Da y  2 2  of 
4 2 -da y c ycles  
C o h orts 4 a n d 5:  Da y 3 
of 2 1 -da y c ycles  
P e m br oliz u ma b 
(all c o h orts) 
I V i nf usi o n 
C o h orts 1, 2, a n d 3:  
4 0 0  m g  
Q 4 2 d 
( Q 6 W 
d osi n g)  
Da y  8 of 4 2 -da y c ycles  
C o h orts 4 a n d 5:  
2 0 0  m g  
Q 2 1 d 
( Q 3 W 
d osi n g)  
Da y  1 of 2 1 -da y c ycles  
P e metre xe d 
( C o h orts 4 a n d 
5 o nl y)  
I V i nf usi o n 
5 0 0  m g/ m 2 
Q 2 1 d  
Da y  1 of 2 1 -da y c ycles  
Car b o plati n 
( C o h orts 4 a n d 
5 o nl y)  
I V i nf usi o n 
A U C 5  m g/ m L / mi n 
Q 2 1 d  
Da y  1 of 2 1 -da y 
C ycles  1 – 4  
If a n y st u d y treat me nt is eli mi nate d fr o m a c ycl e, treat me nt s h o ul d be res u me d o n t he sa me 
sc he d ule w he n cli nicall y a p pr o priate. 
F or C o h orts 4 a n d 5 , on da ys w he n b ot h pe m br oli z u ma b a n d c he m ot hera p y are a d mi nistere d, t he 
or der of a d mi nistrati o n s h o ul d be  
1.  Pe m br oliz u ma b i nf usi o n  
2.  C he m ot hera p y pre -me dicati o ns  
3.  Pe metre x e d  
4.  Car b o plati n  
5. 1. 1.  
S E A -C D 4 0  
T he pre p arati o n, a d mi nistrati o n, a n d st ora ge of S E A -C D 4 0  is detaile d i n t he P har mac y 
I nstr u cti o ns. 
5. 1. 1. 1.  
D e s cri pti o n  
S E A -C D 4 0 is a sterile, preser vati ve -free, c ol orless t o sli g htl y yell o w, cl ear t o sli g htl y o pales ce nt 
s ol uti o n f or a d mi nistrati o n. S E A-C D 4 0 dr u g pr o d uct c o nsists of S E A -C D 4 0 ( 1 0  m g/ m L), 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 1  of 1 3 5  
tre hal ose, histi di ne, a n d p ol ys or bat e 2 0. T he p H of t he pr o d uct is a p pr o xi matel y  5. 5. S E A -C D 4 0 
is s u p plie d b y Sea ge n  i n si n gle-d os e glass vials. S E A -C D 4 0 dr u g pr o d u ct is la bele d wit h a 
n o mi nal c o nte nt of 1 0 0  m g/ vial. Eac h vi al c o ntai ns 1 0 5  m g of S E A -C D 4 0, w hic h all o ws t he 
la bel q ua ntit y t o be wit h dra w n f or use. 
5. 1. 1. 2.  
D o s e a n d A d mi ni str ati o n  
S E A -C D 4 0 will be a d mi nistere d b y I V i nf usi o n  Q 2 1 d  at a d ose of 1 0  mc g/ k g   
S E A -C D 4 0  re q uires dil uti o n pri or t o a d mi nistrati o n.  
I nitiall y, S E A -C D 4 0 is a d mi nistere d via I V i nf usi o n at a fi x e d i nf usi o n rate n ot t o e xcee d 
1 0  mc g/ mi n. T h e mi ni m u m all o wa ble d urati o n of i nf usi o n s h o ul d be calc ulate d i n t he f oll o wi n g 
ma n ner:  
T otal D ose ( mc g) ÷ 1 0  m c g/ mi n  = I nf usi o n D urati o n ( mi n utes)  
If t he i nitial i nf usi o n at a rate of 1 0 mc g/ mi n  is a de q uatel y t olerate d wit h n o i nf usi o n-relate d 
reacti o n (I R R) ≥ Gra d e 1, f or t he sec o n d d ose  ( per i n vesti gat or discreti o n), S E A-C D 4 0 ma y b e 
a d mi nistere d m ore ra pi dl y b ut s h o ul d be a d mi nistere d n o faster t ha n 1 5  mc g/ mi n .  
If t he i nf usi o n re mai ns a de q uatel y t olerat e d wit h t he i ncrease d rate wit h n o I R R ≥ Gra de 1, f or 
s u bse q ue nt d oses  ( per i n vesti gat or discreti o n), S E A-C D 4 0 ma y be a d mi nistere d m ore ra pi dl y b ut 
s h o ul d be a d mi nistere d n o faster t ha n 2 0  mc g/ mi n . H o we ver, gi ve n t he varia bilit y of i nf usi o n 
p u m ps fr o m site t o site, a wi n d o w bet wee n  – 5  mi n utes a n d + 1 0  mi n utes is per mitte d ( eg , if t he 
i nf usi o n ti me is 30  mi n utes [ – 5  mi n/ + 1 0  mi n ]). 
See t he P har mac y I nstr ucti o ns f or details.  
I R Rs relat e d t o S E A-C D 4 0 ha ve bee n o bser ve d. T o re d uce t he ris k of I R Rs wit h S E A -C D 4 0, 
s u bjects will recei ve pre me dicati o n/ p ost me dicati o n as descri be d i n Secti o n  5. 3 . A d diti o nall y, 
after c o m pleti o n of t he first i nf usi o n of S E A -C D 4 0, s u bjects wi ll be o bser ve d f or at least 2  h o urs 
f or p ote ntial I R Rs a n d m ust ha ve sta ble vital si g ns pri or t o disc har ge fr o m cli nic. S u bse q ue nt 
i nf usi o ns will n ot re q uire t his o bser vati o n peri o d u nless i n dicate d b y t he i n v esti gat or. 
5. 1. 1. 3.  
St or a g e a n d H a n dli n g  
T he c o ntr olle d l oc ati o n f or st ora ge of vi als a n d s ol uti o ns c o ntai ni n g S E A -C D 4 0  m ust be 
accessi ble o nl y t o t he p h ar macist, t he i n vesti gat or, or a d ul y desi g nate d pers o n. S E A -C D 4 0  d oes 
n ot c o ntai n preser vati ves; t heref ore, o pe ne d a n d rec o nstit ute d vials s h o ul d be use d i m me diatel y. 
I nf or mati o n o n st ora ge a n d ha n dli n g of rec o nstit ute d pr o d uct is pr o vi de d i n t he P har mac y 
I nstr u cti o ns. It is r ec o m me n de d t hat S E A -C D 4 0  vials a n d s ol uti o ns be st ore d pr otecte d fr o m 
direct s u nli g ht u ntil t he ti me of use. Rec o nstit ute d vials m ust  n ot be s ha ke n.  
Dr u g acc o u nta bilit y pr oce d ures are pr o vi d e d i n t he P har mac y Bi n der.  
5. 1. 1. 4.  
P a c k a gi n g a n d L a b eli n g  
S E A -C D 4 0 is s u p plie d i n a clear glass, si n gl e -d ose vial. T he vials will be la bele d as c o ntai ni n g 
S E A -C D 4 0.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 2  of 1 3 5  
5. 1. 1. 5.  
Pr e p ar ati o n  
Detaile d dr u g pre parati o n i nst r ucti o ns are pr o vi de d i n t he P har mac y I nstr u cti o ns. 
5. 1. 2.  
P e m br oli z u m a b  
5. 1. 2. 1.  
D e s cri pti o n  
Pe m br oliz u ma b is a h u ma niz e d m A b t hat bl oc ks t he i nteracti o n bet w ee n P D -1 a n d its li ga n ds, 
P D -L 1 a n d P D -L 2. Pe m br oliz u ma b is a n I g G 4 ka p pa I g wit h a n a p pr o xi mate m olec ular wei g ht  
of 1 4 9  k Da.  
Pe m br oliz u ma b is s u p plie d as a 1 0 0  m g/ 4  m L ( 2 5  m g/ m L) s ol uti o n i n a si n gle -us e vial.  
Pe m br oliz u ma b f or i njecti o n is a sterile, preser vati ve -free, cl ear t o sli g htl y o palesce nt, c ol orless 
t o sli g htl y yell o w s ol uti o n t hat re q uires dil uti o n f or I V i nf usi o n. Eac h vial c o ntai ns 1 0 0 m g of 
pe m br oliz u ma b i n 4  m L of s ol uti o n. Eac h 1  m L of s ol uti o n c o ntai ns 2 5  m g of pe m br oliz u ma b 
a n d is f or m ulate d i n L-histi di ne, p ol ys or bate  8 0 , s ucr ose, L -m et hi o ni ne  a n d Water f or I njecti o n , 
U nite d States P har ma c o p eia (U S P ). 
5. 1. 2. 2.  
M et h o d of Pr o c ur e m e nt  
Pe m br oliz u ma b will be pr o vi de d t o all st u d y sites b y t he s p o ns or. P e m br oli z u ma b will be 
rela bele d b y t h e s p o ns or t o meet c o u ntr y-s pecific re g ulat or y re q uire me nts. 
5. 1. 2. 3.  
D o s e a n d A d mi ni str ati o n  
C o h orts 1 , 2 , a n d 3 ( Mel a n o m a) 
Pe m br oliz u ma b will be a d mi nistere d usi n g I V i nf usi o n o n Da y  8  of eac h 4 2 -da y treat me nt c ycle.  
Pe m br oliz u ma b will be a d mi nistere d as a d ose of 4 0 0  m g usi n g a 3 0 -mi n ut e I V i nf usi o n. Sites 
s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n ti mi n g t o be as cl ose t o 30  mi n utes as p ossi ble. 
H o we ver, gi ve n t he varia bilit y of i nf usi o n p u m ps fr o m site t o site, a wi n d o w bet wee n  – 5  mi n utes 
a n d + 10  mi n utes is per mitte d (ie, i nf usi o n ti me is 3 0  mi n utes [– 5  mi n/ + 1 0  mi n ]). 
Pe m br oliz u ma b will be disc o nti n ue d after  1 8 a d mi nistrati o ns Q 6 W (a p pr o xi matel y 2  years ; se e 
Secti o n  4. 4. 1 ). 
C o h orts 4 a n d 5 ( N S C L C) 
Pe m br oliz u ma b will be a d mi nistere d o n Da y  1  of eac h 2 1 -d a y treat me nt c ycle.  Pe m br oliz u ma b 
will be a d mi nistere d as a d ose of 2 0 0  m g usi n g a 3 0 -mi n ute I V i nf usi o n. Site s s h o ul d ma ke e ver y 
eff ort t o tar get i nf usi o n ti mi n g t o be as cl os e t o 3 0  mi n utes as p ossi ble. H o we ver, gi ve n t he 
varia bilit y of i nf usi o n p u m ps fr o m site t o site, a wi n d o w bet wee n  – 5  mi n ut es a n d + 1 0  mi n utes is 
per mitte d (ie, i nf usi o n ti me is 3 0  mi n utes ( – 5  mi n/ + 1 0  mi n).  
Pe m br oliz u ma b will be disc o nti n ue d after  3 5 a d mi nistrati o ns Q 3 W (a p pr o xi matel y 2  years; see 
Secti o n  4. 4. 1 ). 
5. 1. 2. 4.  
St or a g e a n d H a n dli n g  
Pe m br oliz u ma b s h o ul d be st ore d a n d h a n dle d per t he pe m br oliz u ma b P har mac y Ma n ual . 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 3  of 1 3 5  
5. 1. 2. 5.  
Pr e p ar ati o n  
T he pe m br oliz u ma b P har mac y Ma n ual c o nt ai ns s pecific i nstr ucti o ns f or t h e pr e parati o n of t he 
pe m br oliz u ma b i nf usi o n a n d a d mi nistrati o n of i nf usi o n s ol uti o n.  
5. 1. 3.  
P e m etr e x e d  a n d C ar b o pl ati n  
Pe metre x e d a n d car b o plati n will  be a d mi nistere d t o s u bjects i n C o h orts 4  a n d 5  ( N S C L C) o nl y. 
5. 1. 3. 1.  
D e s cri pti o n  
Pe metre x e d  
Pe metre x e d is a p yri mi di ne -base d  f olate a nti meta b olite t hat i n hi bits t he e nz y m es i n v ol ve d i n 
p uri ne a n d p yri mi di ne n u cle oti de s y nt h esis (t h y mi d ylate s y nt has e, di h y dr of olate re d uct ase, 
gl yci na mi de ri b o n ucle oti de f or m yltra nsferas e, a n d a mi n oi mi daz ole car b o xa mi de f or m yl 
tra nsferase). N ota bly, t his m ultie nz y me i n hi biti o n is u ni q ue t o pe metre x e d as ot her 
a nti meta b olites, s uc h as met h otre x ate a n d 5 -fl ur o uracil, o nl y i n hi bit si n gle e nz y mes. T hr o u g h 
i n hi biti o n of n ucle oti de s y nt hesis, D N A a n d R N A pr o d ucti o n is li mite d, re d uci n g cell gr o wt h 
t hr o u gh o ut t he b o d y.  
C ar b o pl ati n  
Car b o plati n is a cis plati n a nal o g t hat re places t he c hl ori de at o ms wit h a car b o x yc ycl o b uta ne 
m oiet y, re d u ci n g its t o xicit y pr ofile. T h e dr u g is cell c ycl e n o n -s pecific, pr o d uci n g D N A 
cr ossli n ks bet wee n D N A stra n ds, t h us i n hi biti n g D N A s y nt hesis a n d ca ncer cell gr o wt h.  
5. 1. 3. 2.  
M et h o d of Pr o c ur e m e nt  
I n t he U S  a n d Ca na d a, p e metre x e d a n d car b o plati n will be s o urce d b y st u d y sites fr o m 
c o m mercial s u p pl y.  I n ot her c o u ntries, p e metre x e d a n d car b o pl ati n  ma y  b e pr o vi de d t o st u d y 
sites b y t he s p o nsor  or  i n vesti gati o nal sites ma y use l ocall y a vaila ble m ar kete d pr o d u cts 
a ut h orize d  f or use i n t heir res pecti ve c o u ntr y.  
5. 1. 3. 3.  
D o s e a n d A d mi ni str ati o n  
A d mi nister pe metre xe d  at a d ose of 5 0 0  m g/ m 2. 
A d mi nister c ar b o pl ati n  at a d ose of A U C 5 ( usi n g Cal vert f or m ula). Car b o plati n d ose is n ot t o 
e x cee d 7 5 0  m g . Cr Cl s h o ul d be calc ulate d usi n g t h e C oc kcr oft -Ga ult e q u ati o n .  
•  Cal vert F or m ula : T otal D ose ( m g) = (tar get A U C) x ( Cr Cl + 2 5)  
T he Cr Cl use d i n t he Cal vert f or m ula s h o ul d n ot e x cee d 1 2 5  m L/ mi n .  
•  Ma xi m u m car b o plati n d ose ( m g) = tar get A U C 5 ( m g• mi n/ m L) x ( 1 2 5 + 2 5)  =  5  x  
1 5 0  m L/ mi n  =  7 5 0  m g  
5. 1. 3. 4.  
St or a g e a n d H a n dli n g  
Pe metre x e d a n d car b o plati n s h o ul d be st ore d a n d ha n dle d per t heir res p ecti ve U nite d States 
P rescri bi n g I nf or m ati o n (U S PI ) or l o cal la bels . 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 4  of 1 3 5  
5. 1. 3. 5.  
P a c k a gi n g a n d L a b eli n g  
Refer t o t he pe m etre x e d a n d car b o pl ati n pac ka ge i nsert s f or pac ka gi n g a n d la beli n g i nf or mati o n. 
O utsi de of t he U S, pe metre x e d a n d car b o plati n will be rela bel e d b y t he s p o ns or.  
5. 1. 3. 6.  
Pr e p ar ati o n  
Pe metre x e d  a n d car b o plati n s h o ul d be prepare d p er t he ir res p ecti ve U S PI s or l ocal la bels . 
5. 2.  
D o s e M o difi c ati o n s  
5. 2. 1.  
D o s e M o difi c ati o n s a n d T o xi cit y M a n a g e m e nt f or I m m u n e -R el at e d A E s  
A s s o ci at e d wit h P e m br oli z u m a b  a n d /or S E A -C D 4 0  
A Es  ass ociate d wit h pe m br oliz u ma b c o m bi nati o n e x p os ure, i ncl u di n g c o a d mi nis trati o n wit h 
a d diti o nal c o m p o u n ds, ma y re prese nt a n i m m u ne -relate d eti ol o g y. T hes e ir A Es ma y o cc ur 
s h ortl y aft er t he first d ose or se veral m o nt hs after t he last d ose of pe m br oli z u ma b c o m bi nati o n 
treat me nt a n d ma y affect m ore t ha n o ne b o d y s yste m si m ulta ne ousl y. T h eref ore, earl y 
rec o g niti o n a n d i nitiati o n of treat me nt is critical t o re d uce c o m plicati o ns. Base d o n e xisti n g 
cli nical st u d y dat a, m ost ir A Es were re v ersi ble a n d c o ul d be ma na ge d wit h i nterr u pti o ns of 
pe m br oliz u ma b c o m bi nati o n treat me nt, a d mi nistra ti o n of c ortic oster oi ds a n d/ or ot her s u p p orti ve 
care. F or s us p ecte d ir A Es, e ns ure a d e q uate e val uati o n t o c o nfir m eti ol o g y or e x cl u de ot her 
ca uses. A d diti o nal pr oce d ures or tests s uc h as br o nc h osc o p y, e n d osc o p y, s ki n bi o ps y ma y be 
i ncl u de d as part of t h e e val uati o n. Bas e d o n t he se verit y of ir A Es, wit h h ol d or per ma n e ntl y 
disc o nti n ue pe m br oliz u ma b  a n d/ or S E A -C D 4 0  a n d a d mi nister c ortic oster oi ds. D ose 
m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes f or ir A Es ass o ciate d wit h pe m br oliz u ma b 
a n d/or S E A -C D 4 0 are pr o vi de d i n  Ta ble 9 .  
N ote: If aft er t he e val uati o n of t he e ve nt, it is deter mi ne d n ot t o be relate d t o pe m br oliz u ma b  or 
S E A -C D 4 0 , t he i n vesti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce.  
Attri b uti o n of T o xicity  
W he n st u d y i nter ve nti o ns are a d mi nistere d i n c o m bi nati o n, attri b uti o n of a n A E t o a si n gle 
c o m p o ne nt is li kel y t o be diffic ult. T heref ore, w hile t he i n vesti gat or ma y attri b ute a t o xicit y 
e ve nt t o t he c o m bi nati o n, t o S E A-C D 4 0 al o ne, or t o pe m br oliz u ma b al o ne, f or A Es  liste d i n 
T a ble 7 , S E A-C D 4 0 a n d pe m br oliz u ma b m ust be hel d acc or di n g t o t he c rit eria i n T a ble 7 . 
H ol di n g St u dy Dr u gs  
W he n st u d y dr u gs are a d mi nistere d i n c o m bi nati o n, if t he A E is c o nsi dere d i m m u ne -relate d, b ot h 
S E A -C D 4 0 a n d pe m b r oli z u ma b s h o ul d be hel d acc or di n g t o rec o m me n d e d d ose m o dificati o ns. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 5  of 1 3 5  
T a bl e 7 : 
D o s e M o difi c ati o n a n d T o xi cit y M a n a g e m e nt G ui d eli n e s f or I m m u n e -r el at e d AE s A s s o ci at e d wit h P e m br oli z u m a b a n d/ or 
S E A -C D 4 0  
Ge neral i nstr ucti o ns:  
1.  Se vere a n d life -t hreate ni n g ir A Es s h o ul d be treate d wit h I V c ortic oster oi ds f oll o we d b y oral ster oi ds. Ot her i m m u n os u p pressi ve treat me nt s h o ul d 
be gi n if t he ir A Es are n ot c o ntr olle d b y c ortic oster oi ds.  
2.  P e m br oliz u ma b a n d/ or S E A -C D 4 0 m ust be per ma ne ntl y dis c o nti n ue d if t he ir A E d oes n ot res ol ve or t he c ortic oster oi d d ose is n ot ≤1 0  m g/ da y 
wit hi n 1 2  wee ks of t he last p e m br oliz u ma b/ S E A -C D 4 0 treat me nt.  
3.  T he c ortic oster oi d ta per s h o ul d be gi n w he n t he ir A E is ≤ Gra de 1 a n d c o nti n ue at least 4  wee ks.  
4.  If pe m br oliz uma b a n d S E A -C D 4 0 ha ve bee n wit h hel d, pe m br oliz u ma b a n d S E A -C D 4 0 ma y res u me after t he ir A E decrease d t o ≤ Gra d e  1 after 
c ortic oster oi d ta per. 
I m m u ne-relate d 
A Es  
T o xicit y gr a de or 
c o n diti o ns ( N CI 
C T C A E v 5. 0)  
Acti o n wit h 
pe m br oliz u ma b a n d 
S E A -C D 4 0  
ir A E ma na ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t h era pies  
M o nit ori n g a n d f oll o w -u p  
P ne u m o nitis  
Gra de  2  
Wit h h ol d  
A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2  m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per 
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns  
M o nit or s u bjects f or si g ns a n d s y m pt o ms of p ne u m o nitis  
E val u ate s u bjects wit h s us pecte d p ne u m o nitis wit h 
ra di o gra p hic i ma gi n g a n d i nitiate c ortic oster oi d treat me nt 
Rec urre nt Gra de  2,  
Gra de  3 or 4  
P er ma ne ntl y 
disc o nti n ue  
Diarr hea/ C olitis  
Gra de 2 or 3  
Wit h h ol d  
A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2 m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per 
M o nit or s u bjects f or si g ns a n d s y m pt o ms of e nter oc olitis ( ie, 
diarr hea, a b d o mi n al pai n, bl o o d,  or m uc us i n st o ol wit h or 
wit h o ut fe ver) a n d of b o wel perf orati o n ( ie, perit o neal si g ns 
a n d ile us ) 
S u bjects wit h ≥Gra de 2 diarr hea s us pecti n g c olitis s h o ul d 
c o nsi der GI c o ns ultati o n a n d perf or mi n g e n d osc o p y t o r ule o ut 
c olitis 
S u bjects wit h diarr hea/c olitis s h o ul d be a d vise d t o dri n k li beral 
q ua ntities of clear fl ui ds. If s ufficie nt oral fl ui d i nta ke is n ot 
fe asi ble, fl ui d a n d electr ol ytes s h o ul d be s u bstit ute d via I V 
i nf usi o n 
Rec urre nt Gra de  3 
or Gra de 4  
P er ma ne ntl y 
disc o nti n ue  
A S T or A L T 
ele vati o n or 
I ncrease d bilir u bi n 
Gra de 2 a 
Wit h h ol d  
A d mi nister c ortic oster oi ds 
(i nitial d ose of 0. 5 t o 1 m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per 
M o nit or wit h li ver f u ncti o n tests (c o nsi der wee kl y or m ore 
fre q ue ntl y u ntil li ver e nz y me val u e ret ur ne d t o baseli ne or is 
sta ble) 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 6  of 1 3 5  
I m m u ne-relate d 
A Es  
T o xicit y gr a de or 
c o n diti o ns ( N CI 
C T C A E v 5. 0)  
Acti o n wit h 
pe m br oliz u ma b a n d 
S E A -C D 4 0  
ir A E ma na ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t h era pies  
M o nit ori n g a n d f oll o w -u p  
Gra de 3 b or 4 c 
P er ma ne ntl y 
disc o nti n ue  
A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2 m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per 
T y pe 1 dia betes 
mellit us ( T 1 D M) 
or H y per gl yce mi a  
Ne w o nset T 1 D M 
or  
Gra de 3 or 4 
h y per gl yce mi a 
ass ociate d wit h 
e vi d e nce of β -cell 
fail ure 
Wit h h ol d  
I nitiate i ns uli n re place me nt 
t h era p y f or patie nts  wit h T 1 D M  
A d mi nister a nti h y per gl yce mic 
i n s u bjects wit h h y per gl yce mia  
M o nit or s u bjects f or h y per gl yce mia or ot h er si g ns a n d 
s ym pt o ms of dia betes  
H y p o p h ysitis  
Gra de 2  
Wit h h ol d  
A d mi nister c ortic oster oi ds a n d 
i nitiate h or m o nal re place me nts 
as cli nicall y i n dicate d  
M o nit or f or si g ns a n d s y m pt o ms of h y p o p h ysitis (i ncl u di n g 
h y p o pit uitaris m a n d a dre nal i ns ufficie nc y)  
Gra de 3 or 4  
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d  
H y pert h yr oi dis m  
Gra de 2  
C o nti n ue  
Treat wit h n o nselecti ve 
beta -bl o c kers (e g, pr o pra n ol ol) 
or t hi o na mi d es as a p pr o priate  
M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d dis or ders  
Gra de 3 or 4  
Wit h h ol d or  
per ma ne ntl y 
disc o nti n ue d  
H y p ot h yr oi dis m  
Gra de 2, 3, 4  
C o nti n ue  
I nitiate t h yr oi d re place me nt 
h or m o nes (e g, le v ot h yr o xi n e or 
li ot h yr o ni ne) per sta n dar d of 
care  
M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d dis or ders  
Ne p hritis: gra di n g 
acc or di n g t o 
i n crease d 
creati ni n e or ac ute 
ki d ne y i nj ur y  
Gra de 2  
Wit h h ol d  
A d mi nister c ortic oster oi ds 
( pre d nis o ne 1 t o 2 m g/ k g or 
e q ui vale nt) f oll o we d b y ta per  
M o nit or c ha n ges of re nal f u ncti o n  
Gra de 3 or 4  
P er ma ne ntl y 
disc o nti n ue  
Ne ur ol o gical 
t o xicities 
Gra de 2  
Wit h h ol d  
Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds  
E ns ure a de q uate e val u ati o n t o c o nfir m eti ol o g y a n d/ or e xcl u de 
ot h er ca uses  
Gra de 3 or 4  
P er ma ne ntl y 
disc o nti n ue  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 7  of 1 3 5  
I m m u ne-relate d 
A Es  
T o xicit y gr a de or 
c o n diti o ns ( N CI 
C T C A E v 5. 0)  
Acti o n wit h 
pe m br oliz u ma b a n d 
S E A -C D 4 0  
ir A E ma na ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t h era pies  
M o nit ori n g a n d f oll o w -u p  
M y ocar ditis  
Gra de 2, 3, or 4  
P er ma ne ntl y 
disc o nti n ue  
Base d o n se verit y of A E, 
a d mi nister c ortic oster oi ds 
E ns ure a de q uate e val u ati o n t o c o nfir m eti ol o g y a n d/ or e xcl u de 
ot h er ca uses  
E xf oliati ve 
Der mat ol o gic 
C o n diti o ns  
S us pecte d SJ S, 
T E N, or D R E S S  
Wit h h ol d  
Base d o n se verit y of A E, 
a d mi nister c ortic oster oi ds  
E ns ure a de q uate e val u ati o n t o c o nfir m eti ol o g y a n d/ or e xcl u de 
ot h er ca uses  
C o nfir me d SJ S, 
T E N, or D R E S S  
P er ma ne ntl y 
disc o nti n ue  
All ot h er ir A Es  
P ersiste nt Gra de  2  
Wit h h ol d  
Base d o n se verit y of A E, 
a d mi nister c ortic oster oi ds  
E ns ure a de q uate e val u ati o n t o c o nfir m eti ol o g y or e xcl u de 
ot h er ca uses 
Gra de 3  
Wit h h ol d or disc o nti n ue 
base d o n t h e e ve nt e 
Rec urre nt Gra de 3 
or Gra de 4  
P er ma ne ntl y 
disc o nti n ue  
A E(s) =a d verse e ve nt(s); A L T = ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts; D R E S S = Dr u g Ras h wit h E osi n o p hilia a n d 
S yste mic S y m pt o m; GI = gastr oi ntesti nal; I O =i m m u n o -o nc ol o g y; ir =i m m u ne -relate d; I V =i ntra ve n o us; SJ S = Ste ve ns-J o h ns o n S y n dr o me; T 1 D M =t y pe 1 dia betes mellit us; T E N = T o xic E pi der mal 
Necr ol ysis; U L N = u p per li mit of n or m al. 
a A S T/ A L T: > 3. 0 t o 5. 0 x U L N if baseli ne n or mal; > 3. 0 t o 5. 0 x baseli ne, if baseli ne a b n or mal; bilir u bi n: > 1. 5 t o 3. 0 x U L N if b aseli ne n or mal; > 1. 5 t o 3. 0 x baseli ne if baseli ne a b n or mal  
b  A S T/ A L T: > 5. 0 t o 2 0. 0 x U L N, if baseli ne n or mal; > 5. 0 t o 2 0. 0 x  baseli ne, if baseli ne a b n or mal; bilir u bi n: > 3. 0 t o 1 0. 0 x U L N if baseli ne n or mal; > 3. 0 t o 1 0. 0 x baseli ne if baseli ne a b n or mal  
c A S T/ A L T: > 2 0. 0 x U L N, if baseli ne n or mal; > 2 0. 0 x baseli ne, if baseli ne a b n or mal; bilir u bi n: > 1 0. 0 x U L N if baseli ne n or mal; > 1 0. 0 x baseli ne if baseli ne a b n or mal  
d  T he decisi o n t o wit h h ol d or per ma n e ntl y disc o nti n ue pe m br oliz u ma b a n d/ or S E A -C D 4 0 is at t he discreti o n of t he i n vesti gat or or treati n g p h ysicia n. If c o ntr ol ac hie ve d or ≤ Gra de 2, pe m br oliz u ma b 
ma y be res u me d.  
e E ve nts  t hat re q uire disc o nti n uati o n i ncl u de b ut are n ot li mite d t o: e nce p halitis a n d ot her cli nicall y i m p orta nt ir A Es (e g, vasc ulitis a n d scler osi n g c h ola n gitis). 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 8  of 1 3 5  
Rest arti n g St u dy Dr u gs  
If t he t o xicit y d o es n ot res ol ve or t he criteria f or res u mi ng treat me nt are n ot met, t he s u bject m ust 
be disc o nti n ue d fr o m b ot h S E A -C D 4 0 a n d pe m br oliz u ma b.  
If t he t o xicities d o res ol ve a n d c o n diti o ns are ali g ne d wit h w hat is defi ne d i n T a ble 7 , t he 
c o m bi nati o n of S E A -C D 4 0 a n d pe m br oliz u ma b ma y b e restarte d at t he discreti o n of t he 
i n vesti gat or.  
I n cases w here t he t o xicit y is attri b ute d t o S E A-C D 4 0 b ut n ot pe m br oliz u ma b, re -i nitiati o n of 
pe m br oliz u ma b ma y be c o nsi dere d aft er c o m m u ni cati o n wit h t he s p o ns or. If t o xicit y is attri b ute d 
t o pe m br oliz u ma b b ut n ot S E A-C D 4 0, re -i nitiati o n of S E A-C D 4 0 ma y be c o nsi dere d after 
c o m m u nicati o n wit h t he s p o ns or.  
5. 2. 2.  
D o s e M o difi c ati o n s S E A -C D 4 0  
M o dificati o ns t o t he 1 0  mc g/ k g d ose of S E A -C D 4 0 will n ot be all o we d.  
I m m u ne-relat e d a d verse e ve nts s h o ul d be ma na ge d as o utli ne d i n T a ble 7 . F or n o n-i m m u ne 
S E A -C D 4 0 -relat e d A Es  f or w hic h m ore s p ecific g ui da nce d oes n ot e xist else w here i n t he 
pr ot oc ol:  
F or a n y S E A -C D 4 0 -rel ate d A E, deter mi ne d t o be cli nicall y si g nifica nt b y a n i n vesti gat or, w hi c h  
is o n g oi n g at t he ne xt sc he d ule d d osi n g d a y, t he d ose ma y be dela ye d, at t h e discreti o n of t he 
i n vesti gat or, u ntil res ol uti o n t o baseli ne or ≤ Gra d e 1 i n se verit y. If t h e A E is still o n g oi n g o n a 
s u bse q ue nt sc he d ule d d osi n g da y, S E A-C D 4 0 ma y  be disc o nti n ue d at t he discreti o n of t he 
i n vesti gat or (c o nsi der c o ns ultati o n wit h t he me dical m o nit or).  
F or cli nicall y si g nifica nt  Gra de 3, S E A -C D 4 0 -rel ate d A Es  o n g oi n g at t he n e xt sc he d ule d d osi n g 
da y, t h e d ose of S E A -C D 4 0 s h o ul d be hel d u ntil t he se ver it y res ol ves t o ≤ Gra de 2 or ret ur ns t o 
baseli ne. If t he A E is still o n g oi n g o n a s u bse q ue nt sc he d ule d d osi n g da y, S E A -C D 4 0 ma y be 
disc o nti n ue d at t he discreti o n of t he i n vesti gat or (c o nsi der c o ns ultati o n wit h t he me dical 
m o nit or).  
F or Gra de 4, life -t hreate ni n g S E A -C D 4 0 relate d A Es , S E A-C D 4 0 s h o ul d be per ma ne ntl y 
disc o nti n ue d.  
5. 2. 3.  
D o s e M o difi c ati o n s P e m br oli z u m a b  
5. 2. 3. 1.  
D o s e M o difi c ati o n a n d T o xi cit y M a n a g e m e nt of I nf u si o n -r e a cti o n s 
R el at e d t o P e m br oli z u m a b  
Pe m br oliz u ma b ma y ca use se vere or life -t hreat e ni n g i nf usi o n-reacti o ns i ncl u di n g se v ere 
h y perse nsiti vit y or a na p h yl a xis. Si g ns a n d s y m pt o ms us uall y de vel o p d uri n g or s h ortl y after dr u g 
i nf usi o n a n d ge nerall y res ol ve c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. D ose 
m o dificati o n a n d t o xicit y ma na ge me nt g ui de li nes o n pe m br oliz u ma b ass ociate d i nf usi o n reacti o n 
are pr o vi d e d i n Ta ble 8 . 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 5 9  of 1 3 5  
T a bl e 8 : 
P e m br oli z u m a b I nf u si o n R e a cti o n D o s e M o difi c ati o n a n d Tr e at m e nt G ui d eli n e s  
N CI C T C A E Gr a de  
Tre at me nt Rec o m me n d ati o ns  
Pre me dic ati o n at 
S u bse q ue nt 
Pe m br oliz u m a b 
D osi n g  
Gra d e 1  
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n 
n ot i n dicate d  
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bj ect is dee me d me dicall y sta ble i n 
t he o pi ni o n of t he i n vesti gat or. 
N o ne  
Gra d e 2  
Re q uires t hera p y or 
i nf usi o n i nterr u pti o n b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt 
(e g, a nti hista mi nes, 
N S AI Ds, narc otics, I V 
fl ui ds); pr o p h ylactic 
me dicati o ns i n dicate d 
f or ≤2 4  hrs  
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dical t hera p y ma y  
i ncl u de but is n ot li mite d t o:  
I V fl ui ds 
A nti hista mi nes  
N S AI Ds a 
Aceta mi n o p he n  
Narc otics  
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bj ect is dee me d me dicall y  
sta ble i n t he o pi ni o n of t he i n vesti gat or. 
If s y m pt o ms res ol ve wit hi n 1 h o ur of st o p pi n g 
dr u g  i nf usi o n, t he i nf usi o n ma y be restarte d at 5 0 % 
of  t he ori gi nal i nf usi o n rate (e g, fr o m 1 0 0 m L/ hr t o 
5 0  m L/ hr). Ot her wise d osi n g will be hel d u ntil 
s y m pt o ms res ol ve a n d t he s u bj ect s h o ul d be 
pre me dicate d f or t he ne xt sc he d ule d d ose.  
S u bj ects w h o de vel o p Gra de 2 t o xicit y des pite a de q uate 
pre me dicati o n s h o ul d be per ma ne ntl y disc o nti n ue d 
fr o m f urt her pe m br oliz u ma b treat me nt. 
S u bj ect ma y be 
pre me dicate d 1. 5  h 
(± 3 0  mi n utes) pri or t o 
i nf usi o n of 
pe m br oliz u ma b wit h:  
Di p he n h y dra mi ne 
5 0  m g p o 
( or e q ui vale nt d ose 
of  a nti hista mi ne)  
Aceta mi n o p he n 5 0 0  t o 
1 0 0 0  m g p o 
( or e q ui vale nt d ose 
of  a nal gesic)  
Gra d es 3 or 4  
Gra d e 3:  
Pr ol o n ge d (ie, n ot 
ra pi dl y res p o nsi ve t o 
s y m pt o matic me dicati o n 
a n d/ or brief i nterr u pti o n 
of i nf usi o n); rec urre nce 
of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d 
f or ot her cli nical 
se q uelae (e g, re nal 
i m pair me nt, p ul m o nar y 
i nfiltrates) 
Gra d e 4:  
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de  
b ut is n ot li mite d t o:  
E pi ne p hri ne * *  
I V fl ui ds 
A nti hista mi nes  
N S AI Ds a 
Aceta mi n o p he n  
Narc otics  
O x y ge n  
Press ors  
C ortic oster oi ds  
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bj ect is dee me d me dicall y  
sta ble i n t he o pi ni o n of t he i n vesti gat or. 
N o s u bse q ue nt 
pe m br oliz u ma b d osi n g  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 0  of 1 3 5  
N CI C T C A E Gr a de  
Tre at me nt Rec o m me n d ati o ns  
Pre me dic ati o n at 
S u bse q ue nt 
Pe m br oliz u m a b 
D osi n g  
Life -t hreate ni n g; press or 
or ve ntilat or y s u p p ort 
i n dicate d 
H os pitalizati o n ma y be i n dicat e d.  
* *I n cases of a na p h yla xis, e pi ne p hri ne s h o ul d be  
use d i m me diatel y.  
S u bj ect is per ma ne ntl y disc o nti n ue d fr o m f urt her 
pe m br oliz u ma b treat me nt.  
N S AI D = n o n -ster oi dal a nti-i nfla m mat or y dr u g 
a F or s u bj ects i n C o h orts 4 a n d 5, N S AI Ds s h o ul d n ot be a d mi nistere d i n t he ti mefra mes o utli ne d i n Secti o n  5. 4. 3  
A p pr o priate res us citati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g t he 
peri o d of dr u g a d mi nistrati o n. F or f urt her i nf or mati o n, pleas e refer t o t he N CI C T C A E v 5. 0 at 
htt p://cte p.ca ncer. g o v . 
All  Gra de  3 or  4 e ve nts of I R R m ust be re p orte d t o t he s p o ns or i m me diatel y, re gar dl ess of 
relati o ns hi p t o eit her S E A-C D 4 0, pe m br oliz u ma b, or a n ot her st u d y dr u g. All Gra de  4 e ve nts are 
S A Es a n d are t o b e re p orte d wit hi n t he S A E re p orti n g ti mefra m e of 2 4  h o urs via t he sta n dar d 
S A E f or ms (see Sect i o n 7. 7. 1. 4 ). 
5. 2. 3. 2.  
Ot h er All o w e d D o s e I nt err u pti o n s a n d M o difi c ati o n s f or P e m br oli z u m a b  
Pe m br oliz u ma b ma y b e i nterr u pte d f or sit uati o ns ot her t ha n treat me nt-relat e d A Es  s uc h as 
me dical or s ur gic al e ve nts a n d/ or u nf ores ee n circ u msta nces n ot relate d t o st u d y i nter ve nti o n. If a  
s u bject i n C o h orts 1, 2, or 3 is u na ble t o recei ve t h e first d ose of pe m br oliz u ma b i n a n y gi v e n 
c ycle a n d is c o nsi d ere d a p pr o pr iate t o recei ve pe m br oliz u ma b as sta n dar d of care, t he s u bject 
ma y recei ve a 2 0 0  m g d ose of pe m br oliz u ma b o n D a y 2 9  t o D a y 3 1  of t h e c ycle. T he s u bj ect will 
t he n c o nti n ue t o recei ve pe m br oliz u ma b at Q 6 W as pla n ne d o n D a y 8 of t he ne xt c ycl e, as l o n g 
as t he s u bject c o nti n ues t o be a p pr o pri ate t o recei v e pe m br oliz u ma b. If a s u bject re q uir es a 
l o n ger i nterr u pti o n of pe m br oliz u ma b f or reas o ns ot her t ha n treat me nt-relate d A Es , st u d y 
i nter ve nti o n s h o ul d be restarte d wit hi n 2 1 da ys (f or Q 3 W d osi n g) or 4 2  d a ys (f or  Q 6 W d osi n g) 
of t he ori gi nall y s c he d ule d d ose a n d wit hi n 4 2  da ys (f or Q 3 W d osi n g) or 8 4  da ys (f or Q 6 W 
d osi n g) of t h e pre vi o usl y a d mi nistere d d ose, u nless ot her wise disc usse d wit h t he s p o ns or. T he 
reas o n f or i nterr u pti o n is t o be d oc u me nte d i n t he s u bject’s st u d y rec or d. 
5. 2. 4.  
D o s e M o difi c ati o n s  P e m etr e x e d/ C ar b o pl ati n  
Rec o m me n de d d ose m o dificati o ns f or selecte d pe metre x e d a n d car b o plati n t o xicities are o utli ne d 
i n Ta ble 9  a n d Ta bl e 1 0 . Refer t o t he pe m etre x e d a n d car b o pl ati n U S PIs or l ocal la bels f or f ull 
t o xicit y ma na ge me nt g ui deli nes.  
D ose m o dificati o ns m ust be base d o n t he ma xi m u m t o xicit y e x perie nce d d uri n g a c ycle. T o xicit y 
m ust res ol ve t o Gra de ≤1 or baseli ne pri or t o r es u mi n g s u bse q ue nt c ycle. F or i n di vi d ual s u bjects 
