Conditions: Unresectable, Locally Advanced or Metastatic, Adenocarcinoma of the Stomach, or of the Gastro Esophageal Junction
Keywords: Avelumab Cancer Unresectable Locally advanced Metastatic Adenocarcinoma of the stomach Gastro-esophageal junction
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 499
Healthy volunteers: no

Brief summary:
The purpose of this study was to demonstrate superiority of treatment with avelumab versus continuation of first-line chemotherapy.

Detailed description:

Arms:
arm 1: In Maintenance Phase, participants continued the same regimen of oxaliplatin-fluoropyrimidine doublet chemotherapy (oxaliplatin + 5FU/LV or oxaliplatin + capecitabine) as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. Participants who were not deemed eligible to receive chemotherapy at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on Investigator's discretion. arm 2: In Maintenance phase, participants received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity or discontinuation.

Interventions: intervention 1: Avelumab intervention 2: Oxaliplatin intervention 3: 5-Fluorouracil intervention 4: Leucovorin intervention 5: Capecitabine intervention 6: Best supportive care intervention 7: Oxaliplatin intervention 8: 5-Fluorouracil intervention 9: Leucovorin intervention 10: Capecitabine
Intervention descriptions: intervention 1: Maintenance Phase: Intravenous (IV) infusion (10 mg/kg over 1 hour) once every 2 weeks. intervention 2: Induction Phase: Oxaliplatin was administered at a dose of 85 mg per square meter (mg/m\^2) as a continuous intravenous (IV) infusion on Day 1 along with leucovorin followed by 5-Fluorouracil every 2 weeks up to 12 weeks (or) Oxaliplatin at 130 mg/m\^2 IV on Day 1 along with capecitabine twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. intervention 3: Induction Phase: 5-Fluorouracil was administered at a dose of 2600 mg/m\^2 IV continuous infusion over 24 hours on Day 1 (or) 5-FU at 400 mg/m\^2 IV push on Day 1 and 2400 mg/m\^2 IV continuous infusion over 46-48 hours (Days 1 and 2) along with oxaliplatin and leucovorin every 2 weeks up to 12 weeks. Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. intervention 4: Induction Phase: Leucovorin was administered at a dose of 200 mg/m\^2 IV (or) Leucovorin 400 mg/m\^2 IV on Day 1 along with oxaliplatin and 5-FU every 2 weeks up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. intervention 5: Induction Phase: Capecitabine was administered at a dose of 1000 mg/m\^2 twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks along with oxaliplatin up to 12 weeks.

Maintenance Phase: Participants were continued the same regimen of chemotherapy as they received during the Induction Phase every 3 weeks until disease progression, significant clinical deterioration, unacceptable toxicity, or discontinuation. intervention 6: Treatment administered with the intent to maximize Quality of Life (QoL) without a specific antineoplastic regimen. These may include for example antibiotics, analgesics, antiemetics, thoracentesis, paracentesis, blood transfusions, nutritional support (including jejunostomy), and focal external-beam radiation for control of pain, cough, dyspnea, or bleeding. Best supportive care were administered per institutional guidelines and participants were visit the clinic every 3 weeks. intervention 7: Induction Phase: Oxaliplatin will be administered at a dose of 85 mg per square meter (mg/m\^2) as a continuous intravenous (IV) infusion on Day 1 along with leucovorin followed by 5-Fluorouracil every 2 weeks up to 12 weeks (or) Oxaliplatin at 130 mg/m\^2 IV on Day 1 along with capecitabine twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks up to 12 weeks. intervention 8: Induction Phase: 5-Fluorouracil will be administered at a dose of 2600 mg/m\^2 IV continuous infusion over 24 hours on Day 1 (or) 5-FU at 400 mg/m\^2 IV push on Day 1 and 2400 mg/m\^2 IV continuous infusion over 46-48 hours (Days 1 and 2) along with oxaliplatin and leucovorin every 2 weeks up to 12 weeks. intervention 9: Induction Phase: Leucovorin will be administered at a dose of 200 mg/m\^2 IV (or) Leucovorin 400 mg/m\^2 IV on Day 1 along with oxaliplatin and 5-FU every 2 weeks up to 12 weeks. intervention 10: Induction Phase: Capecitabine will be administered at a dose of 1000 mg/m\^2 twice daily for 2 weeks followed by a 1-week rest period given every 3 weeks along with oxaliplatin up to 12 weeks.

Protocol document:
Prot_000.pdf: 
A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1/ 1 5 0
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
E M R 1 0 0 0 7 0- 0 0 7
Title
A P hase III o pe n -la bel, m ultice nter trial of mai nte na nce 
t hera py 
wit h 
a vel u ma b 
( M S B 0 0 1 0 7 1 8 C) 
vers us 
c o nti n uati o n of first-li ne c he m ot hera p y i n s u bjects wit h 
u nresecta ble, 
l ocall y 
a d va nce d 
or 
metastatic, 
a de n ocarci n o ma 
of 
t he 
st o mac h, 
or 
of 
t he 
gastr o -es o p ha geal j u ncti o n 
S h ort Tri al N a me
J A V E LI N Gastric 1 0 0
P h ase
III
I N D N u m ber
E u dr a C T N u m ber
2 0 1 5 -0 0 3 3 0 0 -2 3
C o or di n ati n g I n vesti g at or
S p o ns or
F or all c o u ntries e xce pt t he U S A:
Merc k K Ga A,
Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
4 5 A Mi d dlese x T ur n pi ke, 
Billerica, M A 0 1 8 2 1- 3 9 3 6 , U S A
Me dical Res p o nsi ble:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
4 5 A Mi d dlese x T ur n pi ke, 
Billerica, M A 0 1 8 2 1- 3 9 3 6 , U S A
+ 1 9 7 8 4 3 5 1 2 5 3
Cli nic al Tri al Pr ot oc ol Versi o n
1 7 J ul y 2 0 1 9/ Versi o n 7 . 0
Re pl aces Versi o n
2 1 J u ne 2 0 1 8 / Versi o n 6. 0
T his d oc u me nt is t he pr o pert y of Merc k K G a A, Dar msta dt, Ger ma n y,  or o ne of its s u bsi diaries.  It 
is i nte n de d f or restricte d use o nl y  an d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
P P D
P P D


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2/ 1 5 0
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K G a A, Dar msta dt, Ger ma n y,  or its 
s u bsi diar y.  C o p y rig ht © 2 0 1 9 b y  Merc k KG a A, or its s u bsi diar y.  All ri g hts reser ve d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3/ 1 5 0
Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 3
Ta ble of I n -Te xt Ta bles ....................................................................................................... 8
Ta ble of I n -Te xt Fi g ures ...................................................................................................... 8
List of A b bre viati o ns ........................................................................................................... 9
1
S y n o psis ..............................................................................................1 2
2
S p o ns or, I n vesti gat ors a n d Trial A d mi nistrati ve Str uct ure ................ 4 0
2. 1
I n vesti gati o nal Sites............................................................................ 4 0
2. 2
Trial C o or di nati o n / M o nit ori n g ......................................................... 4 0
2. 3
Re vie w C o m mittees............................................................................ 4 1
2. 3. 1
I n de pe n de nt Data M o nit ori n g C o m mittee .......................................... 4 1
2. 3. 2
I n de pe n de nt Ra di ol o gist ..................................................................... 4 1
3
Bac k gr o u n d I nf or mati o n ..................................................................... 4 1
3. 1
Gastric Ca ncer .................................................................................... 4 1
3. 2
Pr o gra m me d Deat h Rece pt or a n d L i ga n ds......................................... 4 2
3. 3
A vel u ma b ............................................................................................ 4 2
3. 3. 1
Safet y .................................................................................................. 4 3
3. 3. 2
P har mac o ki netic Res ults ..................................................................... 4 3
3. 4
Rati o nale f or t he C urre nt Cli nical Trial .............................................. 4 5
3. 4. 1
Data fr o m A nti -P D -1/ P D -L 1  T hera pies i n Gastric Ca ncer ................ 4 6
3. 5
S u m mar y  of t he O verall Be nefit a n d Ris k.......................................... 4 7
4
Trial O bjecti ves .................................................................................. 4 8
4. 1
Pri mar y  O bjecti ves ............................................................................. 4 8
4. 2
Sec o n dar y  O bjecti ves ......................................................................... 4 8
5
I n vesti gati o nal Pla n ............................................................................ 4 9
5. 1
O verall Trial Desi g n a n d Pla n ............................................................ 4 9
5. 1. 1
O verall Desi g n .................................................................................... 4 9
5. 1. 2
Trial treat m e nt A d mi nistrati o n a n d Sc he d ule ..................................... 5 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4/ 1 5 0
5. 1. 3
D ose M o dificati o n a n d A d verse Dr u g Reacti o ns Re q uiri n g 
Treat me nt Disc o nti n uati o n ................................................................. 5 4
5. 2
Disc ussi o n of Trial Desi g n ................................................................. 5 7
5. 2. 1
Rati o nale S u p p orti n g t he C h oice of t he First -li ne C he m ot hera p y...... 5 7
5. 2. 2
Rati o nale f or E xcl usi o n of H E R 2 P ositi ve P o p ulati o n ....................... 5 8
5. 2. 3
Rati o nale f or S witc hi n g S u bjects fr o m C he m ot hera p y t o 
A vel u ma b ............................................................................................ 5 8
5. 2. 4
J ustificati o n of O pe n-la bel St u d y Desi g n........................................... 5 8
5. 2. 5
Rati o nale f or t he Pri mar y E n d p oi nt.................................................... 5 9
5. 2. 6
Trial Peri o ds ........................................................................................ 5 9
5. 2. 7
I ncl usi o n of S pecial P o p ulati o ns ........................................................ 6 0
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................6 0
5. 3. 1
I ncl usi o n Criteria................................................................................ 6 0
5. 3. 2
E xcl usi o n Criteria ............................................................................... 6 1
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................ 6 3
5. 5
Criteria f or S u bject Wit h dra wal .......................................................... 6 4
5. 5. 1
Wit h dra wal fr o m Trial T hera p y.......................................................... 6 4
5. 5. 2
Wit h dra wal fr o m t he Trial .................................................................. 6 5
5. 6
Pre mat ure Ter mi nati o n of t he Trial .................................................... 6 5
5. 7
Defi niti o n of E n d of Trial ................................................................... 6 6
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Trial ..................................................................................................... 6 6
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct ........................ 6 6
6. 1. 1
I n d ucti o n C he m ot hera py .................................................................... 6 6
6. 1. 2
A vel u ma b ............................................................................................ 6 6
6. 1. 3
Mai nte na nce C he m ot hera p y ...............................................................6 6
6. 1. 4
Best S u p p orti ve Care .......................................................................... 6 7
6. 2
D osa ge a n d A d mi nistrati o n................................................................ 6 7
6. 2. 1
A vel u ma b D osa ge a n d A d mi nistrati o n ............................................... 6 7
6. 2. 2
C he m ot hera p y D osa ge a n d A d mi nistrati o n ........................................ 6 8
6. 3
Assi g n me nt t o Treat me nt Gr o u ps....................................................... 7 0
6. 4
N o n -i n vesti gati o nal Me dici nal Pr o d ucts t o be Use d .......................... 7 0
6. 5
C o nc o mita nt Me dicati o ns a n d T hera pies ........................................... 7 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5/ 1 5 0
6. 5. 1
Per mitte d Me dici nes ...........................................................................7 1
6. 5. 2
Pr o hi bite d Me dici nes .......................................................................... 7 2
6. 5. 3
Ot her I nter ve nti o ns ............................................................................. 7 2
6. 5. 4
S pecial Preca uti o ns ............................................................................. 7 3
6. 5. 5
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns ............................................................................................. 8 3
6. 6
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct .... 8 3
6. 7
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct ............................................................................... 8 4
6. 8
I n vesti gati o nal Me dici nal Pr o duct Acc o u nta bilit y ............................. 8 4
6. 9
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce ......... 8 6
6. 1 0
Bli n di n g.............................................................................................. 8 6
6. 1 1
E mer ge nc y  U n bli n di ng....................................................................... 8 6
6. 1 2
Treat me nt of O ver d ose ....................................................................... 8 6
6. 1 3
Me dical Care of S u bjects after E n d of Trial ....................................... 8 6
7
Trial Pr oce d ures a n d Assess me nts ...................................................... 8 7
7. 1
Sc he d ule of Assess me nts .................................................................... 8 7
7. 1. 1
Scree ni n g a n d Baseli ne Pr oce d ures a n d Assess me nts ........................ 8 7
7. 1. 2
I n d ucti o n P hase Treat me nt Peri o d...................................................... 8 8
7. 1. 3
Ra n d o mizati o n/ Re -baseli ne ................................................................ 9 0
7. 1. 4
Mai nte na nce P hase Treat me nt Peri o d
................................................ 9 1
7. 1. 5
E n d of Treat me nt ................................................................................ 9 4
7. 1. 6
Safet y  F oll o w-u p Visit ........................................................................ 9 5
7. 1. 7
L o n g -ter m F oll o w- u p.......................................................................... 9 6
7. 1. 8
Bl o o d Dra ws f or Cli nical Assess me nts.............................................. 9 6
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics .............................. 9 6
7. 2. 1
De m o gra p hic Data .............................................................................. 9 6
7. 2. 2
Dia g n osis of Gastric Ca ncer ...............................................................9 6
7. 2. 3
Me dical Hist or y .................................................................................. 9 7
7. 2. 4
Vital Si g ns a n d P h y sical E xa mi nati o n................................................ 9 7
7. 2. 6
Ot her Baseli ne Assess me nts ...............................................................9 8
7. 3
Efficac y  Assess me nts ......................................................................... 9 8
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
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7. 4
Assess me nt of Safet y................................ ..........................................9 9
7. 4. 1
A d verse E ve nts ................................................................................. 1 0 0
7. 4. 2
Pre g na nc y  a n d I n Uter o Dr u g E x p os ure........................................... 1 0 5
7. 4. 3
Cli nical L a b orat or y Assess me nts ..................................................... 1 0 5
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts........... 1 0 7
7. 5. 1
B o d y Fl ui d(s) .................................................................................... 1 0 8
7. 7
Ot her Assess me nts ............................................................................ 1 1 1
7. 7. 1
S u bject -re p orte d O utc o mes / Q ualit y of Life ................................... 1 1 1
8
Statistics ............................................................................................ 1 1 1
8. 1
Sa m ple Size ...................................................................................... 1 1 1
8. 2
Ra n d o mizati o n .................................................................................. 1 1 3
8. 3
E n d p oi nts .......................................................................................... 1 1 3
8. 3. 1
Pri mar y  E n d p oi nt.............................................................................. 1 1 3
8. 3. 2
Sec o n dar y  E n d p oi nts........................................................................ 1 1 3
8. 3. 3
Safet y E n d p oi nts ............................................................................... 1 1 4
8. 4
A nal y sis Sets..................................................................................... 1 1 5
8. 5
Descri pti o n of Statistical A nal y ses ................................................... 1 1 6
8. 5. 1
Ge neral C o nsi derati o ns ..................................................................... 1 1 6
8. 5. 2
A n al ysis of Pri mar y E n d p oi nt .......................................................... 1 1 8
8. 5. 3
A nal y sis of Sec o n dar y E n d p oi nts..................................................... 1 1 9
8. 5. 5
A nal y sis of Safety E n d p oi nts ............................................................ 1 2 2
8. 5. 6
Re p orti n g of Ot her Cli nical Data of I nterest .................................... 1 2 4
8. 6
I nteri m a n d A d diti o nal Pla n ne d A nalys es ........................................ 1 2 5
9
Et hical a n d Re g ulat or y  As pects........................................................1 2 7
9. 1
Res p o nsi bilities of t he I n vesti gat or ................................ ..................1 2 7
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
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9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt ................................ .....1 2 7
9. 3
S u bject I de ntificati o n a n d Pri vac y .................................................... 1 2 8
9. 4
E mer ge nc y  Medical S u p p ort a n d S u bject Car d................................ 1 2 8
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects ................... 1 2 9
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d........ 1 2 9
9. 7
Healt h A ut h orities ............................................................................. 1 3 0
1 0
Trial Ma na ge me nt ............................................................................. 1 3 0
1 0. 1
Case Re p ort F or m Ha n dli n g .............................................................1 3 0
1 0. 2
S o urce Data a n d S u bject Files .......................................................... 1 3 0
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g................................................. 1 3 1
1 0. 4
M o nit ori n g, Q ualit y Ass ura nce a n d I ns pecti o n b y Healt h 
A ut h orities........................................................................................ 1 3 1
1 0. 5
C ha n ges t o t he Cli nic al Trial Pr ot oc ol .............................................. 1 3 1
1 0. 6
Cli nical Trial Re p ort a n d P u blicati o n P olic y .................................... 1 3 2
1 0. 6. 1
Cli nical Trial Re p ort ......................................................................... 1 3 2
1 0. 6. 2
P u blicati o n ........................................................................................ 1 3 2
1 1
Refere nces Cite d i n t he Te xt .............................................................1 3 2
1 2
A p pe n dices ....................................................................................... 1 3 5
A p pe n di x I
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial.................... 1 3 6
Si g nat ure Pa ge – Pr ot oc ol L ea d ....................................................................................... 1 3 7
Si g nat ure Pa ge – C o or di nati n g I n vesti gat or.................................................................... 1 3 8
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 3 9
S p o ns or Res p o nsi ble Pers o ns n ot Na me d o n t he C o ver Pa ge ......................................... 1 4 0
A p pe n di x II
G ui da nce o n C o ntrace pti o n ..............................................................1 4 1
A p pe n di x III
Pr ot oc ol A me n d me nts a n d L ist of C ha n ges ..................................... 1 4 2
Pr ot oc ol Versi o n 7. 0 S u m mar y  of C ha n ges..................................................................... 1 4 2
Rati o nale f or C ha n ges ...................................................................................................... 1 4 2
Pr ot oc ol Versi o n 7. 0 Detaile d L ist of C ha n ges ...............................................................1 4 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8/ 1 5 0
T a ble of I n-Te xt T a bles
Ta ble 1 
Sc he d ule of Assess me nts – Scree ni n g a n d I n d ucti o n P hase 
( O pe n-la bel C he m ot hera p y Treat me nt P hase) f or 
O xali plati n + Ca pecita bi ne ................................................................. 2 1
Ta ble 2 
Sc he d ule of Assess me nts – Scree ni n g a n d I n d ucti o n P hase ( O pe n-
la bel C he m ot hera py Treat me nt P hase) f or O xali plati n + 5-
Fl u or o uracil ( 5 -F U) ............................................................................ 2 4
Ta ble 3
Sc he d ule of Assess me nts – Mai nte na nce P hase a n d F oll o w -U p –
O xali plati n + Ca pecita bi ne ................................................................. 2 6
Ta ble 4
Sc he d ule of Assess me nts – Mai nte na nce P hase a n d F oll o w -U p -
O xali plati n + 5- Fl u or o uracil ( 5 -F U) ................................................... 3 0
Ta ble 5
Sc he d ule of Assess me nts:  Mai nte na nce P hase a n d F oll o w -U p -
Best S u p p orti ve Care O nl y ................................................................. 3 3
Ta ble 6
Sc he d ule of Assess me nts – Mai nte na nce P hase a n d F oll o w - u p –
A vel u ma b ............................................................................................ 3 6
Ta ble 7
Sc he d ule of Assess me nts – P har mac o ki netic, 
 
 a n d 
 Sa m pli n g d uri n g Mai nte na nce a n d 
O pe n -la bel Treat me nt P hases ( A vel u ma b ar m o nl y).......................... 3 9
Ta ble 8
D ose M o dificati o n Ge neral G ui deli nes f or C he m ot hera p y ................ 5 7
Ta ble 9
All o we d T hera p y Re gi me ns ...............................................................7 0
Ta ble 1 0
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n- relate d 
Reacti o ns Ass ociate d wit h A vel u ma b ................................................ 7 4
Ta ble 1 1
Ma na ge me nt of I mm u ne -relate d A d verse E ve nts .............................. 7 7
Ta ble 1 2
Cli nical L a b orat or y Assess me nts ..................................................... 1 0 6
Ta ble 1 3
Pla n ne d La n -De Mets ( O’ Brie n -Fle mi n g) Efficac y  B o u n daries of 
O S ..................................................................................................... 1 2 6
T a ble of I n-Te xt Fi g ures
Fi g ure 1
Sc he matic of Trial Desi g n .................................................................. 5 2
Fi g ure 2
Assess me nt a n d I nitial Ma na ge me nt of T u m or L ys is S yn dr o me ....... 7 6
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
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List of A b bre vi ati o ns
5- F U
fl u or o uracil
A D C C
a nti b o d y-de pe n de nt cell -me diate d c y t ot o xicit y
A D R
ad verse d r u g reacti o n
A E
ad verse eve nt
A E SI
ad verse eve nt of special interest
A L T
ala ni ne ami n otra nsferase
A N C O V A
anal ys is of co varia nce
A S T
as partate ami n otra nsferase
A U C ta u
area u n der t he co nce ntrati o n -ti me cur ve
β- h C G
β- h u ma n c h ori o nic g o na d otr o pi n
B O R
Best O verall Res p o nse
B S C
b est s u p p orti ve care
CI
co nfi de nce inter val
C ma x
m a xi m u m co nce ntrati o n o bser ve d
C mi n
tr o u g h co nce ntrati o n
C H M P
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use
C R
co m plete res p o nse
C R A
cli nical researc h ass ociate
C R O
co ntract researc h o r ga nizati o n
C T
co m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
c T n I
car diac tr o p o ni n I
c T nT
car diac tr o p o ni n T
E C G
electr ocar di o gra m
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us
e C R F
electr o nic case re p ort for m
E O R T C
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer
E Q - 5 D-5 L
E ur o pea n Q ualit y  of Li fe 5- Di me nsi o ns 5 Le vels Q uesti o n naire
F F P E
f or mali n-fi xe d p araffi n-e m be d de d
FI S H
fl u oresce nce i n sit u h y bri dizati o n
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 / 1 5 0
F S H
follicle -sti m ulati n g hor m o ne
G C P
G o o d Cli nical Practice
G EJ
g astr o -es o p ha geal j u ncti o n
G G T
g a m ma -gl uta m y ltra nsferase
H 1
hista mi ne H 1 r ece pt or
H B V
h e patitis B vir us
H C V
h e patitis C vir us
H E R 2 + 
h u ma n e pi der mal gr o wt h fact or rece pt or 2 p ositi ve
H R Q o L
Healt h -Relate d Q ualit y  of Life
I B
I n vesti gat or’s Br oc h ure
I CF
inf or me d co nse nt for m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
I n de pe n de nt Data M o nit ori n g C o m mittee
I E C
I n de pe n de nt Et hics C o m mittee
I H C
im m u n o hist oc he mistr y
I M P
in vesti gati o nal m e dici nal p r o d uct
I P M P
I nte grate d Pr oject Ma na ge me nt Pla n
ir A E
im m u ne -relate d a d verse eve nt
I RB
I nstit uti o nal Re vie w B oar d
I T T
i nte nt-t o-treat
I V
intra ve n o us(l y)
I W R S
interacti ve w e b res p o nse sys te m
L F T
li ver f u ncti o n test
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M RI
m a g netic res o na nce ima gi n g
N CI
Nati o nal Ca ncer I nstit ute
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N S C L C 
n o n- s mall cell lu n g ca ncer
O R R
o bjecti ve res p o nse rate
O S
O verall S ur vi val
P D
p r o gressi ve d isease
P D -1
p r o gra m me d d eat h 1 (rece pt or)
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 / 1 5 0
P D -L( 1 a n d 2)
p r o gra m me d d eat h li ga n d ( 1 a n d 2)
P F S
Pr o gressi o n -free S ur vi val
P P
p er- pr ot oc ol
P R
p artial res p o nse
Q o L
q ualit y  of life
Q Tc
correcte d Q T inter val
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
S A E
seri o us a d verse eve nt
S A P
statistical anal y sis p la n
S D
sta ble d isease
S O C
sta n dar d of care
S U S A R
sus pecte d u ne x pecte d seri o us ad verse reacti o ns
S w M
switc h -mai nte na nce
t1/ 2
ter mi nal h alf-life
T 4
free th y r o xi ne
T E A E
treat me nt-e mer ge nt ad verse eve nt
T E S A E 
t reat me nt-e mer ge nt seri o us a d verse e ve nt
T S H
th y r oi d-sti m ulati n g hor m o ne
U L N
u p per li mit of n or mal
U S A
U nite d States of A merica
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 / 1 5 0
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
E M R 1 0 0 0 7 0 - 0 0 7
Title
A 
P hase 
III 
o pe n -la bel, m ultice nter 
trial of 
mai nte na nce t hera p y wit h a vel u ma b ( M S B 0 0 1 0 7 1 8 C) 
vers us c o nti n uati o n of first-li ne c he m ot hera p y in 
s u bjects wit h 
u nresecta ble, l ocally a d va nce d or 
metastatic, a de n ocarci n o ma of t he st o mac h, or of t he 
gastr o -es o p ha geal j u ncti o n
Tri al P h ase
III
I N D N u m ber
F D A c o vere d tri al
Yes
E u dr a C T N u m ber
2 0 1 5 -0 0 3 3 0 0 -2 3
C o or di n ati n g I n vesti g at or
S p o ns or
F or all c o u ntries e xce pt t he U S A:
Merc k K Ga A,
Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
4 5 A Mi d dlese x T ur n pi ke
Billerica, Massac h usetts 0 1 8 2 1 - 3 9 3 6
U S A
Tri al ce nters/c o u ntries
T he trial will be c o n d ucte d at a p pr o xi matel y  2 3 0 sites 
gl o ball y i n N ort h A merica, S o ut h A merica, 
Asia 
Pacific, a n d E ur o pe , wit h a p pr o xi matel y 47 sites i n t he 
U S A .
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
First s u bject i n: Q 4, 2 0 1 5
Last s u bject o ut: Q 3, 2 0 1 9
Tri al Re gistr y
Cli nical Trials. g o v
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
P P D