re q uiri n g a d ose m o dificati o n, treatme nt f or eac h ne w c ycl e ma y be d ela ye d if t he sc he d ule d 
off -dr u g p eri o ds are n ot a de q uate t o all o w f or rec o ver y t o Gra d e ≤1 or t he b aseli ne stat us of t he 
s u bject. 
Re d ucti o n of o ne c h e m ot hera p y a ge nt a n d n ot t he ot her a ge nt is a p pr o priate if, i n t he o pi ni o n  of 
t he i n vesti gat or, t h e t o xicit y is clearl y relate d t o o n e a ge nt. If, i n t he o pi ni o n of t he i n vesti gat or, 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 1  of 1 3 5  
t he t o xicit y is relate d t o t he c o m bi nati o n of b ot h c he m ot hera p y a ge nts, b ot h dr u gs s h o ul d be 
re d uce d acc or di n g t o rec o m me n de d d ose m o dificati o ns.  
S u bjects ma y ha v e c h e m ot hera p y disc o nti n ue d a n d c o nti n ue o n S E A -C D 4 0 a n d/ or 
pe m br oliz u ma b.  
C he m ot hera p y ma y be i nterr u pte d f or a ma xi m u m of 6  wee ks fr o m last d ose, u nless ot her wise 
disc usse d wit h t he s p o ns or.  
Ta ble 9  a n d T a ble 1 0  ser ve as a g ui de, a n d d o n ot re place i n vesti gat or j u d ge me nt a n d a p plica ble 
l ocal la bel rec o m me n dati o ns if m ore stri n ge nt. 
T a bl e 9 : 
R e c o m m e n d e d D o s e M o difi c ati o n s f or C h e m ot h er a p y H e m at ol o gi c al T o xi cit y  
Pl atelets  
A N C  
Pe metre xe d  
D ose  
C ar b o pl ati n  
D ose  
≥5 0, 0 0 0/ mc L A N D  
≥5 0 0/ mc L  
5 0 0  m g/ m 2 
A U C 5  
Ma xi m u m d ose 7 5 0  m g  
≥5 0, 0 0 0/ mc L A N D  
< 5 0 0/ mc L  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
< 5 0, 0 0 0/ mc L wit h o ut 
blee di n g A N D  
A N Y  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
< 5 0, 0 0 0/ mc L wit h Gra d e 
≥2 blee di n g A N D  
A N Y  
2 5 0  m g/ m 2 
A U C  2 . 5 Ma xi m u m 
d ose  3 7 5  m g  
A N Y A N D  
< 1 0 0 0/ mc L + fe ver 
≥3 8. 5° C ( 1 0 1° F)  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 2  of 1 3 5  
T a bl e 1 0 : 
R e c o m m e n d e d D o s e M o difi c ati o n s f or C h e m ot h er a p y N o n -H e m at ol o gi c al T o xi cit y  
E ve nt  
C T C A E Se verit y Gr a de  
Pe metre xe d  
D ose  
C ar b o pl ati n  
D ose  
Na usea or v o miti n g  
Gra d e 3 or 4  
5 0 0  m g/ m 2  
A U C 5  
Ma xi m u m d ose 7 5 0  m g  
Diarr hea  
Gra d e 3 or 4  
3 7 5  m g/ m 2 
A U C 5  
Ma xi m u m d ose 7 5 0  m g  
M uc ositis  
Gra d e 3 or 4  
2 5 0  m g/ m 2 
A U C 5  
Ma xi m u m d ose 7 5 0  m g  
Ne ur ot o xicit y  
Gra d e 2  
5 0 0  m g/ m 2 
A U C 5  
Ma xi m u m d ose 7 5 0  m g  
Gra d e 3 or 4  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
Tra nsa mi nase ele vati o n  
Gra d e 3  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
Gra d e 4  
Disc o nti n ue  
Disc o nti n ue  
Ot her n o n -he mat ol o gical 
t o xicit y. 
Gra d e 3 or 4  
3 7 5  m g/ m 2 
A U C 3. 7 5  
Ma xi m u m d ose 5 6 2. 5  m g  
5. 3.  
R e q uir e d Pr e m e di c ati o n a n d P o st m e di c ati o n  
Pr o p h yla ctic pre me di cati o n f or I H Rs is re q uir e d pri or t o a d mi nistrati o n of S E A-C D 4 0 . 
Pre me dicati o n  s h o ul d i ncl u de all of t he f oll o wi n g: 
•  B ot h H 1 a n d H 2 hista mi ne rece pt or bl oc kers  
•  Aceta mi n o p he n  
•  I b u pr ofe n or ot her N S AI D s (e x ce pt i n s u bjects i n C o h orts 4 a n d 5 wit h Cr Cl 
< 8 0  m L/ mi n)  
•  A nti -e metic of c h oi ce f or na usea/ v o miti n g s y m pt o m c o ntr ol  (e x cl u di n g ster oi ds) 
F or s u bjects w h o t olerate at lea st 2 c o nsec uti ve c ycles of S E A -C D 4 0 treat me nt wit h o ut a 
Gra de  3 or hi g h er I H R, o ne or all of t he re q uire d pre me dicati o ns ma y b e disc o nti n ue d  at t he 
discreti o n of t he i n vesti gat or  (c o nsi der c o ns ultati o n wit h t he me dical m o nit or ). 
F or ma na ge me nt of I H Rs, see  Secti o n  5. 5. 1 . 
If c o nsiste nt wit h l ocal pr actices, it is rec o m me n d e d t hat c ortic oster oi d pre -me dicati o n f or 
pe metre x e d c o m prise a si n gle d ose of de x a met has o ne I V 1 0 – 2 0  m g o n Da y 1 (Els o uei di 2 0 1 6 ; 
Clar k 2 0 1 9 ; Gr olea u 2 0 2 0 ). 
A ntie metic t hera p y s h o ul d be c o nsiste nt wit h M ulti nati o nal Ass ociati o n of S u p p orti ve Care i n 
Ca ncer ( M A S C C ) g ui deli nes ( a vaila ble at w w w. m ascc. or g/ a ntie metic -g ui d eli nes ). W he n 
car b o plati n is use d  d uri n g t he first 4  c ycles i n s u bjects wit h N S C L C ( C o h orts 4 a n d 5), 
a ntie metic t hera p y s h o ul d i ncl u de a 5-H T 3 rece pt or a nta g o nist, de x a met has o ne, a n d a n N K 1 
a nta g o nist s uc h as a pre pita nt per t he M A S C C g ui deli nes  o n t he da y of car b o plati n d osi n g .  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 3  of 1 3 5  
Ot her t ha n as s p ecifie d a b o ve, use of pr o p h yl actic c ortic oster oi ds f o r c he m ot hera p y d osi n g is 
disc o ura ge d u nless cli nicall y i n dicate d d ue t o t he p ote ntial f or c ortic oster oi ds t o i nterfere wit h 
t he mec ha nis m of S E A-C D 4 0. C o nsi der m e dical m o nit or c o ns ultati o n if a d diti o nal c ortic oster oi d 
use is c o nsi dere d n ecess ar y i n c o nj u n c ti o n wit h c he m ot hera p y, bas e d o n e m er gi n g t o xicit y or 
ot her c o nsi derati o ns.  
T here are n o re q uire d p ost -me dicati o ns.  
5. 4.  
C o n c o mit a nt T h er a p y  
All c o nc o mita nt me dicati o ns, bl o o d pr o d ucts, a n d ra di ot hera p y a d mi nistere d will be rec or de d 
fr o m Da y 1 ( pre d ose) t hr o u g h t he s afet y re p orti n g peri o d. A n y c o n c o mita nt me dicati o n gi v e n f or 
a st u d y pr ot o c ol -rel ate d A E s h o ul d be rec or de d fr o m t he ti me of i nf or me d c o nse nt. 
5. 4. 1.  
R e q uir e d C o n c o mit a nt T h er a p y  
S u bject s recei vi n g pe m etre x e d s h o ul d recei ve f olic aci d a n d vita mi n B 1 2 s u p pleme ntati o n as 
f oll o ws: 
•  F olic Aci d 3 5 0  t o 1 0 0 0  mc g oral: at least 5  d oses of f olic aci d m ust be ta k e n d uri n g t he 
7  da ys prece di n g t he first d ose of pe metre x e d, a n d f olic aci d d osi n g m ust c o nti n ue 
d uri n g t he f ull c o urse of t hera p y a n d f or 2 1  d a ys after t he la st d ose of pe metre x ed . 
•  Vita mi n B 1 2 1 0 0 0  mc g I M i njecti o n i n t he wee k prece di n g t he first d ose of 
pe metre x e d a n d o nce e ver y 3  c ycles t hereafter. S u bse q ue nt vita mi n B 1 2 i njecti o ns 
ma y b e gi ve n t he sa me d a y as pe metre x e d a d mi nistrati o n.  
Re q uire d pre me di cati o n s f or st u d y dr u gs are descri be d i n Secti o n  5. 3 . 
5. 4. 2.  
All o w e d C o n c o mit a nt T h er a p y  
T he use of platel et a n d/ or re d bl o o d cell s u p p orti ve gr o wt h fact ors or tra nsf usi o ns w he n 
a p plica ble is all o we d. T h e use of c ol o n y sti m ulati n g fact ors f or t he treat me nt of ne utr o pe nia per 
i nstit uti o nal practice is per mitte d d uri n g t h era p y.  
C o nc o mita nt pre d nis o ne ( or e q ui vale nt) m a y be us e d at p h ysi ol o gic -re place me nt d ose le vels 
w he n cli nicall y i n dicate d . Inter mitte nt hi g h -d os e c ortic oster oi d treat me nt t o pre ve nt or ma na ge 
h y perse nsiti vit y reacti o ns (i ncl u di n g pre me dicati o n f or k n o w n h y perse nsiti vit y reacti o ns t o 
c o ntrast f or ra di o gra p hi c assess me nts) ma y be us e d at t he i n vesti gat or’s discreti o n . Inter mitte nt 
hi g h -d ose c ortic oster oi d treat me nt f or ot h er reas o ns, i ncl u di n g ma na ge me nt of i m m u ne -me diate d 
A Es , ma y b e use d at t he i n vesti gat or’s discreti o n. 
T he use of a nti bi otics i ncl u di n g pr o p h ylactics, w he n a p plica ble, is all o we d.  
T he use of b o n e m o dif yi n g a ge nts , w he n a p plica ble, is all o we d. 
St u d y treat me nt ma y b e i nterr u pte d b y palliati ve ra di ot hera p y n ot i n v ol vi n g tar get lesi o ns, at t he 
i n vesti gat or’s discreti o n. 
R o uti ne pr o p h yla xis wit h vacci nes is per mitte d; it is rec o m me n de d t hat v acci nes use d d o n ot 
c o ntai n li ve micr o or ga nis ms.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 4  of 1 3 5  
5. 4. 3.  
Pr o hi bit e d C o n c o mit a nt T h er a p y  
S u bject s ma y n ot r ecei v e ot her i n vesti gati o nal dr u gs, i m m u n os u p pressi ve me dicati o ns, 
ra di ot hera p y ( ot her t ha n palliati ve ra di ot hera p y, s ee Secti o n 5. 4. 2 ), or s yst e mic a nti-ne o plastic 
t hera p y d uri n g t he st u d y. I m m u n os u p pressi ve me dicati o ns, s uc h as ster oi ds, ma y n ot be us e d as 
pr o p h yla xis f or I R Rs o n da ys w here S E A -C D 4 0 is a d mi nistere d.  
T he f oll o wi n g a d diti o nal t hera pies are pr o hi bite d f or C o h orts 4 a n d 5 o nl y:  
•  Yell o w fe ver vacci nes  
•  I b u pr ofe n or ot her N S AI Ds (i ncl u di n g pre me dicati o n) i n s u bjects wit h Cr Cl 
< 8 0  m L/ mi n, d uri n g t he 2  da ys b ef ore, t he da y of, a n d 2  da ys aft er pe metre x e d 
a d mi nistrati o n  
•  L o n g acti n g N S AI Ds (s u c h as pir o xica m or r ofec o xi b) f or 5  da ys bef ore, t h e da y of, 
a n d 2 da ys aft er pe metre x e d  a d mi nistrati o n. 
5. 5.  
M a n a g e m e nt of Tr e at m e nt -E m er g e nt A d v er s e E v e nt s  
5. 5. 1.  
M a n a g e m e nt of I nf u si o n/I nj e cti o n or H y p er s e n siti vit y R e a cti o n s  
5. 5. 1. 1.  
S E A -C D 4 0  
I H Rs, i ncl u di n g C R S, ha ve bee n o bser ve d i n s u bj ects a d mi nistere d S E A -C D 4 0 . T he m ost 
c o m m o n I R R -relate d s y m pt o ms were c hills, na us ea, a n d v o miti n g; o nset of s y m pt o ms t y picall y 
occ urre d wit hi n 2  h o urs, a n d i n s o me cases wit hi n mi n utes after starti n g S E A -C D 4 0 a n d res ol ve d 
wit hi n a fe w h o urs after disc o nti n uati o n of t he i nf usi o n a n d s y m pt o matic treat me nt (ie, 
a nti hista mi nes, a ntie metics, a nti p yretics, o pi oi ds, a n d/ or c ortic oster oi ds). If a n y s u c h e ve nts 
occ ur d uri n g t hera p y wit h S E A -C D 4 0, s u p p orti ve care is a d vise d.  
Re q uire d S E A -C D 4 0 pre me dicati o ns f or I H Rs a n d p ossi ble C R S are descri be d i n Secti o n  5. 3 . 
Rec o m me n dati o ns f or m a na ge me nt of I H Rs ass ociate d wit h S E A -C D 4 0  are detaile d i n  Ta ble 1 1 .  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 5  of 1 3 5  
T a bl e 1 1 : 
Tr e at m e nt R e c o m m e n d ati o n s a n d D o s e M o difi c ati o n s f or S E A -C D 4 0 
I nf u si o n/I nj e cti o n or H y p er s e n siti vit y R e a cti o n s  
N CI C T C A E  
Tre at me nt Rec o m me n d ati o ns  
D ose M o dific ati o ns  
Gra d e 1  
Mil d reacti o n; S E A -C D 4 0 
treat me nt i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n n ot 
i n dicate d. 
Tra nsie nt fl us hi n g or ras h, 
dr u g fe ver < 3 8° C 
( < 1 0 0. 4° F); or i nter ve nti o n 
n ot i n dicate d.  
M o nit or vital si g ns m ore fre q ue ntl y 
u ntil s y m pt o m s ha ve res ol ve d a n d 
s u bj ect is me dicall y sta ble. 
A d mi nister s y m pt o matic treat me nt 
as me dicall y i n dicate d.  
C o nsi der a d diti o nal 
pre me dicati o n wit h s u bse q ue nt 
S E A -C D 4 0 treat me nt  if 
cli nicall y i n dicate d . 
Gra d e 2  
S E A -C D 4 0 treat me nt 
i nterr u pti o n i n dicate d b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt (ie, 
a nti hista mi nes, N S AI D s, 
narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns 
i n dicate d f or ≤2 4 hrs.  
H ol d S E A -C D 4 0 treat me nt.  
M o nit or vital si g ns m ore fre q ue ntl y 
a n d a d mi nister s y m pt o matic 
treat me nt as me dicall y i ndicat e d.  
If s u bj ect res p o n ds pr o m ptl y a n d is 
me dicall y sta ble i n t he o pi ni o n of 
t he i n vesti gat or, S E A-C D 4 0 
treat me nt ma y be c o nti n ue d, 
p ote ntiall y at a sl o wer rate .  
C o nsi der a d diti o nal 
pre me dicati o n a n d/ or sl o wer 
i nf usi o n rate wit h s u bse q ue nt 
S E A -C D 4 0 tre at me nt.   
If s u bj ect has a dre nal 
i ns ufficie nc y, c o nsi der 
i ncreasi n g re place me nt ster oi d 
d ose t o 1 0  m g pre d nis o ne 
e q ui vale nt per da y o n 
S E A -C D 4 0 d osi n g da ys.  
Gra d e 3 a 
Pr ol o n ge d (ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of S E A -C D 4 0 
treat me nt); rec urre nce of 
s y m pt o ms f oll o wi n g i nitial 
i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or 
ot her cli nical se q uelae 
(ie, re nal i m pair me nt, 
p ul m o nar y i nfiltrates).  
St o p S E A -C D 4 0 treat me nt.  
A p pr o priate a d diti o nal me dical 
t hera p y s h o ul d be i nstit ute d. 
C o nsi der h os pitalizati o n.  
S u bj ect s wit h a n I H R t hat 
res ol ves t o baseli ne or ≤ Gra de  1 
wit hi n a p pr o xi matel y 2  h o urs 
after i nter ve nti o n ma y c o nti n ue 
o n S E A -C D 4 0 treat me nt at t he 
i n vesti gat or’s j u d ge me nt. 
T he p ossi bilit y of a d diti o nal 
pre -me dicati o n a n d/ or sl o we d 
i nf usi o n rate m a y be disc usse d 
wit h t he me dical m o nit or  
O R  
P er ma ne ntl y disc o nti n ue fr o m 
st u d y treat me nt. 
Gra d e 4 a 
Life -t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d; 
press or or ve ntilat or s u p p ort 
i n dicate d 
St o p S E A -C D 4 0 treat me nt 
im me diatel y.  
H os pitalizati o n.  
P er ma ne ntl y disc o nti n ue fr o m 
st u d y treat me nt. 
a All Gra d e  3 or  4 e ve nts of I H R m ust b e re p orte d t o t he sp o ns or i m me diatel y, re gar dless of relati o ns hi p t o st u d y 
dr u gs. All Gra d e  4 e ve nts are S A Es a n d are t o be re p orte d wit hi n t he S A E re p orti n g ti mefr a me of 2 4  h o urs via t he 
sta n dar d S A E f or ms (see Secti o n  7. 7. 1. 4 ). 
5. 5. 2.  
All er gi c/ H y p er s e n siti vit y R e a cti o n  
Aller gi c/ h y p erse nsiti vit y reacti o ns are c h aracterize d b y a d v erse l o cal or ge n eral r es p o nses fr o m 
e x p os ure t o a n aller ge n ( N CI C T C A E , v 5. 0 ). F or p ur p oses of t his st u d y, aller gi c/ h y p erse nsiti vit y 
reacti o ns are differe ntiate d fr o m I R Rs b y bei n g d efi ne d as occ urri n g > 24  h o urs after i nf usi o n of  
t he st u d y dr u g. Aller gic/ h y perse nsiti vit y reacti o ns ma y ma nifest i n t he sa me ma n ner as I R Rs (ie, 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 6  of 1 3 5  
a c o m bi nati o n of si g ns  or s y m pt o ms i ncl u di n g fe v er, ri g ors, fl us hi n g, itc hi n g, vari o us t y p es of 
ras h, urticaria, d ys p nea, na usea, v o miti n g, b ac k or a b d o mi nal pai n, a n d/ or h y p ote nsi o n ). 
Re q uire d S E A -C D 4 0 pre me dicati o ns are d escri b e d i n Secti o n  5. 3 . 
All o we d meas ur es i ncl u de d ose m o dificati o ns ( Secti o n  5. 2 ) a n d co nc o mita nt me dicati o ns 
(Secti o n  5. 4 ). 
5. 5. 2. 1.  
A n a p h yl a xi s  
A na p h yl a xis is a se vere, life -t hreat e ni n g, ge neralize d or s yste mic aller gic/ h y perse nsiti vit y 
reacti o n. A n a p h yl a xis is c haracteriz e d b y a n ac ute i nfla m mat or y reacti o n res ulti n g fr o m t he 
releas e of hista mi ne a n d hista mi ne-li ke s u bsta nces fr o m mast cells, ca usi n g a h y p erse nsiti vit y 
i m m u ne res p o nse. Cli nicall y, it pres e nts wit h breat hi n g diffic ult y, dizzi ness, h y p ote nsi o n, 
c ya n osis, a n d l oss of c o nsci o us ness a n d ma y lea d t o deat h ( N CI C T C A E, v 5. 0  a n d 
(R osell o  2 0 1 7 ). 
If a na p h yl a xis occ urs, a d mi nistrati o n of t he st u d y dr u g s h o ul d be i m me diat el y a n d per ma n e ntl y 
disc o nti n ue d.  
5. 5. 3.  
M a n a g e m e nt of O v er d o s e  
S E A -C D 4 0  
A n o ver d ose of S E A -C D 4 0  is defi ne d as ≥1 0 % of t he i nte n de d d ose. I n t he e ve nt of a n o v er d ose 
of S E A -C D 4 0 , st u d y p ers o n nel s h o ul d: 
•  Care f or a n d me dicall y st a bilize t he s u bject u ntil t here is n o i m me diate ris k of 
c o m plicati o ns or deat h, if a p plica ble. T here is c urre ntl y n o k n o w n a nti d ote f or a n 
o ver d ose of S E A -C D 4 0 . 
•  N otif y t he m e di cal m o nit or as s o o n as t he y bec o m e a ware of t h e o ver d ose, t o disc uss 
details of t he o ver d os e ( e g, e x act a m o u nt of S E A -C D 4 0  a d mi nistere d, s u bject wei g ht) 
a n d A Es , if a n y. 
Pe m b r oliz u m a b  
F or t his st u d y, a n o ver d ose of pe m br oliz u ma b will be defi ne d as a n y d ose of 1 0 0 0  m g or greater.  
N o s pecific i nf or mati o n is a vaila ble o n t he tr eat me nt of o ver d ose of pe m br oliz u ma b. I n t h e e ve nt 
of o ver d ose, t h e s u bject s h o ul d be o bser ve d cl osel y f or si g ns of t o xicit y. A p pr o priate s u p p orti ve 
treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d. T he o ver d ose s h o ul d be re p ort e d t o t he 
s p o ns or wit hi n 2 4  h o urs  of o bser vi n g or  lear ni n g of t he o ver d ose . 
Pe metre x e d a n d C ar b o pl ati n  
I n t he e ve nt of a n o ver d ose of pe metre x e d a n d/ or car b o plati n , t he e v e nt s h o ul d be ma na ge d 
acc or di n g t o t he pr o d uct la bel a n d/ or i nstit uti o nal sta n dar d of care, a n d pr o m ptl y re p ort e d t o t he 
sp o ns or.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 7  of 1 3 5  
5. 5. 4.  
M a n a g e m e nt of O c ul ar E v e nt s  
I n v esti gat ors s h o ul d m o nit or s u bjects cl osel y f or a n y t y pe of oc ular s y m pt o ms t hat c o ul d be 
i m m u ne-me diate d. If a s u bject has a persiste nt Gra de 2 or hi g her oc ular e v e nt t hat is s us pecte d t o 
be i m m u ne -me diate d, t he i n vesti gat or s h o ul d h ol d pe m br oliz u ma b a n d/ or S E A-C D 4 0 i n 
acc or da nce wit h  T a ble 7  a n d refer t he s u bject f or o p ht hal m ol o gic e x a mi nati o n.  
5. 6.  
Tr e at m e nt C o m pli a n c e  
St u d y dr u g a d mi nistrati o n will be perf or me d b y st u d y site staff a n d d oc u m e nte d i n s o urce 
d oc u me nts a n d t he C R F. I n t he e ve nt of a n o ver d ose ≥1 0 %, t he site s h o ul d n otif y t he s p o ns or or 
desi g nee as s o o n as t he y are a ware of t he o v er d ose.  
5. 7.  
C o nti n u e d A c c e s s t o S E A -C D 4 0  Aft er t h e E n d of t h e St u d y  
A s u bject deri vi n g cli nic al be nefit fr o m S E A -C D 4 0 at t he ti me t he st u d y is c o m plete d ma y be 
per mitte d t o c o nti n ue t o recei ve S E A-C D 4 0, pr o vi de d t he i n vesti gat or c o nsi ders it t o be i n t he 
s u bject’s best i n di vi d ual treat me nt o pti o n a n d t he st u d y was n ot ter mi nate d d ue t o safet y 
c o ncer ns. Re q uests will be disc usse d o n a s u bject -b y -s u bject basis wit h t he s p o ns or. If c o nti n ue d 
access t o S E A -C D 4 0 is per mitte d , s parse d ata ma y be c ollecte d t o m o nit or t he safet y a n d 
t olera bilit y of c o nti nue d a d mi nistrati o n  (see Secti o n 3. 1. 5 ) 
5. 8.  
Vi sit S c h e d uli n g for Si n gl e Tr e at m e nt Di s c o nti n u ati o n  
Eac h ti me a s u bject disc o nti n ues a c o m p o ne nt of c o m bi nati o n t hera p y b ut is c o nti n ui n g wit h 
a n ot her c o m p o ne nt, cli nic visits a n d safet y as sess me nts (i ncl u di n g pre g na n c y t esti n g) ass ociate d 
wit h t he disc o nti n ue d treat me nt ma y b e m o ve d or eli mi nate d (if c o nsi dere d a p pr o priate after 
c o ns ultati o n wit h t he me dical m o nit or), if t here are n o ot her st u d y dr u gs a d mi nistere d o n t hat 
da y. If bi o mar ker/ patie nt -re p orte d o ut c o me (P R O ) assess me nts fall o n a da y t hat n o l o n ger has 
a n y st u d y dr u g a d mi nistere d, t hese ma y b e m o ve d t o t he ne xt sc he d ule d visit or eli mi nate d, if 
c o nsi dere d a p pr o priat e after c o ns ultati o n wit h t he me dical m o nit or . 
6.  
S T U D Y A C TI VI TI E S  
6. 1.  
S c h e d ul e of E v e nt s  
A Es  a n d c o nc o mita nt me dicati o ns will be rec or de d fr o m Da y 1 ( pre d ose) t hr o u g h t h e safet y 
re p orti n g peri o d (s ee Secti o n 7. 7. 1. 3 ). A n y st u d y pr ot oc ol-relat e d A E  ( defi ne d i n Secti o n  7. 7. 1. 1 ) 
as well as a n y c o nc o mi ta nt me dicati o ns gi ve n f or treat me nt of t he A E , s h o ul d be rec or de d fr o m 
t he ti me of i nf or me d c o nse nt.  
Cli nical la b orat or y assess me nts ( c he mistr y pa nel , c o m plete bl o o d c o u nt [ C B C] wit h differe ntial 
[ ma n ual differe ntial if cli nicall y i n dicat e d], t h yr oi d pa nel, a n d uri nal ysis  i n cl u di n g uri ne pr otei n 
creati ni ne rati o  (U P C ) rati o [wit h refle xi ve micr osc o p y f or a b n or mal res ults ]), p h ysi cal 
e x a m i nati o n, wei g ht, a n d E C O G perf or ma nce stat us ma y b e perf or me d wit hi n 3  da y s pri or t o 
a d mi nistrati o n of st u d y dr u g. T h e res ults fr o m all rele va nt cli nical la b orat or y assess me nts m ust 
be re vie we d pri or t o d osi n g.  
Da y  1 of C ycles  2 a n d be y o n d ma y b e dela ye d b y u p t o 4  da ys f or a d mi nistrati ve reas o ns 
(ie, h oli da ys or sc he d uli n g c o nfl icts). 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 8  of 1 3 5  
Sc he d ule of  E ve nts ta bles are pr o vi de d : 
•  Ta ble  1 : Sc he d ule of E ve nts f or C o h orts 1, 2, a n d 3 ( Mela n o ma)  
•  Ta ble  2 : Sc he d ule of E ve nts f or C o h orts 4 a n d 5 ( N S C L C)  
St u d y acti vities are liste d b y visit i n t his secti o n a n d descri pti o ns of all st u d y ass ess me nts are 
prese nte d i n Secti o n 7 . 
N ote: A n y s a m ples a n d d ata c ollecti o n f or e x pl orat or y o bjecti ves w hic h are n ot necessar y t o 
e val uate a n y pri mar y a n d sec o n dar y o bj ecti ve ca n  be disc o nti n ue d at t he dis creti o n of t he 
s p o ns or (f or e x a m ple, b ut n ot li mite d t o: P R Os, S E A -C D 4 0 P K, C D 4 0 a nti dr u g a nti b o d y [A D A ], 
Plas ma, P D fl o w, T u m or bi o ps y , Ge n ot y pi n g, Ser u m, P B M C, cell-free D N A [cf D N A]). 
6. 2.  
C o h ort s 1 , 2 , a n d 3 ( M el a n o m a) 
6. 2. 1.  
S cr e e ni n g Vi sit ( D a y s – 2 8 t o 1)  
•  I nf or me d c o ns e nt 
•  Me dical hist or y  
•  St u d y eli gi bilit y p er i ncl usi o n/e xcl usi o n criteria  
•  Hei g ht ( h ei g ht meas ur e d wit hi n t he pri or 1 2  m o nt hs ma y b e utilize d)  
•  M RI sca n of t he brai n . If a n M RI is n ot me dicall y feasi ble, a C T sca n ma y be d o ne 
i nstea d. 
•  Bl o o d sa m ple c ollecti o n f or  
o  T h yr oi d p a nel  
o  H g b A 1 c  
•  E C G  
•  Dia g n ostic -q ualit y C T a n d/ or M RI of t h e c hest, a b d o me n, a n d pel vis ( as w ell as brai n 
a n d/ or nec k if d o c u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns ), wit h I V 
c o ntrast u nless me dicall y c o ntrai n dicate d ( Secti o n  7. 2 ) 
•  P R O assess me nt, E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer 
q ualit y of life q u esti o n naire  (E O R T C Q L Q -C 3 0 ) (f or s u bjects e ntere d  i n t h e st u d y 
after e nr oll me nt f or t he i nteri m a nal ysis is c o m plete d)  
•  P R O c ollecti o ns ma y be disc o nti n ue d at t he discreti o n of s p o ns or.  
o  Pr oce d ures c o n d ucte d as part of t he s u bject ’s r o uti ne cli nical ma na ge me nt (e g, 
t h yr oi d pa n el) a n d b ef ore si g ni n g of t he i nf or m e d c o nse nt ma y be utilize d f or 
scree ni n g or baseli ne p ur p oses pr o vi de d t he pr o ce d ures met t he 
pr ot oc ol -s pecifi e d criteria a n d were perf or m e d wit hi n t he ti mefra me defi n e d 
i n t he Sc he d ule of E ve nts. 
S u bjects ma y be rescree n e d o nce . If res cree ni n g is c o n d ucte d o utsi de of t he 2 8 -da y scree ni n g 
peri o d, a ne w s u bj ect n u m ber will be assi g n e d.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 6 9  of 1 3 5  
6. 2. 2.  
B a s eli n e Vi sit  
Baseli ne e ve nts a n d assess me nts s h o ul d be perf or me d o n St u d y Da y  – 7  t o Da y  1 u nless 
ot her wise s pecifie d.   
•  P h ysical e x a mi nati o n  i ncl u di n g wei g ht 
•  E C O G perf or ma nce stat us ( A p pe n di x  A ) 
•  Vital si g ns  
•  Bl o o d sa m ple c ollecti o n f or b i o mar ker assess me nts ( wi n d o w of c ollecti o n is Da y – 7  t o 
– 1 ; Ta ble  3 ) 
•  Bl o o d or uri ne s a m ple c ollecti o n f or  ser u m or uri ne β-h C G pre g n a nc y test f or s u bjects 
of c hil d beari n g p ote ntial ( wi n d o w of c ollecti o n is Da y  – 3  t o Da y 1; Secti o n  7. 7. 6 ) 
•  Bl o o d a n d uri ne s a m ple c ollecti o n f or ( Secti o n 7. 7. 3 ): 
o  C B C wit h differe ntial  
o  C he m istr y pa nel 
o  Pr ot hr o m bi n ti me/ acti vate d partial t hr o m b o plasti n ti me/i nter nati o nal 
n or malize d rati o ( P T/ aP T T/I N R)  
o  Uri nal ysis  
•  P R O c ollecti o ns (ma y b e disc o nti n ue d at t he discreti o n of s p o ns or. ) 
•  I nitiate retrie v al of arc hi ve d t u m or bi o ps y s peci me n f or s u b missio n u p o n e nr oll me nt 
(Secti o n  7. 4 ) 
o  F or s u bjects e ntere d i n t h e st u d y after c o m pleti o n of e nr oll me nt f or t he i nteri m 
a nal ysis  i n e ac h of C o h orts 1 a n d 2, arc hi ve d t u m or s peci me n m ust ha ve b ee n 
c ollecte d fr o m t he s u bject wit hi n 3 0  da ys pri or t o a ntici pate d first d ose of 
st u d y dr u g. If t he arc hi ve d t u m or sa m ple is ol der t ha n 3 0  da ys, a b aseli ne 
t u m or bi o ps y is re q uire d.  
6. 2. 3.  
Tr e at m e nt P eri o d ( D a y 1 t o D a y 4 2)  
6. 2. 3. 1.  
D a y 1 ( ± 2 d a y s ) 
•  Pri or t o S E A -C D 4 0 a d mi nistrati o n:  
o  C o nfir m s u bject eli gi bilit y per i ncl usi o n/e xcl usi o n criteria ( C ycl e 1 o nl y)  
o  P h ysical e x a mi nati o n *  
o  Wei g ht *  
o  Vital si g ns  ( wit hi n 3 0 mi n utes pri or t o S E A -C D 4 0 a d mi nistrati o n)  
o  E C O G perf or ma nce stat us ( A p pe n di x  A ) 
o  E C G ( C ycl e 1 a n d 2 o nl y; first 30  s u bjects at U S sites acr oss C o h orts 1 , 2 , a n d 
3  perf or me d pri or t o P K sa m ple c ollecti o n at c orres p o n di n g ti me p oi nts ; see 
Ta ble  4 ) 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 0  of 1 3 5  
o  Bl o o d a n d/ or uri ne s a m ple c ollecti o n f or ( Secti o n 7. 7. 3 ): 
•  C B C wit h differe ntial *  
•  C he mistr y pa nel *  
•  T h yr oi d p a nel *  
•  P K/ a nti dr u g b o d y (A D A ) assess me nts ( Ta ble  3 ) 
•  B i o mar ker assess me nts (Secti o n 7. 4 ; Ta ble  3 ) 
•  Uri nal ysis ( C ycl e 3 a n d e ver y 3  c ycl es t hereafter) *  
•  Ser u m or uri ne β -h C G pre g n a nc y test ( o nl y s u bjects of c hil d beari n g 
p ote ntial ; n ot re q uire d if c ollecte d wit hi n 7  da ys pri or t o d osi n g)  
•  P R O assess me nt, E O R T C Q L Q -C 3 0  (f or s u bjects e ntere d i n t he st u d y after e nr oll me nt 
f or t he i nteri m a nal ysis is c o m plete d; f or C ycle 1 ( E O R T C Q L Q -C 3 0; N o n -S mall Cell 
L u n g Ca n cer S y m pt o m Assess me nt Q uesti o n nair e [N S C L C -S A Q) a n d C ycle 2 
(Patie nt Gl o bal I m pressi o n of S y m pt o m C ha n ge [P GI -C) a n d e v er y c ycle t hereafter ) 
o  P R O c ollecti o ns ma y be disc o nti n ue d at t he discreti o n of s p o ns or.  
•  Res ults fr o m cli nica l la b orat or y assess me nts m ust be re vie we d a n d m ust c o nfir m 
eli gi bilit y pri or t o st u d y dr u g i nf usi o n  
•  S E A -C D 4 0 i nf usi o n  
•  D uri n g S E A -C D 4 0 i nf usi o n  
o  Bl o o d sa m ple c ollecti o n f or P K assess me nts  ( C ycles 1 a n d 2 o nl y) 
•  1 -h o ur i ntra -d os e  
•  2 -h o urs i ntra -d ose  
•  After c o m pl eti o n of S E A -C D 4 0 a d mi nistrati o n:  
o  Vital si g ns  ( wit hi n 30  mi n utes after t he e n d of S E A-C D 4 0 i nf usi o n)  
o  Bl o o d sa m ple f or P K assess me nts ( C ycl es 1 a n d 2 o nl y; Ta ble  3 ) 
o  E C G f or t he first 30  s u bj ects acr oss C o h orts 1, 2 , a n d 3 perf or me d pri or t o P K 
sa m ple c ollecti o n at c orres p o n di n g ti me p oi nts (C ycl es 1 a n d 2 o nl y;   
* I n dic ate d ass ess me nts ma y b e c ollecte d w it hi n 3 da ys pri or t o d osi n g.  
6. 2. 3. 2.  
D a y 2 ( C y cl e s 1 a n d 2 o nl y)  
•  E C G (first 3 0  s u bjects at U S sites acr oss C o h orts 1 , 2 , a n d 3 perf or me d pri or t o P K 
sa m ple c ollecti o n at c orres p o n di n g ti me p oi nts) (Ta ble  4 ) 
•  Bl o o d sa m ple f or P K a n d bi o mar ker ass ess me nts ( Ta ble  3 ) 
6. 2. 3. 3.  
D a y  8 ( ± 2  d a y s)  
•  Bef ore pe m br oli z u ma b i nf usi o n  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 1  of 1 3 5  
o  Vital si g ns  ( wit hi n 30  mi n utes pri or t o pe m br oliz u ma b  a d mi nistrati o n)  
o  C B C wit h differe ntial  ( m a y b e c ollecte d wit hi n 3  da ys pri or t o d osi n g)  
o  C he mistr y pa nel  ( ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g)  
o  Res ults fr o m cli nical la b orat or y assess me nts m ust be re vie we d a n d m ust 
c o nfir m eli gi bilit y pri or t o st u d y dr u g i nf usi o n  
•  Pe m br oliz u ma b i nf usi o n  
•  After c o m pleti o n of p e m br ol iz u ma b a d mi nistrati o n:  
o  Vital si g ns ( wit hi n 3 0  mi n utes after t he e n d of p e m br oliz u ma b i nf usi o n) 
6. 2. 3. 4.  
D a y  2 2  (± 2  d a y s)  
•  Bef ore S E A -C D 4 0 i nf usi o n  
o  Vital si g ns  ( wit hi n 30  mi n utes pri or t o S E A -C D 4 0 a d mi nistrati o n)  
o  Bl o o d sa m ple c ollecti o n f or  
̵ 
C B C wit h differe ntial  ( m a y b e c ollecte d wit hi n 3  da ys pri or t o d osi n g)  
̵ 
C he mistr y pa nel  ( ma y be c ollecte d wit hi n 3  da ys pri or t o d osi n g)  
̵ 
Bl o o d sa m ple f or P K a n d bi o mar ker ass ess me nts ( C ycles 1 a n d 2 o nl y;  
Ta ble  3 ) 
̵ 
Ser u m or uri ne β -h C G pre g n a nc y test ( o nl y s u bjects of c hil d beari n g 
p ote ntial; n ot re q uire d if c ollecte d wit hi n 7  da ys pri or t o d osi n g)  
̵ 
Res ults fr o m cli nical la b orat or y assess me nts m ust be re v ie we d a n d m ust 
c o nfir m eli gi bilit y pri or t o st u d y dr u g i nf usi o n  
•  S E A -C D 4 0 i nf usi o n  
•  After S E A -C D 4 0 i nf usi o n  
o  Vital si g ns ( wit hi n 3 0  mi n utes after t he e n d of S E A -C D 4 0 i nf usi o n)  
o  Bl o o d sa m ple f or P K  assess me nt ( C ycl es 1 a n d 2 o nl y;  Ta ble  3 ) 
6. 2. 3. 5.  
D a y  3 6 ( – 2/ + 5  d a y s ; C y cl e  1 o nl y ) 
•  T u m or bi o ps y is re q uir e d f or s u bjects e ntere d i n t h e st u d y after c o m pleti o n of 
e nr oll me nt f or t he i nteri m a nal ysis i n C o h orts 1 a n d 2. T his bi o ps y is o pti o nal f or all 
ot her s u bjects. T he sa m e t u m or site s h o ul d be bi o psie d f or t he bas eli ne a n d 
o n -treat me nt bi o psies.  
6. 2. 4.  
R e s p o n s e A s s e s s m e nt s  
•  C T a n d/ or M RI of t he c h est, a b d o me n, a n d pel vis (as well as brai n a n d/ or n ec k if 
d o c u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns) Q 6 W  [± 3  da ys] fr o m C ycle 1 
Da y  1, re gar dless of d os e dela ys, f or t he first 2 4  wee ks . After 2 4  wee ks, i ma gi n g will 
be re q uir e d e ver y 1 2  wee ks  (±  1  wee k)  u ntil d oc u me ntati o n of P D ( c o nfir me d 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 2  of 1 3 5  
pr o gressi ve dise ase [ i C P D] per i R E CI S T),  i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y, 
st u d y ter mi nati o n b y t he s p o ns or, or deat h, w hic he ver occ urs first. Sca ns m ust be of 
dia g n ostic q ualit y a n d I V c o ntrast m ust be use d u nless me dicall y c o ntrai n di cate d. F or 
eac h asses se d lesi o n, t he sa me m o dalit y s h o ul d be use d t hr o u g h o ut t he d urati o n of t he 
st u d y. 
6. 3.  
C o h ort s 4  a n d 5  ( N S C L C) 
6. 3. 1.  
S cr e e ni n g Vi sit ( D a y s – 2 8 t o 1)  
•  I nf or me d c o ns e nt 
•  St u d y eli gi bilit y p er i ncl usi o n/e xcl usi o n criteria  
•  Me dical hist or y  
•  Hei g ht ( h ei g ht meas ur e d wit hi n t he pri or 1 2 m o nt hs ma y b e utilize d ) 
•  M RI sca n of t he brai n . If a n M RI is n ot me dicall y feasi ble, a C T sca n ma y be d o ne 
i nstea d. 
•  Bl o o d sa m ple c ollecti o n f or  
o  T h yr oi d p a nel  
o  H g b A 1 c  
•  Vital si g ns  
•  E C G  
•  Dia g n ostic -q ualit y C T a n d/ or M RI of t h e c hest  a n d a b d o me n (a nd p el vis, nec k, a n d/ or  
brai n if d oc u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns ), wit h I V c o ntrast 
u nless me dicall y c o ntrai n dicate d ( Secti o n  7. 2 ) 
6. 3. 2.  
B a s eli n e Vi sit  
Baseli ne e ve nts a n d assess me nts s h o ul d be perf or me d o n St u d y Da y  – 7  t o Da y 1 u nless 