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 / 1 5 0
O bjecti ves:
Pri m ar y o bjecti ves: T he pri mar y  objecti ves are t o de m o nstrate s u peri orit y of mai nte na nce 
t hera py wit h a vel u ma b vers us c o nti n uati o n of first-li ne c he m ot hera p y wit h re gar d t o O verall 
S ur vi val ( O S) i n all ra n d o mize d s u bjects or i n P D -L 1 + s u bjects w h o ha ve n ot pr o gresse d o n 
first-li ne c he m ot hera py.
Sec o n d ar y o bjecti ves:

T o de m o nstrate s u peri orit y of mai nte na nce t hera p y wit h a vel u ma b vers us c o nti n uati o n of 
first-li ne c he m ot hera p y wit h re gar d t o Pr o gressi o n -Free S ur vi val ( P F S) as per 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 CIS T v 1. 1) acc or di n g t o I nvesti gat or 
assess me nt.

T o de m o nstrate s u peri orit y of mai nte na nce t hera p y wit h a vel u ma b vers us c o nti n uati o n of 
first-li ne c he m ot hera p y wit h re gar d t o o bjecti ve res p o nse rate ( O R R) as per R E CI S T v 1. 1
a n d per I n vesti gat or assess me nt .

T o c o m pare t he s u bject-re p orte d o utc o mes / q ualit y  of life ( Q o L) of s u bjects w he n treate d 
wit h a vel u ma b vers us c o nti n uati o n of first -li ne c he m ot hera p y as assesse d b y  t he E ur o pea n 
Q o L 5- di me nsi o ns 5- le vels q uesti o n naire (E Q -5 D -5 L ), a n d 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 ( E O R T C) Q L Q- C 3 0 a n d m o d ule Q L Q -S T O 2 2 .

T o deter mi ne t he safet y a n d t olera bilit y of a vel u ma b .
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 / 1 5 0
Met h o d ol o g y:
T his is a m ultice nter, i nter nati o nal, ra n d o mize d, o pe n -la bel P hase III trial of a vel u ma b i n 
s u bjects wit h a d va nce d ( u nresecta ble, l ocall y ad va nce d or metastatic) a de n ocarci n o ma of t he 
st o mac h, or of t he gastr oes o p ha geal j u ncti o n ( G EJ) w h o are treat me nt naï ve a n d ha ve n ot ye t 
recei ve d c he m ot hera py f or t he treat me nt of metastatic or l ocall y a d va nce d disease.  
T his st u d y incl u des a S cree ni n g peri o d, I n d ucti o n P hase, Mai nte na nce P hase, a n d F oll o w -u p 
P hase .
T he act ual n u m ber of s u bjects e nr olle d i n t he I n d ucti o n P hase will be dri ve n b y  obser ve d 
i n d ucti o n fail ure rates a n d will be s uc h t o all o w f or a p pr o xi matel y 46 6 s u bjects t o b e 
ra n d o mize d i n t he M ai nte na nce P hase. S u bject s e nr olle d i n t he I nd ucti o n P hase will recei ve 
i n d ucti o n c he m ot hera p y c o m prise d of o xali plati n a n d eit her 5-fl u or o uracil ( 5-F U) or 
ca pecita bi ne (I n d ucti o n P hase) f or 1 2 wee ks.  F oll o wi n g t he I n d ucti o n P hase, s u bjects w h o 
e x perie nce a c o m plete res p o nse ( C R), partial res p o nse ( P R), or sta ble disease ( S D) will e nter 
t he Mai nte na nce P hase a n d be ra n d o ml y assi g ne d t o recei ve eit her a vel u ma b, or c o nti n uati o n 
of t he sa me c he m ot hera p y re gi me n fr o m t he I n ducti o n P hase ( Mai nte na nce P hase).
T he d ose a n d sc he d ule of t he c he m ot hera p y d uri n g t he I n d ucti o n P hase are as f oll o ws or i n 
acc or da nce t o t he la bel i nstr ucti o ns a n d per l ocal g ui deli nes:

O xali plati n at 8 5 m g/ m 2 i ntra ve n o us (I V) o n D a y  1 wit h le uc o v ori n 2 0 0 m g/ m 2 I V o n Da y 1
( or e q ui vale nt le v ole uc o v ori n d ose ) f oll o we d b y  5-F U at 2 6 0 0 m g / m2 I V co nti n u o us 
i nf usi o n o ver 2 4 h o urs o n Da y  1, gi ve n e ver y 2 wee ks (f or u p t o 1 2 wee ks)
O R

O xali plati n at 8 5 m g/ m 2 I V o n Da y  1 wit h le uc o v ori n 4 0 0 m g/ m 2 I V on Da y 1 ( or e q ui vale nt 
le v ole uc o v ori n d ose) f oll o we d b y  5-F U at 4 0 0 m g / m2 I V p us h o n Da y  1 an d 2 4 0 0 m g/ m 2
I V co nti n u o us i nf usi o n o ver 4 6- 4 8 h o urs (Da y s 1 a n d 2) gi ve n e ver y 2 wee ks (f or u p t o 
1 2 wee ks)
O R

O xali plati n at 1 3 0 m g/ m 2 I V on Da y 1 wit h ca pe cita bi ne at 1 0 0 0 m g/ m 2, t wice dail y  for 
2 wee ks f oll o we d b y a 1-wee k rest peri o d gi ve n e ver y  3 wee ks (f or u p t o 1 2 wee ks).  
L ocal la bel a n d g ui deli nes s h o ul d be f oll o we d f or s pecific starti n g d oses d ue t o re nal or he patic 
i m pair me nts a n d f or s u bse q ue nt d ose m o dificati o ns d ue t o differe nt t o xicities.
U p o n c o m pleti o n of c he m ot hera p y i n t he I n d ucti o n P hase, s u bjects wit h o ut disease pr o gressi o n 
(s u bjects wit h S D, P R, or C R) will be eli gi ble f or ra n d o mizati o n t o t he Mai nte na nce P hase 
w here t he y  will recei ve eit her a vel u ma b, or c o nti n ue t he sa me re gi me n of c he m ot hera p y fr o m 
t he In d ucti o n P hase.  
Treat me nt d uri n g t he Mai nte na nce P hase are as f oll o ws:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 5 / 1 5 0
1.
F or s u bjects ra n d o mly assi g ne d t o a vel u ma b: a vel u ma b will be gi ve n at a d ose of 
1 0 m g/ k g as a 1 -h o ur I V i nf usi o n o nce e ver y  2 wee ks u ntil disease pr o gressi o n
2.
F or 
s u bjects 
ra n d o ml y 
assi g ne d 
t o c he m ot hera p y:  the 
sa me 
re gi me n of 
o xali plati n -fl u or o p yri mi di ne d o u blet as i n t he I n d ucti o n P hase will be c o nti n ue d u ntil 
disease pr o gressi o n.

S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her c he m ot hera p y will 
recei ve best s u p p orti ve care ( B S C) al o ne wit h n o acti ve t hera p y.  Pri or t o 
ra n d o mizati o n, In vesti gat ors m ust s pecif y  B S C treat me nt f or t hese s u bjects.   

F or s u bjects recei vi n g c he m ot hera p y ( o xali plati n + 5- F U or o xali plati n + 
ca pecita bi ne), d ose m o dificati o ns after t he starti n g d ose are all o we d if t he 
c o nti n uati o n of t he o xali plati n -fl u or o p yri mi di ne d o u blet, or a c o m p o ne nt 
t here of, is pr o hi bite d b y t o xicit y.  For s u bjects i nt olera nt t o f urt her o xali plati n, 
si n gle-a ge nt ca pecita bi ne or 5- F U + le uc o v ori n will be a n o pti o n f or d ose 
m o dificati o n.
S u bjects will ret ur n t o t he cli nic at re g ular i nter vals f or assess me nts.  T u m or meas ure me nts b y 
c o m p ute d t o m o gra p hy ( C T) sca n or ma g netic res o na nce i ma gi n g ( M RI) will be perf o r me d 
e ver y 6 wee ks f or t he first 1 2 m o nt hs a n d e ver y 1 2 wee ks t hereafter t o deter mi ne res p o nse t o 
treat me nt.  Cli nical decisi o n ma ki n g 
a n d st u d y en d p oi nt e val uati o n will be base d o n 
I n vesti gat or assess me nt of t he sca ns usi n g R E CI S T v 1. 1 .  
St u d y  treat me nt will c o nti n ue u ntil:

Disease pr o gressi o n 

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n) b y  In vesti gat or’s o pi ni o n 

U nacce pta ble t o xicit y  b y In vesti gat or’s o pi ni o n, or

A n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d.
S u bjects recei vi n g a vel u ma b m a y  co nti n ue treat me nt past t he i nitial deter mi nati o n of disease 
pr o gressi o n per R E CI S T versi o n 1. 1 as l o n g t he f oll o wi n g criteria are met:

I n vesti gat or-assesse d cli nical be nefit, wit h o ut a n y ra pi d disease pr o gressi o n