ot her wise s pecifie d.  
•  P h ysical e x a mi nati o n  i ncl u di n g wei g ht 
•  E C O G perf or ma nce stat us ( A p pe n di x  A ) 
•  Bl o o d sa m ple c ollecti o n f or bi o mar ker assess me nts ( wi n d o w of c ollecti o n is Da y  – 7  t o 
– 1 ; Ta ble  5 ) 
•  Bl o o d or uri ne s a m ple c ollecti o n f or ser u m or uri ne β -h C G pre g n a nc y test f or s u bjects 
of c hil d beari n g p ote ntial ( wi n d o w of c ollecti o n is Da y  – 3  t o Da y 1 ; Secti o n  7. 7. 6 ) 
•  Bl o o d a n d uri ne s a m ple c ollecti o n f or ( Secti o n 7. 7. 3 ): 
o  C B C  wit h differe ntial  
o  C he mistr y pa nel  
o  P T/ aP T T/I N R  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 3  of 1 3 5  
o  Uri nal ysis  
•  I nitiate retrie v al of arc hi ve d t u m or bi o ps y s peci me n f or s u b missi o n u p o n e nr oll me nt 
(Secti o n  7. 4 ) 
•  P R O assess me nt  (f or s u bjects e ntere d i n t he st u d y after e nr oll me nt f or t he i nteri m 
a nal ysis is c o m plete d)  E O R T C Q L Q -C 3 0  
o  Patie nt Gl o bal I m pr essi o n of S y m pt o m Se verit y ( P GI -S) .  
o  P R O c ollecti o ns  ma y be disc o nti n ue d at t he discreti o n of s p o ns or.  
o  N S C L C -S A Q  
6. 3. 3.  
Tr e at m e nt P eri o d ( D a y  1 t o D a y  2 1)  
6. 3. 3. 1.  
D a y  1 ( ± 2 d a y s)  
•  Pri or t o st u d y dr u g a d mi nistrati o n:  
o  C o nfir m s u bject eli gi bilit y per i ncl usi o n/e xcl usi o n criteria ( C ycl e  1 o nl y)  
o  P h ysical e x a mi nati o n *  
o  Wei g ht *  
o  Vital si g ns  ( wit hi n 30  mi n utes pri or t o t he start of t he first st u d y dr u g 
a d mi nistrati o n ) 
o  E C O G perf or ma nce stat us ( A p pe n di x  A ) * 
o  Bl o o d a n d/ or uri ne s a m ple c ollecti o n f or ( Secti o n 7. 7. 3 ): 
•  C B C wit h differe ntial *  
•  C he mistr y pa nel *  
•  T h yr oi d p a nel (C ycle 1 a n d e ver y sec o n d c ycl e t h ereafter )*  
•  Bl o o d sa m ple  f or P K/ A D A assess me nts (C ycles 1, 2, 3, 4, 6, a n d 8 
o nl y;  Ta ble  5 ) 
•  Bl o o d sa m ples f or bi o mar ker ass ess me nts ( Secti o n 7. 4 ; Ta ble  5 ) 
•  Uri nal ysis ( C ycl e 6 a n d e ver y 6 c ycl es t hereafter) *  
•  Ser u m or uri ne β -h C G pre g n a nc y test ( o nl y s u bjects of c hil d beari n g 
p ote ntial) ( i n C ycl e 1, n ot re q uire d if perf or m e d wit hi n 3  da ys pri or t o 
visit. I n all ot her c ycles, n ot re q uire d if perf or m e d wit hi n 7  da ys pri or 
t o visit.) 
o  P R O assess me nts (f or s u bjects entere d  i n t he st ud y after e nr oll me nt f or t he 
i nteri m a nal ysis is c o m pl ete d; f or C ycle 1 [E O R T C  Q L Q -C 3 0; N S C L C -S A Q ] 
a n d C ycl e 2  [P GI -C ] a n d e ver y c ycle t hereafter) 
•  E O R T C Q L Q -C 3 0  
•  N S C L C -S A Q  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 4  of 1 3 5  
•   P GI -C  
o  Res ults fr o m cli nical la b orat or y assess me nts m ust be re vie we d a n d m ust 
c o nfir m eli gi bilit y pri or t o st u d y dr u g i nf usi o n  
•  Pe m br oliz u ma b a d mi nistrati o n  
•  Pe metre x e d a d mi nistrati o n  
•  Car b o plati n a d mi nistrati o n ( C ycl es 1 – 4  o nl y)  
•  After st u d y dr u g a d mi nistrati o n:  
o  Vital si g ns ( wit hi n 3 0  mi n utes after t he e n d of t he last st u d y dr u g 
a d mi nis trati on ) 
* I n dic ate d ass ess me nts ma y b e c ollecte d wit hi n 3  da ys pri or t o d osi n g.  
6. 3. 3. 2.  
D a y  3  
•  Bef ore S E A -C D 4 0 i nf usi o n  
o  Bl o o d sa m ple c ollecti o n f or P K / A D A a n d bi o mar ker assess me nts ( C ycl es 1 
a n d 2 o nl y; Ta bl e  5 ) 
o  Vital si g ns  ( wit hi n 30  mi n utes pri or t o S E A -C D 4 0 a d mi nistrati o n)  
•  Bl o o d sa m ple c ollecti o n f or  
o  C B C wit h differe ntial  
o  C he mistr y pa nel  
•  S E A -C D 4 0 i nf usi o n  
o  O bser vati o n is re q uir e d f oll o wi n g i nf usi o n (see Secti o n 5. 1. 1. 2 ) 
o  I ntr a-d ose a n d p ost -d ose bl o o d sa m ple c ollecti o n f or P K assess me nt ( C ycles 1 
a n d 2 o nl y; Ta bl e  5 ) 
•  After c o m pleti o n of S E A -C D 4 0 a d mi nistrati o n:  
o  Vital si g ns ( wit hi n 3 0  mi n utes after t he e n d of S E A -C D 4 0 i nf usi o n)  
6. 3. 3. 3.  
D a y 4  ( C y cl e s 1 a n d 2 o nl y) 
•  Bl o o d sa m ple c ollecti o n f or P K a n d bi o mar ker ass ess me nts ( Ta ble  5 ) 
6. 3. 3. 4.  
D a y 1 5 ( – 2/ + 5 d a y s; C y cl e 2 o nl y)  
•  O pti o nal t u m or bi o ps y. T he sa me t u m or site s h o ul d be bi o psie d f or bas eli ne a n d 
o n -treat me nt bi o psies. 
6. 3. 4.  
R e s p o n s e A s s e s s m e nt s  
•  C T a n d/ or M RI of t he c h est  a n d a b d o me n ( a n d pel vis, nec k, a n d/ or  brai n if 
d oc u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns ) Q 6 W  [± 3  da ys] fr o m C ycle  1 
Da y  1, re gar dless of d os e dela ys, f or t he first 2 4  wee ks . After 2 4  wee ks , i ma gi n g will 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 5  of 1 3 5  
be re q uir e d e ver y 1 2  wee ks  (± 1  wee k)  u ntil d oc u me ntati o n of P D (i C P D per 
i R E CI S T), i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y, st u d y t er mi nati o n b y t he 
s p o ns or, or deat h, w hic h e ver occ urs first. Sca ns m ust be of dia g n ostic q ualit y a n d I V 
co ntrast m ust be use d u nl ess me dicall y c o ntrai n dicate d. F or eac h assess e d lesi o n, t he 
sa me m o dalit y s h o ul d be use d t hr o u g h o ut t he d urati o n of t he st u d y. 
N ote: A n y s a m ples a n d d ata c ollecti o n f or e x pl orat or y o bjecti ves w hic h are n ot necessar y t o 
e val uate a n y pri mar y a n d sec o n dar y o bj ecti ve  ca n be disc o nti n ue d at t he dis creti o n of t he 
s p o ns or (f or e x a m ple, b ut n ot li mite d t o: P R Os, S E A -C D 4 0 P K, C D 4 0 A D A, Plas ma, P D fl o w, 
T u m or b i o ps y, G e n ot y pi n g, Ser u m, P B M C, cf D N A). 
6. 4.  
E n d of Tr e at m e nt Vi sit ( 3 0 t o 3 7  d a y s aft er  l a st d o s e of st u d y dr u g; all 
c o h ort s ) 
E n d of treat me nt ( E O T ) visits s h o ul d occ ur 3 0 t o 3 7  da ys after t h e last d ose of st u d y dr u g u nless 
dela ye d d ue t o a n A E. N ote: T he ti me t o E O T visit ma y be l o n ger t ha n 3 7  da ys, b ut i n n o case 
s h o ul d it be < 3 0 da ys. H o we ver, E O T e val u ati o ns m ust be perf or me d b ef ore i nitiati o n of a ne w 
a ntica ncer treat me nt. If E O T e val uati o ns are c o m plete d bef ore 3 0  da ys after t he last st u d y 
treat me nt, t he s u bject will be c o ntacte d 3 0 t o 3 7  d a ys f oll o wi n g t he l ast treat me nt t o assess f or 
A Es .  
•  E C O G perf or ma nce stat us ( A p pe n di x  A ) 
•  P h ysical e x a mi nati o n  i ncl u di n g wei g ht 
•  C B C wit h differe ntial  
•  C he mistr y pa nel  
•  T h yr oi d p a nel  
•  H g b A 1 c  
•  Vita l si g ns 
•  P T/a P T T/I N R  
•  Ser u m or uri ne β -h C G pre g n a nc y test ( o nl y s u bjects of c hil d beari n g p ote nti al) 
•  E C G  
•  Bl o o d sa m ple f or P K/ A D A assess me nts ( Secti o n  7. 4 ) 
•  Bl o o d sa m ples f or bi o mar ker ass ess me nts ( Secti o n 7. 4 ) 
•  F or s u bjects disc o nti n ui n g treat me nt d ue t o diseas e pr o gressi o n: if a t u m or bi o ps y was 
perf or me d p er sta n d ar d of care at t he ti me of dise ase pr o gressi o n, s u b mit sa m ple of 
t u m or s peci me n, if availa ble (see Secti o n  7. 4 ) 
•  C o h orts 1, 2, a n d 3:  Dia g n ostic -q u alit y C T  or M RI  of c hest, a b d o me n, a n d pel vis 
( pl us nec k a n d/ or brai n if d oc u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns), wit h 
I V c o ntrast u nless me dic all y c o ntr ai n dicate d ( n ot re q uire d if d o n e 4 wee ks pri or t o 
E O T; Secti o n  7. 2 ) 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 6  of 1 3 5  
•  C o h ort s 4 a n d 5:  Dia g n ostic -q ualit y C T or M RI of c hest a n d a b d o me n ( pl us pel vis, 
nec k, a n d/ or brai n if d oc u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns), wit h I V 
c o ntrast u nless me dicall y c o ntrai n dicate d ( n ot re q uire d if d o ne 4  wee ks pri or t o E O T; 
Sect i o n 7. 2 ) 
•  P R O Assess me nt s (f or s u bjects e nr olle d i n t he st u d y after e nr oll me nt f or t h e i nteri m 
a nal ysis is c o m plete d) . P R O c ollecti o ns ma y b e disc o nti nue d at t he discreti o n of 
s p o ns or.  
o  E O R T C Q L Q -C 3 0  
o  N S C L C -S A Q ( C o h orts 4 a n d 5 o nl y)  
o  P GI -S ( C o h orts 4 a n d 5 o nl y)  
6. 5.  
F oll o w -u p  (a ll c o h ort s)  
T he first f oll o w -u p visit will occ ur 1 2  wee ks ( ± 1  wee k) ( u nless ot her wise state d) fr o m t he m ost 
rece nt pri or res p o ns e e val uati o n. S u bse q ue nt f oll o w -u p visits will be sc he d ule d f or 1 2  wee ks 
(± 1  wee k) fr o m t he pre vi o us f oll o w -u p visit. S u bject s will be f oll o we d at t his sc he d ule u ntil 
wit h dra wal of c o nse nt, d eat h, or st u d y cl os ure, w hic he ver occ urs first.   
S u bject s w h o disc onti n ue treat me nt will  c o nti n ue t o be assesse d f or res p o nse after E O T u ntil 
c o nfir me d P D or i nitiati o n of ne w a ntica ncer treat me nt.  After S E A -C D 4 0 dr u g e x pir y , res p o ns e 
assess me nt i n t hese patie nts ma y be c o nti n ue d  per sta n dar d of care (S o C ) at t he discreti o n of t he 
i n vesti gat or. S u bject s w h o disc o nti n ue treat me nt d ue t o c o nfir me d P D or w h o ha ve i nitiate d ne w 
a ntica ncer treat me nt will n ot be assesse d f or res p o nse b ut will  be f oll o we d f or s ur vi val a n d 
s u bse q ue nt a ntica n cer treat me nt. F oll o w-u p  ma y b e c o n d ucte d wit h cli nic visits or tele p h o ne 
calls. S ur vi val f oll o w -u p ma y b e disc o nti n ue d at t he discreti o n of s p o ns or . 
T he f oll o wi n g assess me nts will be perf or me d u ntil c o nfir me d diseas e pr o gressi o n or i nitiati o n of 
s u bse q ue nt a ntica n cer treat me nt ; s u bjects will be f oll o we d f or s ur vi val a n d s u bse q ue nt 
a ntica ncer treat me nt t hereafter.  
•  P h ysical e x a mi nati o n  
•  Ser u m or uri ne β -h C G pre g n a nc y test ( o nl y s u bjects of c hil d beari n g p ote nti al). 
S u bjects ma y d o h o me pre g n a nc y tests a n d re p ort i nteri m res ults at t h e f oll o w-u p 
visits.  
o  C o h orts 1, 2, a n d 3: perf or me d m o nt hl y f or 1 2 0  d a ys  after t h e last recei ve d 
d ose of st u d y dr u g, or per l ocal re g ul ati o ns, w here a p plica ble. 
o  C o h orts 4 a n d 5: perf or m e d m o nt hl y f or 6  m o nt hs after t he l ast recei ve d d os e 
of st u d y dr u g , or per l o cal re g ul ati o ns, w here a p plica ble . 
•  Dia g n ostic -q ualit y C T a n d/ or M RI wit h I V c o ntrast u nless me dicall y c o ntrai n dicate d  
o  C o h orts 1, 2 , a n d 3: c hest, a b d o me n, a n d pel vis (as well as brai n a n d/ or n ec k 
if d oc u me nte d or s us pect e d i n v ol ve me nt i n t hese re gi ons) .  
o  C o h orts 4 a n d 5: c hest a n d a b d o me n (as w ell as pel vis, brai n a n d/ or nec k if 
d oc u me nte d or s us pecte d i n v ol ve me nt i n t hese re gi o ns) .  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 7  of 1 3 5  
•  C ollecti o n of A Es  if seri o us a n d c o nsi dere d t o be relate d t o st u d y treat me nt (e x ce pt as 
o utli ne d bel o w)  
•  Disease stat us  
•  S ur vi val stat us  
•  C ollecti o n of first s u bse q ue nt a ntica ncer treat me nt  
I n a d diti o n, t he f oll o wi n g will be perf or me d at t he first f oll o w-u p visit o nl y:  
•  C he mistr y pa nel  
•  T h yr oi d p a nel  
•  C ollecti o n of all S A Es f or 9 0  da ys after t he last d ose of st u d y tr eat me nt a n d  c ollecti o n 
of all ir A Es (e x ce pt as o utli ne d i n Secti o n 7. 7. 1. 3 ). 
6. 6.  
S ur vi v al F oll o w -u p  ( all c o h ort s) 
All s u bjects will be f oll o we d f or l o n g -t er m s ur vi v al. Assess me nt of s ur vi val ca n be d o ne vi a 
p u blic or h os pital/ me dical rec or ds or a p h o ne call. After disea s e pr o gressi o n or i nitiati o n of a 
ne w a ntica n cer treat me nt, s ur vi val f oll o w-u p will be c o n d ucte d, at t he discreti o n of t he s p o ns or, 
e ver y 1 2  w ee ks (± 1  w ee k)  f or s ur vi val stat us u ntil deat h or st u d y cl os ure, w hic he ver c o mes first. 
D uri n g t his ti me, if a ne w  a ntica ncer treat me nt is i nitiate d, i nf or mati o n re gar di n g t h e first 
a ntica ncer t hera p y s u bse q ue nt t o disc o nti n ui n g st u d y treat me nt will be c ollecte d.  
T he first s ur vi val f oll o w -u p will occ ur 1 2  wee ks (± 1  wee k ) ( u nless ot her wise state d) fr o m t he 
last ra di o gra p hic s ca n t hat de m o nstrate d disease pr o gressi o n or fr o m i nitiati o n of t he ne w 
a ntica ncer treat me nt, as a p plica ble. S u bse q ue nt s ur vi val f oll o w -u p will  be s c he d ule d f or 
1 2  wee ks  (± 1  w ee k ) ( u nl ess ot her wise state d) fr o m t he pre vi o us s urvi val f oll o w-u p . Ti mi n g of 
s u bse q ue nt s ur vi val f oll o w-u p ma y be m o difie d , or c ollecti o n will be st o p pe d, at t he discreti o n of 
s p o ns or.  
6. 7.  
E n d of F oll o w -u p  ( all c o h ort s) 
T he date t he s u bject met criteria f or st u d y dis c o nti n uati o n a n d t he reas o n f or st u d y 
disc o nti n uati o n will be rec or de d.   
7.  
S T U D Y A S S E S S M E N T S  
7. 1.  
S cr e e ni n g/ B a s eli n e A s s e s s m e nt s  
O nl y s u bjects w h o meet t he eli gi bilit y criteria s p ecifie d i n Secti o n 4  will be e nr olle d i n t his 
st u d y. 
S u bject  me dical hist or y i ncl u des a t h or o u g h re vie w of si g nifi ca nt past me dical hist or y, c urre nt 
c o n diti o ns, a n y tr eat me nt f or pri or mali g na n cies a n d res p o nse t o pri or tr eat me nt, a n d a n y 
c o nc o mita nt me dicati o ns.  
P h ysical e x a mi nati o ns s h o ul d i ncl u de assess me nts of t he f oll o wi n g b o d y p arts/s yste ms: 
a b d o me n, e xtre mities, hea d, heart, l u n gs, nec k, a n d ne ur ol o gical. Wei g ht a n d hei g ht will als o be 
meas ure d; meas ure me nt s of hei g ht o btai n e d wit hi n t he pri or 1 2 m o nt hs ma y be utilize d 
(Secti o n  7. 7. 4 ). 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 8  of 1 3 5  
Bl o o d a n d uri ne t ests will i ncl u de C B C wit h differe ntial, c he mistr y pa nel, t h yr oi d pa nel, 
H g b  A 1 c, P T/ aP T T/I N R, a n d uri nal ysis. A ser u m or uri ne β -h C G pre g na nc y test will be 
c o n d ucte d f or s u bjects of c hil d beari n g p ote ntial (S ecti o n 4. 3 ). S p ot uri ne U P C rati o calc ulati o n is 
s ufficie nt. F urt her det ails of t hese tests are pr o vi de d i n Secti o n 7. 7. 3 . 
Bl o o d sa m ples a n d t u m or bi o psies will be c ollecte d f or bi o mar ker assess me nts ( see Secti o n  7. 4 ). 
A n M RI of t h e brai n will be perf or me d at scree ni n g. If M RI is me dicall y c o ntrai n dicate d , C T 
wit h c o ntrast is a n acce pt a ble alter nati ve . 
A n E C G will be perf or me d at scree ni n g a n d at E O T f or a ll s u bjects (Secti o n 7. 7. 5 ). A d diti o nal 
o n -treat me nt E C Gs will be c ollecte d f or select s u bjects (Ta ble  4 ). 
7. 2.  
R e s p o n s e/ A ntit u m or A cti vit y A s s e s s m e nt s  
T he deter mi nati o n of a ntit u m or acti vit y will be bas e d o n o bjecti ve res p o nse assess me nts as 
defi ne d b y R E CI S T v 1. 1 (Eise n ha uer 2 0 0 9 ) a n d i R E CI S T (Se y m o ur  2 0 1 7 ) (A p pe n di x  D ). 
Tre at me nt de cisi o ns b y t he i n vesti gat or will be base d o n i R E CI S T. Cli nical res p o nse of P D, S D, 
partial res p o nse ( P R), or c o m plete res p o nse ( C R) will be deter mi ne d at eac h assess me nt.  
Res p o nse will be assesse d b y ra di o gra p hic t u m or e val uati o n  Q 6 W  (± 3  da ys) f or t he first 
2 4  wee ks  a n d e ver y 1 2  w ee ks  (± 1  w ee k)  t hereafter t hr o u g h d o c u me ntati o n of P D (i C P D per 
i R E CI S T), i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y, st u d y t er mi nati o n b y t he s p o ns or, or 
deat h, w hic he v er occ urs first . T u m or e val uati o n will  be perf or me d b y C T a n d/ or M RI sca n of t he 
c hest a n d a b d o me n (a n d pel vis  f or C o h orts 1, 2, a n d 3). I m a gi n g of t he pel vis, nec k , a n d/ or brai n  
m ust als o be o btai ne d if t here is d oc u me nt e d or s us pecte d i n v ol ve me nt i n t hese re gi o ns. If brai n 
sca ns are perf or me d, M RI is pr eferre d; h o w e ver, C T sca ns are acce pta ble if M RI is me dicall y 
c o ntrai n dicate d. Sca ns m ust be of dia g n ostic q ualit y a n d I V c o ntr ast m ust be use d u nless 
me dicall y c o ntrai n dicate d. F or eac h ass esse d lesi o n, t he sa me m o da lit y s h o ul d be use d 
t hr o u g h o ut t he d urati o n of t he st u d y. 
S u bject s’ cli nical data m ust be a vaila ble f or C R F s o urce verificati o n. C o pies of all t u m or i ma ges 
m ust be ma de  after ac q uisiti o n a n d f or war de d t o t he s p o ns or/ desi g n ee as p er t he i nstr ucti o ns 
pr o vi de d i n t he ce ntr al i ma gi n g ma n u al . 
7. 3.  
P h ar m a c o ki n eti c a n d I m m u n o g e ni cit y A s s e s s m e nt s  
Bl o o d sa m ples f or S E A -C D 4 0 P K  ( plas ma) a n d AD A  (ser u m) a nal ys es will  be c ollecte d 
t hr o u g h o ut t he st u d y per t he sa m ple c ollecti o n sc h e d ules pr o vi de d i n  Ta ble  3  a n d Ta ble  5 . 
Se nsiti ve, vali date d assa ys will be use d t o meas ure S E A -C D 4 0 c o nce ntrati o ns i n plas ma a n d 
A D A i n ser u m. P K para meters f or S E A -C D 4 0 t o be esti mate d ma y i ncl u de, b ut are n ot li mite d 
t o, A U C a n d C ma x  i n plas ma. A n y s a m ples a n d dat a c ollecti o n f or e x pl orat or y o bjecti ves w hic h 
are n ot ne cessar y t o e val uate a n y pri mar y a n d sec o n dar y o bjecti ve ca n be disc o nti n ue d at t he 
discreti o n of t he s p o ns or (f or e x a m ple, b ut n ot li mite d t o: P R Os, S E A -C D 4 0 P K, C D 4 0 A D A, 
Plas ma, P D fl o w, T u m or b i o ps y, Ge n ot y pi n g, Ser u m, P B M C, cf D N A).  
7. 4.  
P h ar m a c o d y n a mi c a n d Bi o m ar k er A s s e s s m e nt s  
Bi o mar ker assess me nts will  be perf or me d i n p eri p heral bl o o d a n d t u m or tiss ue as o utli ne d i n t his 
secti o n, Ta ble  3 , a n d T a ble  5 . E x pl orat or y, pre dicti ve, a n d pr o g n ostic bi o mar kers ass ociate d wit h 
res p o nse, resista nce, or safet y o bser vati o ns will  be m o nit ore d bef ore a n d d uri n g tr eat me nt wit h 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 7 9  of 1 3 5  
S E A -C D 4 0 . Bi o mar ker assess me nts ma y b e disc o nti n ue d at a n y p oi nt at t he s p o ns ors discreti o n. 
P har mac o d y na mic assess me nts w ill i ncl u de fl o w c yt o metr y e v al uati o n of circ ulati n g i m m u ne 
s u bsets, s uc h as b ut n ot li mite d t o B cells, T cells, m o n oc ytes, D C,  a n d N K cells . C yt o ki ne le vels 
i n peri p heral bl o o d will als o be assesse d. C orrelati ve st u dies will be c o n d ucte d t o gai n a better  
u n dersta n di n g of tar get -res p o nse relati o ns hi p, pre dicti ve/ pr o g n ostic bi o mar kers, M O A, 
resista nce me c ha nis ms, a n d p har mac o d y n a mics. O n -treat me nt bi o psies i n a s u bset of s u bjects 
will be use d t o i n vesti gat e t he M O A of S E A -C D 4 0 . 
Arc hi val t u m or s h o ul d be c ollecte d f or all s u bjects. T u m or tiss ue s h o ul d be fr o m l ocati o ns n ot 
ra diate d pri or t o bi o ps y; f or mali n fi x e d s peci me ns after t he s u bject has bee n dia g n ose d wit h 
metastatic disease are preferre d. Bi o psies o btai n e d pri or t o recei pt of a dj u va nt/ ne oa dj u va nt 
c he mot hera p y will be per mitte d if rece nt bi o ps y is n ot feasi ble.  If an arc hi val t u m or sa m ple is 
n ot a vaila ble, a fres h bas eli ne bi o ps y is re q uire d . 
After e nr oll me nt f or t he i nteri m a nal ysis is c o m plete i n C o h orts 1 a n d 2, o n -treat me nt bi o psies 
will be re q uire d  f or s u bse q ue nt s u bjects i n C o h orts 1 a n d 2. O n -treat me nt bi o psies are o pti o nal 
f or all ot her s u bjects. F or s u bjects fr o m w h om  a n o n-treat me nt bi o ps y will be c ollecte d, t he 
arc hi val bi o ps y m ust ha v e bee n c ollecte d wit hi n 3 0  da ys pri or t o t he a ntici pate d first d ose of 
st u d y dr u g; ot her wise, a fres h baseli ne bi o ps y is re q uire d. If a t u m or sa m ple is o btai ne d as part of 
sta n dar d of care d uri n g t he st u d y, a part of t hat s a m ple s h o ul d be s u b mitte d t o t he s p o ns or f or 
bi o mar ker testi n g.  Bi o psi es s h o ul d be c ollect e d b y a p pr o priatel y tr ai ne d cli nical site pers o n nel 
(e g, a n i nter ve nti o nal ra di ol o gist f or i nter nal t u m or bi o psies; trai ne d pers o n nel s uc h as a 
der mat ol o gist f or c uta n e o us t u m or bi o psies). It is str o n gl y rec o m me n de d t h at a pat h ol o gist be 
prese nt d uri n g bi o psies w he n feasi ble t o e ns ure s ufficie nt t u m or c o nte nt of t he bi o ps y l ocati o n, 
a n d t o c o nfir m t hat bi o ps y ac q uisiti o n a n d pr ocessi n g tec h ni q u es are o pti mal 
(Ferr y -G al o w  2 0 1 8 ). 
T he i m m u ne m o d ulat or y effects of S E A -C D 4 0  ma y lea d t o c ha n ges i n t he acti vati o n state of 
l ocal, t u m or-ass ociat e d, a n d peri p heral i m m u ne cells. T o c haract erize t he mali g na n c y a n d 
i m m u ne res p o nse, b i o mar ker ass ess me nts i n peri p heral bl o o d ma y i ncl u de, b ut are n ot li mite d t o, 
meas ure me nt of b aseli ne a n d dr u g -i n d uce d c ha n ges i n circ ulati n g bl o o d cell p o p ulati o ns, 
c yt o ki ne/ c he m o ki nes , ge ne e x pressi o n, c yt o ge neti cs, ge netic p ol y m or p his ms, s o matic m utati o ns 
ass ociate d wit h ca ncer, a n d circ ulati n g i m m u ne f u ncti o n a n d disease mar kers . S E A -C D 4 0  
i nteracti o ns wit h peri p heral bl o o d cells a n d tiss ues ma y als o b e m o nit ore d. Assa ys m a y i ncl u de, 
b ut are n ot li mite d t o, ne xt ge nerati o n se q u e nci n g of w h ole bl o o d, pr ote o mic met h o d ol o gies, 
i m m u n oassa ys as a mar k er of t u m or res p o nse or t hera p y resista nce, a n d m ar kers of i m m u ne 
f u ncti o n, i ncl u di n g a b u n da nce of i m m u ne cell s u bsets a n d c yt o ki nes. Met h o ds of a nal ysis ma y 
i ncl u de, b ut are n ot li mite d t o, I H C, ne xt ge nerati o n se q ue nci n g of R N A a n d D N A, a n d 
i m m u n oassa ys s uc h as fl o w c yt o m etr y a n d e nz y m e-li n ke d i m m u n os or be nt assa y (E LI S A ). T hese 
ma y pr o vi d e i nsi g ht i nt o treat me nt -relate d c h a n ges ass ociate d wit h S E A -C D 4 0 . 
T o u n dersta n d t he relati o ns hi p bet wee n t he bi ol o gical c haracteristics of t u m ors bef ore tr eat me nt 
a n d s u bject o utc o mes, tiss ue fr o m pre -treat me nt (arc hi val or fres hl y o btai ne d s peci me ns) a n d 
o n -treat me nt t u m or bi o psies (f or a s u bs et of s u bjects) will be e x a mi ne d. If tiss ue is a vaila ble 
fr o m a sta n dar d cli nical c are bi o ps y c ollecte d aft er e nr oll me nt, it ma y als o b e e x a mi ne d. Bi o psies 
will be a ssesse d f or s p ecific p har mac o d y na mic, pre dicti ve, a n d pr o g n ostic bi o mar kers i n t he 
t u m or. T o c haracteriz e t h e mali g n a nc y a n d res p o nse t o st u d y treat me nt, b i o mar ker assess me nts 
i n t u m or bi os peci me ns ma y i n cl u de, b ut are n ot li mite d t o, meas ure me nts of S E A -C D 4 0  a n d its 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 0  of 1 3 5  
p ote ntial meta b olites as well as c haract erizati o n of t he t u m or micr oe n vir o n me nt  i ncl u di n g P D-L 1 
e x pressi o n , dr u g tar get(s), t u m or s u bt y pi n g, pr ofili n g of s o matic m utati o ns a n d/ or ge ne 
e x pressi o n . Assa ys ma y i ncl u de, b ut are n ot li mite d t o, I H C a n d n e xt ge nerati o n se q ue nci n g of 
R N A a n d D N A.  
7. 5.  
Bi o s p e ci m e n R e p o sit or y  
I n t he U S o nl y, f or s u bjects w h o pr o vi de a d diti o n al c o nse nt, re m ai ni n g d e-i de ntifie d u n use d 
bl o o d a n d/ or tiss ue will be retai ne d b y Sea ge n  a n d use d f or f ut ure res earc h, i ncl u di n g b ut n ot 
li mite d t o t he e val uati o n of tar gets f or n o vel t hera pe utic a ge nts, t he bi ol o g y of A D C  se nsiti vit y 
a n d resista nce mec h a nis ms, a n d t he i de ntificati o n of bi o mar kers of A D Cs. Bl o o d a n d tiss ue 
sa m ples d o nate d f or f ut ure res earc h will be ret ai ne d f or a p eri o d of u p t o 2 5 years. If a d diti o nal 
c o nse nt is n ot pr o vi de d, a n y re mai ni n g bi ol o gi cal sa m ples will be destr o ye d after t he st u d y has 
bee n c o m plete d a n d all a p plica ble re g ulat or y o bli gati o ns ha v e bee n m et.  
7. 6.  
P ati e nt -R e p ort e d O ut c o m e s A s s e s s m e nt s  
After e nr oll me nt f or t he i nteri m a nal ysis is c o m plete  i n a c o h ort, P R Os will be a d mi nistere d t o 
all s u bse q ue nt su bjects  i n t hat c o h ort t o c haracterize t he cli nical pr ofile of S E A-C D 4 0 m ore f ull y 
i n c o m bi nati o n wit h ot her treatme nts . P R Os will be a d mi nistere d at ti me p oi nts s pecifie d i n 
Secti o n 6 , Ta ble  1 , a n d T a ble  2 . P R O c ollecti o ns ma y b e disc o nti n ue d at t he discreti o n of 
s p o ns or.  
P R O  data  will be o btai ne d t hr o u g h use of t he f oll o wi n g i nstr u me nts:  
•  All c o h orts: E O R T C Q L Q -C 3 0  
•  C o h orts 4  a n d 5  o nl y ( N S C L C):  N S C L C -S A Q, P GI -S , a n d P GI-C   
T he E O R T C Q L Q -C 3 0 is a vali date d, relia ble self -re p orte d m eas ure (Aar o ns o n 1 9 9 3 ) 
(Fitzsi m m o ns 1 9 9 9 ) (see A p pe n di x  F ). It c o nsists of 3 0 q uesti o ns t hat assess fi ve as pects of 
patie nt f u ncti o ni n g ( p h ysical, e m oti o nal, r ole, c o g niti ve, a n d s ocial), t hree s y m pt o m scales 
(fati g ue, na us ea a n d v o miti n g, pai n), gl o bal healt h/ Q o L, a n d 6  si n gle ite ms ( d ys p n ea, i ns o m nia, 
a p petite l oss, c o nsti pati o n, diarr hea, a n d fi na n cial diffic ulties) wit h a recall peri o d of t he pre vi o us 
wee k. T he E O R T C Q L Q -C 3 0 m o d ule ta kes a p pr o xi matel y 1 0  mi n utes t o c o m plete. Eac h sc ore is 
tra nsf or me d o nt o a 0 t o 1 0 0-p oi nt scale. I n t he 5  f u ncti o nal scales a n d t h e gl o bal healt h stat us 
scale, a hi g h sc ore me a ns a “hi g h le vel of f u ncti o ni n g or gl o bal healt h stat us .” F or t he s y m pt o m 
scales a n d si n gle ite ms, a hi g her s c ore i m plies a “ hi g h le vel of s y m pt o ms or pr o ble ms .” 
Pre vi o usl y p u blis he d mi ni mall y i m p orta nt differe n ces will be use d t o i de ntif y mea ni n gf ul 
c ha n ges fr o m baseli ne i n eac h tr eat me nt gr o u p o n t he disease a n d treat me nt -relate d s y m pt o m 
scales (Os o b a 1 9 9 8 ). 
T he N S C L C -S A Q w as d e vel o pe d t o assess s y m pt o ms of N S C L C i n cli nical tr ials i n ali g n me nt 
wit h F D A rec o m me n dati o ns a n d i ncl u de d i n p ut fr o m s u bjects wit h N S C L C (Mc Carrier 2 0 1 6 ), 
see A p pe n di x  G ). T he N S C L C -S A Q q u esti o n nair e is a 7 -ite m P R O i nstr u me nt t hat assesses 
i nte nsit y of c o u g h a n d pai n s y m pt o ms a n d fre q u e n c y of d ys p nea, fati g ue, a n d a p petite. T he 
7  q uesti o ns of t his i nstr u me nt, w hic h uses a 7 -d a y recall peri o d, are o n a ver bal rati n g scal e fr o m 
eit her “ N o <s y m pt o m > at all” (a sc ore of 0) t o “ Ver y se vere <s y m pt o m >” (a sc ore of 4) f or 
i nte nsit y q u esti o ns or fr o m “ Ne ver” (a sc ore of 0) t o “ Al wa ys” (a sc ore of 4) f or fre q ue n c y 
q uesti o ns ( F D A C O A). N S C L C -S A Q will be a d mi nistere d at baseli ne , o n Da y 1 of  eac h 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 1  of 1 3 5  
treat me nt c ycl e, a n d at E O T t o s u bjects e nr olle d i n C o h orts 4 a n d 5  after c o m pleti o n of 
e nr oll me nt f or t he i nteri m a nal ysis. S y m pt o m d o mai ns a n d t otal sc ores will be calc ulate d 
acc or di n g t o t he s c ori n g ma n ual a n d will be descri be d i n s u bst u d y pr ot oc ols . 
T he P GI -S a n d t he P GI -C are si n gle-q uesti o n  5 -p oi nt  scales use d t o assess ge n eral s y m pt o m 
se verit y a n d s y m pt o m c h a n ge o ver ti me (see A p pe n di x  H  a n d A p pe n di x  I for e x a m ples).  
S u bjects will use a n a p plicati o n o n a s mart p h o ne or ta blet de vice t o c o m plete P R O assess me nts. 
S u bjects will be pr o vi de d a de vice or  ma y use t heir o w n de vice if a p pr o priate. I nstr u cti o ns a n d 
trai ni n g o n c o m pleti n g t h e P R O will be pr o vi de d t o t he s u bject b y t h e site staff. T he d ata will be 
tra ns mitte d via a pres p ecifie d tra ns missi o n met h o d (e g, cell ular or wifi net w or ks) a ut o maticall y 
after e ntr y t o a ce ntralize d data base at t he  P R O ve n d or. T he data ca n b e accesse d b y a p pr o priate 
st u d y pers o n n el sec urel y via t he i nter net. 
T he P R O i nstr u me nts will be tra nslate d as a p pr o priate i n t he c o u ntr y la n g ua ge(s) a n d as feasi ble 
i n t he l ocal la n g ua ge. T o e ns ure i nstr u me nt vali dit y a n d t h at data sta n dar ds meet healt h a ut h orit y 
re q uire me nts, q uesti o n naires will be sc he d ule d t o be c o m plete d b y t he s u bj ect d uri n g a cli nic 
visit bef ore t he s u bject recei ves a n y i nf or mati o n o n disease stat us a n d pri or t o a n y n o n -P R O 
assess me nts a n d t he a d mi nistrati o n of st u d y treat me nt.  
7. 7.  
S af et y A s s e s s m e nt s  
T he assess me nt of s afet y d uri n g t he c o urse of t his st u d y will c o nsist of t he s ur veilla nce a n d 
rec or di n g of A Es  i ncl u di n g S A Es, r ec or di n g of c o nc o mita nt me dicati o n, a n d meas ure me nts of 
pr ot oc ol -s pecifi e d p h ysi cal e x a mi nati o n fi n di n gs , vital si g ns, pr ot oc ol-s pecifie d la b orat or y tests, 
E C O G stat us, E C Gs, a n d pre g na nc y t esti n g .  
Safet y will be m o nit ore d o ver t he c o urse of t he st u d y b y a n S M C as des cri b e d i n Secti o n 3. 1. 7  
a n d Secti o n 9. 3. 1 0 . 
7. 7. 1.  
A d v er s e E v e nt s  
7. 7. 1. 1.  
D efi niti o n s  
A d verse E ve nt  
Acc or di n g t o t he I nt er nati o nal C o u ncil f or Har m o nisati o n (I C H) E 2 A g ui d eli ne Defi niti o ns a n d 
Sta n dar ds f or E x pe dite d Re p orti n g, a n d 2 1 C F R 3 1 2. 3 2, i n vesti gati o nal ne w dr u g (I N D) Safet y 
Re p orti n g, a n A E is a n y u nt o war d me dical o cc urre nce i n a s u bject or cli nical i n vesti gati o nal 
s u bject a d mi nistere d a m e dici nal pr o d uct a n d w hic h d oes n ot necessaril y h a ve a ca usal 
relati o ns hi p wit h t his treat me nt. 
T he  foll o wi n g  i nf or mati o n s h o ul d be c o nsi dere d w he n deter mi ni n g w het her or n ot t o rec or d a 
test res ult, me dical c o n diti o n, or ot her i ncide nt o n t he A Es C R F:  
•  Fr o m t he ti me of i nf or m e d c o nse nt t hr o u g h t he da y pri or t o st u d y Da y 1 , o nl y st u d y 
pr ot oc ol -relat e d A Es  s h o ul d be rec or de d. A pr ot oc ol-relat e d A E is defi ne d as a n 
u nt o war d me dical e ve nt occ urri n g as a res ult of a pr ot oc ol ma n date d pr o c e d ure.  
•  All me dical c o n diti o ns prese nt or o n g oi n g pre d os e o n st u d y Da y 1  t h at i ncrease i n 
N CI  C T C A E gra de s h o ul d be rec or de d.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 2  of 1 3 5  
•  Me dical c o n diti o ns prese nt or o n g oi n g pre d ose o n st u d y Da y 1  t h at w orse n i n se verit y, 
i ncreas e i n fre q u e nc y, b ec o me relat e d t o st u dy dr u g, or w orse n i n a n y ot h er wa y b ut d o 
n ot meet t he t hres h ol d f or i ncrease i n N CI C T C A E gra de s h o ul d be rec or de d.  
•  All A Es  (re gar dless of relati o ns hi p t o st u d y dr u g) s h o ul d be rec or de d fr o m st u d y 
Da y  1  ( d uri n g a n d p ost d ose) t hr o u g h t he e n d of t he safet y re p orti n g peri o d (see 
Secti o n  7. 7. 1. 3 ). C o m plicati o ns t hat occ ur i n ass ociati o n wit h a n y pr oce d ure (e g, 
bi o ps y) s h o ul d be rec or de d as A Es  w het her or n ot t he pr oce d ure was pr ot o c ol 
ma n date d.  
•  I n ge neral, a n a b n or mal la b orat or y v al ue s h o ul d n ot be rec or de d as a n A E u nless it is 