T olera nce of trial treat me nt

Sta ble Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us ( E C O G P S [ P S = 0 or 1])

Treat me nt b e y o n d pr o gressi o n will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n (f or e xa m ple, ce ntral ner v o us s yste m metastases).
T he decisi o n t o c o nti n ue a vel u ma b treat me nt b e y o n d pr o gressi o n s h o ul d be disc usse d wit h t he 
M e dical M o nit or a n d d oc u me nte d i n t he st u d y rec or ds.
F or s u bjects c o nti n ui n g a vel u ma b after i nitial pr o gressi ve disease (P D ), a ra di o gra p hic 
assess me nt s h o ul d be perf or me d wit hi n 6 wee ks of ori gi nal P D t o deter mi ne w het her t here has 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 6 / 1 5 0
bee n a decrease i n t he t u m or size, or c o nti n ue d P D.  T he assess me nt of cli nical be nefit s h o ul d 
be bala nce d b y  cli nical j u d g me nt as t o w het her t he s u bject is cli nicall y deteri orati n g a n d 
u nli kel y  t o recei ve a n y be nefit fr o m c o nti n ue d treat me nt wit h a vel u ma b.
F or s u bjects recei vi n g a vel u ma b, if disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve 
dia g n osis/ra di o gra p hic c o nfir mati o n is n ot ma de at the ti me of disc o nti n uati o n, a sec o n d 
i ma gi n g sca n m a y  be all o we d f or c o nfir mati o n of pr o gressi o n.  If pr o gressi o n at t he sec o n d 
i ma gi n g sca n is n ot c o nfir me d a n d t he s u bject wis hes t o restart, t he s u bject will be all o we d t o 
c o nti n ue recei vi n g a vel u ma b as lo n g as t he y meet t he criteria f or c o nti n uati o n of treat me nt 
be y o n d pr o gressi o n. 
If t he I n vesti gat or feels t hat t he s u bject c o nti n ues t o ac hie ve cli nical be nefit b y  co nti n ui n g 
treat me nt, t he s u bject s h o ul d re mai n o n t he trial a n d c o nti n ue t o recei ve m o nit ori n g acc or di n g 
t o t he Sc he d ule of Assess me nts.
A n y  ad diti o nal c o nti n uati o n of a vel u ma b pl us B S C b e y o n d f urt her pr o gressi o n m ust be 
disc usse d a n d a gree d u p o n wit h t he M e dical M o nit or.  Furt her disease pr o gressi o n is defi ne d 
as a n a d diti o nal i ncrease i n t u m or b ur de n of 2 0 % a n d ≥ 5 m m a bs ol ute i ncrease i n t u m or b ur de n 
fr o m ti me of i nitial P D.   T his i ncl u des a n i ncrease i n t he s u m of all tar get lesi o ns a n d/ or t he 
de vel o p me nt of ne w meas ura ble lesi o ns.  
S u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o u l d be treate d f or a mi ni m u m of 
1 2 m o nt hs or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after c o nfir mati o n of res p o nse.   
I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, b ut pri or t o t he e n d of 
t he trial, 1 re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t he I nvesti gat or a n d after 
a gree me nt wit h t he Me dical M o nit or.  T o be eli gi ble f or retreat me nt, t he s u bject m ust n ot ha ve 
e x perie nce d a n y t o xicit y that le d t o treat me nt disc o nti n uati o n of t he i nitial a vel u ma b t hera p y.   
S u bjects w h o re-i nitiate treat me nt will sta y on trial a n d will be treate d a n d m o nit ore d acc or di n g 
t o t he pr ot oc ol a n d f oll o w t he Sc he d ule of Assess me nts u ntil disease pr o gressi o n .
S u bjects i n t he m ai nte na nce c he m ot hera p y ar m will recei ve trial treatme nt u ntil P D per 
R E CI S T v 1. 1, si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), u nacce pta ble t o xicit y, 
wit h dra wal of c o nse nt, or if a n y criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is 
f ulfilled.  
O n -st u d y su bject ma na ge me nt a n d st ud y  en d p oi nt e val uati o n will be base d o n I nvesti gat or 
assess me nts.  
S u bjects will atte n d cli nic visits at re g ular i nter vals t o recei ve trial treat me nt a n d f or efficac y 
a n d safet y assess me nts.
After c o m pleti o n of t he Mai nte na nce P hase, s u bjects will e nter t he F oll o w -u p P hase.  
Pl a n ne d n u m ber of s u bjects:
A p pr o xi matel y  4 6 6 s u bjects are pla n ne d t o be ra n d o ml y assi g ne d i nt o t he Mai nte na nce P hase.
T he act ual n u m ber of s u bjects e nr olle d i n t he I n d ucti o n P hase will be dri ve n b y  obser ve d 
i n d ucti o n fail ure rates a n d will be s uc h t o all o w f or a p pr o xi matel y 4 6 6 patie nts t o be 
ra n d o mize d i n t he M ai nte na nce P hase. 
At t he ti me of t his pr ot oc ol a me n d me nt, s ubject 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 7 / 1 5 0
e nr oll me nt i n t he Mai nte na nce P hase is c o m plete, wit h
4 9 9 s u bjects ra n d o mize d i nt o t he 
Mai nte na nce P hase .
Pri m ar y e n d p oi nt:  
T he pri mar y  e n d p oi nt of t he trial is:

O S, defi ne d as t he ti me (i n m o nt hs) fr o m ra n d o mizati o n t o t he date of deat h, re gar dless of 
t he act ual ca use of t he s u bject’s deat h .
Sec o n d ar y e n d p oi nts:  
T he ke y  sec o n dar y e n d p oi nts are:

P F S
defi ne d as t he ti me (i n m o nt hs) 
fr o m ra n d o mizati o n t o t he date of t he first 
d oc u me ntati o n of disease pr o gressi o n ( per RE CI S T v 1. 1 a n d as e val uate d b y  In vesti gat or) 
or deat h d ue t o a n y ca use ( w hic he ver occ urs first).

Best O verall Res p o nse ( B O R) i n Mai nte na nce P hase acc or di n g t o R E CI S T v 1. 1 a n d per 
I n vesti gat or assess ment.
Ot her sec o n dar y  e n d p oi nts i ncl u de s u bject-re p orte d o utc o mes / Q o L (assesse d b y t he E Q- 5 D-
5 L , E O R T C Q L Q-C 3 0, a n d E O R T C m o d ule Q L Q- S T O 2 2 q uesti o n naires).
S afet y e n d p oi nts:
Safet y  en d p oi nts i ncl u de a d verse e ve nts ( A Es), assesse d t hr o u g h o ut t he trial a n d e val uate d 
usi n g 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 ve nts
( C T C A E) v 4. 0 3, p h y sical e xa mi nati o ns, cli nical la b orat or y assess me nts, c o nc o mita nt 
me dicati o ns, vital si g ns, electr ocar di o gra m ( E C G) para meters, a n d E C O G P S.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 8 / 1 5 0
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a:
Ke y i ncl usi o n criteri a
Male or fe male s u bjects a ge d ≥ 1 8 years, wit h a n E C O G P S of 0 t o 1 at trial e ntr y, wit h t he 
a vaila bilit y of a rece ntl y-o btai ne d ( wit hi n 6 m o nt hs) bi o ps y  fr o m a n o n -irra diate d area, 
f or mali n-fi xe d, paraffi n -e m be d de d ( F F P E) bl oc k c o ntai ni n g t u m or tiss ue or a mi ni m u m of 
1 0 ( prefera bly 2 5) u nstai ne d t u m or sli des (c ut wit hi n 1 wee k) s uita ble f or P D -L 1  ex pressi o n 
assess me nt, at least 1 meas ura ble t u m or lesi o n, a n d wit h hist ol o gicall y c o nfir me d u nresecta ble, 
l ocall y a d va nce d or metastatic, a de n ocarci n o ma of t he st o mac h or t he G EJ.
Ke y e xcl usi o n criteri a
Pri or t hera py wit h a n y a nti b o d y or dr u g tar geti n g T- cell c ore g ulat or y pr otei ns, c o nc urre nt 
a ntica ncer treat me nt, or i m m u n os u p pressi ve a ge nts.  
Ot her e xcl usi o n criteria: se vere 
h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies ( Gra de ≥ 3 N CI -C T C A E v 4. 0 3), a n y 
hist or y  of a na p h yla xis or u nc o ntr olle d ast h ma (t hat is, 3 or m ore feat ures of partiall y  co ntr olle d 
ast h ma), persisti n g t o xicit y relate d t o pri or t hera p y of Gra de ≥ 2 N CI -C T C A E v 4. 0 3 a n d pri or 
c he m ot hera p y f or u nresecta ble l ocall y a d va nce d or metastatic a de n ocarci n o ma of t he st o mac h 
or G EJ.
I n vesti g ati o n al Me dici n al Pr o d uct: d ose/ m o de of a d mi nistr ati o n / d osi n g sc he d ule:
A vel u ma b will be a d mi nistere d as a 1- h o ur I V inf usi o n at 1 0 m g/ k g o nce e ver y 2-wee k 
treat me nt c ycle u ntil P D or u nacce pta ble t o xicit y.  T o miti gate i nf usi o n-relate d reacti o ns, 
p re me dicate patie nts wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) pri or t o t he 
first 4 i nf usi o ns of a vel u ma b.  P re me dicati o n s h o ul d be a d mi nistere d f or s u bse q ue nt a vel u ma b 
d oses base d u p o n cli nical j u d g me nt a n d prese nce/se verit y of pri or i nf usi o n reacti o ns.  T his 
re gi me n m a y  be m o difie d base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate 
pr o vi de d it d oe s n ot i ncl u de s yste mic c ortic oster oi ds a n d has t o be rec or de d as c o nc o mita nt 
me dicati o n.
Refere nce t her a p y: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: C he m ot hera p y d uri n g 
t he Mai nte na nce P hase will be a d mi nistere d acc or di n g t o t he f oll o wi n g r ules:
1.
F or 
s u bjects 
ra n d o ml y 
assi g ne d 
t o c he m ot hera p y:  the 
sa me 
re gi me n of 
o xali plati n -fl u or o p yri mi di ne d o u blet as i n t he I n d ucti o n P hase will be c o nti n ue d u ntil 
disease pr o gressi o n.

S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her c he m ot hera p y will 
recei ve B S C al o ne wit h n o acti ve t hera py.  Pri or t o ra n d o mizati o n, I nvesti gat ors 
m ust s pecif y  B S C treat me nt f or t hese s u bjects.