ass ociate d wit h cli nical si g ns or s y m pt o ms, re q uir es a n i nter ve nti o n, res ults i n a S A E, 
or res ults i n st u d y ter mi n ati o n or i nterr u pti o n/ disc o nti n uati o n of st u d y treat me nt. 
W he n rec or di n g a n A E res ulti n g fr o m a  l a b orat or y a b n or malit y, t he res ulti n g me dical 
c o n diti o n rat her t ha n t he a b n or malit y itself s h o ul d be rec or de d ( e g, rec or d “a ne mia” 
rat her t ha n “l o w he m o gl o bi n”). 
Seri o us A d verse E ve nts  
A n A E s h o ul d be classifi e d as a n S A E if it meets o ne of t he f oll o wi n g criteria:  
Fatal:  
A E res ulte d i n deat h  
Lif e t hreat e ni n g:  
T he A Es  place d t he s u bject at i m me diate ris k of deat h. T his 
classificati o n d oes n ot a p pl y t o a n A E t hat h y p ot h eticall y mi g ht 
ca use deat h if it were m ore se vere.  
H os pitalizati o n:  
T he A E res ulte d i n h os pitalizati o n or pr ol o n ge d a n e xisti n g 
i n patie nt h os pitalizati o n. H os pitalizati o ns f or electi ve me dical or 
s ur gic al pr oce d ures or treat me nts pla n ne d bef ore t he si g ni n g of 
i nf or me d c o nse nt i n t he st u d y or r o uti ne c hec k-u ps are n ot S A Es b y 
t his criteri o n. A d missi o n t o a palliati ve u nit or h os pice care facilit y 
is n ot c o nsi dere d t o be a h os pitalizati o n. H os pitalizati o ns or 
pr ol o n ge d h os pitalizati o ns f or sc he d ule d t h era p y of t he u n derl yi n g 
ca ncer or st u d y tar get disease nee d n ot be ca pt ure d as S A Es.  
Disa bli n g/i nca p acitati n g:  A n A E t hat res ulte d i n a persiste nt or si g nifi ca nt i nca pacit y or 
s u bsta ntial disr u pti o n of t he s u bject’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
C o n ge nital a n o mal y or 
birt h defect:  
A n a d vers e o utc o me i n a c hil d or fet us of a s u bject e x p ose d t o t he 
m olec ule or st u d y treat m e nt re gi me n bef ore c o nce pti o n or d uri n g 
pre g na nc y.  
Me dicall y si g nifica nt:  
T he A E di d n ot meet a n y of t he a b o ve criteria b ut  c o ul d ha ve 
je o par dize d t he s u bject a n d mi g ht ha ve re q uire d me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve or 
i n v ol ves s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 3  of 1 3 5  
i nfecti o us a ge nt. P ote ntial dr u g -i n d u ce d li ver i nj ur y (DI LI ) als o is 
c o nsi dere d a me dical l y si g nifica nt e ve nt (s ee Secti o n 7. 7. 1. 2  f or t he 
defi niti o n of p ote ntial DI LI) . 
A d verse E ve nt Se verit y  
A E se verit y s h o ul d be gra de d usi n g t he N CI  C T C A E , v 5. 0 . T hese criteria are pr o vi d e d i n t he 
st u d y ma n ual. 
A E se verit y a n d s eri o us n ess are assesse d i n de pe n de ntl y. ‘ Se verit y’ c h aract erizes t he i nte nsit y of 
a n A E. ‘ Seri o us’ is a re g ulat or y d efi niti o n a n d ser ves as a g ui de t o t he s p o ns or f or defi ni n g 
re g ulat or y re p orti n g o bli gati o ns (s ee defi niti o n f or S A Es, a b o ve).  
Rel ati o ns hi p of t he A d verse E ve nt t o St u d y Tre at me nt  
T he relati o ns hi p of eac h A E t o eac h st u d y treat me nt ( S E A -C D 4 0 , pe m br oliz u ma b, pe metre x e d, 
car b o plati n ) s h o ul d be e v al uate d b y t he i n vesti gat or usi n g t he f oll o wi n g criteria: 
Relate d:  
T here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E, s uc h 
as:  
•  
A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be 
str o n gl y ass ociate d wit h dr u g e x p os ure ( e g, a n gi oe de ma, he patic i nj ur y, 
Ste ve ns -J o h ns o n S y n dr o me) 
•  
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d 
wit h dr u g e x p os ure, b ut is ot her wise u nc o m m o n i n t he p o p ulati o n 
e x p ose d t o t he dr u g ( e g, te n d o n r u pt ure) 
U nre late d: 
A n ot her ca use of t he A E is m ore pla usi ble ( e g, d ue t o u n derl yi n g disease or occ urs 
c o m m o nl y i n t he st u d y p o p ulati o n), or a te m p oral se q ue nce ca n n ot be esta blis he d wit h 
t he o nset of t he A E a n d a d mi nistrati o n of t he st u d y treat me nt, or a ca usal relatio ns hi p 
is c o nsi dere d bi ol o gicall y i m pla usi ble 
7. 7. 1. 2.  
Pr o c e d ur e s f or Eli citi n g a n d R e c or di n g A d v er s e E v e nt s  
I n v esti gat or a n d st u d y pers o n nel will re p ort all A Es  a n d S A Es w het her elicite d d uri n g s u bject 
q uesti o ni n g, disc o vere d d uri n g p h ysic al e xa mi nati o n, la b orat o r y testi n g a n d/ or ot her mea ns b y 
rec or di n g t he m o n t he C R F a n d/ or S A E f or m, as a p pr o priate. 
Eliciti n g A d verse E ve nts  
A n o pe n -e n d e d or n o n -directe d met h o d of q uesti o ni n g s h o ul d be use d at eac h st u d y visit t o elicit 
t he re p orti n g of A Es . 
Rec or di n g A d verse E v e nts 
T he f oll o wi n g i nf or mati o n s h o ul d be rec or de d o n t he A Es C R F:  
•  Descri pti o n i ncl u di n g o nset a n d res ol uti o n dates  
•  W het her it met S A E criteria  
•  Se verit y  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 4  of 1 3 5  
•  Relati o ns hi p t o st u d y tr eat me nt or ot her ca usalit y  
•  O utc o me  
Di a g n osis vs. Si g ns or S y m pt o ms  
I n ge neral, t he use of a u nif yi n g dia g n osis is preferre d t o t he listi n g o ut of i n di vi d ual s y m pt o ms. 
Gr o u pi n g of s y m pt o ms i nt o a dia g n osis s h o ul d o nl y be d o n e if eac h c o m p o ne nt si g n a n d/ or 
s y m pt o m is a me dicall y c o nfir me d c o m p o ne nt of a dia g n osis as e vi de nce d b y sta n dar d me dical 
te xt b o o ks. If a n y as p ect of a si g n or s y m pt o m d oes n ot fit i nt o a classic patter n of t he dia g n osis, 
re p ort t he i n di vi d ual s y m pt o m as a se parate A E . 
I m p ort a nt e x ce pti o ns f or t his st u d y are a d verse reacti o ns ass ociate d wit h t he i nf usi on of st u d y 
dr u g.  F or I H Rs, rec or d t h e N CI C T C A E ter ms of ‘c yt o ki ne release s y n dr o m e,’ ‘i nf usi o n r elate d 
reacti o n,’ ‘aller gic or h y p erse nsiti vit y reacti o n,’ or ‘a na p h yla xis’ wit h a n o verall le vel of s e verit y 
( per N CI C T C A E; se e Ta ble 1 1 ). I n a d diti o n, rec or d eac h si g n or s y m pt o m of t he reacti o n as a n 
i n di vi d ual A E. If m ulti ple si g ns or s y m pt o ms occ ur wit h a gi ve n i nf usi o n-relate d e v e nt, eac h 
si g n or s y m pt o m s h o ul d be rec or de d se p aratel y wit h its le vel of se verit y. 
Rec or di n g Seri o us A d verse E ve nts  
F or S A Es, rec or d t he e ve nt(s) o n b ot h t he C R F a n d a n S A E f or m.  
T he f oll o wi n g s h o ul d be c o nsi dere d w he n rec or di n g S A Es:  
•  Deat h is a n o utc o me of a n e ve nt. T he  e v e nt t hat res ulte d i n t he deat h s h o ul d be 
rec or de d a n d re p orte d o n b ot h a n S A E f or m a n d C R F. 
•  F or h os pitalizati o ns, s ur gical, or dia g n ostic pr oce d ures, t he ill ness lea di n g t o t he 
s ur gic al or dia g n ostic pr o ce d ure s h o ul d b e rec or de d as t he S A E, n ot t he pr oc e d ure 
itself. T he pr oce d ure s h o ul d be ca pt ure d i n t he n arrati ve as part of t he acti o n ta ke n i n 
res p o nse t o t he ill ness. 
Pr o g ressi o n of U n derl yi n g M ali g n a nc y  
Si nce pr o gressi o n of u n d erl yi n g mali g na n c y is bei n g ass esse d as a n efficac y varia ble, it s h o ul d 
n ot  be re p orte d as a n A E or S A E.  T he ter ms “ Disease Pr o gressi o n ,” “ Pr o gressi o n of Disease , ” or 
“ Mali g n a nt disease pr o gressi o n” a n d ot her si milar ter ms s h o ul d n ot be use d t o descri be a n A E or 
S A E.  H o we ver, cli nical s y m pt o ms of pr o gressi o n ma y b e re p orte d as A E s or S A Es if t he 
s y m pt o m ca n n ot be d eter mi ne d as e x cl usi vel y d ue t o pr o gressi o n of t he u n derl yi n g mali g na n c y 
or d oes n ot fit t he e x pecte d patter n of pr o gressi o n f or t he diseas e u n der st u d y. I n a d diti o n, 
c o m plicati o ns fr o m pr o gressi o n of t he u n derl yi n g mali g na n c y s h o ul d be re p orte d as A Es  or 
S A Es.  
Pre g n a nc y  
N otific ati o n t o Dr u g S afety  
C o m plete a Pre g na nc y R e p ort F or m f or all pre g n a ncies , i ncl u di n g a n y pre g na ncies t hat occ ur i n 
t he part ner of a st u d y s u bject w h o ca n get s o me o n e pre g na nt , t hat o cc ur fr o m t he ti me of first 
st u d y dr u g d ose u ntil t he e n d of t he f oll o wi n g ti me peri o ds, as a p plica bl e: 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 5  of 1 3 5  
•  C o h orts 1,  2, a n d 3:  
o  S u bject s of c hil d beari n g p ote ntial, as defi ne d i n S ecti o n 4. 3 : 1 2 0 da y s after t he 
last d ose of st u d y dr u g  or 3 0  da ys after t h e last d ose of st u d y dr u g if t he 
s u bject i nitiates a ne w a ntica ncer t h era p y 
o  S u bject s w h o ca n get s o me o ne pre g n a nt , as defi n e d i n Secti o n 4. 3 : u ntil  t he 
last d ose of st u d y dr u g 
•  C o h orts 4 a n d 5:  
o  All s u bjects: 6 m o nt hs  after t he last d ose of st u d y dr u g  
O nl y re p ort pre g na ncies t hat occ ur i n a s u bj ect’s part ner if t he esti mate d dat e of c o nce pti o n is 
after t he s u bject’s first st u d y dr u g d os e. E mail or fa x t o t he s p o ns or’s Dr u g Safet y De part me nt 
wit hi n 2 4  h o urs of bec o mi n g a w are of a pre g na n c y. All pre g na n cies will be m o nit ore d f or t he 
f ull d urati o n; all peri natal a n d ne o natal o utc o mes s h o ul d be re p orte d. I nfa nts s h o ul d be f oll o we d 
f or a mi ni m u m of 8 wee ks.  
C ollecti o n of D at a o n t he C R F  
All pre g n a ncies (as des cri be d a b o ve) will als o be rec or de d o n t h e A Es C R F.  
A b orti o n, w het her acci d e ntal, t hera pe utic, or s p o nta ne o us, s h o ul d be re p orte d as a n S A E. 
C o n ge nital a n o malies or birt h defects, as d efi ne d b y t he ‘s eri o us’ criteri o n a b o ve (see defi niti o ns 
Secti o n 7. 7. 1. 1 ) s h o ul d be re p ort e d as S A Es. 
P ote nti al Dr u g -I n d uce d Li ver I nj ur y 
H y’s La w ca n be us e d t o esti mate se verit y a n d t he li keli h o o d t hat a st u d y dr u g ma y ca use a n 
i ncreas e d i nci de nce of se vere he p at ot o xicit y. 
T he a bse n ce of he pat ot o xicit y i n cli nical trials pr o vi des a li mite d pre dicti ve val ue f or p ote ntial 
DI LI i n t he cli nical s etti n g(s) bei n g st u die d. H o we ver, fi n di n g 1  H y’s La w case i n cli nical trials 
is o mi n o us; fi n di n g 2 cas es is hi g hl y pre dicti ve of a p ote ntial f or se v ere DI LI.  
Defi niti o n  
Briefl y, p ote ntial H y’s La w cas es i ncl u de t he f oll o wi n g 3  c o m p o n e nts:  
1.  A mi n otra nsferase ( A L T a n d/ or A S T) ele vati o n > 3 x U L N  
A N D  
2.  T otal bilir u bi n > 2 x U L N, wit h o ut i nitial fi n di n gs of c h olestasis ( ie, el e vate d ser u m 
al kali ne p h os p hatase), 
A N D  
3.  N o ot her i m me diatel y a p pare nt p ossi ble ca us es of a mi n otra nsferase el e vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre -e xisti n g c hr o nic or 
ac ute li ver dise ase, or t h e a d mi nistrati o n of ot her dr u g(s) k n o w n t o be h e pat ot o xic.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 6  of 1 3 5  
Re p orti n g Re q uire m e nts  
A n y p ote nti al H y’s L a w c ase s h o ul d be h a n dle d as a n  S A E  a n d re p orte d pr o m ptl y t o t he 
sp o ns or . 
Re p orti n g s h o ul d i ncl u de all a vaila ble i nf or mati o n a n d s h o ul d i nitiate cl ose f oll o w -u p u ntil 
c o m plete res ol uti o n of t h e pr o ble m a n d c o m pleti o n of all atte m pts t o o btai n s u p ple me ntar y data. 
F oll o w -u p f or A b n or m al L a b or at ory Res ults S u g gesti n g P ote nti al DI LI  
I n ge neral, a n i ncreas e of ser u m A L T or A S T t o > 3 x  U L N s h o ul d be f oll o we d b y re p eat testi n g 
wit hi n 4 8 t o 7 2  h o urs of ser u m A L T, A S T, al kali ne p h os p hatase, a n d t otal bilir u bi n, t o c o nfir m 
t he a b n or malities a n d t o deter mi ne w het h er t he y are w ors e ni n g. 
A p pr o priate me di cal assess me nt s h o ul d be i nitiate d t o i n vesti gate p ote ntial c o nf o u n di n g fact ors 
a n d alter nati ve ca uses o f he pat ot o xicit y. D uri n g t his i n vesti gati o n, c o nsi der wit h h ol di n g st u d y 
dr u g.  
Re gi o nal or c o u ntr y -s pecific g ui deli nes s h o ul d be f oll o we d. A d diti o nal i nf or mati o n is pr o vi de d 
i n t he F D A G ui da n ce f or I n d ustr y, Dr u g-I n d u ce d Li ver I nj ur y: Pre mar keti n g Cli nical 
E val uati o n , 2 0 0 9.  
7. 7. 1. 3.  
R e p orti n g P eri o d s f or A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
T he safet y re p orti n g peri o d f or all A Es  is fr o m st u d y Da y 1 ( pre d ose) t hr o u g h t he E O T visit or 
3 0  da ys after t h e last st u d y treat me nt, w hic he v er is later. H o we v er, all st u d y pr ot oc ol -relat e d 
A Es  are t o be rec or de d fr o m t he ti me of i nf or me d c o nse nt. T he re p orti n g peri o d f or S A Es is fr o m 
st u d y Da y 1 ( pre d os e) t hr o u g h 9 0 da ys after t he last st u d y treat me nt, or 3 0  da ys f oll o wi n g 
cessati o n of st u d y treat m e nt if t he s u bject i nitiate s a ne w a ntica ncer t hera p y. All S A Es t hat occ ur 
after t he s afet y re p orti n g peri o d a n d are c o nsi dere d st u d y treat me nt -rel ate d i n t he o pi ni o n of t he 
i n vesti gat or s h o ul d als o be re p ort e d t o t he s p o ns or. 
A d diti o nall y, be y o n d t he safet y re p orti n g p eri o d, s u bjects i n disease-pr o gressi o n f oll o w -u p after 
disc o nti n ui n g st u d y tr eat me nt will be assesse d at t he first f oll o w -u p visit f or p ote ntial ir A Es.  
S A Es will be f oll o we d u ntil si g nifica nt c ha n ges ret ur n t o baseli ne, t he e ve nt sta bilizes 
(rec o v eri n g/res ol vi n g) or is n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or, or t he 
s u bject dies or wit h dra ws c o nse nt. All n o n -seri o us A Es  will be f oll o we d t hr o u g h t he s afet y 
re p orti n g peri o d. Cert ai n n o n-seri o us A Es  of i nterest ma y b e f oll o we d u ntil res ol uti o n, ret ur n t o 
baseli ne, or st u d y cl os ure.  
7. 7. 1. 4.  
S eri o u s A d v er s e E v e nt s R e q uir e I m m e di at e R e p orti n g  
Wit hi n 2 4  h o urs of o bser vi n g or lear ni n g of a n S A E, i n vesti gat ors are t o r e p ort t he e ve nt t o t he 
s p o ns or, re gar dless of t he relati o ns hi p of t he e ve nt t o t he st u d y treat me nt re gi me n. 
F or i nitial S A E re p orts, a vaila ble cas e details are t o be rec or de d o n a n S A E f or m. At a mi ni m u m, 
t he f oll o wi n g s h o ul d be i ncl u de d: 
•  S u bject  n u m ber  
•  Date of e v e nt o nset  
•  Descri pti o n of t he e v e nt  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 7  of 1 3 5  
•  St u d y treat me nt, if k n o w n  
•  I n v esti gat or ca us alit y assess me nt 
T he c o m plete d S A E f or m is t o be e maile d or fa x e d t o t he s p o ns or’s Dr u g Safet y De part me nt 
wit hi n 2 4  h o urs (see e mail or fa x n u m ber s pecifie d o n t he S A E re p ort f or m)  
Rele va nt f oll o w -u p i nf or mati o n is t o be s u b mitte d t o t he s p o ns or as s o o n as it bec o mes a vaila ble.  
7. 7. 1. 5.  
E v e nt s of Cli ni c al I nt er e st  
Selecte d n o n -seri o us a n d seri o us A Es  are als o k n o w n as e ve nts of cli nical i nterest ( E CIs ) a n d 
m ust be re p orte d t o t he sp o ns or.  
E CIs are t o be re p orte d t o t he s p o ns or irres pecti ve of re g ul at or y seri o us ness criteria or ca usalit y 
wit hi n 2 4  h o urs ( Secti o n 7. 7. 1. 4 ).  
E CIs  f or t his p ur p ose i ncl u de:  
•  A n o ver d ose of st u d y pr o d uct, as defi ne d i n Secti o n 5. 5. 3  (S E A -C D 4 0  a n d 
pe m br oliz u ma b) t hat is n ot ass ociate d wit h cli nical s y m pt o ms or a b n or mal la b orat or y 
res ults. 
•  A n ele vate d A S T or A L T la b val ue t hat is ≥3 x U L N, a n d a n el e vate d t otal bilir u bi n 
la b val ue t hat is ≥2 x U L N a n d, at t he sa me ti me, a n al kal i ne p h os p hatas e l a b val ue 
t hat is < 2 x U L N, as deter mi ne d b y wa y of pr ot oc ol -s pecifie d la b orat or y testi n g, or 
u nsc he d ule d la b orat or y t esti n g.  
A L T a n d A S T  criteria are base d u p o n a vaila ble re g ulat or y g ui da nce d o c u me nts. T he p ur p ose of 
t he criteria is t o s pecif y a t hres h ol d of a b n or mal h e patic tests t hat ma y re q uire a n a d diti o nal 
e val uati o n f or a n u n derl yi n g eti ol o g y. T he trial sit e g ui d a nce f or ass ess me nt a n d f oll o w -u p of 
t hese criteri a ca n b e f o u n d i n t he I n v esti gat or Trial File Bi n der ( or e q ui vale nt). 
7. 7. 1. 6.  
S p o n s or S af et y R e p orti n g t o R e g ul at or y A ut h oriti e s  
I n v esti gat ors are re q uir e d t o re p ort all S A Es t o t he s p o ns or (see Secti o n 7. 7. 1. 4 ). T he s p o ns or 
will re p ort all S A Es, i ncl u di n g s us pect e d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) t o 
re g ulat or y a ut h orities as re q uire d p er l ocal le gislati o n or re g ulat or y re p orti n g re q uire me nts. 
7. 7. 2.  
Vit al Si g n s  
Vital si g ns meas ur es are t o i ncl u de heart rate, res pirati o ns, bl o o d press ure, a n d te m perat ure. O n 
st u d y treat me nt d osi n g d a ys f or eac h st u d y dr u g, vital si g ns will be meas ure d a n d rec or de d  
wit hi n 3 0  mi n utes pri or  t o t he start of st u d y dr u g a d mi nistrati o n a n d wit hi n 3 0  mi n utes after 
c o m pleti o n of st u d y dr u g a d mi nistrati o n. If m ulti ple dr u gs are b ei n g a d mi nistere d o n t he sa me 
da y, a si n gle set of vital si g ns, bef ore t he first dr u g a n d after t he last dr u g, is acce pta ble. I n t he 
e ve nt of a n  I H R, vital si g ns will be m o nit ore d m ore fre q u e ntl y as descri be d i n Secti o n 5. 5. 1 , 
Ta ble 1 1 . Vital si g ns will als o be meas ure d at t he E O T visits. All vital si g ns s h o ul d be meas ure d 
after t he p atie nt has bee n sitti n g/resti n g f or at least 5  mi n utes . If pre - a n d p ost -d ose 
meas ure me nts o verla p wit h t he 3 0 -mi n ute wi n d o w, o nl y a  si n gle set of vital si g ns is re q uir e d. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 8  of 1 3 5  
7. 7. 3.  
Cli ni c al L a b or at or y T e st s  
Sa m ples will be dra w n f or l ocal la bs. L ocal la b orat or y testi n g will i ncl u de i nstit uti o nal sta n dar d 
tests f or e val uati n g safet y a n d m a ki n g cli nical decisi o ns. T he f ollo wi n g la b orat or y assess me nts 
will be perf or me d b y l o cal la borat ories  t o e val uat e safet y at sc he d ule d ti m e p oi nts (see Ta bl e  1  
a n d Ta ble  2 ) d uri n g t h e c o urse of t he st u d y: 
•  T he c he mistr y pa n el  is t o i ncl u de t he f oll o wi n g t ests: al b u mi n, al kali ne p h os p hatase, 
A L T, A S T, bl o o d urea nitr o ge n, calci u m, creati ni n e, c hl ori de,  gl uc os e,  lactate 
de h y dr o ge nas e ( L D H), p h os p h or us, p otassi u m, s o di u m, a n d t otal bilir u bi n.  
•  T he C B C wit h differe ntial is t o i ncl u de t he f oll o wi n g tests: w hite bl o o d cell c o u nt wit h 
differe ntial ( i ncl u di n g n e utr o p hils, l y m p h o c yt es, m o n oc ytes), platelet c o u nt, H g b , a n d 
he mat ocrit. Ma n ual differe ntial s h o ul d be perf or m e d if cli nicall y i n dicate d. 
•  T he t h yr oi d pa nel is t o i ncl u de trii o d ot h yr o ni n e ( T 3) or free trii o d ot h yr o ni n e ( F T 3), 
free t h yr o xi ne ( F T 4), a n d t h yr oi d sti m ulati n g h or m o ne ( T S H) 
•  H g b  A 1 c  
T he f oll o wi n g l a b orat or y assess me nt(s) will be perf or me d b y l ocal la b orat ories at sc he d ule d ti me 
p oi nts (see Ta ble  1  a n d T a ble  2 ) d uri n g t he c o urse of t he st u d y: 
•  P T /aP T T /I N R 
•  Uri nal ysis  
o  Sta n dar d uri nal ysis i ncl u di n g pr otei n, gl uc os e, le u k oc yt e e sterase, p H, s p ecific 
gra vit y, a n d b l o o d ( wit h refle xi ve micr osc o p y, if a b n or mal)  
o  Uri ne pr otei n a n d uri ne creati ni ne f or U P C  rati o calc ulati o n  
o  A ser u m or uri ne β -h C G pre g na nc y t est f or s u bjects of c hil d beari n g p ote nti al 
7. 7. 4.  
P h y si c al E x a mi n ati o n  
P h ysical e x a mi nati o ns s h o ul d i ncl u de assess me nts of t he f oll o wi n g b o d y p arts/s yste ms: 
a b d o me n, e xtre mities, hea d, heart, l u n gs, nec k, a n d ne ur ol o gical. Wei g ht will be c ollecte d at 
s pecifie d ti me p oi nts (see Secti o n 6 ) a n d a d diti o nall y per i nstit uti o nal sta n dar ds, if a p plica bl e, 
b ut d oes n ot nee d t o be c ollecte d at visits f oll o wi n g E O T . M eas ure me nts of hei g ht o btai ne d 
wit hi n t he pri or 1 2  m o nt hs ma y b e u tilize d. 
7. 7. 5.  
El e ctr o c ar di o gr a m s  
All s u bjects will recei ve 1 2-lea d E C Gs i n tri plicat e at scree ni n g a n d E O T. T he first 3 0  s u bjects 
e nr olle d acr oss C o h orts 1 , 2 , a n d 3 at U S sites  will recei v e a d diti o nal E C G m o nit ori n g.  
S u bject s will be m o nit ore d f or c h a n ges i n car diac re p olarizati o n t hr o u g h assess me nt of 1 2 -lea d 
E C Gs c o n d ucte d i n tri plicate at ti mes o utli ne d i n  Ta ble  4  an d Secti o n  6 . E C Gs s h o ul d be 
perf or me d w hile t he s u bj ect is at rest (f or at least 1 0 mi n utes pri or t o E C G c ollecti o n) a n d pri or 
t o o btai ni n g P K a n d bi o mar kers sa m ples. 
Waiti n g peri o ds bet we e n eac h E C G are n ot r e q uir e d. Electr o nic or pa per c o pies of t he traci n gs 
ma y b e s u b mitte d t o t he s p o ns or’s desi g n ee f or p ossi ble ce ntral assess me nt.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 8 9  of 1 3 5  
7. 7. 6.  
Pr e g n a n c y T e sti n g  
F or s u bjects of c hil d beari n g p ote ntial, a s er u m or uri ne β-h C G pre g n a nc y test wit h se nsiti vit y of 
at least 2 5  mI U/ m L will be perf or me d at bas eli ne  ( wit hi n 3 da ys pri or t o Da y  1) , wit hi n 7  da ys 
pri or t o Da y  1 a n d D a y  2 2  of eac h 4 2 -da y c ycle ( C o h orts 1, 2, a n d 3) wit hi n 7  da ys pri or t o 
Da y  1 of eac h 2 1 -d a y c ycle ( C o h orts 4 a n d 5), a n d at the E O T visit  (all c o h orts). I n a d diti o n, 
pre g na nc y t esti n g will be d o ne  o nce a m o nt h f or 1 2 0  da y s after t h e last recei ve d d ose of st u d y 
dr u g f or s u bjects i n C o h orts 1, 2, a n d 3 a n d o nce a m o nt h f or 6  m o nt hs after t he last recei ve d 
d ose of st u d y dr u g f or  s ubjects i n C o h orts 4 a n d 5 , or per l ocal re g ulati o ns, w here a p plica ble. A 
ne gati ve pre g n a nc y res ult is re q uire d bef ore t he s u bject ma y recei ve st u d y dr u g. Pre g na nc y t ests 
ma y als o be re p eate d as r e q ueste d per i nstit uti o nal re vie w b oar d/i n de pe n d e nt et hics c o m mittee 
(I R B/I E C) or if re q uir e d b y l oc al re g ulati o ns.  
7. 7. 7.  
E C O G P erf or m a n c e St at u s  
E C O G perf or ma nce Stat us ( A p pe n di x  A ) will be e val uate d at pr ot oc ol-s pecific ti me p oi nts. See 
Ta ble  1 , Ta ble  2 , a n d Secti o n  6 . 
7. 8.  
A p pr o pri at e n e s s of M e a s ur e m e nt s  
T he safet y me as ures t h at will be use d i n t his trial are c o nsi dere d sta n dar d pr oce d ures f or 
e val uati n g t he p ote ntial a d verse effects of st u d y me dicati o ns.  
Res p o nse will be assesse d acc or di n g t o R E CI S T v 1. 1, w hic h are sta n dar dize d criteri a f or 
e val uati n g res p o nse i n s oli d t u m ors. T he i nter vals of e val uati o n i n t his pr ot oc ol are c o nsi dere d 
a p pr o priate f or diseas e m a na ge me nt.  
I m m u n o ge nicit y is c o m m o nl y assesse d f or bi ol o gics; t heref ore, sta n dar d tests will be perf or me d 
t o detect t he p ossi ble prese nce of s p ecific a nti b o dies t o S E A -C D 4 0 . P har mac o ki netic 
assess me nts are als o c o m m o n i n cli nical st u dies t o hel p c haracter ize d ose-e x p os ure-res p o nse 
relati o ns hi ps. 
8.  
D A T A Q U A LI T Y C O N T R O L A N D Q U A LI T Y  A S S U R A N C E  
8. 1.  
Sit e Tr ai ni n g a n d M o nit ori n g Pr o c e d ur e s  
A st u d y ma n u al wit h i nstr ucti o ns f or st u d y c o m plia nce a n d C R F c o m pleti o n will be pr o vi de d. 
Pri or t o t he e nr oll me nt of s u bjects at t he site, Sea ge n  or its desi g n ate d cli nical a n d me dical 
pers o n nel will re vie w t h e f oll o wi n g ite ms wit h t he i n vesti gat or a n d cli nic staff:  
•  T he pr ot oc ol, st u d y o bj ecti ves, eli gi bilit y re q uire m e nts, st u d y pr oce d ures, re gistrati o n, 
a n d wit h dra w al pr ocess e s 
•  C urre nt I B/ p ac ka ge i nsert 
•  Rec or di n g a n d re p orti n g A Es  a n d S A Es  
•  E nr oll me nt g oals a n d st u d y ti meli nes  
•  T he C R F c o m pleti o n pr o cess a n d s o urce d oc u m e ntati o n re q uire me nts  
•  M o nit ori n g re q uir e me nts  
•  I R B/I E C re vie w a n d a p pr o val pr ocess 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 0  of 1 3 5  
•  I nf or me d c o ns e nt pr ocess 
•  G o o d  cli nical practice g ui deli nes a n d relate d re g ul at or y d o c u me ntati o n re q uire me nts  
•  Ke y st u d y t ea m r oles a n d res p o nsi bilities  
•  I n v esti gati o nal pr o d uct st ora ge, acc o u nta bilit y, la beli n g, dis pe nsi n g, a n d rec or d 
kee pi n g  
•  S u bject  c o di n g a n d ra n d o mizati o n (if a p plica ble)  
•  St u d y s a m ples/s peci me n c ollecti o n, ha n dli n g , a n d s hi p pi n g  
•  Pr ot oc ol c o m plia nce  
•  Cli nical st u d y rec or d kee pi n g, d oc u me nt rete nti o n, a n d a d mi nistrati ve re q uire me nts  
M o nit ori n g visits will occ ur peri o dicall y, wit h fre q ue nc y de p e n de nt o n t he rate of e nr oll m e nt a n d 
w or kl oa d at e ac h site. D uri n g m o nit ori n g visits, t he Sea ge n  re prese ntati ve will t y pi call y re vie w 
re g ulat or y d oc u m e ntati o n, C R Fs, s o urce d oc u m e ntati o n, a n d i n vesti gati o n al pr o d uct st ora ge, 
pre parati o n, a n d acc o u nt a bilit y. T he C R Fs will be re vie we d f or c o m plet e ness, a d here n ce t o t he 
pr o vi de d g ui deli nes, a n d acc urac y c o m pare d t o t he s o urce d o c u me nts. T he i n vesti gat ors m ust 
e ns ure t hat t he m o nit or is all o we d t o i ns pect all s o urce d oc u m e nts perti ne nt t o st u d y s u bjects a n d 
m ust c o o perate wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms n ote d i n t he c o urse of t he trial are 
res ol ve d. T he i n vesti gat or m ust mai ntai n a c o m pre he nsi ve a n d ce ntralize d fili n g s yste m of all 
st u d y-relate d d oc u m e ntati o n t hat is s uita ble f or i ns pecti o n b y Sea ge n  or its desi g nat e d m o nit ors 
a n d b y q u alit y ass ura nce a u dit ors, or re prese ntati v es of re g ulat or y a ut h orities.  
8. 2.  
D at a M a n a g e m e nt Pr o c e d ur e s  
Sea ge n  will pr o vi de C R F C o m pleti o n G ui deli nes f or electr o ni c C R F (e C R F) data e ntr y. St u d y 
s pecific dat a ma na ge m e nt pr oce d ures will be mai ntai ne d i n t he data ma na ge me nt pla n. Q ueries 
res ulti n g fr o m e dit c hec ks a n d/ or data verificati o n pr oce d ures will be p oste d electr o nicall y i n t he 
e C R F. 
8. 3.  
A c c e s s t o S o ur c e D at a  
T he i n vesti gat or will per mit t he s p o ns or’s re pres e ntati ves t o m o nit or t he st u d y as fre q u e ntl y as 
t he s p o ns or dee ms ne cessar y t o deter mi ne t hat pr ot oc ol a d here n ce a n d dat a rec or di n g are 
satisfact or y. A p pr o priate meas ures t o pr otect s u bject c o nfi de ntialit y are t o b e e m pl o ye d d uri n g 
m o nit ori n g. T he C R Fs a n d relate d s o ur ce d oc u m e nts will t y picall y b e r e vie we d i n detail b y t he 
m o nit or at eac h site visit. Ori gi nal s o urce d o c u me nts or certifie d c o pies are nee de d f or re vi e w. 
T his re vie w i ncl u des i ns pecti o n of data ac q uire d as a re q uir e me nt f or parti ci pati o n i n t his st u d y 
a n d ot her me dical rec or ds as re q uire d t o c o nfir m t hat t he i nf or mati o n c ollecte d is c orrect. Ot her 
st u d y rec or ds, s uc h as c orres p o n de n ce wit h t he s p o ns or a n d t he I R B/I E C a n d scree ni n g a n d dr u g 
acc o u nta bilit y l o gs will als o be i ns pecte d. All s o urce data a n d st u d y rec or ds m ust als o be 
a vaila ble f or i ns pecti o n b y re pres e ntati ves of re g ul at or y a ut h orities a n d t he I R B/I E C. 
8. 4.  
A c c ur a c y a n d R eli a bilit y of D at a  
Ste ps t o be ta ke n t o ass ure t he acc urac y a n d relia bilit y of data i ncl u d e:  
•  T he selecti o n of q u alifie d i n vesti gat ors a n d a p pr o priate st u d y ce nters.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 1  of 1 3 5  
•  Re vie w of pr ot oc ol pr o ce d ures wit h t he i n vesti gat ors a n d ass ociat e d pers o n nel pri or t o 
t he st u d y. 
•  Peri o dic m o nit ori n g visits b y t he desi g n ate d m o nit or(s).  
•  C R Fs will be re vie we d f or acc urac y a n d c o m plet e ness d uri n g m o nit ori n g visits t o t he 
st u d y ce nt ers a nd/ or b y ce ntralize d m o nit ori n g. A n y discre pa n cies will be res ol ve d 
wit h t he i n vesti gat or or d esi g nees as a p pr o priate.  
8. 5.  
Q u alit y A s s ur a n c e Pr o c e d ur e s  
T he Researc h a n d De vel o p me nt Q ualit y gr o u p or its desi g nee m a y c o n d uct a u dits at t he cli nical 
site or ot her st u d y-rel ate d facilities a n d or ga nizati o ns. A u dit re p orts will be retai ne d b y t he 
Researc h a n d De v el o p me nt Q ualit y gr o u p of Sea ge n  as part of t h e writte n rec or d.  
8. 6.  
D at a H a n dli n g a n d R e c or d K e e pi n g  
8. 6. 1.  
D at a H a n dli n g  
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, l e gi bilit y, a n d 
ti meli ness of t he data re p orte d t o t he s p o ns or i n t he C R Fs a n d i n all re q uir e d re p orts. Dat a 
re p orte d o n t he C R F t h at is deri ve d fr o m s o urce d o c u me nts s h o ul d be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discr e p a ncies s h o ul d be e x plai ne d.  
A n y c ha n ge or c orrecti o n t o a C R F will be mai ntai ne d i n a n a u dit trail wit hi n t he electr o nic d ata 
ca pt ure s yste m. D ata c h a n ges ma y o nl y b e ma de b y t h ose i n di vi d uals s o a ut h orize d. T he 
i n vesti gat or s h o ul d r etai n rec or ds of t he c h a n ges a n d c orrecti o ns, writte n a n d/ or electr o nic.  
8. 6. 2.  
I n v e sti g at or R e c or d R et e nti o n 
T he i n vesti gat or s hall ret ai n st u d y dr u g dis p ositi o n rec or ds a n d all s o urce d oc u me ntati o n (s uc h 
as ori gi n al E C G traci n gs, la b orat or y re p orts, i n patie nt or office patie nt rec o r ds) f or t he ma xi m u m 
peri o d re q uir e d b y t he c o u ntr y a n d i nstit uti o n i n w hic h t he st u d y will be c o n d ucte d, or f or t he 
peri o d s pecifie d b y Sea ge n , w hic he v er is l o n ger. T he i n vesti gat or m ust c o ntact Sea ge n  pri or t o 
destr o yi n g a n y rec or ds ass ociate d wit h t he s t u d y. If t he i n vesti gat or wit h dra ws fr o m t he st u d y 
( d ue t o rel oc ati o n, retire me nt, etc.), t he rec or ds s hall be tra nsferre d t o a m ut uall y a gree d u p o n 
desi g nee, s uc h as a n ot her i n vesti gat or or I R B/I E C. N otice of s uc h tr a nsfer will be pr o vi de d i n 
writi n g t o S ea ge n. 
9.  
D A T A  A N A L Y SI S  M E T H O D S  
9. 1.  
D et er mi n ati o n of S a m pl e Si z e  
U p t o a p pr o xi matel y 2 0 0  s u bjects ma y b e e nr olle d i n t his st u d y. T his i ncl u d es u p t o 
a p pr o xi matel y 4 0  s u bjects e nr olle d i n eac h c o h ort. 
F or a s a m ple siz e of 4 0  s u bjects per c o h ort, ass u mi n g c o nfir me d O R R is bet wee n 3 0 % a n d 8 0 %, 
t he 2-si de d 9 5 % e x act c o nfi de nce i nter val ( CI ) are s u m marize d bel o w:  
C o nfir me d O R R  
9 5 % E xact CI ( N = 4 0)  
3 0 %  
(1 7 %, 4 7 %)  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 2  of 1 3 5  
C o nfir me d O R R  
9 5 % E xact CI ( N = 4 0)  
4 0 %  
(2 5 %, 5 7 %)  
5 0 %  
(3 4 %, 6 6 %)  
6 0 %  
(4 3 %, 7 5 %)  
7 0 %  
( 53 %, 8 3 %)  
8 0 %  
( 64 %, 9 1 %)  
 