F or s u bjects recei vi n g c he m ot hera p y ( o xali plati n + 5- F U or o xali plati n + 
ca pecita bi ne) d ose m o dificati o ns after t he starti n g d ose are all owe d if t he 
c o nti n uati o n of t he o xali plati n -fl u or o p yri mi di ne d o u blet, or a c o m p o ne nt 
t here of, is pr o hi bite d b y t o xicit y.  For s u bjects i nt olera nt t o f urt her o xali plati n, 
si n gle-a ge nt ca pecita bi ne or 5- F U + le uc o v ori n will be a n o pti o n f or d ose 
m o dificati o n.
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 9 / 1 5 0
T hera p y will be a d mi nistere d u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, or f or t he 
acce pte d ma xi mal d urati o n of t he a ge nt(s) selecte d.
T hera p y will be st o p pe d after t he first o n- treat me nt ra di ol o gical e val uati o n of disease 
pr o gressi o n.
Pl a n ne d tri al a n d tre at me nt d ur ati o n per s u bject:
I n this trial, treat me nt wit h c he m ot hera p y d uri n g t he I n d ucti o n P hase will last f or 1 2 wee ks, 
f oll o we d by t he Mai nte na nce P hase wit h eit her a vel u ma b or c o nti n uati o n of t he sa me re gi me n 
of c he m ot hera p y fr o m t he I n d uctio n P hase, w hic h will c o nti n ue u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y.  Su bjects recei vi n g a vel u ma b d uri n g t he Mai nte na nce 
P hase m a y 
c o nti n ue
treat me nt past t he i nitial deter mi nati o n of disease pr o gressi o n acc or di n g t o 
R E CI S T v 1. 1 if t he y meet t he criteria prese nte d u n der Met h o d ol o g y  (I n vesti gat or-assesse d 
be nefit; t olera nce of treat me nt; sta ble E C O G P S ; a n d d oes n ot dela y  ot her i m mi ne nt 
i nter ve nti o n).  S u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or 
a mi ni m u m 
of 1 2 m o nt hs or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after 
c o nfir mati o n of res p o nse.
St atistic al met h o ds: 
T he pri mar y  o bjecti ves of t his trial are t o de m o nstrate s u peri ority o f mai nte na nce t hera py wit h 
a vel u ma b vers us c o nti n uati o n of first-li ne c he m ot hera p y wit h re gar d t o O S i n all ra n d o mize d 
s u bjects or i n P D -L 1 + s u bjects w h o ha ve n ot pr o gresse d o n first-li ne c he m ot hera p y.   T he 
pri mar y  en d p oi nt i n t his st u d y is O S . A n i m bala nce d t ype I err or all ocati o n will be use d f or 
t he 2 pri mar y  hy p ot heses a n d c o ntr ol o verall fa mil y wise t ype I err or rate at 2. 5 % ( 1-si de d) 
wit h 0. 5 % ( 1-si de d) all ocate d t o P D -L 1 + s u bjects a n d 2 % ( 1-si de d) all ocate d t o all ra n d o mize d 
s u bjects.
T he sa m ple size f or t his st u d y is dri ve n b y  the pri mar y  en d p oi nt of O S . T he sa m ple size is 
base d o n calc ulati o n ass u mi n g a n 1 8- m o nt h e nr oll me nt peri o d i n t he M ai nte na nce P hase a n d 
f oll o w- u p of a p pr o xi matel y 18 m o nt hs after e nr oll me nt c o m pleti o n.
Ap pr o xi matel y 4 6 6 
s u bjects will be e nr olle d a n d ra n d o mize d usi n g 1: 1 ra n d o mizati o n rati o, stratifie d b y  re gi o n 
( Asia vs. n o n- Asia) i n t he Mai nte na nce P hase. T he act ual n u m ber of s u bjects e nr olle d i n t he 
I n d ucti o n P hase will be dri ve n b y  obser ve d i n d ucti o n fail ure rates a n d will be s uc h t o all o w f or 
a p pr o xi matel y 4 6 6 patie nts t o be ra nd o mize d i n t he M ai nte na nce P hase .
At t he ti me of t his 
pr ot oc ol a me n d me nt, s u bject e nr oll me nt i n t he Ma i nte na nce P hase is c o m plete, wit h 4 9 9 
s u bjects ra n d o mize d i nt o t he Mai nte na nce P hase.
F or t he O S
i n all ra n d o mize d s u bjects, ass u mi n g a me dia n d urati o n of 1 0. 5 m o nt hs i n t he 
c o ntr ol ar m a n d 1 5 m o nt hs i n t he a vel u ma b ar m c orres p o n di n g t o a hazar d rati o of 0. 7 0 a n d a 
dr o p -o ut rate of 5 %, t he n 3 5 6 e ve nts are re q uire d t o ac hie ve 9 0 % p o wer of t he l o g -ra n k test at 
a 1-si de d o verall 2 % al p ha le vel . 
T he data c ut-off f or t he pri mar y  a nal ys is will ta ke place o n a pr os pecti vel y -deter mi ne d date, 
u p o n w hic h t he tar get n u m ber of 3 5 6 O S e ve nts i n all ra n d o mize d s u bjects are pr oject e d t o 
ha ve bee n reac he d a n d t he last s u bject ra n d o mize d i n t he st u d y h as bee n f oll o we d f or at least 
1 8 m o nt hs
fr o m ra n d o mizati o n. T his calc ulati o n i ncl u des a n i nteri m efficac y anal ys is a n d 
assu mes it will be perf or me d after 7 5 % of O S e ve nts ha ve bee n o bser ve d . F or O S i n all 
D oc u me nt N o.
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 0 / 1 5 0
ra n d o mize d s u bjects, the i nteri m a n d pri mar y a nal ys es will f oll o w a se q ue ntial al p ha s pe n di n g 
f u ncti o n a p pr oac h de vel o pe d b y  La n a n d De Mets usi n g a n O’ Brie n a n d Fle mi n g b o u n dar y  
f u ncti o n. A p pl yi n g t his a p pr oac h wit h a n ass u me d 2 6 7 a n d 3 5 6 o bser ve d e ve nts, res pecti vely,
1- si de d si g nifica nce le vels of 0. 0 0 7 2 a n d 0. 0 1 7 8 f or t he i nteri m a n d fi nal a nal yses will preser ve 
a n o verall ty pe I err or rate of 2 % f or O S i n all ra n d o mize d s u bjects.
F or O S i n P D -L 1 + s u bjects, at pla n ni n g sta ge a pre vale nce rate of 3 5 % i n all ra n d o mize d 
s u bjects wa s ass u me d, a n d a me dia n O S of 1 9. 3 m o nt hs i n t he a vel u ma b ar m c orres p o n di n g t o 
a hazar d rati o of 0. 5 4.
T he st u d y will be c o nsi dere d s uccessf ul if t he n ull h y p ot hesis testi n g f or O S i n eit her all 
ra n d o mize d s u bjects or P D-L 1 + s u bjects will be rejecte d as statisticall y si g nifica nt.
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 1 / 1 5 0
T a ble 1
Sc he d ule of Assess me nts 
–
Scree ni n g a n d I n d ucti o n P h ase (O pe n -l a bel C he m ot her a p y 
Tre at me nt P h ase ) f or 
O x ali pl ati n + C a pecit a bi ne
Scree ni n g
I n d ucti o n P h ase (-4/ + 2 d a ys) a
E n d -of -Tre at me nt b
S afet y F oll o w -u p 
Visit
D a y -2 8 t o E nr oll me nt
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4 c
Wit hi n 7 D a ys of 
Decisi o n t o Disc o nti n ue 
Tre at me nt
3 0 D a ys after L ast 
Tre at me nt 
( ± 5 d a ys)
W 1  
W 4
W 7
W 1 0
D 1
D 2 2
D 4 3
D 6 4
Writte n i nf or me d c o nse nt
X
I ncl usi o n / e xcl usi o n criteria
X
Me dical hist or y
X
Disease hist or y
X
De m o gra p hic data
X
S u bject -re p orte d o utc o mes / q ualit y of life 
assess me nts d
X
X d
P h ysical e xa mi nati o n 
X
X
X
X
X
X
Vital si g ns (i ncl u di n g hei g ht at Scree ni n g)
X
X
X
X
X
X
Wei g ht
e
X
X
X
X
X
X
E C O G P S f
X
X
X
X
X
X
1 2 -lea d E C G
X
X
C o nc o mita nt me dicati o ns 
C ollecte d fr o m Scree ni n g t hr o u g h E n d -of -Treat me nt Visit
C o nc o mita nt pr oce d ures
C ollecte d fr o m Scree ni n g t hr o u g h E n d -of -Treat me nt Visit 
A E a n d S A E c ollecti o n
C ollecte d fr o m I nf or me d C o nse nt t hr o u g h E n d -of -Treat me nt Visit b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d he m ostase ol o g y g
X
X
X
X
X
X
X
F ull ser u m c he mistr y h
X
X
C ore ser u m c he mistr y h
X
X
X
X
X
Uri nal ysis i
X
X
X
β- h C G pre g na nc y test j
X
X
X
X
X
X
H B V a n d H C V test k
X
T 4 a n d T S H
X
X
X
D oc u me nt N o.
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 2 / 1 5 0
D osi n g
Pre me dicati o n p
X
X
X
X
C he m ot hera p y a d mi nistrati o n
X
X
X
X
A E = a d verse e ve nt; β - hC G = β -h u ma n c h ori o nic g o na d otr o pi n; C T = c o m p ute d t o m o gra p h y; D = da y; E C G = electr ocar di o gra m, E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce 
Stat us; E O T = e n d of treat me nt; H B V = he patitis B vir us; H C V = he patitis C vir us; I C F = i nf or me d c o nsent f or m; 
; 
; R N A = ri b o n ucleic 
aci d; S A E = seri o us a d verse e ve nt; T 4 = free t h yr o xi ne; T S H = t h yr oi d-sti m ulati n g h or m o ne; W = wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 da ys after t he sc he d ule d Da y 1 visit ( -4 / + 2 d a y s) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  S u bjects s h o ul d als o 
ret ur n t o t he trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y.
b
S u bjects w h o disc o nti n ue t he I n d ucti o n P hase d ue t o a n y reas o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y.  All s u bjects w h o d o n ot e nter t he Mai nte na nce 
P hase will ha ve a 3 0- da y after last treat me nt Safet y F oll o w -u p visit.  S u bj ects e nteri n g t he Mai nte na nce P hase will ha ve t he Re -baseli ne visit (Ta ble 3 t o Ta ble 6 as a p plica ble).  S u bjects wit h 
a n A E o n g oi n g at t he E O T visit m ust be f oll owe d u p f or fi nal o utc o me u ntil t h e 3 0 -da y Safet y F oll o w -u p visit .  S u bjects wit h a n S A E o n g oi n g at t he 3 0 -da y Safet y F oll o w -u p visit m ust be 
m o nit ore d a n d f oll o we d u p b y t he I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject
is d oc u me nte d as “l ost t o f oll o w-u p.”   
c
S u bjects w h o c o m plete C ycle 4 w ill ret ur n t o cli nic f or t he Re -baseli ne visit (see Ta ble 3 t o Ta ble 6 de pe n di n g o n re gi me n).  T he Re -baseli ne visit is t o occ ur -1 0 t o -1 da ys bef ore t he first 
a d mi nistrati o n i n t he Mai nte na nce P hase .
d
S u bject -re p orte d o utc o mes / q ualit y of  life assess me nts s h o ul d be c o m plete d b y  su bjects after t he I C F is si g ne d a n d pri or t o a n y st u d y-relate d pr oce d ures at t he i n dicate d visits.  T he assess me nts 
s h o ul d be c o n d ucte d at Scree ni n g; i n t he e ve nt t hat t his d oes n’t occ ur, it ca n be d o ne at C ycle 1 ( Da y 1) pri or t o treat me nt.
e 
T he d ose of c he m ot hera p y will be calc ulate d base d o n t he wei g ht or b o d y s urface area, as a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. 
f 
If t he Scree ni n g E C O G P S was perfor m e d wit hi n 3 da ys pri or t o C ycle 1 Da y 1, it d oes n ot ha ve t o be re peate d at C ycle 1 Da y 1.
g  
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  F ollicle-sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble ( Secti o n 7. 1. 1 ).  C o m plete 
bl o o d c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
h
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
i