9. 2.  
St u d y E n d p oi nt D efi niti o n s  
9. 2. 1.  
C o nfir m e d O R R  
C o nfir me d O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a c o nfir me d C R or P R 
acc or di n g t o R E CI S T v 1. 1 as assesse d b y t he i n v esti gat or. S u bject s w h o d o n ot ha ve at least 
2  p ost -baseli ne res p o ns e assess me nts (i nitial res p o nse a n d c o nfir m ati o n sca n) will be c o u nte d as 
n o n -res p o n ders. 
9. 2. 2.  
Di s e a s e C o ntr ol R at e  
Disease c o ntr ol rate ( D C R ) is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a c o nfir me d C R 
or P R acc or di n g t o R E CI S T v 1. 1 as assesse d b y t h e i n vesti gat or or meet t h e S D criteria at least 
o nce aft er start of st u d y treat me nt at a mi ni m u m i nter val of 5  wee ks. S u bject s w h o d o n ot ha ve at 
least 1 p ost‑ baseli ne res p o nse assess me nt will be c o u nte d as  n ot ac hie vi n g disease c o ntr ol . 
9. 2. 3.  
D ur ati o n of R e s p o n s e  
D urati o n of res p o ns e ( D O R ) is defi ne d as t he ti m e fr o m t he first d oc u m e ntati o n of o bjecti ve 
res p o nse ( C R or P R t hat is s u bse q ue ntl y c o nfir me d) t o t he first d oc u me ntati o n of P D or deat h 
d ue t o a n y ca us e, w hic he ver c o mes first.  
D O R data will be ce ns ore d as descri be d bel o w:  
1.  S u bjec ts w h o d o n ot ha ve P D a n d are still o n st u d y at t he ti me of a n a n al ysis will be 
ce ns ore d at t he date of last disease assess me nt d oc u me nti n g a bse n ce of P D.  
2.  S u bject s w h o starte d a ne w a ntica ncer treat me nt pri or t o d oc u me ntati o n of P D or deat h 
will be ce ns ore d at t he date of last disease assess me nt pri or t o t he start of ne w treat me nt.  
3.  S u bject s w h o are re m o ve d fr o m t he st u d y pri or t o d oc u me ntati o n of P D will be ce ns ore d 
at t he date of last disease assess me nt d oc u me nti n g a bse nce of P D.  
4.  S u bjects wit h d oc u me nte d P D or deat h i m me diatel y aft er 2 or m or e misse d disease 
assess me nts will be ce ns ore d at t he dat e of t he last disease assess me nt pri or t o t he misse d 
visits.  
D O R will o nl y be calc ulate d f or s u bjects w h o ac hi e ve a c o nfir me d C R or P R as meas ure d b y 
R E CI S T v 1. 1 f or all t u m ors.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 3  of 1 3 5  
9. 2. 4.  
Pr o gr e s si o n -Fr e e S ur vi v al  
P F S is defi ne d as t he ti me fr o m t he start of st u d y treat me nt t o t he first d oc u me ntati o n of P D b y 
R E CI S T v 1. 1 or deat h d ue t o a n y ca us e, w hic he v er c o mes first.  
T he sa me ce ns ori n g r ules as o utli ne d i n Secti o n 9. 2. 3  f or D O R will be a p plie d t o P F S. S u bject s 
lac ki n g a n e v al uati o n of t u m or res p o nse after t heir first d ose of st u d y dr u g will ha ve t heir e ve nt 
ti me ce ns ore d at Da y 1. 
9. 2. 5.  
O v er all S ur vi v al  
O S is defi ne d as t he ti me fr o m t he start of st u d y tr eat me nt t o date of d eat h d ue t o a n y ca us e. I n 
t he a bse nce of deat h, s ur vi val ti me will be ce ns ore d at t he last date t he s u bject is k n o w n t o be 
ali ve (ie, date of last c o nt act).  
9. 2. 6.  
P R O E n d p oi nt s  
E O R T C Q L Q -C 3 0  s u bsc ales a n d N S C L C -S A Q d o mai ns a n d t otal sc ore will be calc ulate d 
acc or di n g t o  t he ass ociat e d sc ori n g ma n uals. 
9. 3.  
St ati sti c al a n d A n al yti c al Pl a n s  
T he statistical a n d a nal ytical pla ns prese nt e d bel o w s u m marize t he m ore c o m plete pla ns t o be 
detaile d i n t he s tatistical a nal ysis pla n ( S A P). A c ha n ge t o t he data a nal ysis met h o ds descri be d i n 
t he pr ot oc ol will re q uire a pr ot oc ol a me n d me nt o nl y if it alters site c o n d u ct (e g, a d di n g bas eli ne 
assess me nts t o defi ne a s u b gr o u p). T he S A P will be fi nalize d pri or t o data base l oc k. A n y k e y 
c ha n ges t o t he met h o ds d escri be d i n t he fi n al S A P will be descri be d i n t he cli nical st u d y re p ort.  
9. 3. 1.  
G e n er al C o n si d er ati o n s  
I n ge neral, descri pti ve statistics will be prese nte d t hat i ncl u de t he n u m ber of o bser vati o ns, mea n, 
me dia n, sta n dar d  d e viati o n, mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bles, a n d t he n u m ber 
a n d perce nta ges p er cate g or y f or cate g orical varia bles.  
T he 2 -si de d 9 5 % e x act CI usi n g Cl o p per -Pears o n met h o d  (Cl o p per 1 9 3 4 ) will be calc ulate d f or 
t he res p o nse rates w h ere a p plica ble (e g, O R R). 
F or ti me -t o-e v e nt e n d p oi nts, t he me dia n s ur vi val ti me will be esti mate d usi n g t he Ka pla n -M eier 
met h o d; t he ass ociate d 9 5 % CI  will be calc ulat e d base d o n t he c o m ple me nt ar y l o g -l o g 
tra nsf or mati o n (C ollett 1 9 9 4 ). 
Safet y m eas ur e me nts will be s u m marize d b y des cri pti ve statistics base d o n t he safet y a n al ysis 
set. T he safet y a nal ysis set will i ncl u de all s u bjects w h o recei ve d a n y a m o u nt of  st u d y treat me nt. 
P R O o utc o mes e n d p oi nts will be s u m marize d usi n g des cri pti ve statistics.  
9. 3. 1. 1.  
R a n d o mi z ati o n a n d Bli n di n g  
T his is a si n gle ar m, o p e n -la bel st u d y. Bli n di n g will n ot be perf or me d. 
9. 3. 1. 2.  
A dj u st m e nt s f or C o v ari at e s  
N o a dj ust me nts f or c o variates are pl a n ne d.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 4  of 1 3 5  
9. 3. 1. 3.  
H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
Missi n g data will n ot be i m p ute d u nless ot her wise s pecifie d. Missi n g A E start date a n d/ or e n d 
date will be i m p ute d w hile calc ul ati n g d urati o n of e ve nts a n d treat me nt -e m er ge nt stat us. Missi n g 
s u bse q ue nt a ntica n cer tr eat me nt start date will be i m p ute d w hile deri vi n g t h e ti me-t o-e ve nt 
e n d p oi nts as a p plica ble. Ce ns ori n g r ul es will be a p plie d f or t he a n al ysis of ti me -t o-e ve nt 
e n d p oi nts. Details will be pr o vi de d i n t he S A P.  
9. 3. 1. 4.  
M ulti c e nt er St u di e s  
N o a dj ust me nts f or m ultice n ter st u dies are pla n ne d.  
9. 3. 1. 5.  
M ulti pl e C o m p ari s o n s a n d M ulti pli cit y  
N o a dj ust me nts f or m ulti plicit y a re pla n ne d. 
9. 3. 1. 6.  
D at a Tr a n sf or m ati o n s a n d D eri v ati o n s  
Ti me varia bles bas e d o n 2  dates ( e g, start date a n d e n d date) will be calc ulate d as (e n d d ate –  
start date + 1 [i n da ys]) u nless ot her wise s pecifie d i n t he pla n ne d a nal ysis s ecti o n. 
Baseli ne v al ues use d i n all statistical a nal yses will be t he m ost rece nt n o n -missi n g meas ure m e nt 
pri or t o t he first d ose of st u d y dr u g u nless ot her wise s pecifie d i n t he a nal ysis pla n.  
9. 3. 1. 7.  
A n al y si s S et s  
T he F A S i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g. T he P F S a n d O S a nal yses 
will be base d o n t he F A S.  
T he safet y a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g, a n d t h us is 
e q ui vale nt t o t he F A S. All safet y a nal yses will be base d o n t he safet y a nal ysis set. 
T he P K a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of S E A -C D 4 0 a n d ha d at 
least o ne P K sa m ple. 
T he res p o nse e val ua bl e ( R E) a nal ysis set i ncl u des all s u bjects wit h meas ura ble disease a t 
baseli ne  w h o recei v e d a n y a m o u nt of st u d y dr u g a n d ha d at least 1 p ost baseli ne disease 
assess me nt per R E CI S T v 1. 1 or disc o nti n ue d st u d y  treat me nt. T he R E will be t he pri mar y 
a nal ysis s et f or O R R a n d D C R.  
T he P R O a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g a n d ha v e at 
least o ne P R O assess me nt. All P R O a nal yses will be base d o n t he P R O a n al ysis set. 
A d diti o nal a nal ysis sets of s u bjects ma y be defi ne d i n t he S A P. 
9. 3. 1. 8.  
E x a mi n ati o n of S u b gr o u p s  
As e x pl orat or y a nal yses, s u b gr o u p a nal yses  ma y b e c o n d ucte d f or selecte d e n d p oi nts. Detaile d 
met h o d ol o g y will be pr o vi de d i n t he S A P.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 5  of 1 3 5  
9. 3. 1. 9.  
Ti mi n g of A n al y s e s  
T he pri mar y a n al ysis will be c o n d ucte d w h e n all treate d s u bjects i n a c o h ort ha ve bee n f oll o we d 
f or at least 6 m o nt hs or c o me off st u d y, w hic he v er c o mes first. S u bse q ue nt data c ut off d ates ma y 
be defi ne d t o all o w f or m ore precise esti mates of ti me -t o-e ve nt e n d p oi nts.  
I nteri m a nal ysis f or f utilit y will be perf or me d s e paratel y f or eac h c o h ort after a p pr o xi matel y 
1 5  s u bjects of a gi ve n c o h ort ha ve bee n treate d a n d are res p o nse e v al ua ble p ost‑ baseli ne.  
9. 3. 2.  
S u bj e ct  Di s p o siti o n  
A n acc o u nti n g of st u d y s u bjects b y dis p ositi o n will be ta b ulate d a n d t he n u m ber of s u bjects i n 
eac h a nal ysis set will be s u m marize d. S u bject s w h o disc o nti n ue st u d y treat me nt a nd s u bjects 
w h o wit h dra w fr o m t he st u d y will be s u m marize d wit h reas o n f or dis c o nti n uati o n or wit h dra wal.  
9. 3. 3.  
S u bj e ct  C h ar a ct eri sti c s  
De m o gra p hics a n d ot her baseli ne c haracteristics will be s u m marize d  b y c o h ort f or t he F A S . 
Details will be pr o vi de d i n t he S A P.  
9. 3. 4.  
Tr e at m e nt A d mi ni str ati o n  
Treat me nt a d mi nistrati o n will be s u m marize d b y c o h ort f or t he safet y a nal ysis set. S u m mar y 
statistics f or d urati o n of t hera p y, n u m ber of c ycl es per s u bject, a n d t h e n u m ber a n d perce nta ge of 
s u bjects treate d at eac h c ycl e will be pres e nte d. Details will be pr o vi de d i n t he S A P.  
9. 3. 5.  
Effi c a c y A n al y s e s  
T he pri mar y a n al ysis of O R R  a n d D C R will be base d o n t he R E a nal ysis s et . E x pl orat or y 
a nal ys es o f O R R base d o n t he F A S will  als o be perf or me d. T h e pri mar y a n al ysis of P F S a n d O S  
will be base d o n t he F A S .  
9. 3. 5. 1.  
Pri m ar y Effi c a c y A n al y s e s  
T he pri mar y e n d p oi nt of t his st u d y f or all t u m or t y pes is t he c o nfir me d O R R per i n vesti gat or 
assess me nt. T he O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a c o nfir me d C R or 
P R acc or di n g t o R E CI S T v 1. 1. T he O R R of eac h c o h ort a n d its e x act 2 -si de d 9 5 % CI usi n g t he 
Cl o p per -Pears o n met h o d (Cl o p per 1 9 3 4 ) will be calc ulate d.  
9. 3. 5. 2.  
S e c o n d ar y Effi c a c y A n al y s e s  
T he D C R will be esti mate d f or eac h c o h ort a n d t h e 9 5 % C Is will be cal c ulate d usi n g t he 
Cl o p per -Pears o n met h o d.  
T he D O R, P F S, a n d O S f or eac h c o h ort will be esti mate d usi n g t he Ka pla n -Meier met h o d ol o g y, 
a n d t he me dia ns a n d ass ociate d 9 5 % C Is will be calc ulate d. Ka pla n-Mei er pl ots will be pr o vi de d 
as a p pr o priat e.  
9. 3. 6.  
P h ar m a c o ki n eti c a n d I m m u n o g e ni cit y A n al y s e s  
S E A -C D 4 0 c o nce ntr ati o ns will be s u m marize d wit h descri pti ve statistics at eac h P K sa m pli n g 
ti me p oi nt. Selecte d P K para meters will be esti mate d b y n o nc o m part me nt al a nal ysis a n d 
s u m marize d usi n g descri pti ve statistics.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 6  of 1 3 5  
T he i nci de nce of A D A will be s u m marize d u si n g t he safet y a nal ysis set. 
9. 3. 7.  
Bi o m ar k er A n al y s e s  
Relati o ns hi ps of bi o mar ker para meters ( e g, bas eli ne val ues, a bs ol ute a n d relati ve c ha n ges fr o m 
baseli ne) t o efficac y, safet y, a n d P K para meters ma y b e e x pl ore d. Relati o ns hi ps a n d ass ociate d 
data t hat are deter mi ne d t o be of i nterest ma y b e s u m marize d. Details will be descri b e d 
se parat el y i n t he S A P or bi o mar ker a n al ysis pla n. 
9. 3. 8.  
P ati e nt -R e p ort e d O ut c o m e s A n al y s e s  
P R O asses s me nts will be a nal yze d t o d eter mi ne if treat me nt affects P R O sc ores. All s u bscales 
a n d i n di vi d ual ite m sc ores will be ta b ulate d. Descri pti ve s u m maries of o bser ve d data will be 
pr o vi de d at eac h sc h e d ule d assess me nt ti me p oi nt. F urt her a nal yses , if pla n ne d, will be pr o vi de d 
i n t he S A P. 
S u m mar y statistics of act ual a n d c ha n ge fr o m b aseli ne of E O R T C Q L Q -C 3 0 s u bscales f or all 
c o h orts a n d N S C L C -S A Q d o mai ns a n d t otal sc ores f or C o h orts 4  a n d 5  at eac h sc h e d ule d visit 
will be pr o vi de d. N u m ber a n d fre q ue nc y of P GI -S a n d P GI -C res p o nses i n C o h orts 4  a n d 5  will 
be prese nt e d at e ac h sc h e d ule d visit.  
Ti me -t o-deteri or ati o n ( T T D) f or t he N S C L C -S A Q q uesti o n naire is defi n e d as t he ti me fr o m 
baseli ne ( C ycle 1 Da y 1) u ntil t he first c ha n ge fr o m baseli ne t hat is less or e q ual t o t he mi ni mal 
cli nicall y i m p orta nt differe nce a n d t hat was m ai ntai ne d f or 2 or m ore c o ns ec uti ve assess me nts . 
Details o n t he calc ul ati o n of t he M CI D will be pr o vi de d i n t he S A P.  
T he T T D a n al ys es will be perf or me d usi n g t he Ka pla n -Meier met h o d a n d will i ncl u de t he 
s u bjects wit h o ut a missi n g bas eli ne sc ore. Me dia n T T D  a n d 9 5 % CI will be pr o vi de d, if feasi ble.  
9. 3. 9.  
S af et y A n al y s e s  
All safet y a nal yses will be perf or me d b y c o h ort a n d o verall usi n g t h e safet y a nal ysis s et.  
9. 3. 9. 1.  
E xt e nt of E x p o s ur e  
D urati o n of treat me nt, n u m ber of c ycl es, t otal d ose, a n d d ose i nte nsit y will be s u m marize d. D ose 
m o dificati o ns, i ncl u di n g d ose dela y, d ose re d ucti o n, a n d u n pla n ne d d ose a dj ust me nt, will be 
s u m marize d. Details will be pr o vi de d i n t he S A P. 
9. 3. 9. 2.  
A d v er s e E v e nt s  
A n o ver vie w of A Es  will pr o vi de a ta b ulati o n of t he i nci de nce of all A Es , treat me nt-e mer ge nt 
A Es , treat me nt-relate d A Es , Gra de 3 a n d hi g her tr eat me nt-e mer ge nt a d verse e ve nts ( T E A Es ), 
S A Es, treat me nt -rel ate d S A Es, deat hs, a n d A Es  lea di n g t o st u d y treat me nt disc o nti n uati o n. A Es  
will be defi ne d as tr eat m e nt-e mer ge nt if t he y are ne wl y o cc urri n g or w orse n f oll o wi n g st u d y 
treat me nt. 
T E A Es will be liste d a n d s u m mariz e d b y Me dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A), preferre d t er m, se verit y, a n d rel ati o ns hi p t o S E A -C D 4 0 . I n t he eve nt of m ulti ple 
occ urre nces of t he sa me A E wit h t he sa me preferre d ter m i n 1  s u bject, t he A E will be c o u nte d 
o nce as t he o cc urre nce. A Es  lea di n g t o pre mat ure disc o nti n uati o n of S E A -C D 4 0  will be 
s u m marize d a n d liste d i n t he sa me ma n ner. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 7  of 1 3 5  
9. 3. 9. 3.  
D e at h s a n d S eri o u s A d v er s e E v e nt s  
S A Es will be liste d a n d s u m mariz e d i n t he sa me ma n ner as all A Es . E ve nts wit h a fatal o utc o me 
will be liste d.  
9. 3. 9. 4.  
Cli ni c al L a b or at or y R e s ult s  
S u m mar y statistics of la b orat or y res ults a n d c ha n ges fr o m baseli ne will be ta b ulate d b y 
sc he d ule d visit. Gra di n g of la b orat or y v al ues will be assi g n e d pr o gra m maticall y p er t he 
N CI  C T C A E v 5. 0. S hift ta bles c o m pari n g t he w orst p ost -baseli ne t o baseli ne C T C A E gra de will 
be prese nt e d. La b orat or y val ues will be liste d wit h gra de per C T C A E a n d fl a g ge d w he n v al ues  
are o utsi de t he n or m al refere n ce ra n ge.  
9. 3. 9. 5.  
Ot h er S af et y A n al y s e s  
Vit al Si g ns  
Vital si g ns data will be liste d. S u m mar y statistics of vital si g ns a n d c h a n ge fr o m baseli ne ma y b e 
ta b ulate d w here a p pr o pri ate. 
E C O G Perf or m a nce St at us  
E C O G perf or ma nce stat us will be s u m marize d f or eac h sc h e d ule d visit. S hifts fr o m baseli ne t o 
t he best a n d w orst p ost baseli ne sc ore ma y b e ta b ul ate d. 
E C G  
E C G  stat us ( n or mal, a b n or mal cli nicall y si g nifica nt, or a b n or mal n ot cli nicall y si g nifica nt) m a y 
be s u m mariz e d f or eac h s c he d ule d E C G a n d s hifts fr o m baseli ne ma y b e ta b ulate d.  
9. 3. 1 0.  
I nt eri m A n al y s e s 
I nteri m effi cac y a nal yses will be perf or me d s e paratel y f or eac h c o h ort after a p pr o xi matel y 
1 5  s u bjects of a gi ve n c o h ort ha ve bee n treate d a n d are res p o nse e v al ua ble p ost -baseli ne. T he 
Ba yesi a n P p o S a p pr oac h will be use d t o deter mi ne t he criteria  f or c o nti n uati o n (see 
A p p e n di x  E ). A c o h ort is c o nsi dere d “s uccessf ul” if t he 9 0 % CI of t he res p o nse rate at t he 
ma xi m u m sa m ple siz e e xcl u des t he bac k gr o u n d rate. At t he ti me of eac h i nteri m a nal ysis, t he 
P p o S will be calc ulate d. A P p o S < 5 % i n dicates t hat it is u nli kel y t he O R R will be better t ha n t he 
res p o nse rate of c urre nt sta n dar d of care at t he e n d of t he c o h ort gi ve n t he i nteri m res ult. Bas e d 
o n effic ac y a n d s afet y d ata, t o get h er wit h t he P p o S, a c o h ort ma y be st o p p e d earl y b y t he 
s p o ns or. A c o h ort ma y als o be disc o nti n ue d at a n y p oi nt at t he discreti o n of t he s p o ns or.  T he 
details of t he P p o S met h o d are pr o vi d e d i n  A p pe n di x  E . 
T he pre dicti ve pr o ba bilit y met h o d all o ws t he P p o S be c o m p ute d at a n y i nt eri m ti me a n d pr o vi des 
fle xi bilit y i n m o nit ori n g treat me nt a cti vit y c o nti n u o usl y aft er t he i nitial i nteri m a nal ysis. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 8  of 1 3 5  
1 0.  
IN F O R M E D  C O N S E N T , ET HI C A L  R E VI E W , A N D  R E G U L A T O R Y  
C O N SI D E R A TI O N S  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he N ote f or G ui da nce o n G o o d Cli nical 
Practice (I C H Har m o nise d Tri partite G ui deli ne E 6 ( R 2); F D A C F R [ 2 1 C F R  § 5 0, 5 6, 3 1 2]), 
Declarati o n of Helsi n ki ( Brazil 2 0 1 3), a n d all a p plica ble re g ul at or y re q uire me nts.  
1 0. 1.  
I nf or m e d C o n s e nt 
T he i n vesti gat or is res p o nsi ble f or pres e nti n g t he ris ks a n d be nefits of st u d y partici pati o n t o t he 
s u bject i n si m ple ter ms usi n g t he I R B/I E C a p pr o v e d i nf or me d c o ns e nt d oc u me nt a n d f or 
e ns uri n g s u bj ects are re-c o nse nte d w he n t he i nf or me d c o nse nt d oc u me nt is u p date d d uri n g t he 
st u d y, if re q uire d. T he i n vesti gat or will e ns ure t hat writte n i nf or me d c o nse nt is o btai ne d fr o m 
eac h s u bject, or le gall y acce pta bl e re prese ntati ve, if a p plica ble t o t his st u d y, b y o btai ni n g t he 
si g nat ur e a n d dat e o n t he i nf or me d c o nse nt d oc u m e nt pri or t o t he perf or ma nce of pr ot o c ol 
e val uati o ns or pr oce d ures.  
1 0. 2.  
Et hi c al R e vi e w  
T he i n vesti gat or will pr o vi de t he s p o ns or or its  desi g nee wit h d oc u me ntati o n of t he I R B/I E C 
a p pr o val of t he pr ot oc ol a n d t he i nf or me d c o nse nt d oc u me nt bef ore t he st u d y ma y b e gi n at t he 
i n vesti gati ve site(s). T he na me a n d a d dress of t he re vie wi n g et hics c o m mittee are pr o vi de d i n t he 
i n vesti gat or file. 
T h e i n vesti gat or will s u p pl y t he f oll o wi n g t o t he i n vesti gati ve site’s I R B/I E C:  
•  Pr ot oc ol a n d a me n d me nts  
•  I nf or me d c o ns e nt d oc u m e nt a n d u p dates 
•  Cli nical I B a n d u p dat es  
•  Rele va nt c urri c ula vitae, if re q uire d  
•  Re q uire d safet y a n d S A E re p orts  
•  A n y a d diti o nal s u b miss i o ns re q uire d b y t he site’s I R B/I E C 
T he i n vesti gat or m ust pr o vi de t he f oll o wi n g d o c u me ntati o n t o t he s p o ns or or its desi g nee:  
•  T he I R B/I E C peri o dic ( e g, q uarterl y, a n n u al) re-a p pr o val of t he pr ot oc ol.  
•  T he I R B/I E C a p pr o vals of a n y a me n d me nts t o t h e pr ot oc ol or re visi o ns t o t he 
i nf or me d c o nse nt d oc u m e nt. 
•  T he I R B/I E C r ecei pt of safet y a n d S A E re p orts, as a p pr o priate.  
1 0. 3.  
R e g ul at or y C o n si d er ati o n s  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d et hical pri nci ples state d i n t he 
a p plica ble g ui deli nes o n g o o d cli nic al practice, a n d all a p plica ble l ocal a n d/ or re gi o nal la ws, 
r ules, a n d re g ulati o ns. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 9 9  of 1 3 5  
1 0. 3. 1.  
I n v e sti g at or I nf or m ati o n 
T he c o ntact i nf or mati o n a n d q ualificati o ns of t he pri nci pal i n vesti gat or a n d s u bi n vesti gat ors a n d 
na me a n d a d dress of t he researc h fa cilities are i n cl u de d i n t he i n vesti gat or file.  
1 0. 3. 2.  
Pr ot o c ol A m e n d m e nt s a n d St u d y T er mi n ati o n  
A n y i n vesti gat or -i nitiate d c ha n ges t o t he pr ot o c ol ( wit h t he e x ce pti o n of c ha n ges t o eli mi nate a n 
i m me diate hazar d t o a st u d y s u bject) m ust be a p pr o ve d b y t he s p o ns or pri or t o see ki n g a p pr o val 
fr o m t he I R B/I E C, a n d pri or t o i m ple me nti n g. T h e i n vesti gat or is res p o nsi ble f or e nr olli n g 
s u bjects w h o ha ve met pr ot oc ol eli gi bilit y criteria. Pr ot oc ol de viati o ns m ust be re p ort e d t o t he 
s p o ns or a n d t he l ocal I R B/I E C i n acc or da n ce wit h I R B/I E C p olicies.  
T he s p o ns or ma y ter mi nate t he st u d y at a n y ti me. T he I R B/I E C m ust be a d vise d i n writi n g of 
st u d y c o m pleti o n or earl y ter mi nati o n. 
1 0. 4.  
St u d y D o c u m e nt ati o n, Pri v a c y a n d R e c or d s R et e nti o n  
T o pr otect t he s afet y of s u bjects i n t he st u d y a n d t o e ns ure acc urate, c o m pl ete, a n d relia ble data, 
t he i n vesti gat or will kee p rec or ds of la b orat or y tests, cli nical n otes, a n d s u bject me dical r ec or ds 
i n t he s u bject files as ori gi nal s o ur ce d oc u m e nts f or t he st u d y. If re q ueste d, t he i n vesti gat or will 
pr o vi de t he s p o ns or, its lice nsees a n d c olla b orat ors, a p plica ble re g ulat or y a ge ncies, a n d 
a p plica ble I R B/I E C wit h direct access t o ori gi nal s o urce d oc u m e nts or certifie d c o pies.  
Rec or ds c o ntai ni n g s u bject me dical i nf or mati o n m ust be ha n dle d i n acc or da nce wit h l ocal a n d 
nati o nal la ws, r ules, a n d re g ulati o ns a n d c o nsiste nt wit h t he ter ms of t he s u bject a ut h orizati o n 
c o ntai ne d i n t he i nf or me d c o nse nt d oc u me nt f or t he st u d y (t h e A ut h orizati o n). Care s h o ul d be 
ta ke n t o e ns ure t h at s uc h rec or ds are n ot s h are d wit h a n y p ers o n or f or a n y p ur p ose n ot 
c o nte m plate d b y t he A ut h orizati o n. F urt her m ore, C R Fs a n d ot her d oc u me nts t o be tra nsferre d t o 
t he s p o ns or s h o ul d be c o m plete d i n strict acc or da nce wit h t he i nstr ucti o ns  pr o vi de d b y t he 
s p o ns or, i ncl u di n g t he i nstr ucti o ns re gar di n g t he c o di n g of s u bject i de ntities. 
I n c o m plia nce wit h l ocal a n d/ or re gi o nal re g ulati o ns, t his trial ma y be re gistere d a n d tri al res ults 
ma y b e p oste d o n p u blic re gistries, s uc h as Cli nical Trials . g o v. 
1 0. 5.  
Cli ni c al Tri al A gr e e m e nt  
Pa y me nts b y t he s p o ns or t o i n vesti gat ors a n d i nstit uti o ns c o n d ucti n g t he trial, re q uire me nts f or 
i n vesti gat ors’ i ns ur a nce, t he p u blicati o n p olic y f or cli nical trial data, a n d ot her re q uir e me nts are 
s pecifie d i n t he cli nical trial a gree m e nt. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 0  of 1 3 5  
1 1.  
R E F E R E N C E S  
Aar o ns o n N K, A h me d zai S, B er g ma n B, et al. T he E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer 
Q L Q -C 3 0: a q ualit y -of -life i nstr u me nt f or use i n i nter nati o nal cli nical trials i n o nc ol o g y. J Natl Ca ncer I nst. 
1 9 9 3; 8 5( 5): 3 6 5 – 7 6.  
A d va ni R, F orer o -T orres A, F ur ma n R R, et al. P hase I st u d y of t he h u ma nize d a nti -C D 4 0 m o n ocl o nal a nti b o d y 
dacet uz u ma b i n refract or y or rec urre nt n o n -H o d g ki n's l y m p h o ma. J Cli n O nc ol. 2 0 0 9; 2 7( 2 6): 4 3 7 1 – 7 . 
Al gazi A P, Tsai K K, S h o us ht ari A N, et al. Cli nical o utc o mes i n metastatic u veal mela n o ma treate d wit h P D -1 a n d 
P D -L 1 a nti b o dies. Ca ncer. 2 0 1 6; 1 2 2( 2 1): 3 3 4 4 – 5 3.  
B eatt y G L, T ori gia n D A, C hi orea n E G, et al. A p hase I st u d y of a n a g o nist C D 4 0 m o n ocl o nal a nti b o d y 
( C P-8 7 0, 8 9 3) i n c o m bi nati o n wit h ge mcita bi ne i n patie nts wit h a d va nce d pa ncreatic d uctal a de n ocarci n o ma. Cli n 
Ca ncer Res. 2 0 1 3; 1 9( 2 2): 6 2 8 6 – 9 5.  
B e nsi n ger W, Maziarz R T, J a ga n nat h S, et al. A p hase 1 st u d y of l ucat u m u ma b, a f ull y h u ma n a nti -C D 4 0 a nta g o nist 
m o n ocl o nal a nti b o d y a d mi ni st ere d i ntra ve n o usl y t o patie nts wit h rela pse d or refract or y m ulti ple m yel o ma. Br J 
Hae mat ol. 2 0 1 2; 1 5 9( 1): 5 8 – 6 6.  
Bla n k C, Br o w n I, P eters o n A C, et al. P D -L 1/ B 7 H -1 i n hi bits t he effect or p hase of t u m or rej ecti o n b y T cell rece pt or 
( T C R) tra ns ge nic C D 8 + T cells. Ca ncer Res. 2 0 0 4; 6 4( 3): 1 1 4 0 – 5 . 
B uri n gt o n B, Y ue P, S hi X, et al. C D 4 0 pat h wa y acti vati o n stat us pre dicts res p o nse t o C D 4 0 t hera p y i n diff use lar ge 
B cell l y m p h o ma. Sci Tra nsl Me d. 2 0 1 1; 3( 7 4): 7 4ra 2 2.  
B yr d J C, Ki p ps TJ, Fli n n I W, et al. P hase I st u d y of t he a nti -C D 4 0 h u ma nize d m o n ocl o nal a nti b o d y l ucat u m u ma b 
( H C D 1 2 2) i n rela pse d c hr o nic l y m p h oc ytic le u ke mia. Le u k L y m p h o ma. 2 0 1 2; 5 3( 1 1): 2 1 3 6 – 4 2.  
B yr ne K T, Leise nri n g N H, B aj or D L, V o n der hei de R H. C S F -1 R -de pe n de nt let hal he pat ot o xicit y w he n a g o nistic 
C D 4 0 a nti b o d y is gi ve n bef or e b ut n ot after c he m ot hera p y. J I m m u n ol. 2 0 1 6a; 1 9 7( 1): 1 7 9 – 8 7.  
B yr ne K T, V o n der hei de R H. C D 4 0 sti m ulati o n o b viates i n nate se ns ors a n d dri ves T cell i m m u nit y i n ca ncer. Cell 
Re p. 2 0 1 6 b; 1 5( 1 2): 2 7 1 9 – 3 2.  
Car b o ne A, Gl o g hi ni A, Pi nt o A. C D 4 0: a se nsiti ve mar ker of Ree d -Ster n ber g cells. Bl o o d. 1 9 9 6; 8 7( 1 1): 4 9 1 8 – 9 . 
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t yr osi ne-base d s witc h m otif of pr o gra m me d deat h 1 u p o n pri mar y h u ma n T cell sti m u lati o n, b ut o nl y rece pt or 
li gati o n pre ve nts T cell acti vati o n. J I m m u n ol. 2 0 0 4; 1 7 3( 2): 9 45 – 5 4.  
Clar k S K, A nsel m o L M. I nci d e nce of c uta ne o us reacti o ns wit h pe metre xe d: c o m paris o n of patie nts w h o recei ve d 
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Cl o p per CJ, P ears o n E S. T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n t he case of t he bi n o mial. Bi o metri ka. 
1 9 3 4; 2 6( 4): 4 0 4 – 1 3.  
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1 9 9 4: 2 3 7 – 5 1.  
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C o veler A L, Baj or D L, Mas o o d A, et al. P hase 1 st u d y of S E A -C D 4 0, ge mcita bi ne, na b -paclita xel, a n d 
pe m br oliz u ma b i n patie nts wit h metastatic pa ncreatic d uctal a de n ocarci n o ma ( P D A C). J Cli n O nc ol. 2 0 2 0; 3 8( S u p pl 
1 5): A bstract T P S 4 6 7 1.  
C urra n M A, M o ntal v o W, Ya gita H, Allis o n J P. P D -1 a n d C T L A -4 c o m bi nati o n bl oc ka d e e x pa n ds i nfiltrati n g T 
cells a n d re d uces re g ulat or y T a n d m yel oi d cells wit hi n B 1 6 mela n o ma t u m ors. Pr oc Natl Aca d Sci U S A. 
2 0 1 0; 1 0 7( 9): 4 2 7 5 – 8 0.  
Da vies J, P atel M, Gri delli C, et al. Real -w orl d treat me nt patter ns f or patie nts recei vi n g sec o n d -li ne a n d t hir d-li ne 
treat me nt f or a d va nce d n o n -s mall cell l u n g ca ncer: a s yste matic re vie w of rece ntl y p u blis he d st u dies. P L o S O ne. 
2 0 1 7; 1 2( 4):e 0 1 7 5 6 7 9.  
de V os S, F orer o -T orres A, A nsell S M, et al. A p hase II st u d y of dacet uz u ma b ( S G N -4 0) i n patie nts wit h rela pse d 
diff use lar ge B -cell l y m p h o ma ( D L B C L) a n d c orrelati ve a nal yses of patie nt -s pecific fact ors. J He mat ol O nc ol. 
2 0 1 4; 7: 4 4.  
Disis M L. I m m u ne re g ulati o n of ca ncer. J Cli n O nc ol. 2 0 1 0; 2 8( 2 9): 4 5 3 1 – 8 . 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 1  of 1 3 5  
D u dle y M E, W u n derlic h J R, Ya n g J C, et al. A d o pti ve cell tra nsfer t hera p y f oll o wi n g n o n -m yel oa blati ve b ut 
l y m p h o de pleti n g c he m ot hera p y f or t he treat me nt of patie nts wit h refract or y metastatic mel a n o ma. J Cli n O nc ol. 
2 0 0 5; 2 3( 1 0): 2 3 4 6 – 5 7.  
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: re vise d R E C I S T 
g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5( 2): 2 2 8 – 4 7.  
El g ueta R, B e ns o n MJ, de Vries V C, et al. M olec ular mec ha nis m a n d f u ncti o n of C D 4 0/ C D 4 0 L e n ga ge me nt i n t he 
i m m u ne s yste m. I m m u n ol Re v. 2 0 0 9; 2 2 9( 1): 1 52 – 7 2.  
Els o uei di R, La n der MJ, Ric ha E M, A da ne E D. Si n gle -d ose de xa met has o ne f or t he pre ve nti o n of pe metre xe d 
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Fa nale M, Ass o uli ne S, K ur u villa J, et al. P hase I A/II, m ultic e ntre, o pe n -la bel st u d y of t he C D 4 0 a nta g o nistic 
m o n ocl o nal a nti b o d y l ucat u m u ma b i n a d ult patie nts wit h a d va nce d n o n -H o d g ki n or H o d g ki n l y m p h o ma. Br J 
Hae mat ol. 2 0 1 4; 1 6 4( 2): 2 5 8 – 6 5.  
Ferr y -Gal o w K V, Datta V, M a k hl o uf H R, et al. W hat ca n be d o ne t o i m pr o ve researc h bi o ps y q ualit y i n o nc ol o g y 
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Fitzsi m m o ns D, J o h ns o n C D, Ge or ge S, et al. De vel o p me nt of a disease s pecific q ualit y 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 ncreatic ca ncer. 
E O R T C St u d y Gr o u p o n Q ualit y of Life. E ur J Ca ncer. 1 9 9 9; 3 5( 6): 9 3 9 – 4 1.  
Flies wasser T, Va n L oe n h o ut J, Freire B o ull osa L, et al. Cli nicall y rele va nt c he m ot hera pe utics ha ve t he a bilit y t o 
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F orer o -T orres A, B artlett N, Bea ve n A, et al. Pil ot st u d y of dacet uz u ma b i n c o m bi nati o n wit h rit u xi ma b a n d 
ge mcita bi ne f or rela pse d or refract or y diff use lar ge B -cell l y m p h o ma. Le u k L y m p h o ma. 2 0 1 3; 5 4( 2): 2 7 7 – 8 3.  
Fra ncisc o L M, Sa ge P T, S har pe A H. T he P D -1 pat h wa y i n t olera nce a n d a ut oi m m u nit y. I m m u n ol Re v. 
2 0 1 0; 2 3 6: 2 1 9 – 4 2.  
Fre nc h R R, C ha n H T, T utt A L, Gle n nie MJ. C D 4 0 a nti b o d y e v o kes a c yt ot o xic T -cell res p o nse t hat era dicates 
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a nti -C D 4 0 m o n ocl o nal a nti b o d y) i n patie nts wit h c hr o nic l y m p h oc ytic le u ke mia. Le u k L y m p h o ma. 2 0 1 0; 5 1( 2): 2 2 8 –
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Ga d geel S, R o dri g uez -A bre u D, S pera nza G, et al. U p date d a nal ysis fr o m K E Y N O T E -1 8 9: pe m br oliz u ma b or 
place b o pl us pe metre xe d a n d plati n u m f or pre vi o usl y u ntreate d metastatic n o ns q ua m o us n o n -s mall-cell l u n g ca ncer. 
J Cli n O nc ol. 2 0 2 0; 3 8( 1 4): 1 5 05 – 1 7.  
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2 0 1 3; 1 4( 1 0): 1 0 1 4 – 2 2.  
Gar dai SJ, E p p A, Li nares G, et al. A s u gar e n gi neere d n o n -f uc os ylate d a nti-C D 4 0 a nti b o d y, S E A -C D 4 0, wit h 
e n ha nce d i m m u ne sti m ulat or y acti vit y al o ne a n d i n c o m bi nati o n wit h i m m u ne c hec k p oi nt i n hi bit ors. J Cli n O nc ol. 
2 0 1 5; 3 3( 1 5 S u p pl): A bstract 3 0 7 4.  
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a nti b o dies i n precli nical i m m u ne -c o m pete nt r o de nt t u m or m o dels. Ca ncer Res. 2 0 1 7; 7 7( 1 3 s u p pl): A bstract 3 6 4 7.  
Gree n wal d RJ, Free ma n GJ, S har pe A H. T he B 7 fa mil y re visite d. A n n u Re v I m m u n ol. 2 0 0 5; 2 3: 5 1 5 – 4 8.  
Gr olea u A, C ôté J. C o m paris o n bet wee n t w o pre me dicati o n re gi me ns of de xa met has o ne b e f ore a pe metre xe d-base d 
c he m ot hera p y: a si n gle -ce nter e x perie nce st u d y. J O nc ol P har m Pract. 2 0 2 0; 2 6( 3): 6 1 2 – 8 . 
Gr uss HJ, Herr ma n n F, Gattei V, et al. C D 4 0/ C D 4 0 li ga n d i nteracti o ns i n n or mal, reacti ve a n d mali g na nt 
l y m p h o-he mat o p oietic tiss ues. Le u k L y m p h o m a. 1 9 9 7; 2 4( 5 – 6 ): 3 93 – 4 2 2.  
Ha mi d O, P uza n o v I, D u m mer R, et al. Fi nal a nal ysis of a ra n d o mise d trial c o m pari n g pe m br oliz u ma b vers us 
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Ha mi d O, R o bert C, Da u d A, et al. Safet y a n d t u m or res p o nses wit h la m br oliz u ma b (a nti -P D -1) i n mela n o ma. N 
E n gl J Me d. 2 0 1 3; 3 6 9( 2): 1 3 4 – 4 4.  
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a n d o n g oi n g cli nical trials.  I m m u n o p har mac ol I m m u n ot o xic ol. 2 0 1 4; 3 6( 2): 96 – 1 0 4.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 2  of 1 3 5  
He p pt M V, Hei nzerli n g L, Kä hler K C, et al. Pr o g n ostic fact ors a n d o utc o mes i n metastati c u veal mela n o ma treate d 
wit h pr o gra m me d cell deat h -1 or c o m bi ne d P D -1/c yt ot o xic T -l y m p h oc yte a nti ge n-4 i n hi biti o n. E u r J Ca ncer. 
2 0 1 7; 8 2: 5 6 – 6 5.  
Hira n o F, Ka ne k o K, T a m ura H, et al. Bl oc ka de of B 7 -H 1 a n d P D -1 b y m o n ocl o nal a nti b o dies p ote ntiates ca ncer 
t hera p e utic i m m u nit y. Ca ncer Res. 2 0 0 5; 6 5( 3): 1 0 89 – 9 6.  
H o di F S, O' Da y SJ, Mc Der m ott D F, et al. I m pr o ve d s ur vi val wit h i pil i m u ma b i n patie nts wit h metastatic mela n o ma. 
N E n gl J Me d. 2 0 1 0; 3 6 3( 8): 7 1 1 – 2 3.  
H u n der N N, W alle n H, Ca o J, et al. Treat me nt of metastatic mela n o ma wit h a ut ol o g o us C D 4 + T cells a gai nst 
N Y -E S O -1. N E n gl J Me d. 2 0 0 8; 3 5 8( 2 5): 2 6 9 8 – 7 0 3.  
H ussei n M, B ere ns o n J R, Nies viz k y R, et al. A p hase I m ulti d ose st u d y of dacet uz u ma b ( S G N -4 0; h u ma nize d 
a nti -C D 4 0 m o n ocl o nal a nti b o d y) i n patie nts wit h m ulti ple m yel o ma. Hae mat ol o gica. 2 0 1 0; 9 5( 5): 8 4 5 – 8 . 
J o h ns o n P W, C hallis R, C h o w d h ur y F, et al. A trial of a g o nistic a nti -C D 4 0 a nti b o d y: bi ol o gical effects i n a Ca ncer 
Researc h U K p hase I st u d y. C a ncer Res. 2 0 1 3; 7 3( 8 S u p pl 1): A bstract L B -1 4 2.  
Ka nt off P W, Hi ga n o C S, S h or e N D, et al. Si p ule ucel -T i m m u n ot hera p y f or castrati o n -resista nt pr ostate ca ncer. N 
E n gl J M e d. 2 0 1 0; 3 6 3( 5): 4 1 1 – 2 2.  
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a p o pt osis i n classical H o d g ki n's l y m p h o ma. P at h ol o g y. 2 0 0 3; 3 5( 5): 4 2 8 – 3 5.  
K urts C, R o bi ns o n B W, K n olle P A. Cr oss -pri mi n g i n healt h a n d disease. Nat Re v I m m u n ol. 2 0 1 0; 1 0( 6): 4 0 3 – 1 4.  
Lala M, Li M, Si n ha V, et al. A si x -wee kl y ( Q 6 W) d osi n g s c he d ule f or pe m br oliz u ma b base d o n a n 
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Lee JJ, Li u D D. A pre dicti ve pr o ba bilit y desi g n f or p hase II ca ncer cli nical trials. Cli n Trials. 2 0 0 8a; 5( 2): 9 3 – 1 0 6.  
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m ulti ple m yel o ma cli nical trial. J Bi o p har m Stat. 2 0 0 8 b; 1 8( 6): 1 1 36 – 4 9.  
Le o netti A, W e ver B, Mazzasc hi G, et al. M olec ular basis a n d rati o nale f or c o m bi ni n g i m m u ne c hec k p oi nt 
i n hi bit ors wit h c he m ot hera p y i n n o n-s mall cell l u n g ca ncer. Dr u g Resist U p dat. 2 0 1 9; 4 6: 1 0 0 6 4 4. 
Mc Carrier K P, At ki ns o n T M, De B us k K P, et al. Q ualitati ve de vel o p me nt a n d c o nte nt vali dit y of t he N o n -s mall Cell 
L u n g Ca ncer S y m pt o m Assess me nt Q uesti o n naire ( N S C L C -S A Q), a patie nt -re p orte d o utc o me i nstr u me nt. Cli n 
T her. 2 0 1 6; 3 8( 4): 7 9 4 – 8 1 0.  
Mell ma n I, C o u k os G, Dra n off G. Ca ncer i m m u n ot hera p y c o mes of a ge. Nat ure. 2 0 1 1; 4 8 0( 7 3 7 8): 4 8 0 – 9 . 
M orris o n A H, Dia m o n d M S, Ha y C A, B yr ne K T, V o n der hei de R H. S ufficie nc y of C D 4 0 acti vati o n a n d i m m u ne 
c hec k p oi nt bl oc ka d e f or T cell pri mi n g a n d t u m or i m m u nit y. Pr oc Natl Aca d Sci U S A. 2 0 2 0; 1 1 7( 1 4): 8 0 2 2 – 3 1.  
N o mi T, S h o M, A ka h ori T, et al. Cli nical si g nifica nce a n d t hera pe utic p ote ntial of t he pr o gra m me d deat h -1 
li ga n d/ pr o gra m me d deat h-1 p at h wa y i n h u ma n pa ncreatic c a ncer. Cli n Ca ncer Res. 2 0 0 7; 1 3( 7): 2 1 5 1 – 7 . 
N o n -s mall Cell L u n g Ca ncer C olla b orati ve Gr o u p. C he m ot hera p y i n n o n -s mall cell l u n g ca ncer: a meta-a nal ysis 
usi n g u p date d data o n i n di vi d ual patie nts fr o m 5 2 ra n d o mis e d cli n ical trials. N o n-s mall C ell L u n g Ca ncer 
C olla b orati ve Gr o u p. B MJ. 1 9 9 5; 3 1 1( 7 0 1 0): 8 9 9 – 9 0 9.  
N o v osia dl y R, Sc haer D, A mala das N, et al. P e metre xe d e n ha nces a nti -t u m or efficac y of P D 1 pat h wa y bl oc ka d e b y 
pr o m oti n g i ntra t u m or i m m u n e res p o nse via i m m u n o ge nic t u m or cell deat h a n d T cell i ntri nsic mec ha nis ms. Ca ncer 
Researc h. 2 0 1 8; 7 8( 1 3 S u p ple me nt): 4 5 4 9.  
N o wa k A K, R o bi ns o n B W, La ke R A. S y ner g y bet wee n c he m ot hera p y a n d i m m u n ot hera p y i n t he treat me nt of 
esta blis he d m uri ne s oli d t u m ors. Ca ncer Res. 2 0 0 3; 6 3( 1 5): 4 4 9 0 – 6 . 
O' Hara M H, O' Reill y E M, Vara d hac har y G, et al. C D 4 0 a g o nistic m o n ocl o nal a nti b o d y A P X 0 0 5 M (s oti gali ma b) 
a n d c he m ot hera p y, wit h or wit h o ut ni v ol u ma b, f or t he treat me nt of metastatic pa ncreatic a de n ocarci n o ma: a n 
o pe n -la bel, m ultice ntre, p hase 1 b st u d y. Lancet O nc ol. 2 0 2 1; 2 2( 1): 1 1 8 – 3 1.  
O kaza ki T, Mae d a A, Nis hi m ura H, K ur osa ki T, H o nj o T. P D -1 i m m u n orece pt or i n hi bits B cell rece pt or -me diate d 
si g nali n g b y recr uiti n g src h o m ol o g y 2 -d o mai n -c o ntai ni n g t yr osi ne p h os p hatase 2 t o p h os p h ot yr osi ne. Pr oc Natl 
Aca d Sc i U S A. 2 0 0 1; 9 8( 2 4): 1 3 8 66 – 7 1.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 3  of 1 3 5  
Os o ba D, R o dri g ues G, M yles J, Zee B, P ater J. I nter preti n g t he si g nifica nce of c ha n ges i n healt h -relate d 
q ualit y -of -life sc ores. J Cli n O nc ol. 1 9 9 8; 1 6( 1): 1 39 – 4 4.  
Ottaia n o A, Pisa n o C, De C hi ara A, et al. C D 4 0 acti vati o n as p ote ntial t o ol i n mali g na nt ne o plas ms. T u m ori. 
2 0 0 2; 8 8( 5): 3 6 1 – 6 . 
P ar d oll D M. T he bl oc ka d e of i m m u ne c hec k p oi 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.  
P arr y R V, C he m nitz J M, Fra u wirt h K A, et al. C T L A -4 a n d P D -1 rece pt ors i n hi bit T -cell acti vati o n b y disti nct 
mec ha nis ms. M ol Cell Bi ol. 2 0 0 5; 2 5( 2 1): 9 5 4 3 – 5 3.  
Pil o n -T h o mas S, Mac ka y A, V o hra N, M ule JJ. Bl oc ka de of pr o gra m me d deat h li ga n d 1 e n ha nces t he t hera pe utic 
efficac y of c o m bi nati o n i m m u n ot hera p y a gai nst mela n o ma. J I m m u n ol. 2 0 1 0; 1 8 4( 7 ): 3 4 42 – 9 . 
P ol o vic h M, Olse n M, Le Fe b vre K B. I nf usi o n -relate d c o m plicati o ns. C he m ot hera p y a n d bi ot hera p y g ui deli nes a n d 
rec o m me n dati o ns f or practice. ( F o urt h e diti o n). Pitts b ur g h, P e n ns yl va nia, O nc ol o g y N ursi n g S ociet y. 2 0 1 4: 1 5 5 – 7 0.  
Rile y J L. P D -1 si g nali n g  i n pri mar y T cells. I m m u n ol Re v. 2 0 0 9; 2 2 9( 1): 1 14 – 2 5.  
R o bert C, Ri bas A, W olc h o k J D, et al. A nti -pr o gra m me d -de at h -rece pt or-1 treat me nt wit h pe m br oliz u ma b i n 
i pili m u ma b-refract or y a d va nc e d mela n o ma: a ra n d o mise d d ose-c o m paris o n c o h ort of a p hase 1 trial. La ncet. 
2 0 1 4; 3 8 4( 9 9 4 8): 1 1 0 9 – 1 7.  
R o bert C, Sc hac hter J, L o n g G V, et al. P e m br oliz u ma b vers us i pili m u ma b i n a d va nce d mela n o ma. N E n gl J Me d. 
2 0 1 5; 3 7 2( 2 6): 2 5 2 1 – 3 2.  
R osell o S, Blasc o I, Garcia Fa bre gat L, et al. Ma na ge me nt of i nf usi o n reacti o ns t o s yste mi c a ntic a ncer t hera p y: 
E S M O Cli nical Practice G ui d eli nes. A n n O nc ol. 2 0 1 7; 2 8( S u p pl 4):i v 1 0 0 – 1 8.  
R uter J, A nt o nia SJ, B urris H A, H u h n R D, V o n der hei de R H. I m m u ne m o d ulati o n wit h wee kl y d osi n g of a n a g o nist 
C D 4 0 a nti b o d y i n a p hase I st u d y of patie nts wit h a d va nce d s oli d t u m ors. Ca ncer Bi ol T her. 2 0 1 0; 1 0( 1 0): 9 8 3 – 9 3.  
Sca gli otti G V, P ari k h P, v o n P a wel J, et al. P hase III st u d y c o m pari n g cis plati n pl us ge mcita bi ne wit h cis plati n pl us 
pe metre xe d i n c he m ot hera p y -nai ve patie nts wit h a d va nce d -sta ge n o n-s mall-cell l u n g ca nc er. J Cli n O nc ol. 
2 0 0 8; 2 6( 2 1): 3 5 4 3 – 5 1.  
Sc haer D A, Gee ga na ge S, A mala d as N, et al. T he f olate pat h wa y i n hi bit or pe metre xe d plei otr o picall y e n ha nces 
effects of ca ncer i m m u n ot hera p y. Cli n Ca ncer Res. 2 0 1 9; 2 5( 2 3): 7 1 7 5 – 8 8.  
Sc hiller J H, Harri n gt o n D, B ela ni C P, et al. C o m paris o n of f o ur c he m ot hera p y re gi me ns f or a d va nce d n o n -s mall-cell 
l u n g ca ncer. N E n gl J Me d. 2 0 0 2; 3 4 6( 2): 92 – 8 . 
Se y m o ur L, B o gaerts J, P err o ne A, et al. i R E CI S T: g ui deli nes f or res p o nse criteria f or use i n trials testi n g 
i m m u n ot hera p e utics. La ncet O nc ol. 2 0 1 7; 1 8( 3):e 1 4 3 – 5 2.  
S he p par d K A, Fitz LJ, Lee J M, et al. P D -1 i n hi bits T -cell r ece pt or i n d uce d p h os p h or ylati o n of t he Z A P 7 0/ C D 3zeta 
si g nal os o me a n d d o w nstrea m si g nali n g t o P K Ct heta. F E B S Lett. 2 0 0 4; 5 7 4( 1 – 3 ): 37 – 4 1.  
S pra n ger S, K o blis h H K, H ort o n B, et al. Mec ha nis m of t u m or rej ecti o n wit h d o u blets of C T L A -4, P D -1/ P D -L 1, or 
I D O bl oc ka d e i n v ol ves rest ore d I L-2 pr o d ucti o n a n d pr oliferati o n of C D 8( +) T cells directl y wit hi n t he t u m or 
micr oe n vir o n me nt. J I m m u n ot her Ca ncer. 2 0 1 4; 2: 3.  
Str o me S E, D o n g H, T a m ura H, et al. B 7 -H 1 bl oc ka de a u g me nts a d o pti ve T -cell i m m u n ot hera p y f or s q ua m o us cell 
carci n o ma. Ca ncer Res. 2 0 0 3; 6 3( 1 9): 6 5 0 1 – 5 . 
S u n F, C ui L, Li T, et al. O xali plati n i n d uces i m m u n o ge nic cells deat h a n d e n ha nces t hera pe utic efficac y of 
c hec k p oi nt i n hi bit or i n a m o del of m uri ne l u n g carci n o ma. J Rece pt Si g nal Tra ns d uct Res. 2 0 1 9; 3 9( 3): 2 08 – 1 4.  
T o n g A W, St o ne MJ. Pr os pects f or C D 4 0 -directe d e x peri me ntal t hera p y of h u ma n ca ncer. Ca ncer Ge ne T her. 
2 0 0 3; 1 0( 1): 1 – 1 3.  
T o palia n S L, H o di F S, Bra h mer J R, et al . Safet y, acti vit y, a n d i m m u ne c orrelates of a nti-P D -1 a nti b o d y i n ca ncer. N 
E n gl J Me d. 2 0 1 2; 3 6 6( 2 6): 2 4 4 3 – 5 4.  
va n K o ote n C, B a nc herea u J. F u ncti o ns of C D 4 0 o n B cells, de n dritic cells a n d ot her cells. C urr O pi n I m m u n ol. 
1 9 9 7; 9( 3): 3 3 0 – 7 . 
va n K o ote n C, B a nc herea u J. C D 4 0 -C D 4 0 li ga n d. J Le u k oc Bi ol. 2 0 0 0; 6 7( 1): 2 – 1 7.  
V o n der hei de R H, B aj or D L, Wi n o gra d R, et al. C D 4 0 i m m u n ot hera p y f or pa ncreatic ca ncer. Ca ncer I m m u n ol 
I m m u n ot her. 2 0 1 3a; 6 2( 5): 9 49 – 5 4.  
V o n der hei de R H, B ur g J M, Mic k R, et al. P hase I st u d y of t he C D 4 0 a g o nist a nti b o d y C P -8 7 0, 8 9 3 c o m bi ne d wit h 
car b o plati n a n d paclita xel i n p atie nts wit h a d va nce d s oli d t u m ors. O nc oi m m u n ol o g y. 2 0 1 3 b; 2( 1):e 2 3 0 3 3.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 4  of 1 3 5  
W e b er J. I m m u ne c hec k p oi nt pr otei ns: a ne w t hera pe utic para di g m f or ca ncer --precli nical bac k gr o u n d: C T L A -4 a n d 
P D -1 bl oc ka d e. Se mi n O nc ol. 2 0 1 0; 3 7( 5): 4 3 0 – 9 . 
Wi n gett D G, Vestal R E, F orcier K, Ha dj o kas N, Niels o n C P. C D 4 0 is f u ncti o nall y e x press e d o n h u ma n breast 
carci n o mas: varia ble i n d uci bilit y b y c yt o ki nes a n d e n ha nce me nt of Fas -me diate d a p o pt osis. Breast Ca nce r Res 
Treat. 1 9 9 8; 5 0( 1): 2 7 – 3 6.  
Wi n o gra d R, B yr ne K T, E va ns R A, et al. I n d ucti o n of T -cell i m m u nit y o verc o mes c o m plet e resista nce t o P D -1 a n d 
C T L A -4 bl oc ka d e a n d i m pr o ves s ur vi val i n pa ncreatic carci n o ma. Ca ncer I m m u n ol Res. 2 0 1 5; 3( 4): 3 9 9 – 4 1 1.  
Ze n g W, Neff -Laf or d H, A nsari S, et al. S y ner g y bet wee n S E A -C D 4 0 a n d c he m ot hera pe utics dri ves c urati ve 
a ntit u m or acti vit y i n precli nic al m o dels. J I m m u n ot her Ca nc er. 2 0 2 0; 8( S u p pl 3): A 4 5 4.  
Z ha n g X, Sc h wartz J C, G u o X, et al. Str uct ural a n d f u ncti o nal a nal ysis of t he c os ti m ulat or y rece pt or pr o gra m me d 
deat h -1. I m m u nit y. 2 0 0 4; 2 0( 3): 3 3 7 – 4 7.  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 5  of 1 3 5  
A P P E N DI X  A.  
P E R F O R M A N C E  S T A T U S  S C A L E S  C O N V E R SI O N  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 6  of 1 3 5  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 7  of 1 3 5  
A P P E N DI X  B.  
C O N T R A C E P TI V E  A N D  B A R RI E R  G UI D A N C E  
Defi niti o ns of Re pr o d ucti ve P ote nti al  
A pers o n of c hil d beari n g p ote ntial is a n y o ne w h o has e x perie nce d m e narc h e a n d w h o has n ot 
u n der g o ne per ma ne nt  steriliz ati o n (e g, h ysterect o m y, bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y) or h as n ot c o m plete d me n o pa use. Me n o pa use is defi n e d cli nicall y as 1 2  m o n t hs 
of a me n orr hea i n a p ers o n o ver a ge 4 5 i n t he a bse nce of ot her bi ol o gical, p h ysi ol o gical, or 
p har mac ol o gic al ca uses.  
A s u bject w h o ca n get s o me o ne pre g n a nt is a n y o n e w h o has testes a n d w h o has n ot u n der g o ne  
per ma ne nt  steriliz ati o n ( defi ne d as bilateral orc hi dect o m y).  
Birt h C o ntr ol/ C o ntr ace pti ve G ui d a nce  
F or t he p ur p os es of t his g ui da nce, c o m plete a bsti ne nce, if c o nsiste nt wit h t he s u bject’s preferre d 
lifest yle, is a hi g hl y effecti ve met h o d  of birt h c o ntr ol ( c o ntrace pti o n ). C o m plete a bsti ne nce is 
defi ne d as a bsti ne nce starti n g fr o m t he ti me of i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he 
st u d y a n d u ntil t he e n d of s yste mic e x p os ure (see  Secti o n  4. 1 ). 
Acce pt a ble Effecti ve Met h o ds of Birt h C o ntr ol ( C o ntr ace pti o n)  
S u bjects w h o are of c hil d beari n g p ote ntial or w h os e part ners are of c hil d beari n g p ote ntial, a n d 
w h o are s e x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g na nc y m ust c h o os e T W O of t he 
f oll o wi n g acce pt a ble met h o ds of birt h c o ntr ol (c o ntrace pti o n), at least O N E  of w hic h m ust be  
hi g hl y effecti ve : 
Hi g hl y Effecti ve M et h o ds of Birt h C o ntr ol  
Effecti ve M et h o ds of Birt h C o ntr ol  
A bsti ne nce (as defi ne d a b o ve).  
Pr o gest o ge n -o nl y oral 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.  
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) oral, 
i ntra va gi nal, or tra ns der mal h or m o nal c o ntrace pti o n 
wit h i n hi biti o n of o v ulati o n.  
Male or fe male c o n d o m wit h or wit h o ut s per mici de.  
Oral, i m pla nta ble, or i nj ecta ble pr o gest o ge n -o nl y 
h or m o nal c o ntrace pti o n ass oci ate d wit h i n hi biti o n of 
o v ulati o n.  
Ca p, dia p hra g m, or s p o n ge wit h s per mici de.  
I ntra uteri ne h or m o ne-releasi n g s yste m. 
A c o m bi nati o n of a male c o n d o m wit h eit her a ca p, 
dia p hra g m, or s p o n ge wit h s per mici de ( d o u ble barrier).  
I ntra uteri ne de vice with fail ure rate < 1 %.  
Bilateral t u bal occl usi o n/li gati o n.  
Vasect o m y (at least 9 0  da ys fr o m t he date of s ur ger y 
wit h a se me n a nal ysis d oc u me nti n g az o os per mia) . 
T he f oll o wi n g met h o ds of birt h c o ntr ol (c o ntr a ce pti o n) are n ot c o nsi dere d acce pt a ble or 
effecti ve 
•  Peri o dic a bsti ne nce (cal e n dar, s y m pt ot her mal, p ost-o v ulati o n met h o ds)  
•  Wit h dra wal (c oit us i nterr u pt us)  
•  S per mici des o nl y  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 8  of 1 3 5  
•  Lactati o nal a me n orr hea met h o d ( L A M)  
Acce pt a ble met h o ds f or pre ve nti n g sec o n d ar y e x p os ure t o se mi n al fl ui d  
S u bjects b or n male a n d w h o are s e x uall y acti ve wit h a pre g na nt pers o n m ust use a male c o n d o m 
(e ve n if t he s u bject has h a d a vasect o m y). 
S u bjects b or n male a n d w h o are s e x uall y acti ve wit h a breastf ee di n g pers o n m ust use a male 
c o n d o m (e ve n if t h e s u bject has ha d a vasect o m y) . I n a d diti o n, it is rec o m me n de d t hat t he 
breastfee di n g part n er use a hi g hl y effecti ve fe m ale c o ntrace pti ve met h o d as liste d i n secti o n 
“ Acce pta ble Effecti ve Met h o ds of Birt h C o ntr ol ( C o ntrace pti o n)”.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 0 9  of 1 3 5  
A P P E N DI X  C.  
N E W Y O R K H E A R T A S S O C I A TI O N F U N C TI O N A L 
C L A S SI FI C A TI O N O F  H E A R T F AI L U R E  
O nli ne s o urce: htt ps:// w w w. he art. or g/e n/ healt h -t o pics/ heart-fail ure/ w hat-is-heart -fail ure/classes-of -heart -fail ure 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 0  of 1 3 5  
A P P E N DI X  D.  
IM M U N E -B A S E D  R E S P O N S E  E V A L U A TI O N  C RI T E RI A  F O R  
S O LI D  T U M O R S  A N D  R E CI S T  V E R SI O N  1. 1  
Res p o nse E val uati o n Criteria f or S oli d T u m ors 
( R E CI S T) Versi o n 1. 1 
(Eise n ha uer 2 0 0 9 ) 
M o difie d R E CI S T 1. 1 f or I m m u ne -base d T hera pe utics 
(i R E CI S T) 
(Se y m o ur 2 0 1 7 ) 
T er m  
Defi niti o n  
T er m  
Defi niti o n  
C o m plete 
res p o nse ( C R) 
•  
Disa p peara nce of all tar get 
lesi o ns. A n y pat h ol o gical 
l y m p h n o des ( w het her tar get 
or n o n -tar get) m ust ha ve 
re d ucti o n i n s h ort a xis t o 
< 1 0  m m  
•  
Ca n n ot ha ve pre vi o usl y met 
criteria f or P D  
•  
C o nfir mati o n re q uire d o nl y 
f or n o n-ra n d o mize d st u dies 
i C R ( b ot h 
tar get a n d 
n o n -tar get 
lesi o ns) 
•  
Defi ne d per R E CI S T 1. 1 criteria  
•  
Ca n be assi g ne d f oll o wi n g i U P D 
( b ut n ot i C P D) 
•  
C o nfir mati o n per R E CI S T 1. 1  
 