A f ull uri nal ysis is re q uire d at Scree ni n g a n d t he E O T visit (see  Ta ble 1 2 f or details).
j 
β- hC G m ust be deter mi ne d fr o m ser u m at Scree ni n g a n d fr o m eit her uri ne or ser u m sa m ple t hereafter as re q uire d per l ocal g ui deli nes.  Res ults of t he m ost rece nt pre g na nc y test ha s t o be 
a vaila ble pri or t o ne xt d osi n g.
k
A n H B V s urface a nti ge n a n d a nti-H C V tests m ust be perf or me d at Scree ni n g t o e xcl u de s u bjects wit h he patitis i nfecti o n.  If t he a nti-H C V a nti b o d y test is p ositi ve, t he i nfecti o n m ust b e 
c o nfir me d b y a n H C V R N A test.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 3 / 1 5 0
p
A nti -e metic pre me dicati o ns s h o ul d be a d mi nistere d i n acc or da nce wit h eit her t he 2 0 0 6 A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes or l ocal i nstit uti o nal g ui deli nes.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 4 / 1 5 0
T a ble 2
Sc he d ule of Assess me nts 
–
Scree ni n g a n d I n d ucti o n P h ase ( O pe n-l a bel C he m ot her a p y 
Tre at me nt 
P h ase) f or 
O x ali pl ati n + 5- Fl u or o ur acil ( 5 -F U)
Scree ni n g
I n d ucti o n P h ase (-4/ + 2 d a ys) a
E n d -of -
Tre at me nt b
S afet y F oll o w -u p 
Visit
D a y -2 8 t o 
E nr oll me nt
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4
C ycle 5
C ycle 6 c
Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt
3 0 D a ys after L ast 
Tre at me nt
( ± 5 d a ys)
W 1
W 3
W 5
W 7
W 9
W 1 1
D 1
D 1 5
D 2 9
D 4 3
D 5 7
D 7 1
Writte n i nf or me d c o nse nt
X
I ncl usi o n / e xcl usi o n 
criteria
X
Me dical hist or y
X
Disease hist or y
X
De m o gra p hic data
X
S u bject -re p orte d 
o utc o mes / q ualit y of life 
assess me nts d
X
X d
P h ysical e xa mi nati o n 
X
X
X
X
X
X
X
X
Vital si g ns (i ncl u di n g 
hei g ht at Scree ni n g)
X
X
X
X
X
X
X
X
Wei g ht
e
X
X
X
X
X
X
X
X
E C O G P S f
X
X
X
X
X
X
X
X
1 2 -lea d E C G
X
X
C o nc o mita nt me dicati o ns 
C ollecte d fr o m Scree ni n g t hr o u g h E n d -of - Treat me nt Visit
C o nc o mita nt pr oce d ures
C ollecte d fr o m Scree ni n g t hr o u g h E n d -of -Treat me nt Visit 
A E a n d S A E c ollecti o n
C ollecte d fr o m I nf or me d C o nse nt t hr o u g h E n d-of -Treat me nt Visit b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d 
he m ostase ol o g y g
X
X
X
X
X
X
X
X
X
F ull ser u m c he mistr y h
X
X
C ore ser u m c he mistr y h
X
X
X
X
X
X
X
Uri nal ysis i
X
X
X
β- h C G pre g na nc y testj
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 5 / 1 5 0
H B V a n d H C V test k
X
T 4 a n d T S H
X
X
X
Res p o nse Assess me nts
D osi n g
Pre me dicati o n p
X
X
X
X
X
X
C he m ot hera p y 
a d mi nistrati o n
X
X
X
X
X
X
A E = a d verse e ve nt; β - hC G = β -h u ma n c h ori o nic g o na d otr o pi n; C T = c o m p ute d t o m o gra p h y; D = da y; E C G = electr ocar di o gra m, E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce 
Stat us; E O T = e n d of treat me nt; H B V = he patitis B vir us; H C V = he patitis C vir us; I C F = i nf or me d c o nsent f or m; 
;
; R N A = ri b o n ucleic 
aci d; S A E = seri o us a d verse e ve nt; T 4 = free t h yr o xi ne; T S H = t h yr oi d-sti m ulati n g h or m o ne; W = wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 d a y s after t he sc he d ule d Da y 1 visit ( -4 / + 2 da ys) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  S u bjects s h o ul d als o 
ret ur n t o t he trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y.
b
S u bjects w h o disc o nti n ue t he I n d ucti o n P hase d ue t o a n y reas o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y.  All s u bjects w h o d o n ot e nter t he Mai nte na nce 
P hase will ha ve a 3 0- da y after last treat me nt Safet y F oll o w- u p visit.  S u bj ects e nteri n g t he Mai nte na nce P hase will ha ve t he Re- baseli ne visit (Ta ble 3 t o Ta ble 6 as a p plica ble).  S u bjects wit h 
a n A E o n g oi n g at t he E O T visit m ust be f oll owe d u p f or fi nal o utc o me u ntil t he 3 0 -da y Safet y F oll o w -u p visit .  S u bjects wit h a n S A E o n g oi n g at t he 3 0 -da y Safet y F oll o w -u p visit m ust be 
m o nit ore d a n d f oll o we d u p b y t he I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject
is d oc u me nte d as “l ost t o f oll o w-u p.”   
c
S u bjects w h o c o m plete C ycle 6 will ret ur n t o cli nic f or t he Re -baseli ne visit (see Ta ble 3 t o Ta ble 6 d e pe n di n g o n re gi me n).  T he Re -baseli ne visit is t o occ ur -1 0 t o -1 da ys bef ore t he first 
a d mi nistrati o n i n t he Mai nte na nce P hase .
d
S u bject -re p orte d o utc o mes / q ualit y of life assess me nts s h o ul d be c o m plete d b y s u bjects after t he I C F is si g ne d a n d pri or t o a n y st u d y -relate d pr oce d ures at t he i n dicate d visits.  T he assess me nts 
s h o ul d be c o n d ucte d at Scree ni n g; i n t he e ve nt t hat t his d oes n’t occ ur, it ca n be d o ne at C ycle 1 ( Da y 1) pri or t o treat me nt.
e 
T he d ose of c he m ot hera p y will be calc ulate d base d o n t he wei g ht or b o d y s urface area, as a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. 
f 
If t he Scree ni n g E C O G P S was perfor m e d wit hi n 3 da ys pri or t o C ycle 1 Da y 1, it d oes n ot ha ve t o be re peate d at C ycle 1 Da y 1.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CIC CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 6 / 1 5 0
g
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  F ollicle-sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble (Secti o n  7. 1. 1 ).  C o m plete 
bl o o d c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
h
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
i
A f ull uri nal ysis is re q uire d at Scree ni n g a n d t he E n d-of -Treat me nt visit (see  Ta ble 1 2 f or details).
j 
β- hC G m ust be deter mi ne d fr o m ser u m at Scree ni n g a n d fr o m eit her uri ne or ser u m sa m ple t hereafter as re q uire d per l ocal g ui deli nes.  Res ults of t he m ost rece nt pre g na nc y test ha s t o be 
a vaila ble pri or t o ne xt d osi n g
k
A n H B V s urface a nti ge n a n d a nti-H C V tests m ust be perf or me d at Scree ni n g t o e xcl u de s u bjects wit h he patitis i nfecti o n.  If t he a nti-H C V a nti b o d y test is p ositi ve, t he i nfecti o n m ust be 
c o nfir me d b y a n H C V R N A test.
p
A nti -e metic pre me dicati o ns s h o ul d be a d mi nistere d i n acc or da nce wit h eit her t he 2 0 0 6 A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes or l ocal i nstit uti o nal g ui deli nes.
T a ble 3
Sc he d ule of Assess me nts – M ai nte n a nce P h ase a n d F oll o w -U p – O x ali pl ati n + C a pecit a bi ne
M ai nte n a nce P h ase ( -4/ + 2 d a ys) a
E n d of Tre at me nt
F oll o w -u p b
Re -
b aseli ne 
( D a y - 1 0 
t o 
D a y -1) c
V 1  
V 2  
V 3  
V 4  
V 5
E n d -of -Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -u p
W 1
D a y 1
W 4
D a y 
2 2
W 7
D a y 
4 3
W 1 0
D a y 
6 4
W 1 3
D a y 
8 5
U ntil 
Pr o gressi o n
Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 
3 0 D a ys after L ast 
Tre at me nt ( ± 5 d a ys) e
P h o ne C all
9 0 D a ys after 
L ast Tre at me nt 
( ± 1 wee k)
E ver y 1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k) 
St u d y Pr oce d ures
Re vie w eli gi bilit y Criteria f
X
P h ysical e xa mi nati o n g
X  
X  
X  
X  
X  
X
6 wee ks
X
X
Vital si g ns
X  
X  
X  
X  
X  
X
3 wee ks
X
X
Wei g ht
h
X  
X  
X  
X  
X  
X
3 wee ks
X
X
E C O G P S i
X  
X  
X  
X  
X  
X
3 wee ks
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 7 / 1 5 0
M ai nte n a nce P h ase ( -4/ + 2 d a ys) a
E n d of Tre at me nt
F oll o w -u p b
Re -
b aseli ne 
( D a y - 1 0 
t o 
D a y -1) c
V 1  
V 2  
V 3  
V 4  
V 5
E n d -of -Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -u p
W 1
D a y 1
W 4
D a y 
2 2
W 7
D a y 
4 3
W 1 0
D a y 
6 4
W 1 3
D a y 
8 5
U ntil 
Pr o gressi o n
Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 
3 0 D a ys after L ast 
Tre at me nt ( ± 5 d a ys) e
P h o ne C all
9 0 D a ys after 
L ast Tre at me nt 
( ± 1 wee k)
E ver y 1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k) 
1 2 -lea d E C G
X
X
S u bject -re p orte d o utc o mes / 
q ualit y of life assess me nts j
X  
X j
X  
X
X
6 wee ks
X
X
C o nc o mita nt me dicati o ns 
a n d pr oce d ures 
C ollecte d t hr o u g h t he 3 0 -da y Safet y F oll o w -u p Visit
A nti -ca ncer t hera p y b
X
X
X
A E c ollecti o n
All A Es are c ollecte d t hr o u g h t he 3 0 -da y Safet y F oll o w -u p Visit; 
Treat me nt -relate d n o n-seri o us A Es are c ollecte d u ntil t he 9 0-da y Safet y F oll o w -u p P h o ne Call b
X
S A E c ollecti o n
All S A Es are d oc u me nte d u ntil t he 9 0- da y Safet y F oll o w -u p P h o ne Call;
O n g oi n g S A Es at t he 9 0- da y Safet y F oll o w -u p Call will be f oll o we d b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d 
he m ostase ol o g y k
X  
X  
X  
X  
X  
X
3 wee ks
X
X
F ull ser u m c he mistr y l
X
X
X
C ore ser u m c he mistr y l
X  
X  
X  
X  
X
3 wee ks
Uri nal ysis m
X  
X
X
X
1 2 wee ks
X
X
β- h C G pre g na nc y test n
X  
X  
X  
X  
X  
X
3 wee ks
X
X
T 4 a n d T S H
X
X
X
6 wee ks
X
X
Car diac tr o p o ni n o
X  
X  
X  
X  
X  
X
Res p o nse Assess me nts
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 8 / 1 5 0
M ai nte n a nce P h ase ( -4/ + 2 d a ys) a
E n d of Tre at me nt
F oll o w -u p b
Re -
b aseli ne 
( D a y - 1 0 
t o 
D a y -1) c
V 1  
V 2  
V 3  
V 4  
V 5
E n d -of -Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -u p
W 1
D a y 1
W 4
D a y 
2 2
W 7
D a y 
4 3
W 1 0
D a y 
6 4
W 1 3
D a y 
8 5
U ntil 
Pr o gressi o n
Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 
3 0 D a ys after L ast 
Tre at me nt ( ± 5 d a ys) e
P h o ne C all
9 0 D a ys after 
L ast Tre at me nt 
( ± 1 wee k)
E ver y 1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k) 
Ra n d o mizati o n r
X
D osi n g
Pretreat me nt
X  
X  
X  
X  
X
3 wee ks
C he m ot hera p y 
a d mi nistrati o n
X  
X  
X  
X  
X
3 wee ks
A E = a d verse e ve nt; β - hC G = β -h u m a n c h ori o nic g o na d otr o pi n; C R = c o m plete res p o nse; C T = c o m p ute d t o m o gra p h y; E C G = electr ocar di o gra m, E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p 
Perf or ma nce Stat us; E O T = e n d of treat me nt; I M P = i n vesti gati o nal me dici nal pr o d uct; I C F = i nf or me d c o nse nt f or m; 
 P D = pr o gressi ve disease; 
 