 
 
P artial res p o nse 
( P R) 
•  
A ≥3 0 % decrease i n t he s u m 
of dia meters of tar get lesi o ns 
(l o n gest f or n o n -n o dal tar get 
lesi o ns a n d t he s h ort a xes f or 
n o dal tar get lesi o ns), ta ki n g 
as refere nce t he baseli ne s u m 
dia meters  
•  
Ca n n ot ha ve pre vi o usl y met 
criteria f or P D 
•  
C o nfir mati o n re q uire d o nl y 
f or n o n-ra n d o mize d st u dies 
i P R (tar get 
lesi o ns o nl y) 
•  
Defi ne d per R E C I S T 1. 1 criteria 
•  
Ca n be assi g ne d f oll o wi n g i U P D 
( b ut n ot i C P D) 
•  
C o nfir mati o n per R E CI S T 1. 1  
 
 
 
Sta ble disease 
( S D) 
•  
Neit 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 dia meters 
w hile o n st u d y  
•  
Ca n n ot ha ve pre vi o usl y met 
criteria f or P D 
•  
C o nfir mati o n is n ot re q uire d  
i S D (tar get 
lesi o ns o nl y) 
•  
Defi ne d per R E CI S T 1. 1 criteria  
•  
Ca n be assi g ne d f oll o wi n g i U P D 
( b ut n ot i C P D) 
•  
C o nfir mati o n per R E CI S T 1. 1  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 1  of 1 3 5  
Res p o nse E val uati o n Criteria f or S oli d T u m ors 
( R E CI S T) Versi o n 1. 1 
(Eise n ha uer 2 0 0 9 ) 
M o difie d R E CI S T 1. 1 f or I m m u ne -base d T hera pe utics 
(i R E CI S T) 
(Se y m o ur 2 0 1 7 ) 
T er m  
Defi niti o n  
T er m  
Defi niti o n  
 
—  
N o n -i C R/ 
n o n -i U P D 
( n o n-tar get 
lesi o ns o nl y) 
•  
Neit her C R n or P D criteria met per 
R E CI S T 1. 1  
•  
Ca n be assi g ne d f oll o wi n g i U P D 
( b ut n ot i C P D) 
•  
O verall res p o nse assi g ne d base d o n 
tar get lesi o ns 
Pr o gressi ve 
disease ( P D)  
•  
A ≥2 0 % relati ve i ncrease i n 
t he s u m of dia meters of 
tar get lesi o ns, ta ki n g as 
refere nce t he s mallest s u m 
o n st u d y (i ncl u di n g baseli ne 
s u m if t hat is t he s mallest o n 
st u d y). I n a d diti o n, t he s u m 
m ust als o de m o nstrate a n 
a bs ol ute i ncrease ≥5  m m  
•  
T he a p peara nce of 1 or m ore 
ne w lesi o ns is als o 
c o nsi dere d pr o gressi o n  
•  
C o nfir mati o n is n ot  re q uire d 
u nless e q ui v ocal  
U nc o nfir me
d P D (i U P D) 
( b ot h tar get 
a n d 
n o n -tar get 
lesi o ns) 
•  
Pr o gressi o n defi ne d per R E CI S T 
1. 1 criteria  
•  
C o nfir mati o n of pr o gressi o n is 
re q uire d 
•  
Pr o gressi o n c o nfir me d b y ( 1) 
f urt her i ncrease i n size or n u m ber 
of ne w lesi o ns i n cate g or y (ie, 
tar get or n o n-tar get) i n w hic h 
pr o gressi o n was first i de ntifie d O R 
( 2) pr o gressi o n per R E CI S T 1. 1 i n 
lesi o n cate g ories t hat ha d n ot 
pre vi o usl y met P D criteria  
•  
If pr o gressi o n is n ot c o nfir me d 
A N D t u m or s hri n ka ge occ urs 
c o m pare d t o baseli ne (ie, i C R, i P R, 
or i S D criteria met), t he stat us is 
reset a n d i U P D m ust occ ur a gai n 
(c o m pare d t o na dir val ues) a n d be 
c o nfir me d b y f urt her gr o wt h at 
ne xt assess me nt f or i C P D t o be 
assi g ne d 
•  
If pr o gressi o n is n ot c o nfir me d 
A N D n o c ha n ge i n t u m or size or 
e xte nt fr o m i U P D occ urs, t he n 
res p o nse w o ul d a gai n be i U P D 
•  
i U P D ca n be assi g ne d m ulti pl e 
ti mes as l o n g as i C P D is n ot 
c o nfir me d at ne xt assess me nt  
 
 
 
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 2  of 1 3 5  
Res p o nse E val uati o n Criteria f or S oli d T u m ors 
( R E CI S T) Versi o n 1. 1 
(Eise n ha uer 2 0 0 9 ) 
M o difie d R E CI S T 1. 1 f or I m m u ne -base d T hera pe utics 
(i R E CI S T) 
(Se y m o ur 2 0 1 7 ) 
T er m  
Defi niti o n  
T er m  
Defi niti o n  
 
 
 
 
 
—  
C o nfir me d 
P D (i C P D) 
( b ot h tar get 
a n d 
n o n -tar get 
lesi o ns) 
•  
Pr o gressi o n c o nfir me d as descri be d 
f or i U P D 
•  
Criteria f or i C P D (after i U P D) are 
N O T met if C R, P R, or S D occ ur at 
assess me nt f oll o wi n g i U P D; t he 
stat us is reset 
Ne w 
meas ura ble or 
n o n -meas ura ble 
lesi o ns 
•  
Al wa ys re prese nt P D  
Ne w tar get 
or n o n -tar get 
lesi o ns 
•  
Res ult i n assi g n me nt of i U P D  
•  
F or ne w lesi o ns, i C P D is o nl y 
assi g ne d if at ne xt assess me nt ( 1) 
a d diti o nal ne w lesi o ns a p pear O R 
( 2) i ncrease d size of ne w lesi o ns is 
see n ( ≥5 m m f or s u m of ne w t ar get 
lesi o n, or a n y i ncrease i n ne w 
n o n -tar get lesi o n) O R ( 3) ne w 
lesi o ns a p pear w he n n o ne were 
pre v i o usl y rec or de d 
N o n -tar get 
lesi o ns 
•  
C ha n ges c o ntri b ute t o 
defi ni n g C R, P R, S D, a n d 
P D  
N o n -tar get 
lesi o ns 
•  
C ha n ges c o ntri b ute t o defi ni n g C R, 
n o n -i C R/ n o n-i C P D, i U P D, a n d 
i C P D 
C R =c o m plete res p o nse; i C P D =i m m u ne c o nfir me d pr o gressi ve disease; i C R =i m m u ne c o m plete res p o nse; 
i P R =i m m u ne partial res p o nse (tar get lesi o ns o nl y); i S D =i m m u ne sta ble disease (tar get lesi o ns o nl y); i U P D =i m m u ne 
u nc o nfir me d pr o gressi ve disease; n o n -i C R/ n o n-i U P D = neit her C R n or P D ( n o n-tar get lesi o ns o nl y); P D = pr o gressi ve 
disease; P R = p artial res p o nse; S D =sta ble disease.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 3  of 1 3 5  
A P P E N DI X  E.  
IN T E RI M  A N A L Y SI S  U SI N G  P R E DI C TI V E  P R O B A BI LI T Y  O F  
S U C C E S S  
I nteri m e val uati o n of effi cac y will be p erf or m e d s e parat el y f or eac h c o h ort after a p pr o xi matel y 
1 5  s u bjects of a gi ve n c o h ort ha ve bee n treate d a n d ha d at least o ne res p o nse assess me nt 
p ost -baseli ne. T he Ba yesia n pre dicti ve pr o b a bilit y of s uccess ( P P o S ) met h o d (Lee 2 0 0 8 a ) will be 
use d t o deter mi ne t he c o nti n uati o n criteria. P P o S  is t he pr o ba bilit y of ac hie vi n g “s uccess ” s h o ul d 
t he c o h ort be c o nti n ue d t o t he ma xi m u m sa m ple size of 4 0  gi ve n t he d ata o bser ve d at i nteri m, 
a n d a c o h ort is c o nsi dere d “s uccessf ul” if t he 9 0 % c o nfi de nce i nter val  ( CI) of t he res p o nse rate at 
t he ma xi m u m sa m ple size e x cl u des t he bac k gr o u n d rate. 
Usi n g t he P D -( L)1 -n ai ve  mela n o ma  c o h ort ( C o h ort 3 ) as a n e x a m ple, t he P P o S  is c o m p ute d as 
f oll o ws: 
1.  Let N m ax = 4 0  be t he ma xi m u m sa m ple siz e of a c o h ort, a n d n = 1 5 be t h e n u m ber of 
s u bjects treate d a n d e val uate d f or t he res p o nse stat us at t he ti me of i nteri m e val uati o n.  
2.  Ass u me t he pri or distri b uti o n of t he res p o nse rate p  f oll o ws a beta distri b uti o n 
p  ~ beta( a 0, b 0), wit h a 0 = 0. 4 1 a n d b 0 = 0. 5 9 t o reflect a pri or b elief t hat t he res p o nse rate 
f or t he st u d y treat me nt is half wa y bet w ee n t he bac k gr o u n d rate p 0= 3 3 % a n d t he esti mate d 
res p o nse rate t hat is 1 5 % hi g her ( 4 8 %). 
3.  Let X  b e t he n u m ber of res p o n ders i n t he first n  s u bjects, a n d X  f oll o ws a bi n o mial 
distri b uti o n X ~ bi n o mial( n, p). T he li keli h o o d f u n cti o n f or t he o bser ve d dat a x is 
L( p | X = x) 
 p x ( 1- p) n –  x 
4.  T he p osteri or distri b uti o n of t he res p o nse rate gi ve n X = x  f oll o ws a b eta distri b uti o n 
p | x ~ bet a( a 0 + x, b 0 + n –  x) 
5.  Let Y  be t he n u m ber of res p o n ders i n t he p ote ntial m  f ut ure s u bjects, w here m  = ( N m ax  –  
n ), t h us Y  f oll o ws a beta-bi n o mial distri b uti o n, Y ~ beta -bi n o mial ( m, a 0 + x, b 0 + n –  x).  
Gi ve n Y = i , t he p osteri or distri b uti o n of p  f oll o ws beta (a 0 + x + i, b 0 + N m ax  –  x –  i). 
6.  Let CI l be t he 9 0 % e x act CI  of  t he res p o nse rate p  usi n g t he Cl o p per -Pears o n met h o d , 
gi ve n x res p o n d ers i n t he first n  s u bjects a n d i res p o n ders i n t he m  f ut ure s u bjects. 
7.  C o m p ute P P o S  = 
Pr( Y  = i | x) 
 I(CI l > p 0)}.  
o  If P P o S  > 0. 0 5 , t he n t he c o h ort will c o nti n ue. If P P o S  < 0. 0 5 , t he n t he s p o ns or 
i n c o ns ultati o n wit h t he S M C ma y deci de t o st o p f urt her e nr oll me nt i n t he 
c o h ort after caref ul assess me nts of t he t otalit y of data.  
T he esti mate d P P o S  base d o n n u m ber of res p o n ders o bser ve d a m o n g t h e first 1 5  s u bjects are 
prese nte d i n  Ta bl e  1 . O p erati n g c haracteristics are prese nte d i n  Ta bl e 2 . 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 4  of 1 3 5  
T a bl e  1: E sti m at e d P P o S  B a s e d o n N u m b er of R e s p o n d er s A m o n g t h e Fir st 1 5  S u bj e ct s  
N u m ber of res p o n ders  
a m o n g first 1 5  s u bj ects 
C o h orts 1 a n d 2 
(p 0= 4 %)  
C o h ort 3 
(p 0= 3 3 %)  
C o h ort 4 
(p 0= 4 9 %)  
C o h ort 5 
(p 0= 3 2 %)  
0  
0. 0 0 4 4  
0. 0 0 0 0  
0. 0 0 0 0  
0. 0 0 0 0  
1  
0. 1 6 3 1  
0. 0 0 0 0  
0. 0 0 0 0  
0. 0 0 0 0  
2  
0. 5 4 6 7  
0. 0 0 0 3  
0. 0 0 0 0  
0. 0 0 0 3  
3  
0. 8 7 4 3  
0. 0 0 3 7  
0. 0 0 0 0  
0. 0 0 3 7  
4  
0. 9 8 7 0  
0. 0 2 3 6  
0. 0 0 0 1  
0. 0 2 3 4  
5  
1. 0 0 0 0  
0. 0 9 5 1  
0. 0 0 1 0  
0. 0 9 4 4  
6  
1. 0 0 0 0  
0. 2 5 8 3  
0. 0 0 8 4  
0. 2 5 7 0  
7  
1. 0 0 0 0  
0. 5 0 2 5  
0. 0 4 3 9  
0. 5 0 0 9  
8  
1. 0 0 0 0  
0. 7 4 5 2  
0. 1 5 0 9  
0. 7 4 3 9  
9  
1. 0 0 0 0  
0. 9 0 5 8  
0. 3 5 9 9  
0. 9 0 5 1  
1 0  
1. 0 0 0 0  
0. 9 7 6 0  
0. 6 2 5 0  
0. 9 7 5 8  
T he pri or distri b uti o n is ass u me d t o be beta ( 0. 1 2 , 0.8 8 ), beta ( 0.4 1 , 0.5 9 ), beta ( 0. 5 7 , 0.4 3 ), a n d beta ( 0. 4, 0. 6), 
res pecti vel y, t o a p pr o xi mate t he bac k gr o u n d rate i n eac h disease c o h ort.  
T he bac k gr o u n d rate i n C o h ort 1 is ass u me d t o be 4 % base d o n (Ha mi d 2 0 1 7 )  
T he bac k gr o u n d rate i n C o h ort 2 is ass u me d t o be 4 % base d o n (Al gazi 2 0 1 6 ) a n d (He p pt 2 0 1 7 ) 
T he bac k gr o u n d rate i n C o h ort 3 is ass u me d t o be 3 3 % base d o n (R o bert 2 0 1 5 ) 
T he bac k gr o u n d rate i n C o h ort 4  is ass u me d t o be 4 9 % base d o n  (Ga d geel 2 0 2 0 ) 
T he bac k gr o u n d rate i n C o h ort 5 is ass u me d t o be 3 2 % base d o n (Ga d geel 2 0 2 0 ) 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 5  of 1 3 5  
T a bl e 2: O p er ati n g C h ar a ct eri sti c s  
B ac k gr o u n d 
rate (p 0) 
Sce nari o  
Tr ue res p o nse rate 
Pr o ba bilit y of 
futilit y st o ppi n g  
Pr o ba bilit y of 
success  
A vera ge n u m ber 
of  s u bj ects 
4 %  
1  
5 %  
0. 4 6 3 3  
0. 0 4 8 0  
2 8. 4  
 
2  
1 0 %  
0. 2 0 5 9  
0. 3 7 1 0  
3 4. 9  
 
3  
1 5 %  
0. 0 8 7 4  
0. 7 3 6 7  
3 7. 8  
 
4  
2 0 %  
0. 0 3 5 2  
0. 9 2 4 1  
3 9. 1  
 
5  
2 5 %  
0. 0 1 3 4  
0. 9 8 4 0  
3 9. 7  
3 3 %  
1  
1 0 %  
0. 9 8 7 3  
0. 0 0 0 0  
1 5. 3  
 
2  
2 0 %  
0. 8 3 5 8  
0. 0 0 0 1  
1 9. 1  
 
3  
3 0 %  
0. 5 1 5 5  
0. 0 1 4 8  
2 7. 1  
 
4  
4 0 %  
0. 2 1 7 3  
0. 2 0 8 9  
3 4. 6  
 
5  
5 0 %  
0. 0 5 9 2  
0. 6 8 2 1  
3 8. 5  
4 9 %  
1  
3 0 %  
0. 9 5 0 0  
0. 0 0 0 0  
1 6. 3  
 
2  
4 0 %  
0. 7 8 6 9  
0. 0 0 1 2  
2 0. 3  
 
3  
5 0 %  
0. 5 0 0 0  
0. 0 4 0 3  
2 7. 5  
 
4  
6 0 %  
0. 2 1 3 1  
0. 3 1 7 4  
3 4. 7  
 
5  
7 0 %  
0. 0 5 0 0  
0. 8 0 7 4  
3 8. 7  
3 2 %  
1  
1 0 %  
0. 9 8 7 3  
0. 0 0 0 0  
1 5. 3  
 
2  
2 0 %  
0. 8 3 5 8  
0. 0 0 0 1  
1 9. 1  
 
3  
3 0 %  
0. 5 1 5 5  
0. 0 1 4 8  
2 7. 1  
 
4  
4 0 %  
0. 2 1 7 3  
0. 2 0 8 9  
3 4. 6  
 
5  
5 0 %  
0. 0 5 9 2  
0. 6 8 2 1  
3 8. 5  
T he pri or distri b uti o n is ass u me d t o be beta ( 0. 1 2, 0. 8 8), beta ( 0. 4 1, 0. 5 9), beta ( 0. 5 7, 0. 4 3), a n d beta ( 0. 4, 0. 6), 
res pecti vel y, t o a p pr o xi mate t he bac k gr o u n d rate i n eac h disease c o h ort. A c o h ort is c o nsi dere d “s uccessf ul” if t he 
9 0 % CI of t he res p o nse rate at t he ma xi m u m sa m ple size e xcl u des t he bac k gr o u n d rate.   
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 6  of 1 3 5  
A P P E N DI X  F.  
E U R O P E A N  O R G A NI S A TI O N  F O R  R E S E A R C H A N D 
T R E A T M E N T O F  C A N C E R  ( E O R T C) Q U A LI T Y -O F -LI F E 
Q U E S TI O N N AI R E F O R C A N C E R  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 7  of 1 3 5  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 8  of 1 3 5  
© C o p yri g ht 1 9 9 5 E O R T C Q ualit y of Lif e Gr o u p. All ri g hts res er ve d. Versi o n 3. 0  
  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 1 9  of 1 3 5  
A P P E N DI X  G.  
N O N -S M A L L C E L L L U N G  C A N C E R  S Y M P T O M  A S S E S S M E N T  
Q U E S TI O N N AI R E  ( N S C L C-S A Q) V 1. 0  
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 0  of 1 3 5  
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)
C O P Y RI G H T E D M A T E RI A L


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 1  of 1 3 5  
A P P E N DI X  H.  
P A TI E N T  G L O B A L  IM P R E S SI O N O F  S E V E RI T Y  ( P GI S) SC A L E  
Please c h o ose t he res p o nse bel o w t hat best descri bes t he se verit y of y o ur l u n g ca ncer s y m pt o ms 
o ver t he past w ee k.  
0  
 N o ne  
1  
 Mil d  
2  
 M o derate  
3  
 Se vere  
4  
 Ver y se v ere  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 2  of 1 3 5  
A P P E N DI X  I. 
P A TI E N T  G L O B A L  IM P R E S SI O N O F  C H A N G E  ( P GI C) SC A L E  
P lease c h o ose t he res p o nse bel o w t hat best descri bes t he o verall c ha n ge i n y o ur l u n g ca ncer 
s y m pt o ms si nce y o u start e d ta ki n g t h e st u d y me di cati o n. 
1  
 M uc h better  
2  
 A little better  
3  
 N o c ha n ge  
4  
 A little w orse  
5  
 M uc h w orse  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 3  of 1 3 5  
A P P E N DI X  J.  
IN V E S TI G A T O R  S I G N A T U R E P A G E  
In vesti g at or St ate me nt a n d Si g n at ure  
I h a ve rea d t he attac he d pr ot oc ol e ntitle d “A n O p e n -la bel, P hase 2 Bas k et St u d y of S E A -C D 4 0 
C o m bi nati o n T hera pies i n A d va nce d M ali g n a ncies ”  
I u n d ersta n d a n d a gree t o t he pr o visi o ns of t he pr ot oc ol, a n d I acce pt t he res p o nsi bilities liste d 
a b o ve i n m y r ole as pri n ci pal i n vesti gat or f or t he st u d y . 
 
 
 
I n vesti gat or Si g nat ure 
 
Date  
 
 
 
 
 
 
 
 
 
I n vesti gat or Na me, Pri nte d  
 
 
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 4  of 1 3 5  
A P P E N DI X  K.  
D O C U M E N T  H I S T O R Y 
Versi o n  
Date  
Ori gi nal  
0 6 -Ma y -2 0 2 1  
Gl o bal A me n d me nt 1  
1 0 -J u n-2 0 2 1  
Gl o bal A me n d me nt 2  
0 4 -A pr -2 0 2 2  
Gl o bal A me n d me nt 3  
0 5 -A pr -2 0 2 3  
 
S u m m ar y of C h a n ges i n A me n d me nt 1  
Secti o n(s)  
C h a n ge  
R ati o n ale  
5. 2. 2  
A d d S E A -C D 4 0 i nf usi o n rate a n d a p ost -d ose 
o bser vati o n peri o d after t he first i nf usi o n 
I ncl u de rele va nt i nf or mati o n fr o m t he P har mac y 
I nstr ucti o ns i n t he pr ot oc ol f or clarit y 
5. 2. 3  
A d d a d diti o nal g ui da nce f or A Es  re q uiri n g 
S E A -C D 4 0 disc o nti n uati o n  
Clarificati o n  
6. 3. 3. 2  
A d d o bser vati o n peri o d f oll o wi n g S E A -C D 4 0 
i nf usi o n 
Clarificati o n  
7. 7. 1. 3  
C ha n ge d re p orti n g peri o d f or all S A Es t o 
9 0  da ys p ost -last d ose 
Sta n dar dize S A E re p orti n g ti meli ne f or all st u d y 
dr u gs  
 
S u m m ar y of C h a n ges i n A me n d me nt 2  
Secti o n(s)  
C h a n ge  
R ati o n ale  
S y n o psis ; 
T a ble  1 , T a ble  2 , a n d T a ble  3 ; 
Secti o ns  3. 1. 1  a n d  4. 1  
I ncl usi o n criteri o n 1.a. vi has b ee n a d de d t o 
i n dicate t hat s u bj ects i n Fra nc e will n ot be 
e nr olle d i n C o h ort 1.  
T here is a differe nt sta n dar d of 
care i n Fra nce.  
S y n o psis;  
T a ble  1 , T a ble  3 , a n d T a ble 7 ; 
Secti o ns  6. 2. 3. 4  a n d  7. 7. 6   
F or C o h orts 1, 2, a n d 3 t he sec o n d d ose per 
c ycle a n d all acc o m pa n yi n g e val uati o ns will 
be d o ne o n Da y  2 2 ( n ot Da y  2 1)  
T o c orrect err or.  
S y n o psis;  
Secti o n  4. 1  
I ncl usi o n criteria 1.a. v has bee n a d de d s o 
t hat s u bj ects i n C o h ort 1 wit h a tar geta ble 
B R A F m utati o n m ust ha ve bee n treate d 
wit h, bee n i nt olera nt of, or decli ne d 
treat me nt wit h B R A F/ M E K tar gete d t hera p y 
pri or t o st u d y e ntr y.  
T o all o w i n vesti gat ors t o 
deter mi ne, i n part ners hi p wit h 
t he s u bj ects w het her 
B R A F/ M E K s h o ul d be 
a d mi nistere d pri or t o t he st u d y 
vers us reser vi n g t his treat me nt 
f or a s u bse q ue nt li ne of t hera p y. 
 
S y n o psis;  
Secti o n  3. 1. 3   
T he le n gt h of st u d y treat me nt f or s u bj ects 
w h o ac hie ve sta ble disease has bee n c ha n ge d 
fr o m “ 2 years” t o  “a p pr o xi mat el y 2  years”.  
T o all o w s u bj ects t o disc o nti n ue 
treat me nt at t he e n d of a c ycle. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 5  of 1 3 5  
Secti o n(s)  
C h a n ge  
R ati o n ale  
T a ble  1   
A f o ot n ote (I) has bee n a d de d t o i n dicate t he 
wi n d o w f or c ollecti o n of la b orat or y sa m ples 
is 3 da ys o n Da y  8  
C orrecti o n of o missi o n.  
T a ble  1  a n d T a ble  2  
A wi n d o w of ( ± 1  wee k) has b ee n a d de d f or 
C T sca ns c o m plete d after t he first 2 4  wee ks.  
C orrecti o n of o missi o n.  
T a ble  1  a n d T a ble  2 ; 
Secti o n  5. 8   
Ne w Secti o n 5. 8 a d de d t o all o w s u bj ects 
w h o disc o nti n ue 1 c o m p o ne nt of a 
c o m bi nati o n t hera p y b ut c o nti n ue o n a n ot her 
c o m p o ne nt t o s ki p or m o ve st u d y visit 
assess me nts o n da ys w he n t he disc o nti n ue d 
c o m p o ne nt w o ul d ha ve bee n a d mi nistere d.  
T o re d uce s u bj ect visit b ur de n 
i n t he e ve nt of disc o nti n uati o n 
of a si n gle treat me nt.  
T a ble  1  a n d T a ble  2 ; 
Secti o n  6. 1   
T he assess me nt “ uri nal ysis” has bee n 
c ha n ge d t o “ uri nal ysis, i ncl u di n g U P C 
rati o.” 
Clarificati o n.  
T a ble  1  a n d T a ble  2 ; 
Secti o ns  6. 5  a n d  7. 7. 6   
Pre g na nc y test after t he last d ose of st u d y 
dr u g will be perf or me d m o nt hl y  or per l oc al 
re g ul ati o ns. 
Clarificati o n.  
T a ble  1  a n d T a ble  2 ; 
Secti o ns  6. 5  a n d  7. 7. 1. 3   
C he mistr y a n d t h yr oi d pa nels ha ve bee n 
a d de d t o assess me nts re q uire d f or t he first 
f oll o w-u p visit.  
T e xt has bee n u p date d/a d de d t o c ollect S A Es 
f or 9 0 da ys after t he last st u d y treat me nt a n d 
ir A Es will be c ollecte d t hr o u g h t he first 
f oll o w-u p visit. If a s u bj ect starts a ne w 
a ntica ncer t hera p y, c ollecti o n of S A Es t hat 
are n ot relate d t o st u d y treat me nt a n d ir A Es 
ma y be st o p pe d 3 0  da ys after t he cessati o n 
of st u d y treat me nt. St u d y treat me nt -relate d 
S A Es t hat oc c ur after t he safet y re p orti n g 
peri o d s h o ul d als o be re p orte d t o t he 
s p o ns or. 
T o f urt her e ns ure s u bj ect safet y 
b y e xte n di n g t he ti me t o c olle ct 
i m m u ne-relate d A Es . 
T a ble  1  a n d T a ble  2 ; 
Secti o n  6. 6   
T he ti mi n g of t he first s ur vi val f oll o w -u p 
visit has bee n  c ha n ge d fr o m 1  m o nt h t o 
1 2  wee ks ( ± 1  wee k) after t he l ast 
ra di o gra p hic sca n t hat de m o nstrates disease 
pr o gressi o n or fr o m i nitiati o n of a ne w 
a ntica ncer treat me nt. T he ti mi n g of 
s u bse q ue nt s ur vi val f oll o w-u p visit has bee n 
c ha n ge d fr o m m o nt hl y t o e ver y 1 2  wee ks 
(± 1  wee k).  
T o re d uce s u bj ect b ur de n.  
T a ble  3  a n d T a ble  5  
T he wi n d o w f or all pre d ose sa m ples has 
bee n c ha n ge d fr o m “ – 4  h o urs” t o “ wit hi n 
4  h o urs pri or t o”.  
F o ot n ote place me nt a n d n u m b eri n g has bee n 
m o difie d.  
Clarificati o n.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 6  of 1 3 5  
Secti o n(s)  
C h a n ge  
R ati o n ale  
T a ble  3  a n d T a ble  5   
A n ote has bee n a d de d t o i n dicate t hat if 
c ollecti o n kits are n ot a vaila ble o n t he 
i nte n de d c ollecti o n da y, t he sa m ple ma y be 
o mitte d i n c o ns ultati o n wit h t he s p o ns or.  
T o all o w f or misse d 
assess me nts base d o n kit 
s u p pl y. 
T a ble  3   
T he Da y 1 e n d of i nf usi o n w i n d o w f or P K 
sa m ple c ollecti o n has bee n i ncrease d fr o m 
1 5  mi n utes t o 3 0  mi n utes.  
T o all o w s ufficie nt ti me f or t he 
e n d of i nf usi o n E C G.  
Secti o n  4. 1   
I ncl usi o n criteri o n 1.a.ii has bee n m o difie d 
t o i n dicate t hat pri or a dj u va nt/ ne oa dj u va nt 
i m m u n ot hera p y ma y n ot c o u nt as a li ne of 
pri or t hera p y.  
Clarificati o n.  
Secti o n  4. 1   
I ncl usi o n Criteria 1.a.i v a n d 1. b.iii ha ve bee n 
m o difie d t o i n dicate t hat, f or s u bj ects 
e ntere d i nt o t he st u d y after e nr oll me nt f or 
t he i nteri m a nal ysis is c o m plet e d, fres h 
bi o ps y sa m pli n g is preferre d; h o we ver, a n 
arc hi val sa m ple ma y be s u bstit ute d f or a 
fres h baseli ne sa m ple if it is i n t he s u bj ect’s 
best i nterest.  
Clarificati o n.  
Secti o n  4. 1   
T he f oll o wi n g has bee n a d de d t o i ncl usi o n 
criteri o n 1.c.ii: S u bj ects wit h a tar geta ble 
B R A F m utati o n w h o are ra pi dl y pr o gressi n g 
s h o ul d be treate d wit h B R A F/ M E K tar gete d 
t hera p y t o sta bilize disease pri or t o st u d y 
e ntr y, u nless c o ntrai n dicate d.  
T o ali g n wit h i nter nati o nal 
sta n dar d of care. 
Secti o n  4. 1   
I ncl usi o n criteri o n 2 has bee n m o difie d t o 
all o w a fres h t u m or bi o ps y at baseli ne if 
arc hi val tiss ue is n ot a vaila ble.  
T o all o w fres h t u m or bi o ps y at 
baseli ne a n d ali g n t his criteri o n 
wit h criteria 1.a.i v a n d 1. b.iii 
a n d wit h Secti o n 7. 4.  
Secti o n  4. 1   
I ncl usi o n criteri o n 6 has bee n m o difie d t o 
re quire a n A N C ≥2 0 0 0  μ L  f or s u bj ects i n 
C o h orts 4 a n d 5.  
T o ali g n wit h re q uire me nt f or 
si milar a ge nts w he n use d i n 
N S C L C.  
Secti o n  4. 2   
E xcl usi o n criteri o n 1 5  has bee n delete d.  
T his criteri o n is alrea d y c o ver e d 
i n greater detail i n I ncl usi o n 
criteri o n 7.  
Secti o ns  4. 2 , 5. 3 , a n d 5. 4. 3 ; 
T a ble 8   
F or C o h orts 4 a n d 5, t he f oll o wi n g 
pr o hi bite d c o nc o mita nt me dic ati o ns ha ve 
bee n a d de d:  
•  
Yell o w fe ver vacci nes.  
•  
I b u pr ofe n or ot her n o n-ster oi dal 
a nti -i nfla m mat or y dr u gs ( N S AI Ds) 
(i ncl u di n g pre me dicati o n) i n p atie nts 
wit h Cr Cl < 8 0  m L/ mi n, d uri n g t he 
F or c o nsiste nc y wit h c urre nt 
pe metre xe d a n d car b o plati n 
S u m maries of Pr o d uct 
C haracteristics ( S m P Cs).  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 7  of 1 3 5  
Secti o n(s)  
C h a n ge  
R ati o n ale  
3 2  da ys bef ore, t he da y of, a n d 2  da ys 
after pe metre xe d a d mi nistrati o n.  
•  
L o n g acti n g N S AI Ds (s uc h as 
pir o xica m or r ofec o xi b) f or 5  da ys 
bef ore, t he da y of, a n d 2  da ys after 
pe metre xe d a d mi nistrati o n.  
Secti o n  5   
Secti o n rec o nfi g ure d t o clarif y d ose 
m o dificati o ns  
Clarificati o n.  
Secti o n  5. 1. 1. 2   
T he refere nce t o o verall S E A -C D 4 0 i nf usi o n 
d urati o n of u p t o 1 0  h o urs has bee n delete d.  
T o c orrect i nc o nsiste nc y wit h 
t he p har mac y ma n ual. 
Secti o n  5. 1. 1. 2   
T he ter m “c ycles” has bee n c ha n ge d t o 
“ d oses.” 
T o c orrect err or as s o me 
re gi me ns i ncl u de m ore t ha n 1 
d ose i n a c ycle.  
Secti o n  5. 1. 3. 2   
S o urce f or pe metre xe d a n d car b o plati n 
s pecifie d b y c o u ntr y. 
Clarificati o n.  
Secti o n  5. 1. 3. 3   
T e xt m o difie d t o i n dicate t hat Cr Cl s h o ul d 
be calc ulate d usi n g t he C oc kcr oft -Ga ult 
e q uati o n.  
T o c orrect err or.  
Secti o n  5. 2. 1  a n d  
T a ble 7   
T he d ose m o dificati o n a n d t o xicit y 
ma na ge me nt f or ir A Es ha ve b ee n u p date d t o 
i ncl u de t hat s uc h t o xicit y ma y be ass ociate d 
wit h pe m br oliz u ma b a n d/ or S E A -C D 4 0.  
Clarificati o n.  
Secti o n  5. 3   
C ortic oster oi d pre me dicati o n f or pe metre xe d 
d ose has bee n c ha n ge d fr o m 2 0  m g t o 1 0 t o 
2 0  m g . 
T o all o w fle xi bilit y i n 
pr o p h yla xis d osi n g.  
Secti o n  5. 3   
T e xt has bee n m o difie d t o i n di cate t he 
s u g geste d a ntie metic t hera p y a p plies t o 
N S C L C s u bj ects d uri n g t he first 4  wee ks of 
treat me nt wit h car b o plati n.  
Clarificati o n.  
Secti o n s 5. 3  a n d  5. 4. 3  
A d de d te xt t o clarif y t hat 
i m m u n os u p pressi ve me dicati o ns, s uc h as 
ster oi ds, ma y n ot be use d as pr o p h yla xis f or 
I R Rs o n da ys w here S E A -C D 4 0 is 
a d mi nistere d.  
Clarificati o n.  
Secti o n  5. 4. 2   
A d de d t hat use of b o ne m o dif yi n g a ge nts, 
w he n a p plica ble, is all o we d.  
Clarificati o n.  
Secti o n  5. 5. 4   
Ne w secti o n a d de d f or ma na ge me nt of 
oc ular e ve nts.  
S u bj ect safet y.  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 8  of 1 3 5  
Secti o n(s)  
C h a n ge  
R ati o n ale  
Secti o n  5. 7   
Ne w secti o n a d de d o utli ni n g c o n diti o ns f or 
c o nti n ue d access t o st u d y dr u g after t he e n d 
of t he st u d y.  
T o all o w f or c o nti n ue d access t o 
st u d y dr u g f or s u bj ects w h o are 
be nefiti n g fr o m treat me nt.  
Secti o n  6. 2. 1   
T e xt a d de d t o all o w pr oce d ures c o n d ucte d as 
part of a s u bj ect’s r o uti ne cli ni cal 
ma na ge me nt a n d bef ore e xec uti o n of 
i nf or me d c o nse nt ma y be use d f or scree ni n g 
or baseli ne p ur p oses.  
T o re d uce s u bj ect b ur de n.  
Secti o n  6. 2. 1   
T e xt a d de d t o all o w s u bj ects t o be 
rescree ne d o nce. 
T o all o w rescree ni n g.  
Secti o ns  6. 2. 1 , 
 6. 2. 3 , 6. 3. 1 , 6. 3. 2 , 6. 3. 3 , a n d 
6. 4   
Eac h secti o n has m o difie d t o clarif y t hat 
P R O assess me nts will be c olle cte d f or 
s u bj ects e ntere d i n t he st u d y after e nr oll me nt 
f or t he i nteri m a nal ysis has bee n c o m plete d. 
Clarificati o n a n d t o ma ke t hes e 
secti o ns c o nsiste nt wit h t he 
Sc he d ule of E ve nts a n d 
Secti o n  6  
Secti o n  6. 2. 3. 3 , 6. 2. 3. 4 , 
6. 3. 3. 1 , 6. 3. 3. 2 , a n d 7. 7. 2   
Pre - a n d p ost -d ose vital si g ns  a n d/ or 
wi n d o ws a d de d/ u p date d as a p pr o priate  
T o c orrect o missi o n a n d e ns ur e 
c o nsiste nc y.  
Secti o n  6. 5  
C T/ M RI sca n la n g ua ge has bee n m o difie d t o 
i n dicate sca ns of t he c hest, a b d o me n, a n d 
pel vis are re q uire d f or C o h orts 1 – 3  a n d 
sca ns of t he c hest a n d a b d o me n are re q uire d 
f or C o h orts 4 a n d 5. 
T o c orrect err or a n d ma ke te xt 
c o nsiste nt wit h t he res pecti ve 
Sc he d ules of E ve nts.  
Secti o n  7. 2   
T e xt has bee n u p date d t o i n dic ate t hat c o pies 
of t u m or i ma ges will be f or war de d t o t he 
s p o ns or/ desi g nee per t he instr ucti o ns i n t he 
ce ntral i ma gi n g ma n ual.  
Clarificati o n.  
Secti o n  7. 7. 1. 2   
C ha n ge d t he pre g na nc y re p orti n g ti meli ne 
fr o m wit hi n 4 8 h o urs t o wit hi n 2 4  h o urs of 
bec o mi n g a ware of a pre g na nc y.  
S u bj ect safet y.  
Secti o n  7. 7. 3   
H b A 1c has bee n a d de d t o t he list of 
la b orat or y tests. 
T o ma ke c o nsiste nt wit h t he 
Sc he d ule of E ve nts a n d 
Secti o n  6.  
Secti o n  7. 7. 3   
A d de d t hat sta n dar d uri nal ysis i ncl u des 
pr otei n, gl uc ose, le u k oc yte est erase, p H, 
s pecific gra vit y, a n d bl o o d. 
Gl uc ose has bee n a d de d t o t he list of tests i n  
t he c he mistr y pa nel 
Clarificati o n.  
Secti o n  7. 7. 6   
A d de d t hat pre g na nc y testi n g will be d o ne 
o nce a m o nt h f or 1 2 0  da ys aft er t he last d ose 
of st u d y dr u g f or s u bj ects i n C o h orts 1, 2, 
a n d 3 a n d o nce a m o nt h f or 6  m o nt hs after 
t he last d ose of st u d y dr u g f or s u bj ects i n 
C o h orts 4 a n d 5, or per l ocal re g ulati o ns, 
w here a p plica ble  
T o ma ke c o nsiste nt wit h 
pre g na nc y testi n g re q uire me nts 
i n t he Secti o ns 4 a n d 6. 5. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 2 9  of 1 3 5  
Secti o n(s)  
C h a n ge  
R ati o n ale  
Secti o n  9. 3. 1. 7   
T e xt has bee n u p date d t o i n dic ate t hat t he 
a nal yses of P F S a n d O S will b e base d o n t he 
F A S.  
T o better a nal yze t he res p o nse 
e n d p oi nts.  
Secti o n  9. 3. 1. 7  a n d t hr o u g h o ut 
d oc u me nt as a p plica ble  
T he “efficac y e val ua ble” a nal ysis set has 
bee n c ha n ge d t o “res p o ns e e val ua ble” 
a nal ysis set a n d defi ne d as all s u bj ects wit h 
meas ura ble disease at baseli ne w h o recei ve d 
a n y a m o u nt of st u d y dr u g a n d ha d at least 
1  p ost baseli ne disease assess me nt per 
R E CI S T v 1. 1 or disc o nti n ue d st u d y 
treat me nt. T he R E will be t he pri mar y 
a nal ysis set f or O R R a n d D C R.  
T o better a nal yze t he res p o nse 
e n d p oi nts.  
Secti o n  9. 3. 5  
Secti o n has bee n u p date d t o i n dicate t ha n a n 
ex pl orat or y a nal yses of O R R base d o n t he 
F A S will als o be perf or me d.  
T he pri mar y e n d p oi nt has bee n m o difie d t o 
i n dicate it will be e val uate d i n t he R E 
a nal ysis set.  
T o better defi ne efficac y.  
Secti o n  9. 3. 1 0   
A refere nce t o A p pe n di x E has bee n a d de d.  
T o direct t he rea der t o 
a d diti o nal i nf or mati o n.  
 
S u m m ar y of C h a n ges i n A me n d me nt 3  
Secti o n(s)  
C h a n ge  
R ati o n ale  
Pr ot oc ol S y n o psis; S O E ta ble; 
Secti o n  6. 1 ; Secti o n  6. 2 ; 
Secti o n  7. 2 ; Secti o n  7. 3 ; 
Secti o n  7. 4 ; Secti o n 7. 6  a n d 
t hr o u g h o ut d oc u me nt as 
a p plica ble 
T he f oll o wi n g te xt was a d de d:  
Bi o m ar ker assess me nts m a y be 
disc o nti n ue d at a n y p oi nt at t he s p o ns ors 
discreti o n.  
P R O c ollecti o ns m a y be disc o nti n ue d at 
t he discreti o n of s p o ns or. 
N ote: A n y s a m ples a n d d at a c ollecti o n 
f or t he e x pl or at or y o bjecti ves w hic h are 
n ot necess ar y t o e v al u ate a n y 
pri m ar y/sec o n d ar y o bjecti ves c a n be 
disc o nti n ue d at t he discreti o n of t he 
s p o ns or (f or e x a m ple, b ut n ot li mite d t o: 
P R Os, S E A -C D 4 0 P K, C D 4 0 A D A, 
Pl as m a, P D fl o w, T u m or bi o ps y, 
Ge n ot y pi n g, Ser u m, P B M C, cf D N A).  
T o all o w fle xi bilit y i n data 
c ollecti o n of e x pl orat or y 
o bj ecti ves t o re d uce trial b ur de n.  
Secti o n  1. 6   
T e xt u p date d t o a d d data fr o m re peat -d ose 
st u d y i n c y n o m ol g us m o n ke ys at 3 0 m g/ k g 
d ose.  
A d d e d  ne w n o ncli nical safet y 
i nf or mati o n. 
Secti o n  2   
T he f oll o wi n g re visi o n s were ma de:  
C orrecti o n  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 0  of 1 3 5  
T o c haracterize t he p har mac o ki netics ( P K) 
of S E A -C D 4 0 a n d pe m br o liz u ma b a n d 
i nci de nce of a nti dr u g a nti b o dies ( A D As) 
w he n S E A -C D 4 0 is a d mi nistere d i n 
c o m bi nati o n wit h ot her t hera pies  
Secti o n  3. 1. 5   
T he f oll o wi n g re visi o n s w ere m a de:  
If t he s p o ns or ter mi n ates t he st u d y e arl y, 
i n vesti g at ors are i nstr ucte d t o c o nti n ue 
dise ase assess me nts per pr ot oc ol, u nless 
ot her wise i n dic ate d b y t he s p o n s or, u ntil 
t he st u d y ter mi n ati o n d ate. S u bjects  
disc o nti n ui n g tre at me nt will be f oll o w e d 
f or 3 0  d a ys p ost -tre at me nt f or 
S E A -C D 4 0  a n d/ or c he m ot he r a p y a n d 
9 0  d a ys p ost -tre at me nt f or 
p e m br oliz u m a b, u nless s afet y c o ncer ns 
w arr a nt f urt her f oll o w -u p. P atie nts i n  
s ur vi v al f oll o w-u p at t he ti me of e arl y 
st u d y ter mi n ati o n will be c o nt a cte d o ne 
l ast ti me, re g ar dless of t he d ate of t he 
pri or assess me nt, f or fi n al s ur vi v al 
assess me nt. T he i n vesti g at or will be 
e x pecte d t o m o nit or f or a n d re p ort a n y 
S A Es a n d pre g n a ncies,  as det aile d i n 
Secti o n  7. 7. 1. 3  a n d Secti o n  7. 7. 6 . 
Tr u nc ate d  d at a m a y be c olle cte d  at t he 
discreti o n of t he s p o ns or .  
P r o vi de m ore fle xi bilit y t o st u d y 
sites f or t he treat me nt a n d 
ma na ge me nt of s u bj ects i n t he 
st u d y.  
Secti o n  3. 1. 8   
T he f oll o wi n g te xt was a d de d:  
Tri al O per ati o ns a n d D at a C ollecti o n 
after S E A -C D 4 0 e x pir y  
If at le ast 6 m o nt hs h as el a pse d si nce t he 
l ast s u bject w as e nr olle d i n t he st u d y, 
a n d if t here are n o m ore t h a n 1 5  s u bjects 
still o n st u d y recei vi n g o nl y dr u g(s) wit h 
a k n o w n s afet y pr ofile (s uc h as 
pe m br oliz u m a b/ pe metre xe d c o m bi n ati o n 
t her a p y or pe m br oliz u m a b 
m o n ot her a p y), a d at a b ase l oc k of t he 
st u d y m a y occ ur t o all o w t he a n al ysis of 
t he S E A-C D 4 0 -relate d st u d y d at a.  
A n y re m ai ni n g s u bjects m a y c o nti n ue t o 
recei ve st u d y tre at me nts ot h er t h a n 
S E A -C D 4 0 ( pe m br oliz u m a b wit h or 
wit h o ut c ar b o pl ati n a n d pe metre xe d) per 
pr ot oc ol a n d be see n b y t he i n vesti g at or 
per us u al st a n d ar d of c are. 
C he m ot her a pies m a y be s u p plie d per 
Secti o n  5. 1. 3. 2 . T he i n vesti g at or will be 
e x pecte d t o m o nit or f or pr o gressi o n a n d 
re p ort a n y S A Es a n d pre g n a ncies, as 
o utli ne d i n Secti o n  7. 7. 1. 3  a n d 
Secti o n  7. 7. 6 . N o ot her d at a will be 
T o all o w c o nti n ue d access t o  
ot her  st u d y dr u gs f or s u bj ects 
w h o are be nefiti n g fr o m 
treat me nt. 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 1  of 1 3 5  
c ollecte d. T he re m ai ni n g s u bjects are 
c o nsi dere d t o be o n st u d y u ntil a 
disc o nti n u ati o n criteri o n is met, or t he 
st u d y is ter mi n ate d b y t he s p o ns or.  
Secti o n  4. 1 , i ncl usi o n 
criteri o n 7  a n d t hr o u g h o ut 
d oc u me nt as a p plica ble  
T he f oll o wi n g re visi o ns were ma de t o 
i ncl usi o n criteri o n 7: 
b. C o h orts 1, 2, a n d 3:  
iii. If se x uall y acti ve i n a wa y t hat c o ul d 
lea d t o pre g na nc y, m ust c o nsiste ntl y use 2 
hi g hl y effecti ve met h o ds of birt h c o ntr ol  
t he acce pt a ble c o m bi n ati o ns of 
c o ntr ace pti ve met h o ds  (as defi ne d i n 
A p pe n di x  B ) starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he 
st u d y a n d f or at least 1 2 0 da ys after t he 
fi nal d ose of st u d y dr u g 
c. C o h orts 4 a n d 5:  
iii. If se x uall y acti ve i n a wa y t hat c o uld 
lea d t o pre g na nc y, m ust c o nsiste ntl y use 2 
hi g hl y effecti ve met h o ds of birt h c o ntr ol  
t he acce pt a ble c o m bi n ati o ns of 
c o ntr ace pti ve met h o ds  (as defi ne d i n 
A p pe n di x  B ) starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he 
st u d y a n d f or at least 6 m o nt hs after t he 
fi nal d ose of st u d y dr u g 
T o e ns ure c o nsiste nc y wit h 
A p pe n di x B a n d c urre nt  Cli ni cal 
Trial Facilitati o n a n d 
C o or di nati o n Gr o u p  (C T F G ) 
g ui da nce  
Secti o n  4. 1 , i ncl usi o n 
criteri o n 8  a n d t hr o u g h o ut 
d oc u me nt as a p plica ble  
T he f oll o wi n g re visi o ns were ma de t o 
i ncl usi o n criteri o n 8: 
8.  S u bj ects  b or n m ale  w h o ca n  fat her 
c hil dre n, u n der t he f oll o wi n g c o n diti o ns:  
a. C o h orts 1, 2, a n d 3:  
ii. If se x uall y acti ve wit h a pers o n of 
c hil d beari n g p ote ntial i n a wa y t hat c o ul d 
lea d t o pre g na nc y, m ust c o nsiste ntl y use t he 
acce pt a ble 2  hi g hl y effecti ve 
c o m bi n ati o ns of c o ntr ace pti ve met h o ds of  
birt h c o ntr ol  (as defi ne d i n A p pe n di x  B ) 
starti n g at ti me of i nf or me d c o nse nt a n d 
c o nti n ui n g u ntil t he fi nal d ose of st u d y 
dr u g.  
iii. If se x uall y acti ve wit h a pers o n w ho is 
pre g na nt or breastfee di n g, m ust c o nsiste ntl y 
use 1 of 2 c o ntrace pti o n o pti o ns  a c o n d o m  
(as defi ne d i n A p pe n di x  B ) starti n g at ti me 
of i nf or me d c o nse nt a n d c o nti n ui n g u ntil 
t he fi nal d ose of st u d y dr u g 
b . C o h orts 4 a n d 5: 
ii. If se x uall y acti ve wit h a pers o n of 
c hil d beari n g p ote ntial i n a wa y t hat c o ul d 
lea d t o pre g na nc y, m ust c o nsiste ntl y use 2  
t he acce pt a ble hi g hl y effecti ve 
T o e ns ure c o nsiste nc y wit h 
A p pe n di x B a n d c u rre nt (C T F G ) 
g ui da nce  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 2  of 1 3 5  
c o m bi n ati o ns of c o ntr ace pti ve met h o ds of 
birt h c o ntr ol  (as defi ne d i n A p pe n di x  B ) 
starti n g at ti me of i nf or me d c o nse nt a n d 
c o nti n ui n g t hr o u g h o ut t he  st u d y a n d f or at 
least 6 m o nt hs after t he fi nal d ose of st u d y 
dr u g  
iii. If se x uall y acti ve wit h a pers o n w h o is 
pre g na nt or breastfee di n g, m ust c o nsiste ntl y 
use 1 of 2 c o ntrace pti o n o pti o ns  a c o n d o m  
(as defi ne d i n A p pe n di x  B ) starti n g at ti me 
of i nf or me d c o nse nt a n d c o nti n ui n g 
t hr o u g h o ut t he st u d y a n d f or at least 
6  m o nt hs after t he fi nal d ose of st u d y dr u g  
Secti o n  4. 3   
T e xt re vise d as f oll o ws:  
A pers o n of c hil d beari n g p ote ntial is 
a n y o ne b or n fe male  w h o has e x perie nce d 
me narc he a n d w h o has n ot u n der g o ne 
per ma ne nt  sterilizati o n (e g, h ysterect o m y, 
bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y) or has n ot c o m plete d 
me n o pa use. Me n o pa use is defi ne d cli nicall y 
as 1 2  m o nt hs of a me n orr hea i n a pers o n 
o ver 4 5  years ol d i n t he a bse nce of ot her 
bi ol o gical, p h ysi ol o gical, or 
p har mac ol o gical ca uses.  
A  pers o n  s u bject w h o ca n  fat her c hil dre n 
get s o me o ne pre g n a nt is a n y o ne b or n male  
w h o has testes a n d w h o has n ot u n der g o ne 
per ma ne nt  sterilizati o n (e g, vasect o m y 
f oll o we d b y a cli nical test pr o vi n g t hat t he 
pr oce d ure was effecti ve).  ( defi ne d as 
bil ater al orc hi dect o m y).   
U p date d t o e ns ure c o nsiste nc y 
wit h A p pe n di x B.  
Secti o n  5. 1. 1. 2   
T he f oll o wi n g re visi o n was ma de t o D ose 
a n d A d mi nistrati o n . 
I n C ycle 1, I niti all y, S E A -C D 4 0 is 
a d mi nistere d via I V i nf usi o n at a fi xe d 
i nf usi o n rate n ot t o e xcee d 1 0 mc g/ mi n.  
C orrecti o n  
Secti o n  5. 1. 1. 2   
A d de d varia bilit y wi n d o w f or i nf usi o n rates  T o pr o vi de fle xi bilit y t o trial 
sites f or mi n or variati o ns i n t heir 
i nf usi o n ti mes d ue t o mec hani cal 
variati o ns i n p u m ps  
Secti o n  5. 1. 2. 1   
T e xt re vise d as f oll o ws:  
Eac h 1  m L of s ol uti o n c o ntai ns 2 5  m g of 
pe m br oliz u ma b a n d is f or m ul ate d i n 
L -histi di ne, p ol ys or bate 8 0 , s ucr ose, 
L -met hi o ni ne  a n d Water f or I nj ecti o n, 
U nite d States P har mac o peia ( U S P).  
C orrecti o n  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 3  of 1 3 5  
Secti o n  5. 1. 3. 2   
T e xt re vise d  as f oll o ws:  
I n t he U S a n d Ca na da, pe metre xe d a n d 
car b o plati n will be s o urce d b y st u d y sites 
fr o m c o m mercial s u p pl y. I n ot her c o u ntries, 
pe metre xe d a n d car b o plati n ma y  will  be 
pr o vi de d t o st u d y sites b y t he s p o ns or or 
i n vesti g ati o n al sites m a y use l oc all y 
a v ail a ble m ar kete d pr o d ucts a ut h orize d 
f or use i n t heir res pecti ve c o u ntr y .  
A d diti o nal i nf or mati o n o n t he 
s u p pl y of pe metre xe d a n d 
car b o plati n  
Secti o n  5. 2. 3. 2   
T e xt re vise d  as f oll o ws: 
Ot her all o we d d ose i nterr u pti o n s a n d 
m o dific ati o ns f or pe m br oliz u ma b 
P e m br oliz u ma b ma y be i nterr u pte d f or 
sit uati o ns ot her t ha n treat me nt-relate d A Es 
s uc h as me dical or s ur gical e ve nts a n d/ or 
u nf oresee n circ u msta nces n ot relate d t o  
st u d y i nter ve nti o n. If a s u bject i n C o h orts 
1, 2, or 3 is u n a ble t o recei ve t he first 
d ose of pe m br oliz u m a b i n a n y gi ve n 
c y cle a n d is c o nsi dere d a p pr o pri ate t o 
recei ve pe m br oliz u m a b as st a n d ar d of 
c a re, t he s u bject m a y recei ve a 2 0 0  m g 
d ose of pe m br oliz u m a b o n D 2 9 t o D 3 1 of 
t he c y cle. T he s u bject will t he n c o nti n ue 
t o recei ve pe m br oliz u m a b at Q 6 W as 
pl a n ne d o n D 8 of t he ne xt c ycle, as l o n g 
as t he s u bject c o nti n ues t o b e 
a p pr o pri ate t o recei v e pe m b r oliz u m a b. If 
a s u bject re q uires a l o n ger i nterr u pti o n 
of pe m br oliz u m a b f or re as o ns ot her t h a n 
tre at me nt-rel ate d A Es, st u d y 
i nter v e nti o n s h o ul d be restart e d wit hi n 
2 1  da ys (f or Q 3 W d osi n g) or 4 2  da ys (f or 
Q 6 W d osi n g) of t he ori gi nall y sc he d ule d 
d ose a n d wit hi n 4 2  da ys (f or  Q 3 W d osi n g) 
or 8 4  da ys (f or Q 6 W d osi n g) of t he 
pre vi o usl y a d mi nistere d d ose, u nless 
ot her wise disc usse d wit h t he s p o ns or. T he 
reas o n f or i nterr u pti o n is t o be d oc u me nte d 
i n t he s u bj ect’s st u d y rec or d. 
T o pr o vi de a d diti o nal g ui da nc e 
re gar di n g d ose i nterr u pti o ns a n d 
M o dificati o ns f or 
pe m br o liz u ma b 
Secti o n  5. 3   
Re vise d t hir d b ullet p oi nt u n der 
pre me dicati o n  a n d p ost me dic ati o n  t o 
i ncl u de; 
I b u pr ofe n or  ot her N S AI D s (e xce pt i n 
s u bj ects i n C o h orts 4 a n d 5 wit h Cr Cl  
< 8 0  m L/ mi n)  
C orrecti o n  
Secti o n  5. 4. 3   
F oll o wi n g re visi o n was ma de t o secti o n 
5. 4. 3 b ullet p oi nt 2:  
I b u pr ofe n or ot her N S AI Ds (i ncl u di n g 
pre me dicati o n) i n patie nts  s u bjects wit h 
Cr C l < 8 0 m L/ mi n, d uri n g t he 3 2 2  da ys 
C orrecti o n  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 4  of 1 3 5  
bef ore, t he da y of, a n d 2  da ys after 
pe metre xe d a d mi nistrati o n  
Secti o n  5. 5. 1. 1 , T a ble 1 1  
T he f oll o wi n g te xt was a d de d f or 
S E A -C D 4 0 d ose m o dificati o ns f or Gra de 2 
i nf usi o n/i nj ecti o n or h y perse nsiti vit y 
reacti o ns: 
If s u bject h as a dre n al i ns uffi cie nc y,  
c o nsi der i ncre asi n g re pl ace me nt ster oi d 
d ose t o 1 0  m g pre d nis o ne e q ui v ale nt per 
d a y o n S E A -C D 4 0 d osi n g d a ys . 
T o pr o vi de a d diti o nal 
ma na ge me nt g ui da nce  
Secti o n  6. 5   
T he f oll o wi n g te xt was a d de d:  
S u bj ects w h o disc o nti n ue treat me nt will 
c o nti n ue t o be assesse d f or res p o nse after 
E O T u ntil c o nfir me d P D or i nitiati o n of 
ne w a ntica ncer treat me nt.  After  
S E A -C D 4 0 dr u g e x pir y, res p o nse 
assess me nt i n t hese p atie nts m a y be 
c o nti n ue d per st a nd ar d of c are ( S o C ) at 
t he discreti o n of t he i n vesti g at or.  
S u bj ects w h o disc o nti n ue treat me nt d ue t o 
c o nfir me d P D or w h o ha ve i nitiate d ne w 
a ntica ncer treat me nt will n ot be as sesse d f or 
res p o nse b ut will be f oll o we d f or s ur vi val 
a n d s u bse q ue nt a ntica ncer treat me nt. 
F oll o w -u p ma y be c o n d ucte d wit h cli nic 
visits or tele p h o ne calls. S ur vi v al 
f oll o w-u p m a y be disc o nti n u e d at t he 
discreti o n of s p o ns or.  
C ha n ge i n  I M Ps 
Secti o n  6. 6 , S O E ta ble a n d 
t hr o u g h o ut d oc u me nt as 
a p plica ble 
T he f oll o wi n g te xt was a d de d:  
All s u bj ects will be f oll o we d f or l o n g -ter m 
s ur vi val. Assess me nt of s ur vi val ca n be 
d o ne via p u blic or h os pital/ me dical rec or ds 
or a p h o ne call. After disease pr o gressi o n or 
i nitiati o n of a ne w a ntica ncer treat me nt, 
s ur vi val f oll o w-u p will be c o n d ucte d, at t he 
discreti o n of t he s p o ns or , e ver y 1 2 wee ks 
( ± 1 wee k) f or s ur v i val stat us u ntil deat h or 
st u d y cl os ure, w hic he ver c o mes first.  
T he first s ur vi val f oll o w -u p will occ ur 
1 2  wee ks ( ± 1  wee k) ( u nless ot her wise 
st ate d) fr o m t he last ra di o gra p hic sca n t hat 
de m o nstrate d disease pr o gressi o n or fr o m 
i nitiati o n of t he ne w a ntica ncer treat me nt, 
as a p plica ble. S u bse q ue nt s ur vi val 
f oll o w-u p will be sc he d ule d f or 1 2  wee ks 
( ± 1 wee k) ( u nless ot her wise st ate d) fr o m 
t he pre vi o us s ur vi val f oll o w-u p. Ti mi n g of 
s u bse q ue nt s ur vi v al f oll o w-u p m a y be 
m o difie d, or c ollecti o n will be st o p pe d, a t 
t he discreti o n of s p o ns or.  
C ha n ge i n st u d y desi g n a n d t o 
ma ke t hese secti o ns c o nsiste nt 
wit h t he Sc he d ule of E ve nts  
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)


 
St u d y S G N S 4 0 -0 0 2  
Cli nical Pr ot oc ol  
A me n d me nt 3 : 0 5 -A pr -2 0 2 3  
S E A -C D 4 0  
Sea ge n I nc. –  C o nfi de ntial  
P a ge 1 3 5  of 1 3 5  
A p pe n di x  B  
A p pe n di x te xt u p date d f or clarit y a n d t o 
reflect c urre nt C T F G g ui da nc e. 
Clarificati o n a n d t o ali g n wit h 
c urre nt (C T F G ) g ui da nce.  
T hr o u g h o ut d oc u me nt  
Mi n or t y p os, f or matti n g, a n d 
i nc o nsiste ncies c orrecte d. 
C orrecti o n  
 
0 9 0 1 7 7 e 1 a 1 3 0 7 2 0 3\ A p pr o v e d\ A p pr o v e d O n: 0 5- A pr- 2 0 2 3 2 0: 1 6 ( G M T)

SAP_001.pdf: 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seagen, Inc. and must not be disclosed or used except as authorized in writing by Seagen, Inc.
STATISTICAL ANALYSIS PLAN
Protocol Number:
SGNS40-002
Version:
2.0; 18-Jan-2024
Protocol Title:
An Open-label, Phase 2 Basket Study of SEA-CD40 
Combination Therapies in Advanced Malignancies
Sponsor:
Seagen, Inc.
21823 30th Drive SE
Bothell, WA 98021, USA
090177e1a1313fe4\Approved\Approved On: 19-Jan-2024 02:55 (GMT)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2  of 2 5  
A P P R O V A L SI G N A T U R E S  
Pr o d uct:  
S E A -C D 4 0  
Pr ot oc ol N u m ber/ A me n d me nt:  
S G N S 4 0 -0 0 2  A 0 3  
S A P Versi o n:  
2 . 0 
Versi o n D ate:  
1 8 -Ja n-2 0 2 4  
S A P A ut h or  
 
 
 
 
T he i n di vi d uals si g ni n g bel o w ha ve re vie we d a n d a p pr o ve t his statistical a nal ysis pla n. 
 
 
 
 
, P h D 
 
 
Date  
 
 
 
 
 
 
, M A 
 
 
Date  
 
 
 
 
 
 
, M D 
 
 
Date  
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D
P P D


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 3  of 2 5  
T A B L E O F C O N T E N T S  
LI S T O F A B B R E VI A TI O N S  ................................................................................................................................ 5  
1  
I N T R O D U C TI O N ........................................................................................................................................... 7  
2  
S T U D Y O BJ E C TI V E S  ................................................................................................................................... 7  
2. 1  
Pri mar y O bjecti ves  ................................................................................................................................ 7  
2. 2  
Sec o n dar y O bjecti ves  ............................................................................................................................ 7  
2. 3  
A d diti o nal O bjecti ves  ............................................................................................................................ 7  
3  
S T U D Y E N D P OI N T S  .................................................................................................................................... 8  
3. 1  
Pri mar y E n d p oi nts  ................................................................................................................................. 8  
3. 2  
Sec o n dar y E n d p oi nts  ............................................................................................................................. 8  
3. 3  
A d diti o nal E n d p oi nts  ............................................................................................................................. 8  
4  
S T U D Y D E SI G N  ............................................................................................................................................ 9  
5  
A N A L Y SI S S E T S  ......................................................................................................................................... 1 0  
5. 1  
F ull A n al ysis Set  ................................................................................................................................. 1 0  
5. 2  
Safet y A nal ysis Set  .............................................................................................................................. 1 0  
5. 3  
Res p o n se-E val ua ble ( R E) A nal ysis Set  ............................................................................................... 1 0  
5. 4  
P K A nal ysis Set  ................................................................................................................................... 1 0  
5. 5  
P R O A nal ysis Set  ................................................................................................................................ 1 0  
6  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................................................... 1 0  
6. 1  
Ge n eral Pri n ci ples  ............................................................................................................................... 1 0  
6. 2  
Deter mi nati o n of Sa m ple Size  ............................................................................................................. 1 1  
6. 3  
Ra n d o mizati o n a n d Bli n di n g  ............................................................................................................... 1 1  
6. 4  
Data Tra nsf or mati o ns a n d Deri vati o ns  ................................................................................................ 1 1  
6. 4. 1  
Ge n eral  ................................................................................................................................... 1 1  
6. 4. 2  
Best Res p o nse  ......................................................................................................................... 1 2  
6. 4. 3  
Res p o nse Assess me nt Dates  ................................................................................................... 1 2  
6. 5  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ............................................................................................. 1 3  
6. 6  
M ultice nter St u dies  ............................................................................................................................. 1 3  
6. 7  
M ulti ple C o m paris o n/ M ulti plicit y ....................................................................................................... 1 3  
6. 8  
E xa mi nati o n of S u b gr o u ps  .................................................................................................................. 1 3  
6. 9  
C o variates  ............................................................................................................................................ 1 3  
6. 1 0  Ti mi n g of A nal yses  ............................................................................................................................. 1 3  
7  
P L A N N E D A N A L Y S E S  .............................................................................................................................. 1 4  
7. 1  
Dis p ositi o n  .......................................................................................................................................... 1 4  
7. 2  
De m o gra p hic a n d Baseli ne C haracteristics  ......................................................................................... 1 4  
7. 3  
Pr ot oc ol De viati o ns  ............................................................................................................................. 1 4  
7. 4  
Treat m e nt A d mi nistrati o n  ................................................................................................................... 1 4  
7. 5  
Efficac y A nal yses  ................................................................................................................................ 1 5  
7. 5. 1  
Pri mar y E n d p oi nts  .................................................................................................................. 1 5  
7. 5. 2  
Sec o n dar y E n d p oi nts  .............................................................................................................. 1 6  
7. 6  
Safe t y A nal yses ................................................................................................................................... 1 7  
7. 6. 1  
A d verse E ve nts  ....................................................................................................................... 1 7  
7. 6. 2  
Cli nical La b orat or y Para meters  .............................................................................................. 1 8  
7. 6. 3  
C o nc o mita nt Me dicati o ns  ....................................................................................................... 1 9  
7. 6. 4  
A d diti o nal Safet y A nal yses  .................................................................................................... 1 9  
7. 6. 5  
Deat hs  ..................................................................................................................................... 1 9  
7. 7  
A d diti o nal A nal yses  ............................................................................................................................ 1 9  
7. 7. 1  
P har mac o ki netics a n d I m m u n o ge nicit y A nal yses  .................................................................. 1 9  
7. 7. 2  
P har mac o d y na mic ( P D) a n d Mec ha nis m of Acti o n Bi o mar kers  ............................................ 1 9  
7. 7. 3  
Patie nt -Re p orte d O utc o me E n d p oi nts  .................................................................................... 1 9  
8  
I N T E RI M A N A L Y SI S.................................................................................................................................. 1 9  
9  
C H A N G E S F R O M P L A N N E D A N A L Y S E S  .............................................................................................. 2 0  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 4  of 2 5  
9. 1  
C ha n ges fr o m t he Ori gi nal Pr ot oc ol  .................................................................................................... 2 0  
9. 2  
C ha n ges fr o m t he Ori gi nal S A P  .......................................................................................................... 2 0  
1 0  R E F E R E N C E S  .............................................................................................................................................. 2 1  
1 1  A P P E N DI C E S  ............................................................................................................................................. 2 2  
A P P E N DI X A: I M P U T A TI O N O F P A R TI A L L Y U N K N O W N A D V E R S E E V E N T D A T E S  ..................... 2 2  
A P P E N DI X B: D E FI NI TI O N O F T H E T E R M “ T R E A T M E N T -E M E R G E N T” WI T H R E S P E C T T O A E 
C L A S SI FI C A TI O N  ...................................................................................................................................... 2 4  
 
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 5  of 2 5  
LI S T O F A B B R E VI A TI O N S  
A D A  
a nti dr u g a nti b o d y  
A E  
a d verse e v e nt 
A L T  
ala ni ne a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
CI  
c o nfi de n ce i nter val  
C R  
c o m plete res p o nse  
C R F  
case re p ort f or m  
C T  
c o m p ute d t o m o gra p h y  
D C R  
disease c o ntr ol rate  
DI LI  
dr u g -i n d uce d li ver i nj ur y 
D O R  
d urati o n of res p o nse  
E C G  
electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E E  
efficac y -e v al ua ble 
E O R T C Q L Q -C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer q ualit y of life q uesti o n naire  
E O T  
e n d of treat me nt  
F A S  
f ull a n al ysis set  
H R Q o L  
healt h -relate d q ualit y of life 
i C P D 
c o nfir me d pr o gressi ve disease per i R E CI S T  
i C R 
i m m u ne c o m plete res p o nse 
I H R 
i nf usi o n or h y perse nsiti vit y reacti o n 
i P R 
i m m u ne partial res p o nse 
ir A E 
i m m u ne-relate d A Es 
i R E CI S T 
I m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors  
I R R 
i nf usi o n-relate d reacti o n 
i U P D 
i m m u ne u nc o nfir me d pr o gressi ve disease 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M RI  
ma g netic res o na nce i ma gi n g  
N CI C T C A E  
Nati o nal Ca n cer 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 
N S C L C -S A Q  
N o n -S mall Cell L u n g Ca ncer S y m pt o m Assess me nt Q uesti o n naire  
O R R  
o bjecti ve res p o nse rate  
O S  
o verall s ur vi val  
P C R  
p ol y merase c h ai n reacti o n  
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 -( L) 1 
pr o gra m me d cell deat h pr otei n 1 ( P D -1) or P D -1 li ga n d 1 ( P D-L 1)  
P F S  
pr o gressi o n -free s ur vi val 
P GI -C  
Patie nt Gl o bal I m pressi o n of S y m pt o m C ha n ge  
P GI -S  
Patie nt Gl o bal I m pressi o n of S y m pt o m Se verit y 
P K  
p har mac o ki netics  
P P o S  
pre dicti ve pr o ba bilit y of s uccess  
P R  
partial res p o nse  
P R O  
patie nt -re p orte d o utc o mes 
Q 6 W  
e v er y 6 wee ks  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 6  of 2 5  
R E  
Res p o nse -e v al ua ble 
R E CI S T v 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  Versi o n 1. 1  
S A E  
seri o us a d verse e ve nt 
S D  
sta ble disease 
S M C  
Safet y M o nit ori n g C o m mittee  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T P S  
t u m or pr o p orti o n sc ore 
T T D  
ti me-t o-deteri orati o n  
U L N  
u p per li mit of n or mal  
 
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 7  of 2 5  
1  
I N T R O D U C TI O N 
T his d oc u me nt o utli nes t he statistical met h o ds t o be i m ple me nte d wit hi n t he sc o pe of 
Pr ot oc ol S G N S 4 0 -0 0 2 , e ntitle d A n O pe n -la bel, P hase 2 Bas ket St u d y of S E A-C D 4 0 
C o m bi nati o n T hera pies i n A d va nce d M ali g na ncies .  Res ults of t he pr o p ose d a nal yses will 
bec o me  t he b asis of t he cli nical st u d y re p ort f or t his pr ot oc ol. 
T he p ur p ose of t his pla n is t o pr o vi de s pecific g ui deli nes fr o m w hic h t he a nal ysis will 
pr ocee d.  All pla n ne d a n al yses s pecifie d i n t his d oc u me nt will be perf or me d.  A n y c ha n g es t o 
t his pla n, i n t he f or m of “ p ost h oc” or “ d ata dri ve n” a nal yses will be i de ntifi e d as s uc h i n t he 
fi nal cli nical st u d y re p ort.  A n y c ha n ges will eit her be reflecte d i n a me n d m e nts t o t his pla n 
bef ore t h e data b ase l oc k or s pecificall y d oc u me nt e d i n t he cli nical st u d y re p ort.  
2  
S T U D Y O B J E C TI V E S  
2. 1  Pri m ar y O bj e cti v e s  
● 
T o e val uate t he a ntit u m or acti vit y of S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies  
2. 2  S e c o n d ar y O bj e cti v e s  
● 
T o e val uate t he s afet y a n d t olera bilit y of S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies  
● 
T o e val uate c o ntr ol of disease  
● 
T o e val u ate d ura bilit y of res p o nse i n s u bjects w h o res p o n d t o st u d y dr u g(s)  
● 
T o e val uate P F S a n d s ur vi val  
2. 3  A d diti o n al O bj e cti v e s  
● 
T o c haracteri ze t he p h ar mac o ki netics ( P K) of S E A C D 4 0 a n d pe m br oliz u ma b a n d 
i nci de nce of a nti dr u g a nti b o dies ( A D As) w h e n S E A-C D 4 0 is a d mi nistere d i n 
c o m bi nati o n wit h ot her t hera pies  
● 
C o h orts 1, 2, a n d 3 ( Mel a n o ma): T o e v al uate selecte d p har mac o d y na mic p ara meters 
of i nterest f or S E A C D 4 0.  
● 
T o assess e x pl orat or y bi o mar kers of res p o nse, t o xi cit y, a n d resista nce of S E A -C D 4 0 
i n c o m bi nati o n with ot her t hera pies  
● 
T o e val uate t he a ntit u m or acti vit y of S E A -C D 4 0 c o m bi ne d wit h ot her t hera pies per 
M o difie d R E CI S T 1. 1 f or I m m u ne -bas e d T hera pe utics (i R E CI S T)  
● 
T o e val uate p atie nt -re p orte d o utc o mes of diseas e/treat me nt-relate d s y m pt o ms, healt h-
relate d q ualit y of life ( H R Q o L), a n d f u ncti o n  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 8  of 2 5  
3  
S T U D Y E N D P OI N T S  
3. 1  Pri m ar y  E n d p oi nt s  
● 
C o nfir me d O bjecti ve Res p o nse Rate ( O R R; c o nfir me d c o m plete res p o ns e [ C R] or 
partial res p o nse [ P R]) acc or di n g t o R E CI S T v 1. 1 per i n vesti gat or assess me nt  
3. 2  S e c o n d ar y  E n d p oi nt s  
● 
T y pe, i nci de nce,  se verit y, seri o us ness, a n d relate d ness of a d verse e v e nts ( A Es) 
● 
T y pe, i nci de nce, a n d se v erit y of la b orat or y a b n or malities  
● 
Fre q u e nc y of treat me nt i nterr u pti o ns, d ose re d u cti o ns, a n d treat me nt disc o nti n uati o ns 
d ue t o A Es  
● 
Disease c o ntr ol rate ( D C R; c o nfir me d C R, P R, a n d sta ble disease [ S D]) per 
i n vesti gat or assess me nt 
● 
D urati o n of res p o ns e ( D O R; d urati o n of c o nfir me d C R or P R) per i n vesti gat or 
assess me nt  
● 
Pr o gressi o n -free s ur vi val ( P F S) per i n vesti gat or assess me nt 
● 
O verall s ur vi val ( O S)  
3. 3  A d diti o n al E n d p oi nt s  
•  Esti m ates of selecte d P K para meters  
•  I n ci de nce of A D As 
•  C o h orts 1, 2, a n d 3 ( Mel a n o ma): E x pl orat or y c orrelati o ns bet wee n Q Tc a n d plas ma 
c o nce ntr ati o ns of S E A -C D 4 0  
•  Act ual a n d c h a n ge fr o m baseli ne val ues i n i m m u ne s u bsets a n d c yt o ki nes i n 
peri p heral bl o o d  
•  C o nfir me d  O R R (i m m u ne c o m plete res p o nse [i C R] or i m m u ne partial res p o nse 
[i P R]) acc or di n g t o i R E CI S T 
•  Act ual a n d c h a n ge fr o m baseli ne sc ores o n t he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer q ualit y of life q uesti o n naire ( E O R T C Q L Q C 3 0)  
•  C o h orts 4 a n d 5 ( N S C L C): Ti me -t o-deteri orati o n ( T T D) i n eit her c o u g h, d ys p nea, or 
c hest pai n ( w hic h e ver deteri orates first) as meas ure d b y t he N o n -S mall Cell L u n g 
Ca ncer S y m pt o m Assess me nt Q uesti o n naire ( N S C L C S A Q)  
•  C o h orts 4 a n d 5  ( N S C L C): Act ual a n d c h a n ge fr o m baseli ne val ues i n N S C L C S A Q 
d o mai ns a n d t otal sc ores  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 9  of 2 5  
4  
S T U D Y D E SI G N  
T his p hase 2, gl o bal, o pe n -la bel, m ultice nter trial is desi g ne d t o assess t he acti vit y, safet y, 
a n d t olera bilit y of S E A -C D 4 0 i n c o m bi nati o n wit h sta n dar d of care t hera pi es i n s u bjects wit h 
selecte d s oli d t u m ors. 
 
T u m or t y pe  
St u d y dr u gs  
C o h ort 1  
Rela pse d/refract or y mela n o ma  
S E A -C D 4 0 a n d pe m br oliz u ma b  
C o h ort 2  
U veal  mela n o ma  
C o h ort 3  
P D -( L)1 -naï ve mela n o ma  
C o h ort 4  
N o ns q ua m o us N S C L C; P D -L 1 1 -4 9 % T P S  
S E A -C D 4 0, car b o plati n, pe metre x e d, 
a n d pe m br oliz u ma b  
C o h ort 5  
N o ns q ua m o us N S C L C ; P D-L 1 < 1 % T P S  
 
F or C o h orts 1, 2, a n d 3 ( mela n o ma), i nitiall y, u p t o 1 5 s u bjects ma y e nr oll i n eac h c o h ort. 
I nteri m safet y a n d efficac y a nal yses will be p erf or me d f or eac h c o h ort aft er 1 5 s u bjects ha ve 
recei v e d st u d y dr u g a n d are effic ac y e v al ua ble ( E E). C o h orts ma y c o ntin ue t o e nr oll u p t o a n 
a d diti o nal 2 5 s u bjects, f or a t otal of u p t o a p pr o xi matel y 4 0 s u bjects i n eac h c o h ort.  
F or C o h orts 4 a n d 5 ( N S C L C), i nitiall y, 6 t otal s u bjects will be e nr olle d acr oss t he 2 c o h orts; 
safet y will be assess e d after t he first treat me nt c ycle. If a p pr o ve d b y t he S M C, C o h orts 4 a n d 
5 ma y c o nti n ue t o e nr oll u p t o 1 5 s u bjects per c o h ort, f oll o we d b y c o nti n uati o n t o u p t o 4 0 
t otal s u bjects per c o h ort if a p pr o priat e.  
Res p o nse will be assesse d e ver y 6 wee ks ( Q 6 W) fr o m t he date of first d ose f or 2 4 wee ks a n d 
e ver y 1 2 w ee ks t hereafter u ntil c o nfir me d disease pr o gressi o n. Dia g n ostic -q ualit y c o m p ute d 
t o m o gra p h y ( C T) sca ns a n d/ or ma g netic res o n a nce i ma gi n g ( M RI) will be perf or me d o n t h e 
c hest a n d a b d o me n (a n d pel vis f or C o h orts 1, 2, a n d 3). T he de ter mi nati o n of a ntit u m or 
acti vit y will be base d o n o bjecti ve res p o nse rate ( O R R) assess me nts as defi ne d b y R E CI S T 
versi o n 1. 1 a n d b y i R E CI S T. Treat me nt decisi o ns b y t he i n vesti gat or will be base d o n 
i R E CI S T.  
T he pri mar y a n al ysis of t he st u d y will be perf o r m e d se paratel y f or eac h c o h ort w he n all 
treate d s u bjects i n t he c o h ort ha ve bee n f oll o we d f or at least 6 m o nt hs or c o me off st u d y, 
w hic he ver c o mes first. T he pri mar y efficac y e n d p oi nt of c o nfir me d O R R per R E CI S T v 1. 1 
will be esti mate d f or eac h c o h ort base d o n t he f ull a nal ysis set ( F A S), c o m prisi n g all s u bjects 
w h o recei ve d a n y a m o u nt of st u d y treat me nt. T he p oi nt esti mate of O R R a n d 9 5 % e xact 
c o nfi de nce i nter vals ( CIs) usi n g t he Cl o p per -Pears o n met h o d will be pr o vi de d f or eac h 
c o h ort.  
I nteri m effi cac y  a nal yses will be perf or me d s e paratel y f or eac h c o h ort after a p pr o xi matel y 1 5 
s u bjects of a gi ve n c o h ort ha ve bee n tr eate d a n d are efficac y e val u a ble. T h e Ba yesia n 
pre dicti ve pr o b a bilit y of s uccess ( P P o S) a p pr oac h will be use d t o i nf or m decisi o n -ma ki n g f or 
c onti n ue d e nr oll me nt. A c o h ort is c o nsi dere d “s uccessf ul” if t he 9 0 % CI of t he res p o nse rate 
at t he ma xi m u m sa m ple size e xcl u d es t he bac k gr o u n d rate. At t he ti me of eac h i nteri m 
a nal ysis, t he P P o S will be calc ul ate d. A P P o S < 5 % i n dicates t hat it is u nli kel y t he O R R will 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 1 0  of 2 5  
be better t ha n t he res p o ns e rate of c urre nt sta n dar d of care at t he e n d of t he c o h ort gi ve n t he 
i nteri m res ult. Base d o n effic ac y a n d s afet y d ata, t o get her wit h t he P P o S, a c o h ort ma y be 
st o p pe d earl y b y t he s p o ns or. A c o h ort ma y als o be disc onti n ue d at a n y p oi nt at t he discreti o n 
of t he s p o ns or.  
5  
A N A L Y SI S S E T S  
T his secti o n defi nes eac h of t he a nal ysis sets t hat will be utilize d.  T he use of eac h a nal ysis 
set will be disc usse d i n Secti o n 7 . 
5. 1  F ull A n al y si s S et  
T he f ull a nal ysis set ( F A S) i ncl u des all s u bjects w h o recei v e d a n y a m o u nt of st u d y dr u g. T he 
pri mar y a nal ysis set f or P F S a n d O S a nal yses will be t he F A S.  
5. 2  S af et y A n al y si s S et  
T he safet y a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g, a n d t h us 
is e q ui vale nt t o t he F A S. All safet y a nal yses will be base d o n t he s afet y a nal ysis set. 
5. 3  R e s p o n s e -E v al u a bl e ( R E ) A n al y si s S et 
T he res p o nse e val ua bl e a nal ysis set i ncl u des all s u bjects wit h meas ura ble disease at b aseli ne 
w h o recei ve d a n y a m o u nt of st u d y dr u g a n d ha d at least o ne p ost -baseli ne disease assess me nt 
per R E CI S T v 1. 1 or disc o nti n ue d st u d y  treat me nt. T he pri mar y a n al ysis set f or O R R a n d 
D C R a nal yses will be t he R E a nal ysis set  
5. 4  P K  A n al y si s S et  
T he P K a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of S E A -C D 4 0 a n d ha d at 
least o ne P K sa m ple. 
5. 5  P R O  A n al y si s S et  
T he P R O a nal ysis set i ncl u des all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g a n d ha v e 
at least o ne P R O assess m e nt. All P R O a nal yses will be base d o n t he P R O a nal ysis set.  
6  
S T A TI S TI C A L C O N SI D E R A TI O N S  
6. 1  G e n er al Pri n ci pl e s  
I n g e neral, all a nal yses will be prese nte d b y c o h ort a n d t otal u nless ot her wis e s pecifie d. 
Descri pti ve statistics will be pre se nt e d t hat i ncl u de t he n u m ber of o bser vati o ns, mea n, 
me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bles, a n d t he 
n u m ber a n d perce nt a ges per cat e g or y f or cat e g ori cal varia bl es.  
U nless ot her wise s pecifie d, c o nfi de nce i nter vals ( CI) wil l be calc ulat e d at 2-si de d 95 % le vel.  
T he 2 -si de d 95 % e xact CI usi n g t he Cl o p per -Pears o n met h o d will be calc ul ate d f or t he 
res p o nse rates w here a p plica ble (e. g., O R R) (Cl o p per 1 9 3 4 ). 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 1 1  of 2 5  
F or ti me -t o-e v e nt e n d p oi nts, t he me dia n s ur vi val ti me will be esti mate d usi n g t he Ka pla n -
Meier met h o d; t he ass oci ate d 9 5 % CI will be calc ulate d base d o n t he c o m ple me ntar y l o g -l o g 
tra nsf or mati o n (C ollett 1 9 9 4 ). 
A n y a nal ysis n ot descri b e d i n t his pla n will be c o nsi dere d e x pl or at or y, a n d will be 
d oc u me nte d i n t he cli nic al st u d y re p ort as a p ost h oc a nal ysis or c h a n ge t o t he pla n ne d 
a nal ysis.  
T o c o m pl y wit h re g ulat or y electr o ni c s u b missi o n g ui deli nes, listi n gs of all cli nical data will 
be s u b mitte d as electr o ni c data sets. T o f acilit ate data re vie w f or t he st u d y re p ort, o nl y 
perti ne nt data listi n gs will be create d a n d attac he d t o Secti o n 1 6 of t he C S R.  
All statistical Ta bles, Listi n gs a n d Fi g ures will be pr o d uce d usi n g S A S ® , versi o n 9. 4 or 
hi g her. Ot her statistical s oft ware, if us e d, will be descri be d i n t he C S R.  
6. 2  D et er mi n ati o n of S a m pl e Si z e  
U p t o a p pr o xi matel y 2 0 0  s u bjects ma y be e nr olle d i n t his st u d y. T his i ncl u des u p t o 
a p pr o xi matel y 4 0 s u bjects e nr olle d i n eac h c o h ort.  
F or a s a m ple size of 4 0 s u bjects per c o h ort, ass u mi n g c o nfir med O R R  is bet wee n 3 0 % a n d 
8 0 %, t he 2 -si de d 95 % e x act c o nfi de n ce i nter val ( CI ) are s u m marize d b el o w:  
C o nfir me d O R R  
9 5 % E xact CI ( N = 4 0)  
3 0 %  
(1 7 %, 4 7 %)  
4 0 %  
(2 5 %, 5 7 %)  
5 0 %  
(3 4 %, 6 6 %)  
6 0 %  
(4 3 %, 7 5 %)  
7 0 %  
( 53 %, 8 3 %)  
8 0 %  
( 64 %, 9 1 %)  
 