 P R = partial res p o nse; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1; S A E = seri o us a d verse e ve nt; S D = s ta ble disease; T4 = free t h yr o xi ne; T S H = t h yr oi d-
sti m ulati n g h or m o ne; W = wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 da ys after t he sc he d ule d Da y 1 visit (-4 / + 2 da ys) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  S u bjects s h o ul d als o ret ur n 
t o t he trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y.
b
All s u bjects will ha ve a n E O T visit wit hi n 7 da ys after t he decisi o n t o disc o nti n ue st u d y treat me nt.  All A Es will be d oc u me nte d u ntil t he 3 0 -da y Safet y F oll o w - up visit.  S u bjects wit h a n o n g oi n g 
S A E at t he 3 0 -da y Safet y F oll o w -u p visit m ust be m o nit ore d a n d f oll o we d u p u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n.  After t his visit, all S A Es a n d all treat me nt -relate d n o n-seri o us A Es 
nee d t o b e d oc u me nte d u ntil t he 9 0 -da y Safet y F oll o w -u p P h o ne Call.  S u bjects wit h a n o n g oi n g S A E at t he 9 0- da y Safet y F oll o w -u p C all m ust be m o nit ore d a n d f oll o we d b y t he I n vesti gat or u ntil 
sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”.  At 9 0 da ys f oll o wi n g t he last treat me nt, s u bjects will be c o ntacte d b y tele p h o ne t o c ollect 
i nfor mati o n o n ne w or o n g oi n g S A Es a n d treat me nt -relate d n o n-seri o us A Es.  A n y S A E assesse d as relate d t o I M P m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he 
last a d mi nistrati o n of I M P.  S u bjects wit h o ut pr o gressi ve disease at E n d -of -Treat me nt visit will be f oll o we d u p f or disease pr o gressi o n ( C T / M RI sca ns e ver y 6 wee ks [ ± 1 wee k] , a n d after 1 2 m o nt hs 
e ver y 1 2 wee ks [ ± 1 wee k] ) u ntil P D.  In a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks f or s ur vi val (i ncl u di n g assess me nt of a n y f urt her a nti-ca ncer t hera p y).  The s ur vi val f oll o w-u p will 
c o nti n ue u ntil 5 years after t he last s u bject recei ves t he last d ose of trial dr u g (see Secti o n  7. 1. 5 f or details).  
c
S u bjects w h o disc o nti n ue treat me nt d ue t o a n y reas o n d uri n g t he Re -baseli ne peri o d a n d bef ore ra n d o mizati o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y 
a n d a 3 0 -da y Safet y F oll o w -u p visit i n acc or da nce wit h t he I n d ucti o n P hase S c he d ule of A ssess me nts.
d
T u m or e val uati o n at t he E n d -of -Treat me nt visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .
e
If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore t he e n d of t his 3 0 -da y peri o d, t he Safet y F oll o w - up visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y.
f
E nr oll me nt a n d ra n d o mizati o n i nt o t he Mai nte na nce P hase will be d o ne after t he c o nfir mati o n of f ulfilli n g all i ncl usi o n criteria ( Secti o n 5. 3. 1 ) wi t h o ut matc hi n g a n y e xcl usi o n criteria ( Secti o n 5. 3. 2 ).
g
T he p h ysical e xa mi nati o n will occ ur e ver y 3 wee ks u ntil Wee k 1 3, a n d e ver y 6 wee ks t hereafter.
h
T he d ose of c he m ot hera p y will be calc ulate d base d o n t he wei g ht or b o d y s urface area, as a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. 
i
If t he Re-baseli ne E C O G P S was perf or me d wit hi n 3 da ys pri or t o Da y 1, it d oes n ot ha ve t o be re peate d at Da y 1.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
2 9 / 1 5 0
j
S u bject -re p orte d o utc o mes / q ualit y of life assess me nts s h o ul d be c o m plete d b y s u bjects pri or t o a n y st u d y-relate d pr oce d ures at t he i n dicate d visits.  T he assess me nts s h o ul d be c o n d ucte d at Re-
baseli ne; i n t he e ve nt t hat t his d oes n’t occ ur, it ca n be d o ne at Visit 1 ( Da y 1) pri or t o treat me nt.
k
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  F ollicle-sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble ( Secti o n 7. 1. 1 ).  C o m plete bl o o d 
c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.  
l
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
m
A f ull uri nal ysis is re q uire d at t he E n d-of -Treat me nt visit a n d t he Re -baseli ne visit a n d a basic uri nal ysis at all ot her i n dicate d visits (see  Ta ble 1 2 f or details).
n
β- h C G s h o ul d be deter mi ne d fr o m eit her u ri ne or ser u m sa m ple.  Res ults of t he m ost rece nt pre g na nc y test has t o be a vaila ble pri or t o ne xt d osi n g.
o
Car diac tr o p o ni n le vels will be c ollecte d fr o m R e- baseli ne u p t o 1 2 wee ks i n t he M ai nte na nce P has e (see Ta ble 1 1 ).  
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 0 / 1 5 0
T a ble 4
Sc he d ule of Assess me nts – M ai nte n a nce P h ase a n d F oll o w -U p - O x ali pl ati n + 5- Fl u or o ur acil ( 5 -F U)
M ai nte n a nce P h ase
(-4/ + 2 d a ys) a
E n d of 
Tre at me nt
F oll o w -u p b
Re -
b aseli ne 
( D a y -
1 0 t o 
D a y -1) c
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7
E n d -of -
Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -
ter m 
F oll o w -u p
W 1
D a y 1
W 3
D a y 
1 5
W 5
D a y 
2 9
W 7
D a y 
4 3
W 9
D a y 
5 7
W 1 1
D a y 
7 1
W 1 3
D a y 
8 5
U ntil 
Pr o gressi o n
Wit hi n 7 
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 3 0 
D a ys after 
L ast 
Tre at me nt
( ± 5 d a ys)e
P h o ne C all 9 0 
D a ys after L ast 
Tre at me nt ( ± 1 
wee k)
E ver y   
1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
St u d y Pr oce d ures
Re vie w of eli gi bilit y criteria f
X
P h ysical e xa mi nati o n g
X  
X  
X  
X  
X  
X  
X  
X
6 wee ks
X
X
Vital si g ns
X  
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
Wei g ht
h
X  
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
E C O G P S i
X  
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
1 2 -lea d E C G
X
X
S u bject -re p orte d o utc o mes / 
q ualit y of life assess me nts j
X  
X j
X
X
X
6 wee ks
X
X
C o nc o mita nt me dicati o ns a n d 
pr oce d ures
C ollecte d t hr o u g h t he 3 0 -da y Safet y F oll o w -u p Visit
A nti -ca ncer t hera p yb
X
X
X
A E c ollecti o n
A Es are c ollecte d t hr o u g h t he 3 0 -da y Safet y F oll o w -u p Visit;
Treat me nt -relate d n o n-seri o us A Es are c ollecte d u ntil t he 9 0-da y Safet y F oll o w -u p P h o ne Call b
X
S A E c ollecti o n
All S A Es are d oc u me nte d u ntil t he 9 0- da y Safet y F oll o w -u p P h o ne Call,
O n g oi n g S A Es at t he 9 0- da y Safet y F oll o w -u p Call will be f oll o we d
b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d 
he m ostase ol o g y k
X  
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
F ull ser u m c he mistr y l
X
X
X
C ore ser u m c he mistr y l
X  
X  
X  
X  
X  
X  
X
2 wee ks
Uri nal ysis m
X  
X
X
X
1 2 wee ks
X
X
β- h C G pre g na nc y test n
X  
X
X
X
X
4 wee ks
X
X
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 1 / 1 5 0
M ai nte n a nce P h ase
(-4/ + 2 d a ys) a
E n d of 
Tre at me nt
F oll o w -u p b
Re -
b aseli ne 
( D a y -
1 0 t o 
D a y -1) c
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7
E n d -of -
Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -
ter m 
F oll o w -u p
W 1
D a y 1
W 3
D a y 
1 5
W 5
D a y 
2 9
W 7
D a y 
4 3
W 9
D a y 
5 7
W 1 1
D a y 
7 1
W 1 3
D a y 
8 5
U ntil 
Pr o gressi o n
Wit hi n 7 
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 3 0 
D a ys after 
L ast 
Tre at me nt
( ± 5 d a ys)e
P h o ne C all 9 0 
D a ys after L ast 
Tre at me nt ( ± 1 
wee k)
E ver y   
1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
T 4 a n d T S H
X
X
X
6 wee ks
X
X
Car diac tr o p o ni n o
X  
X  
X  
X  
X  
X  
X  
X
Res p o nse Assess me nts
Ra n d o mizati o n r
X
D osi n g
Pretreat me nt
X  
X  
X  
X  
X  
X  
X
2 wee ks
C he m ot hera p y a d mi nistrati o n
X  
X  
X  
X  
X  
X  
X
2 wee ks
A E = a d verse e ve nt; β - hC G = β -h u ma n c h ori o nic g o na d otr o pi n; C R = c o m plete res p o nse; C T = c o m p ute d t o m o gra p h y; E C G = electr ocar di o gra m, E C O G P S = Easter n C o o perati ve O nc ol o g y 
Gr o u p Perf or ma nce Stat us; E O T = e n d of treat me nt; I M P = i n vesti gati o nal me dici nal pr o d uct; I C F = i nf or me d c o nse nt f or m; 
; P D = pr o gressi ve disease; 
 