6. 3  R a n d o mi z ati o n a n d Bli n di n g  
T his is a si n gle ar m, o pe n la bel st u d y. Ra n d o mizati o n or bli n di n g will n ot be perf or me d.   
6. 4  D at a Tr a n sf or m ati o n s a n d D eri v ati o n s  
6. 4. 1  G e n er al  
Re p orte d a ge i n y ears will be use d; if n ot a vaila ble, a ge at i nf or m e d c o nse nt i n years will be 
calc ulate d wit h t he S A S ®  I N T C K f u ncti o n ( wit h met h o d s pecifie d as “c o nti n u o us”) usi n g 
i nf or me d c o nse nt dat e a n d birt h date. 
Ti me varia bles bas e d o n t w o dates (e. g., Start D ate a n d E n d Dat e) will be calc ulate d as ( E n d 
Date –  Start Date + 1 [i n da ys])  u nless ot her wise s pecifie d i n t he pla n ne d a nal ysis secti o n.  
S pecificall y, St u d y Da y will be calc ulate d as ( Date – First D ose Date + 1) f or dates o n or aft er 
t he first d ose date. T he d ate of first d ose will be St u d y Da y 1. F or dates pri or t o t he first d ose 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 1 2  of 2 5  
dat e, St u d y Da y will be calc ulate d as ( Date – First D ose Date). F or e xa m ple, t he date bef ore 
t he first d ose date will be St u d y Da y -1.  
T he f oll o wi n g u nit c o n versi o n will be i m ple me nte d u nless ot her wise s pecifie d:  
M o nt hs = Da ys/ 3 0. 4 3 7 5  
Years = Da ys/ 3 6 5. 2 5  
U nless ot h er wise s pecifie d, baseli ne val ues use d i n all a nal yses will be t he m ost rece nt n o n -
missi n g meas ure me nt pri or t o t he first d ose of st u d y dr u g.  
T he e n d -of -treat me nt ( E O T) date will be t he d ate t he E O T visit is perf or me d (or t he decisi o n -
ma ki n g date t o e n d treat me nt if E O T visit date is n ot a vaila ble); if a n E O T visit is n ot 
perf or me d  (a n d n o d ecisi o n of E O T is ma de ) t he n t he E O T date will be eit her t he e n d-of -
st u d y ( E O S) date or 3 0 d a ys after t h e last d ose of a n y st u d y dr u g, w hic he v er is earlier.  
6. 4. 2  B e st R e s p o n s e  
T he deter mi nati o n of a ntit u m or acti vit y will be base d o n o bjecti ve res p o nse assess me nts 
ma de b y t he i n vesti gat or acc or di n g t o t he R E CI S T v 1. 1 (Eise n ha uer 2 0 0 9 ). O nl y res p o nse 
assess me nts o n or pri or t o start date of a n y n e w a ntica ncer t h era p y will be c o nsi dere d f or best 
res p o nse. T he s u bj ect’s b est res p o nse will be t he b est de m o nstrate d res p o nse t o date t hat has 
bee n c o nfir me d, w he n c o nfir mati o n is re q uire d (i. e. f or P R a n d C R o nl y). T he s u bject’s best 
res p o nse will be use d i n deter mi ni n g t he O R R.  
A res p o nse ( C R or P R) w ill be c o nsi dere d c o nfir me d if t he s u bse q ue nt dis ease ass ess me nt 
c o n d ucte d n o earlier t h a n 4 wee ks after t he i nitial r es p o nse still s h o ws C R or P R. A s u bject 
will ha ve a best r es p o nse of S D if t here is at least o ne S D assess me nt ( or better) ≥5 wee ks 
after t he start of treat me nt a n d t he s u bject d oes n ot q ualif y f or c o nfir me d C R or P R. R E CI S T 
v 1. 1 o utli nes sce nari os f or best o verall res p o nses w he n c o nfir m ati o n of C R a n d P R is 
re q uire d.  
6. 4. 3  R e s p o n s e A s s e s s m e nt D at e s  
F or efficac y assess m e nts, if t he ti me p oi nt resp o nse is C R or  P R, t he n t he latest date of all 
ra di ol o gic sca ns at t he gi ve n res p o nse assess me nt visit will be t he date of res p o nse. If t he 
ti me p oi nt res p o nse is sta ble disease ( S D), t h e n t he earliest d ate of all ra di ol o gic sca ns at t he 
gi ve n res p o nse ass ess me nt visit will be t he date of S D. If t h e ti me p oi nt res p o nse is P D, t he n 
t he earliest date t h at P D has bee n d oc u m e nte d will be t he date of P D, i.e. t h e earliest of: 
•  Date of tar get lesi o n assess me nts w he n t he tar get l esi o n res p o nse is P D  
•  Date of n o n -t arget lesi o n assess me nts w he n t he lesi o n stat us is u ne q ui v ocal 
pr o gressi o n  
•  Date of d oc u m e nti n g ne w lesi o ns  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 1 3  of 2 5  
6. 5  H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
Missi n g data will n ot be i m p ute d u nless ot her wise s pecifie d. Missi n g A E start date a n d/ or 
e n d date will be i m p ute d w hile calc ulati n g d urati o n of e ve nts a n d treat me nt -e mer g e nt stat us 
(see A p pe n di x A  f or i m p utati o n details a n d A p pe n di x B f or treat me nt -e m er gent defi niti o n ).   
F or ti me -t o-e v e nt e n d p oi nts, e. g., d urati o n of res p o nse, ti me t o res p o nse, P F S, a n d O S, 
s u bjects w h o ha ve n o s p ecific e ve nt will be ce ns ore d as s pecifi e d f or eac h res pecti ve 
e n d p oi nt i n Secti o n  7. 5 . 
Missi n g s u bse q ue nt a ntica ncer treat me nt start d ate will be i m p ute d w hile deri vi n g t he ti me -
t o-e ve nt e n d p oi nts as a p plica ble (see A p pe n di x C  f or i m p utati o n details). 
U nless ot her wise s pecifie d, if t he n u meric val u e of a cli nical la b orat or y test is n ot a vaila ble 
beca use it is bel o w t he l o wer li mit of q ua ntificati o n ( L L O Q), “< L L O Q ” s h o ul d be use d 
w he ne ver a p plica bl e. I n cases w h ere a n u meric val ue is re q uire d, e. g., calc ulati n g t he mea n 
a n d sta n dar d de viat i o n, t he L L O Q/ 2 will be use d f or t he calc ulati o n. 
6. 6  M ulti c e nt er St u di e s  
T here are m ulti ple ce nt ers i n t his st u d y, h o we ver it is n ot a ntici pate d t hat a n y ce nter will 
accr ue e n o u g h s u bjects t o warra nt a n a n al ysis b y ce nter. 
6. 7  M ulti pl e C o m p ari s o n/ M ulti pli cit y  
N o m ulti ple c o m paris o ns are pla n n e d i n t his st u d y.  
6. 8  E x a mi n ati o n of S u b gr o u p s  
As e x pl orat or y a nal yses, s u b gr o u p a nal yses ma y be c o n d ucte d f or selecte d e n d p oi nts.  
S u b gr o u ps ma y i ncl u de b ut are n ot li mite d t o t he f oll o wi n g:  
● 
A ge ( 1 8 – 6 4 years, ≥6 5 y ears ol d)  
● 
Cate g orize d w ei g ht at baseli ne  ( < 7 0, 7 0– 9 9 , a n d ≥1 0 0 k g)  
● 
C D 4 0  e x pressi o n ( < X X, ≥X X)  
● 
Hist or y of brai n metastasis ( yes, n o)  
● 
F or C o h orts 1 a n d 3 o nl y: mela n o ma t y pe (c uta ne o us vs n o n -c uta ne o us)  
6. 9  C o v ari at e s  
N o a dj ust me nts f or c o variates are pl a n ne d i n t he a nal yses.  
6. 1 0  Ti mi n g of A n al y s e s  
T he pri mar y a n al ysis of t he st u d y wil l be perf or m e d se paratel y f or eac h c o h ort w he n all 
treate d s u bjects i n t he c o h ort ha ve bee n f oll o we d f or at least 6 m o nt hs or c o me off st u d y, 
w hic he ver c o mes first.  
I nteri m effi cac y a nal yses ma y be perf or me d se p aratel y f or eac h c o h ort after a p pr o xi matel y 
1 5 s u bjects of a gi ve n c o h ort ha ve bee n treate d a n d are efficac y e v al ua ble.  
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7  
P L A N N E D A N A L Y S E S  
7. 1  Di s p o siti o n  
S u bject dis p ositi o n will be s u m marize d b y c o h ort a n d t otal  f or all e nr olle d s u bjects wit h 
descri pti ve statistics. S u bjects w h o disc o nti n ue st u d y treat m e nt a n d s u bjects w h o disc o nti n ue 
t he st u d y will be s u m marize d al o n g wit h reas o n f or disc o nti n uati o n. T he n u m ber of s u bjects 
w h o si g ne d i nf or me d c o nse nt a n d t he n u m ber a n d perce nt a ge of s u bjects i n eac h a nal ysis set 
will be s u m marize d.  
7. 2  D e m o gr a p hi c a n d B a s e li n e C h ar a ct eri sti c s 
De m o gra p hics a n d baseli ne c haracteristics, i ncl u di n g a ge, ge n d er, et h nicit y, race, b aseli ne 
hei g ht, wei g ht, a n d E C O G sc ore will be liste d a n d s u m marize d b y c o h ort a n d t otal usi n g t he 
safet y a n al ysis set. Disease s pecific c haracteristics will be liste d a n d s u m marize d b y c o h ort 
a n d t otal usi n g t he safet y a nal ysis set.  
7. 3  Pr ot o c ol D e vi ati o n s  
I m p ort a nt pr ot oc ol de viati o ns ( defi ne d as pr ot oc ol vi olati o ns b y Sea ge n ) are t h ose t hat 
re pres e nt a di ver ge nce fr o m t he pr ot oc ol t hat c o ul d ha ve a si g nifica nt effect o n t he i nte grit y 
of t he st u d y data, or o n t he s u bject’s ri g hts, safet y, or welfare.  I m p orta nt pr ot oc ol de viati o ns 
als o i ncl u de e xe m pti o ns t o t he st u d y i ncl usi o n/e xcl usi o n criteria a n d will be s u m marize d b y 
cate g or y.  A list of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be prese nte d. 
7. 4  Tr e at m e nt A d mi ni str ati o n  
Treat me nt a d mi nistrati o n will be s u m marize d wit h descri pti ve statistics usi n g t he safet y 
a nal ysis set.  
S u m maries f or eac h st u d y dr u g a d mi nistrati o n ma y i ncl u de b ut are n ot li mite d t o t he 
f oll o wi n g: 
•  D urati o n of treat me nt (i n wee ks), w hi c h is defi ne d as ti me fr o m t he first st u d y d ose t o 
t he earliest of:  
o  4 2 da ys after t h e last st u d y d ose f or pe m br oliz u m a b a d mi nistrati o n i n C o h orts 
1, 2, or 3, or 2 1 da ys after t he last st u d y d ose  f or all ot her st u d y dr u g 
a d mi nistrati o n  
o  E O T visit  
o  deat h date or st art date of s u bse q ue nt a ntica n cer t h era p y , if a p plica ble. 
•  N u m be r of c y cles per s u bject 
•  N u m ber a n d p erce nta ge of s u bjects w h o were tr eate d at eac h c ycle  
•  C u m ulati ve d oses  
•  A vera g e d ose per c ycl e  
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S u m maries f or S E A-C D 4 0 , car b o plati n,  a n d p e metre xe d  a d mi nistrati o n ma y a d diti o nall y 
i ncl u de: 
•  A bs ol ute d ose i nte nsit y ( A DI), w hic h is d efi ne d as t he act ual d ose i n m g/ k g per wee k 
t hat a s u bject recei ve d o v er t he e ntire treat me nt p eri o d. T hat is, A DI = C u m ulati ve 
d oses / treat me nt peri o d i n wee ks, w h ere tr eat me nt peri o d is defi ne d as ti me fr o m t he 
first st u d y d ose t o 2 1 da ys after t he last st u d y d ose [(last d ose date + 2 1) –  first d ose 
date]/ 7 re g ar dless of d eat h date.  
•  Relati ve d ose i nte nsit y ( R DI), w hic h is defi n e d as t he A DI di vi de d b y t he i nte n de d 
d ose i nte nsit y (I DI). T h at is, R DI = A DI/I DI × 1 0 0, w here I DI is defi ne d as t he 
i nte n de d d ose (i.e., 1 0  m g/ k g f or S E A-C D 4 0 re g ar dless of d ose re d ucti o n i n later 
c ycles) i n m g/ k g per w ee k  (i.e., 1 0/ 3 m g/ k g/ wee k f or S E A-C D 4 0) . 
•  N u m ber a n d p erce nta ge of s u bjects w h ose d ose was e ver m o difie d, w hic h will be 
s u m marize d b y m o dificati o n t y pe ( dela y, re d ucti o n, u n pla n ne d d ose a dj ust me nt), 
c ycle a n d o v erall (i.e., o v erall dr u g a d mi nistrati o ns f or a s u bject). T he n u m ber a n d 
perce nt a ge of d os es t hat were m o difie d m a y als o be s u m marize d.  
7. 5  Effi c a c y A n al y s e s  
All efficac y e n d p oi nts will be a nal yze d b y c o h o rt a n d t otal. 
7. 5. 1  Pri m ar y E n d p oi nt s  
7. 5. 1. 1  C o nfir m e d O bj e cti v e R e s p o n s e R at e ( O R R)  
T he pri mar y e n d p oi nt of t his st u d y is t he c o nfir me d O R R per i n vesti gat or assess me nt. T he 
c o nfir me d O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a c o nfir me d C R or P R 
acc or di n g t o R E CI S T v 1. 1 (Eise n ha uer 2 0 0 9 ). S u bjects w h o d o n ot ha ve at l east t w o p ost -
baseli ne r es p o ns e assess me nts (i nitial res p o nse a n d c o nfir mati o n sca n) will be c o u nte d as 
n o n -res p o n ders. C o nfir mati o n mea ns a P R is f oll o we d b y a P R or C R at least 4 wee ks later, 
or a C R is f oll o we d b y a sec o n d C R at least 4 wee ks later.   
T he c o nfir me d O R R of eac h  c o h ort a n d its e xact 2 -si de d 95 % CI will be cal c ulate d . 
U p t o 5 of t he lar gest meas ura ble lesi o ns will be q ua ntitati vel y i de ntifie d at baseli ne base d o n 
lesi o n dia meters (Eise n h a uer 2 0 0 9 ). T he lesi o ns b ei n g f oll o we d f or res p o nse assess me nt will 
als o be q ua ntitati vel y ass es se d at eac h pre-s pecifie d ti me p oi nt. A s u m of dia meters will be 
calc ulate d at baseli ne a n d eac h assess me nt visit, a n d is defi ne d as t he s u m of all t he lesi o n 
dia meters (l o n gest dia meter f or n o n -n o d al lesi o ns, s h ort a xis f or n o dal lesi o ns). T he c ha n ge 
fr o m baseli ne, as well as t he c ha n ge fr o m t he pre vi o us res p o nse assess me nt (as a p plica bl e), 
i n t he s u m of dia meters will be deri ve d f or eac h assess me nt visit. T he ma xi m u m perce nt 
re d ucti o n ( or mi ni m u m perce nt i ncrease if t here is n o re d ucti o n) i n t he s u ms of dia meters 
fr o m baseli ne will be deri ve d f or eac h s u bject a n d will be gra p hicall y dis pla ye d (e. g., usi n g a 
waterfall pl ot).  
T his e n d p oi nt ma y als o be s u m marize d b y t he s u b gr o u ps defi ne d i n Secti o n  6. 8 . 
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E x pl orat or y a nal ys is of O R R ma y als o be c o n d ucte d usi n g i R EC I S T g ui deli nes . 
7. 5. 2  S e c o n d ar y E n d p oi nt s  
7. 5. 2. 1  Di s e a s e C o ntr ol R at e ( D C R)  
D C R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a c o nfir me d C R or P R acc or di n g t o 
R E CI S T v 1. 1 as assess e d b y t he i n vesti gat or, or meet t he S D criteria at least o nce after start 
of st u d y treat me nt at a mi ni m u m i nter val of 5 wee ks.  S u bjects  w h o d o n ot ha ve at least 1 
p ost -baseli ne res p o ns e as sess me nt or s u bjects w h ose res p o nse ca n n ot be assesse d will be 
c o u nte d as n ot ac hi e vi n g disease c o ntr ol.  
D C R will be esti mate d f or eac h c o h ort a n d its e x act 2 -si de d 95 % CIs will be calc ulate d.  
7. 5. 2. 2  D ur ati o n of R e s p o n s e ( D O R)  
D O R is defi ne d as t he ti me fr o m t he first d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R 
t hat is s u bse q ue ntl y c o nfir me d) t o t he first d oc u me ntati o n of P D or deat h d u e t o a n y ca us e, 
w hic he ver c o mes first.  
D O R data will be ce ns ore d as descri be d bel o w:  
•  S u bjects w h o d o n ot ha ve P D a n d are still o n st u d y at t he ti me of a n a n al ysis will be 
ce ns ore d at t he date of last disease assess me nt d oc u me nti n g a bse nce of P D.  
•  S u bjects w h o starte d a ne w a ntica ncer treat me nt pri or t o d oc u me ntati o n of P D or 
deat h will be ce ns ore d at t he date of last diseas e assess me nt pri or t o t he start of ne w 
treat me nt. 
•  S u bjects w h o are re m o ve d fr o m t he st u d y pri or t o d oc u me ntati o n of P D will be 
ce ns ore d at t he date of last disease assess me nt d oc u me nti n g a bse nce of P D.  
•  S u bjects wit h d oc u me nte d P D or deat h i m me diatel y after 2 or m o re misse d disease 
assess me nts will be ce ns ore d at t he dat e of t he last disease assess me nt pri or t o t he 
misse d visits.  
D O R will o nl y be calc ulate d f or s u bjects w h o ac hi e ve a c o nfir me d C R or P R.  
D O R will be a nal yze d b y c o h ort usi n g t he Ka pla n -Meier met h o d ol o g y a n d Ka pla n -Mei er 
pl ots will be pr o vi de d. T he me dia n D O R a n d its 2 -si de d 95 % CI will be cal c ulate d as 
a p pr o priate.  
7. 5. 2. 3  Pr o gr e s si o n -Fr e e S ur vi v al ( P F S)  
P F S is defi ne d as t he ti me fr o m t he start of st u d y treat me nt t o t he first d oc u me ntati o n of P D 
b y R E CI S T v 1 . 1 or deat h d ue t o a n y ca us e, w hic h e ver c o m es first.  
T he sa me ce ns ori n g r ules as o utli ne d i n Secti o n 7. 5. 2. 2  f or D O R will be a p plie d t o P F S. 
S u bjects  lac ki n g a n eval u ati o n of t u m or res p o nse after t heir first d ose of st u d y dr u g will ha ve 
t heir e ve nt ti me ce ns ore d at Da y 1. 
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F or c o h orts wit h a de q uat e data, P F S will be a n al yze d b y c o h ort usi n g t he Ka pla n -Mei er 
met h o d ol o g y a n d Ka pla n -Meier pl ots will be pr o vi de d. T he me dia n P F S a n d its 2 -si de d 95 % 
CI will be calc ulate d as a p pr o priate. T he P F S rates at 3 a n d 6 m o nt hs, a n d e ver y 3 m o nt hs 
t hereafter, will be re p orte d a n d t heir 2-si de d 95 % CIs will be calc ulate d.  
7. 5. 2. 4  O v er all S ur vi v al ( O S)  
O S is defi ne d as t he ti me fr o m t he start of st u d y treat me nt t o date of d eat h d ue t o a n y ca us e.  
I n t he a bse n ce of deat h, s ur vi val ti me will be ce ns ore d at t he last dat e t he s u bject is k n o w n t o 
be ali ve (i.e., d ate of last c o ntact).  
O S will be a nal yze d b y c o h ort usi n g Ka pla n -Meier met h o d ol o g y a n d Ka pla n -Meier pl ots will 
be pr o vi de d. T he m e dia n O S a n d its 2 -si de d 95 % CI will be calc ulate d as a p pr o priate. T he 
O S rates at 6 a n d 1 2 m o nt hs, a n d e ver y 6 m o nt hs t hereafter, will be re p orte d a n d t heir 2 -
si de d 95 % CI s will be calc ulate d. 
7. 6  S af et y A n al y s e s  
All safet y a nal yses will be perf or me d b y c o h ort a n d t otal usi n g t he safet y a nal ysis set.  
A d verse e ve nts will be c o de d usi n g Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A, 
Versi o n 2 4 . 0 or hi g her). 
La b orat or y v al ues will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E versi o n 5. 0 or hi g her).  
C o nc o mita nt me dicati o ns will be c o de d usi n g W H O Dr u g Gl o bal ( v ersi o n: Mar 2 0 1 9 B 3 
f or mat or m ore rece nt). 
7. 6. 1  A d v er s e E v e nt s  
A d verse e ve nts will be s u m marize d b y Me d D R A preferre d t er m i n desce n di n g fre q ue n c y of 
occ urre nce u nless ot her wise s pecifie d.  F or i nci de nce re p orti n g, if a s u bject re p orts m ore t ha n 
o ne A E t hat was c o de d t o t he sa me s yste m or ga n cl ass or preferre d ter m, t he s u bject will be 
c o u nte d o nl y o nce f or t hat s pecific s yste m or ga n class or preferre d ter m.  
A treat me nt -e mer ge nt A E is defi ne d as a n e wl y o cc urri n g or w orse ni n g A E after t he first 
d ose of st u d y dr u g t hr o u g h t he e n d of t he safet y r ep orti n g peri o d .  See A p pe n di x B  f or details 
re gar di n g tr eat me nt-e m er ge nt classificati o n.  A n o verall s u m mar y of A Es will be pr o vi d e d 
b y c o h ort a n d t otal.  S u m maries of A Es ma y  als o be pr o vi de d b y c o h ort a n d t otal  f or t he 
f oll o wi n g: 
•  All treat me nt -e mer ge nt A Es  
•  A Es relate d t o S E A -C D 4 0  
•  A Es relate d t o pe m br oliz u ma b  
•  A Es relate d t o c ar b o plati n  
•  A Es relate d t o pe m etre x e d  
•  Seri o us A d verse E v e nts ( S A Es)  
•  S A Es relate d t o S E A -C D 4 0  
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•  S A Es relate d t o pe m br oli z u ma b  
•  S A Es relate d t o car b o plati n  
•  S A Es relate d t o pe metr e xe d  
•  A Es lea di n g t o d ose dela y of S E A -C D 4 0  
•  A Es lea di n g t o d ose i nterr u pti o n (f ull d ose recei ve d) of S E A -C D 4 0  
•  A Es lea di n g t o t he d ose bei n g st o p pe d earl y (f ull d ose n ot recei ve d) of S E A -C D 4 0  
•  A Es lea di n g t o d ose dela y of pe m br oliz u ma b  
•  A Es lea di n g t o d ose i nterr u pti o n (f ull d ose recei ve d) of pe m br oliz u ma b  
•  A Es lea di n g t o t he d ose bei n g st o p pe d earl y (f ull d ose n ot recei ve d) of 
pe m br oliz u ma b  
•  A Es lea di n g t o d ose dela y of car b o pl ati n  
•  A Es lea di n g t o d ose i nterr u pti o n (f ull d ose recei ve d) of car b o plati n  
•  A Es lea di n g t o t he d ose bei n g st o p pe d earl y (f ull d ose n ot recei ve d) of car b o plati n  
•  A Es lea di n g t o d ose dela y of pe metre x e d  
•  A Es lea di n g t o d ose i nterr u pti o n (f ull d ose recei ve d) of pe metre xe d  
•  A Es lea di n g t o t he d ose bei n g st o p pe d earl y (f ull d ose n ot recei ve d) of p e metre xe d  
•  A Es lea di n g t o treat me nt disc o nti n uati o n of a n y st u d y dr u g  
•  A Es lea di n g t o deat h  
•  A Es t hat starte d d uri n g i nf usi o n  
•  A Es t hat starte d wit hi n 2 4 h o urs p ost i nf usi o n  
•  I nf usi o n relate d reacti o ns b y preferre d t er m 
•  H y perse nsiti vit y reacti o ns b y preferre d ter m 
•  Treat me nt -e mer ge nt A Es b y s yste m or ga n class, preferre d t er m a n d ma xi m u m 
se verit y. At eac h s yste m or ga n class or preferre d t er m, m ulti ple occ urre nces of e ve nts 
wit hi n a s u bject are c o u nte d o nl y o nce at t he hi g h est se verit y  
•  Gra de 3 – 5 tr eat me nt-e mer ge nt A Es  
•  Treat me nt -e mer ge nt A Es b y s yste m or ga n class a n d preferre d t er m  
 
All a d verse e ve nts, seri o us a d verse e ve nts, a d v erse e ve nts lea di n g t o tr eat me nt 
disc o nti n uati o n, a n d a d verse e v e nts lea di n g t o deat h will be liste d.  
I m m u ne-me di ate d A d v erse E ve nts  
I m m u ne-me diate d A Es  will be liste d a n d t he i nci de nce will be s u m mari ze d b y preferre d t er m  
a n d ma xi m u m se verit y . 
7. 6. 2  Cli ni c al L a b or at or y P ar a m et er s  
All la b orat or y res ults u p t o t he e n d of treat me nt visit will be prese nte d i n c o n ve nti o nal u nits. 
Gra d i n g of la b orat or y val ues will be assi g ne d pr o gra m maticall y per t he N CI C T C A E v 5. 0.  
S hift ta bles c o m pari n g t he hi g hest p ost -baseli ne t o baseli ne C T C A E gra d e ma y be pres e nte d.   
I n a d diti o n, cli nical la b orat or y data ma y b e pres e nte d gra p hicall y f or selecte d la b tests, b y 
sc he d ule d visit.  
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7. 6. 3  C o n c o mit a nt M e di c ati o n s  
C o nc o mita nt me dicati o ns ma y be liste d b y s u bject. 
7. 6. 4  A d diti o n al S af et y A n al y s e s  
7. 6. 4. 1  E C O G P erf or m a n c e St at u s  
E C O G perf or ma nce stat us ma y be s u m marize d f or eac h visit.  S hifts fr o m baseli ne t o t he 
l o west a n d hi g hest p ost -baseli ne sc ore ma y be ta b ulate d.  
7. 6. 4. 2  Vit al Si g n s  
Vital si g n meas ure me nts ma y be liste d b y s u bject f or eac h ti me p oi nt. S u m mar y statistics of 
vital si g ns a n d c ha n ge fr o m baseli ne ma y be ta b ul ate d w here a p pr o priate.  
7. 6. 4. 3  E C G  
E C G  stat us ( n or mal, a b n or mal cli nicall y si g nifica nt, or a b n or mal n ot cli nicall y si g nifica nt) 
ma y be s u m marize d f or eac h sc he d ul e d E C G a n d s hifts fr o m baseli ne ma y be ta b ulate d.  
7. 6. 5  D e at h s  
T he n u m ber of t otal deat hs, deat hs t hat occ ur wit hi n 3 0 da ys of last st u d y treat me nt, a n d 
deat hs t hat occ ur m ore t h a n 3 0 da ys aft er last st u d y treat me nt as well as t he relati o ns hi p t o 
disease will be s u m mariz e d b y c o h ort a n d t otal.  D eat h  i nf or mati o n will be liste d b y s u bject. 
7. 7  A d diti o n al A n al y s e s  
7. 7. 1  P h ar m a c o ki n eti c s a n d I m m u n o g e ni ci t y A n al y s e s  
S E A -C D 4 0  c o nce ntr ati o ns will be liste d a n d s u m marize d wit h des cri pti ve statistics at eac h 
P K sa m pli n g ti me p oi nt. All P K data will be a nal y ze d b y c o h ort a n d t otal usi n g t he P K 
a nal ysis set.  
N o A D A s u m maries are pla n ne d.  
7. 7. 2  P h ar m a c o d y n a mi c ( P D) a n d M e c h a ni s m of A cti o n Bi o m ar k er s  
Relati o ns hi ps of bi o mar ker para meters (e. g., bas eli ne val ues, a bs ol ute a n d relati ve c ha n g es 
fr o m baseli ne) t o effic ac y, safet y, a n d p har mac o ki netic para met ers ma y be e x pl ore d. 
Relati o ns hi ps a n d ass oci ate d data t hat are d eter mi ne d t o be of i nterest ma y be s u m marize d. 
Details will be descri be d se parat el y i n t he Bi o mar ker A nal ysis Pla n.  
7. 7. 3  P ati e nt -R e p ort e d O ut c o m e  E n d p oi nt s  
8  
N O P R O A N A L Y S E S A R E P L A N N E D. I N T E RI M A N A L Y SI S 
I nteri m effi cac y  a nal yses will be perf o r me d s e paratel y f or eac h c o h ort after a p pr o xi matel y 
1 5  s u bjects of a gi ve n c o h ort ha ve bee n treate d a n d are efficac y e v al ua ble p ost -baseli ne. T he 
Ba yesia n pre dicti ve pr o ba bilit y of s uccess ( P P o S) a p pr oac h will be use d t o deter mi ne t he 
criteria f or c o nti n uati o n. A c o h ort is c o nsi dere d “s uccessf ul”  if t he 9 0 % c o nfi de nce i nter val 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 0  of 2 5  
( CI) of t he res p o nse rate at t he ma xi m u m sa m ple size e xcl u d es t he bac k gr o u n d rate. At t he 
ti me of eac h i nteri m a n al ysis, t he P P o S will be calc ulate d. A P P o S < 5 % i n dicates t hat it is 
u nli kel y t he O R R will be better t ha n t he res p o nse rate of c urre nt sta n dar d of care at t he e n d 
of t he c o h ort gi ve n t he i nteri m res ult. Base d o n efficac y a n d s afet y d ata, t o g et her wit h t he 
P P o S, a c o h ort ma y be st o p pe d earl y b y t he s p o ns or. A c o h ort ma y als o be disc o nti n ue d at 
a n y p oi nt at t he discreti o n of t he s p o ns or.  T he esti mate d P P o S base d o n n u m ber of 
res p o n ders o bs er ve d a m o n g t he first 1 5 s u bjects are prese nt e d bel o w . 
N u m ber of res p o n ders  
a m o n g first 1 5  s u bjects 
C o h orts 1 a n d 2 
(p 0= 4 %)  
C o h ort 3 
(p 0= 3 3 %)  
C o h ort 4 
(p 0= 4 9 %)  
C o h ort 5 
(p 0= 3 2 %)  
0  
0. 0 0 4 4  
0. 0 0 0 0  
0. 0 0 0 0  
0. 0 0 0 0  
1  
0. 1 6 3 1  
0. 0 0 0 0  
0. 0 0 0 0  
0. 0 0 0 0  
2  
0. 5 4 6 7  
0. 0 0 0 3  
0. 0 0 0 0  
0. 0 0 0 3  
3  
0. 8 7 4 3  
0. 0 0 3 7  
0. 0 0 0 0  
0. 0 0 3 7  
4  
0. 9 8 7 0  
0. 0 2 3 6  
0. 0 0 0 1  
0. 0 2 3 4  
5  
1. 0 0 0 0  
0. 0 9 5 1  
0. 0 0 1 0  
0. 0 9 4 4  
6  
1. 0 0 0 0  
0. 2 5 8 3  
0. 0 0 8 4  
0. 2 5 7 0  
7  
1. 0 0 0 0  
0. 5 0 2 5  
0. 0 4 3 9  
0. 5 0 0 9  
8  
1. 0 0 0 0  
0. 7 4 5 2  
0. 1 5 0 9  
0. 7 4 3 9  
9  
1. 0 0 0 0  
0. 9 0 5 8  
0. 3 5 9 9  
0. 9 0 5 1  
1 0  
1. 0 0 0 0  
0. 9 7 6 0  
0. 6 2 5 0  
0. 9 7 5 8  
T h e pri or distri b uti o n is ass u me d t o be beta ( 0. 1 2, 0. 8 8), beta ( 0. 4 1, 0. 5 9), beta ( 0. 5 7, 0. 4 3),  a n d beta ( 0. 4, 0. 6), 
res pecti vel y, t o a p pr o xi mate t he bac k gr o u n d rate i n eac h disease c o h ort.  
 
T he pre dicti ve pr o ba bilit y met h o d all o ws t he P P o S be c o m p ute d at a n y i nt eri m ti me a n d 
pr o vi des fle xi bilit y i n m o nit ori n g treat me nt acti vit y c o nti n u o usl y after t he i nitial i nteri m 
a nal ysis.  
9  
C H A N G E S F R O M P L A N N E D A N A L Y S E S  
9. 1  C h a n g e s fr o m t h e Ori gi n al Pr ot o c ol  
E E a nal ysis set c ha n g e d t o R E a nal ysis set a n d use d as t he pri mar y a n al ysis set f or O RR a n d 
D C R . 
9. 2  C h a n g e s fr o m t h e Ori gi n al S A P  
•  U p date d T E A E d efi niti o n t o ali g n wit h C R Fs  
•  A d de d i m p utati o n f or partiall y missi n g s u bse q ue nt a nti -ca ncer t hera p y dat es  
•  U p dates t o refl ect c urre nt pr ot oc ol a n d pla n ne d a n al yses 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 1  of 2 5  
1 0  R E F E R E N C E S  
Cl o p per, C. J., & Pears o n, E. S. ( 1 9 3 4). T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n t he case of t he 
bi n o mial. Bi o metri ka, 4 0 4 -4 1 3.  
C ollett D ( 1 9 9 4). I nter val -ce ns ore d s ur vi val data. M o delli n g s ur vi val data i n me dical researc h. B oca Rat o n, 
Fla., C ha p ma n & Hall/ C R C:  2 3 7 -2 5 1.  
Eise n ha u er, E. A., T herasse, P., B o gaerts, J., Sc h wartz, L. H., Sar ge nt, D., F or d, R., ... & Ver weij, J. ( 2 0 0 9). 
Ne w res p o nse e v al uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( v ersi o n 1. 1). E ur o pea n j o ur nal of 
ca ncer, 4 5( 2), 2 2 8 -2 4 7.  
F o o d a n d Dr u g A d mi nistrati o n. ( 2 0 1 8). Met h o ds t o I de ntif y W hat Is I m p orta nt t o Patie nts & Select, De v el o p or 
M o dif y Fit -f or-P ur p ose Cli nical O utc o mes Assess me nts.  htt ps:// w w w.f da. g o v/ me dia/ 1 1 6 2 7 7/ d o w nl oa d  
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 2  of 2 5  
1 1  A P P E N DI C E S  
A P P E N DI X A: Im p ut ati o n  of  P arti all y U n k n o w n  A d v er s e  E v e nt  D at e s  
F or a n a d vers e e v e nt  ( A E) wit h a partial start or e n d date, if it ca n be d eter mi ne d t hat t he 
e ve nt occ urre d pri or t o t he date of first d ose of st u d y treat me nt, t he partial date will n ot be 
i m p ute d; Ot her wise, t he partial date will be i m p ute d usi n g t he r ules descri be d bel o w. A E 
start dates s h o ul d be i m p ute d bef ore i m p utati o n of A E c o n diti o n e n d date i n all cases.  
I nc o m plete A E Start D ate:  
A E d a y o nl y is missi n g  
If t he m o nt h/ year is t he s a me as t he m o nt h/ year of first d ose of a n y st u d y tr eat me nt : 
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y treat me nt  
If t he m o nt h/ year is after t he m o nt h/ year of first d ose of a ny st u d y treat me nt : 
A E start date will be i m p ute d as t he first da y of t h e m o nt h  
A E d a y a n d m o nt h are missi n g,  or m o nt h o nl y is missi n g  
If t he year is t he sa me as t he year of first d ose of a n y st u d y treat me nt:  
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y treat me nt  
If t he year is after t he year of first d ose of a n y st u d y treat me nt : 
A E start date will be i m p ute d as Ja n uar y 1st  
A E d a y, m o nt h a n d ye ar  are  missi n g , or ye ar o nl y is missi n g 
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y treat me nt  
 
If A E c o n diti o n e n d dat e * is n ot missi n g, a n d t he i m p ute d start date is after t he e n d date, t he 
start date will be set t o t he A E c o n diti o n e n d date.  
* o nl y use c o n diti o n e n d date if k n o w n a n d f ull e n d date is a vaila ble.  
I nc o m plete A E E n d D ate: 
If A E o utc o me is “ n ot r ec o vere d/res ol ve d”, “ u n k n o w n”, or bla n k:  A E c o n diti o n e n d date will 
n ot be i m p ute d.  
If A E o utc o me is “rec o v eri n g/res ol vi n g”, “rec o vere d/res ol ve d”, “rec o vere d/res ol ve d wit h  
se q uelae”, or “fatal” a p pl y t he f oll o wi n g:  
A E d a y o nl y is missi n g  
A E c o n diti o n e n d date will be i m p ute d as t he mi ni m u m of ( deat h date, d ata e xtracti o n 
date, last da y of t he e n d date m o nt h/ year , E O S date) 
A E d a y a n d m o nt h are missi n g,  or m o nt h o nl y is missi n g  
If t he year is e q ual t o t he year of t h e last d ose date: 
A E c o n diti o n e n d date will be i m p ute d as t he mi ni m u m of (last d ose date + 3 0, deat h 
date, data e xtracti o n dat e, Dece m b er 3 1st of t he e n d date year , E O S date) 
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 3  of 2 5  
 
If t he year is n ot e q ual t o t he year of t he last d ose date:  
A E c o n diti o n e n d date will be i m p ute d as t he mi ni m u m of ( deat h date, d ata e xtracti o n 
date, Dece m ber 3 1st of t he e n d date year , E O S date) 
A E d a y, m o nt h a n d ye ar  are  missi n g , or ye ar o nl y is missi n g 
A E c o n diti o n e n d date will n ot be i m p ute d  
Wit hi n a  si n gle rec or d, if t he i m p ute d st o p date is bef ore t h e start date, t h e n t he i m p ute d st o p 
date will be e q ual t o t he start date.  
E x a m ple  
A E  N u m ber  4:  C o n diti o n/ E ve nt N A U S E A  
First d ose d ate 0 2 A P R 2 0 1 2  
Pri or t o i m p ut ati o n  
L o g Li ne  
Start date  
C o n diti o n e n d date  
Se verit y  
O utc o me  
1  
2 5 A P R 2 0 1 2  
U N A P R 2 0 1 2  
2  
rec o veri n g/res ol vi n
g  
2  
U N A P R 2 0 1 2  
0 4 M A Y 2 0 1 2  
1  
rec o vere d/r es ol ve d 
P ost i m p ut ati o n  
L o g Li ne  
Start date  
C o n diti o n e n d date  
Se verit y  
O utc o me  
1  
2 5 A P R 2 0 1 2  
3 0 A P R 2 0 1 2  
2  
rec o veri n g/res ol vi
n g  
2  
0 2 A P R 2 0 1 2  
0 4 M A Y 2 0 1 2  
1  
rec o vere d/r es ol ve d 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n -2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 4  of 2 5  
A p p e n di x B: D efi niti o n  of t h e T er m “ Tr e at m e nt -E m er g e nt ” wit h R e s p e ct t o A E  
Cl a s sifi c ati o n  
T he al g orit h m bel o w s h o ul d be use d t o deter mi ne w het her a n a d verse e v e nt ( A E) is classifie d 
as a treat me nt -e mer g e nt a d verse e ve nt ( T E A E).  A T E A E is defi ne d as a n y A E w hic h is 
ne wl y occ urri n g or w ors e ni n g i n se verit y, w here ne wl y occ urri n g mea ns t hat t he A E was n ot 
prese nt at bas eli ne.  F or ease of rea di n g, b ot h pre -e xisti n g c o n diti o ns a n d A Es will be 
referre d t o as A Es f or t h e re mai n der of t his d oc u me nt.  A E dates s h o ul d be i m p ute d i n 
acc or da nce wit h t he al g orit h m detaile d i n A p pe n di x A p ri or t o deter mi nati o n of T E A E 
classificati o n.   Details of t he T E A E classificati o n are as f oll o ws:  
1.  F or eac h s u bject, deter mi ne t he first d ose dat e, w hic h is t he earliest date t h e s u bject 
recei v es a n y a m o u nt of st u d y dr u g. 
2.  A n A E rec or d fr o m A E p a ge will be classifie d as a T E A E if it meets t he f oll o wi n g 
c o n diti o ns: 
• 
O nset peri o d = Starte d after first d ose of a n y st u d y treat me nt  
• 
A E Start Date o n or after first d ose date of st u d y tr eat me nt  
• 
If s u bject di d n ot start ne w a ntica ncer t hera p y a n d A E S E R = “ Y” , A E Start Date 
o n or bef ore last d ose dat e  of a n y st u d y treat me nt  + 9 0 . Ot her wise, A E Start Date 
o n or bef ore last d ose dat e of a n y st u d y treat me nt + 3 0  or E O T visit, w hic he ver is 
later 
 
3.  If t he first e pis o de (l o gli ne) is mar ke d as T E A E, t h e n all s u bse q ue nt l o gli nes s h o ul d 
als o be c o nsi dere d as T E A E, e ve n if t he l ater l o gli nes ma y start aft er  t he earlier of last 
d ose date of a n y st u d y treat me nt + 3 0 da ys or E O T visit.  
N O T E:  
1.  F or s u m m aries w hic h i ncl u de o nl y tre at me nt e mer ge nt A Es i ncl u de all A Es w hic h 
are cl as sifie d as T E A Es as well as t h ose A Es f or w hic h T E A E st at us c o ul d n ot be 
deter mi ne d (e. g., t he v al ue of t he T E A E v ari a ble m a y be missi n g if t he e ve nt c a n n ot 
be i de ntifie d as b aseli ne or p ost -b aseli ne - missi n g i nf or m ati o n o n t he A E C R F 
s h o ul d be q uerie d).  O nl y e xcl u de t h ose A Es w hic h were deter mi ne d t o n ot be 
tre at me nt e mer g e nt. 
 
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


St u d y S G N S 4 0 -0 0 2  
Statistical A nal ysis Pla n  
Versi o n 2. 0; 1 8 -Ja n-2 0 2 4  
S E A -C D 4 0  
Sea ge n , I nc. - C o nfi de ntial  
Pa ge 2 5  of 2 5  
A p p e n di x C: I m p ut ati o n of P arti all y Mi s si n g S u b s e q u e nt A nti c a n c er T h er a p y 
D at e  
T he al g orit h m bel o w s h o ul d be use d t o i m p ute s u bse q ue nt a ntica n cer t h era p y start dates f or 
w hic h o nl y da y is missi n g.  
•  If t he m o nt h a n d year of t he start date of s u bs e q ue nt a ntica ncer t hera p y are t he sa me 
as t he m o nt h a n d year of a res p o nse assess me nt date, a n d  
o  If t he res p o ns e is a P D, s u bse q ue nt a ntica n cer t h era p y start date will be 
i m p ute d as t he res p onse assess me nt date or t he da y after t he l ast st u d y 
treat me nt, w hic he v er is l ater. 
o  If t he res p o ns e is n ot a P D, s u bse q ue nt a ntica n cer t hera p y start dat e will be 
i m p ute d as t he first da y of t he m o nt h or t he da y after t he last st u d y treat me nt, 
w hic he ver is l at er.  
•  Else if t he m o nt h a n d year of t he start dat e of s u bs e q ue nt a ntica n cer t h era p y are t he 
sa me as t he m o nt h a n d y ear of t h e e n d dat e of last st u d y treat me nt, s u bse q u e nt 
a ntica ncer t hera p y start d ate will be i m p ute d as t he da y aft er t he last st u d y treat me nt 
e n d date.  
•  Else if t he start date of s u bse q ue nt a ntica n cer t h era p y is later t ha n t he e n d d ate of last 
st u d y treat me nt base d o n a vaila ble m o nt h a n d year, s u bse q ue nt a ntica n cer t hera p y 
start date will be i m p ute d as t he first da y of t he m o nt h. 
 
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)


Si g nat ure Pa ge f or S G N- C LI N- 0 4 2 1 0 4 v 1. 0
Si g nat ure Pa ge f or S G N- C LI N- 0 4 2 1 0 4 v 1. 0
e Si g nat ure A p pr o val
Cli nical De vel o p me nt
1 9-Ja n- 2 0 2 4 0 0: 1 6: 5 9 G M T + 0 0 0 0
e Si g nat ure A p pr o val
Bi ostatistics
1 9-Ja n- 2 0 2 4 2 3: 2 4: 5 5 G M T + 0 0 0 0
e Si g nat ure A p pr o val
Bi ostatistics
2 2-Ja n- 2 0 2 4 1 6: 1 4: 2 8 G M T + 0 0 0 0
0 9 0 1 7 7 e 1 a 1 3 1 3f e 4\ A p pr o v e d\ A p pr o v e d O n: 1 9- J a n- 2 0 2 4 0 2: 5 5 ( G M T)
P P D
P P D
P P D