 P R = partial res p o nse; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1; S A E = seri o us a d verse e ve nt; S D = sta ble disease; T 4 = free t h yr o xi ne; T S H = 
t h yr oi d-sti m ulati n g h or m o ne; W = wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 da ys after t he sc he d ule d Da y 1 visit ( -4 / + 2 da ys) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  S u bjects s h o ul d als o ret ur n 
t o the trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y. 
b
All s u bjects will ha ve a n E O T visit wit hi n 7 da ys after t he decisi o n t o disc o nti n ue st u d y treat me nt.  All A Es will be d oc u me nte d u ntil t he 3 0 -da y Safet y F oll o w - up visit.  S u bjects wit h a n o n g oi n g 
S A E at t he 3 0 -da y Safet y F oll o w -u p visit m ust be m o nit ore d a n d f oll o we d u p u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n.  After t his visit, all S A Es a n d all treat me nt -relate d n o n-seri o us A Es 
nee d t o b e d oc u me nte d u ntil t he 9 0 -da y Safet y F oll o w -u p P h o n e C all.  Su bjects wit h a n o n g oi n g S A E at t he 9 0- da y Safet y F oll o w -u p C all m ust be m o nit ore d a n d f oll o we d b y t he I n vesti gat or 
u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”.  At 9 0 da ys f oll o wi n g t he last treat me nt, s u bjects will be c o ntacte d b y tele p h o ne t o c ollect 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 2 / 1 5 0
i nf or mati o n o n ne w or o n g oi n g S A Es a n d treat me nt-relate d n o n-seri o us A Es.  A n y S A E assesse d as relate d t o I M P m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he 
last a d mi nistrati o n of I M P.  Su bjects wit h o ut pr o gressi ve disease at E n d -of -Treat me nt visit will be f oll o we d u p f or disease pr o gressi o n ( C T / M RI sca ns e ver y 6 wee ks [ ± 1 wee k] , a n d after 
1 2 m o nt hs, e ver y 12 wee ks [ ± 1 wee k] ) u ntil P D.  In a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks f or s ur vi val (i ncl u di n g assess me nt of a n y furt her a nti-ca ncer t hera p y).  The s ur vi val 
f oll o w-u p will c o nti n ue u ntil 5 years after t he last s u bject recei ves t he last d os e of trial dr u g (see Secti o n  7. 1. 5 f or details).  
c
S u bjects w h o disc o nti n ue treat me nt d ue t o a n y reas o n d uri n g t he Re -baseli ne peri o d a n d bef ore ra n d o mizati o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y 
a n d a 3 0 -da y Safet y F oll o w -u p visit i n acc or da nce wit h t he I n d ucti o n P hase S c he d ule of A ssess me nts.
d
T u m or e val uati o n at t he E n d -of -Treat me nt visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .
e
If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore t he e n d of t he 3 0- da y peri o d, t he 3 0-da y Safet y F oll o w -U p visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of a n y ne w t hera p y.
f
E nr oll me nt a n d ra n d o mizati o n i nt o t he Mai nte na nce P hase will be d o ne after t he c o nfir mati o n of f ulfilli n g all i ncl usi o n criteria ( Secti on 5. 3. 1 ) wit h o ut matc hi n g a n y e xcl usi o n criteria 
( Secti o n 5. 3. 2 ).
g 
T he p h ysical e xa mi nati o n will occ ur e ver y 2 wee ks u ntil Wee k 1 3, a n d e ver y 6 wee ks t hereafter. 
h 
T he d ose of c he m ot hera p y will be calc ulate d base d o n t he wei g ht or b o d y s urface area, as a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. 
i
If t he Re- baseli ne E C O G P S was perf or me d wit hi n 3 da ys pri or t o Da y 1, it d oes n ot ha ve t o be re peate d at Da y 1.
j
S u bject -re p orte d o utc o mes / q ualit y of life assess me nts s h o ul d be c o m plete d b y s u bjects pri or t o a n y st u d y-relate d pr oce d ures at t he i n dicate d visits.  The assess me nts s h o ul d be c o n d ucte d at 
Re -baseli ne; i n t he e ve nt t hat t his d oes n’t occ ur, it ca n be d o ne at Visit 1 ( Da y 1) pri or t o treat me nt.
k
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  Follicle -sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble ( Secti o n 7. 1. 1).  Co m plete 
bl o o d c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.  
l
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
m
A f ull uri nal ysis is re q uire d at t he E n d-of -Treat me nt visit a n d t he Re -baseli ne visit a n d a basic uri nal ysis at all ot her i n dicate d visits (see  Ta ble 1 2 f or details).
n 
β- h C G s h o ul d be deter mi ne d fr o m eit her u ri ne or ser u m sa m ple.  Res ults of t he m ost rece nt pre g na nc y test nee d t o be a vaila ble pri or t o ne xt d osi n g.
o
Car diac tr o p o ni n le vels will be c ollecte d fr o m R e- baseli ne u p t o 1 2 wee ks i n t he M ai nte na nce P hase (see Ta ble 1 1 ).  
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 3 / 1 5 0
T a ble 5
Sc he d ule of Assess me nts:  M ai nte n a nce P h ase a n d F oll o w -U p - Best S u p p orti ve C are O nl y
Re -b aseli ne 
( D a y -1 0 t o 
D a y -1) c
Tre at me nt P h ase (-4/ + 2 d a ys) a
E n d -of -Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -
ter m 
F oll o w -
u p b
V 1  
V 2  
V 3  
V 4  
V 5
U ntil 
Pr o gressi o n
Wit hi n 7
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 
3 0 D a ys after L ast 
Tre at me nt ( ± 5 d a ys) e
P h o ne C all 9 0 
D a ys after L ast 
Tre at me nt ( ± 1 
wee k)
E ver y 1 2 
Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
W 1  
W 4  
W 7
W 1 0  
W 1 3
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
St u d y Pr oce d ures
Re vie w eli gi bilit y criteria f
X
P h ysical e xa mi nati o n g
X  
X  
X  
X  
X  
X
6 wee ks
X
X
Vital si g ns
X  
X  
X  
X  
X  
X
3 wee ks
X
X
Wei g ht
h
X  
X  
X  
X  
X  
X
3 wee ks 
X
X
E C O G P S i
X  
X  
X  
X  
X  
X
3 wee ks
X
X
1 2 -lea d E C G
X
X
S u bject -re p orte d o utc o mes / q ualit y 
of life assess me nts j
X  
X j
X  
X
X
6 wee ks
X
X
A nti -ca ncer t hera p y b
X
X
X
C o nc o mita nt me dicati o ns a n d 
pr oce d ures
C ollecte d t hr o u g h t he 3 0- da y Safet y F oll o w -u p Visit
A E c ollecti o n
A Es are c ollecte d t hr o u g h t he Safet y F oll o w -u p Visit;
Treat me nt -relate d n o n-seri o us A Es are c ollecte d u ntil t he 9 0-da y Safet y F oll o w -u p P h o ne Call b
X
S A E c ollecti o n
All S A Es are d oc u me nte d u ntil t he 9 0 -da y Safet y F oll o w -u p P h o ne Call,
O n g oi n g S A Es at t he 9 0 -da y Safet y F oll o w -u p Call will be f oll o we d b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d he m ostase ol o g y k
X  
X  
X  
X  
X  
X
3 wee ks
X
X
F ull ser u m c he mistr y l
X
X
X
C ore ser u m c he mistr y l
X  
X  
X  
X  
X
3 wee ks
Uri nal ysis m
X  
X
X
X
1 2 wee ks
X
X
Β- h C G pre g na nc y test n
X
T 4 a n d T S H
X
X
X
6 wee ks
X
X
Car diac tr o p o ni n o
X  
X  
X  
X  
X  
X
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 4 / 1 5 0
Re -b aseli ne 
( D a y -1 0 t o 
D a y -1) c
Tre at me nt P h ase (-4/ + 2 d a ys) a
E n d -of -Tre at me nt 
Visit
S afet y F oll o w -u p
L o n g -
ter m 
F oll o w -
u p b
V 1  
V 2  
V 3  
V 4  
V 5
U ntil 
Pr o gressi o n
Wit hi n 7
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit 
3 0 D a ys after L ast 
Tre at me nt ( ± 5 d a ys) e
P h o ne C all 9 0 
D a ys after L ast 
Tre at me nt ( ± 1 
wee k)
E ver y 1 2 
Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
W 1  
W 4  
W 7
W 1 0  
W 1 3
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
Ra n d o mizati o n r
X
A E = a d verse e ve nt, β- h C G = β -h u ma n c h ori o nic g o na d otr o pi n, C R = c o m plete res p o nse, C T = c o m p ute d t o m o gra p h y, D = Da y, E C G = electr ocar di o gra m, E O T = e n d of treat me nt; E C O G- P S = 
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us, I C F = i nf or me d c o nse nt f or m, I M P = i n vesti gati o nal me dici nal pr o d uct, 
P D = pr o gressi ve disease, 
, P R = partial res p o nse, R E CI S T = Res p o nse E val ua ti 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, T4 = free t h yr o xi ne, 
T S H = t h yr oi d sti m ulati n g h or m o ne, V = visit, W = Wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 da ys after t he sc he d ule d Da y 1 visit ( -4 / + 2 da ys) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  S u bjects s h o ul d als o ret ur n 
t o t he trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y. 
b
All s u bjects will ha ve a n E O T visit wit hi n 7 da ys after t he decisi o n t o disc o nti n ue st u d y treat me nt.  All A Es will be d oc u me nte d u ntil t he 3 0 -da y Safet y F oll o w - up visit.  S u bjects wit h a n o n g oi n g 
S A E at t he 3 0 -da y Safet y F oll o w -u p visit m ust be m o nit ore d a n d f oll o we d u p u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n.  Aft er t his visit, all S A Es a n d all treat me nt-relate d n o n-seri o us A Es 
nee d t o be d oc u me nte d u ntil t he 9 0 -da y Safet y F oll o w -u p P h o n e Call.  S u bjects wit h a n o n g oi n g S A E at t he 9 0- da y Safet y F oll o w -u p Call m ust be m o nit ore d a n d f oll o we d b y t he I n vesti gat or u ntil 
sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p ”.  At 9 0 da ys f oll o wi n g the last treat me nt, s u bjects will be c o ntacte d b y tele p h o ne t o c ollect 
i nf or mati o n o n ne w or o n g oi n g S A Es a n d treat me nt-relate d n o n-seri o us A Es.  S u bjects wit h o ut pr o gressi ve disease at E n d-of -Treat me nt visit will be f oll o we d u p f or disease pr o gressi o n ( C T / M RI 
sca ns e ver y 6 wee ks [ ± 1 wee k] , a n d aft er 1 2 m o nt hs e ver y 1 2 w ee ks [ ± 1 wee k] ) u ntil P D.  I n a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks f or s ur vi val (i ncl u di n g assess me nt of a n y f urt her 
a nti-ca ncer t hera p y).  T he s ur vi val f oll o w-u p will c o nti n u e u ntil 5 years after t he last s u bject recei ves t he last d ose of trial dr u g (see Secti o n  7. 1. 5 f or details).
c
S u bjects w h o disc o nti n ue treat me nt d ue t o a n y reas o n d uri n g t he Re -baseli ne peri o d a n d bef ore ra n d o mizati o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y 
a n d a 3 0 -da y Safet y F oll o w -u p visit i n acc or da nce wit h t he I n d ucti o n P hase S c he d ule of A ssess me nts.
d
T u m or e val uati o n at t he E n d -of -Treat me nt visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .
e
If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore t he e n d of t he 3 0- da y peri o d, t he 3 0- da y Safet y F oll o w -U p visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 5 / 1 5 0
f
E nr oll me nt a n d ra n d o mizati o n i nt o t he Mai nte na nce P hase will be d o ne after t he c o nfir mati o n of f ulfilli n g all i ncl usi o n criteria ( Secti o n 5. 3. 1 ) wit h o ut matc hi n g a n y e xcl usi o n criteria ( Secti o n 5. 3. 2 ).
g
T he p h ysical e xa mi nati o n will occ ur e ver y 3 wee ks u ntil Wee k 1 3, a n d e ver y 6 wee ks t hereafter.
h
T he d ose of B S C will be calc ulate d base d o n t he wei g ht or b o d y s urface area, as a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. 
i
If t he Re-baseli ne E C O G P S was perf or me d wit hi n 3 da ys pri or t o Da y 1, it d oes n ot ha ve t o be re peate d at Da y 1.
j
S u bject -re p orte d o utc o mes / q ualit y of life assess me nts s h o ul d be c o m plete d b y s u bjects pri or t o a n y st u d y-relate d pr oce d ures at t he i n dicate d visits.  T he assess me nts s h o ul d be c o n d ucte d at Re-
baseli ne; i n t he e ve nt t hat t his d oes n’t occ ur, it ca n be d o ne at Visit 1 ( Da y 1) pri or t o treat me nt.
k
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  F ollicle-sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble ( Secti o n 7. 1. 1 ).  C o m plete bl o o d 
c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.  
l
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
m
A f ull uri nal ysis is re q uire d at t he E n d-of -Treat me nt visit a n d t he Re -baseli ne visit a n d a basic uri nal ysis at all ot her i n dicate d visits (see  Ta ble 1 2 f or details).
n β - hC G s h o ul d be deter mi ne d fr o m eit her u ri ne or ser u m sa m ple.  Res ults of t he m ost rece nt pre g na nc y test nee ds t o be a vaila ble pri or t o ne xt d osi n g.
o
Car diac tr o p o ni n le vels will be c ollecte d fr o m R e- baseli ne u p t o 1 2 wee ks i n t he M ai nte na nce P hase see Ta ble 1 1 ).  
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 6 / 1 5 0
T a ble 6
Sc he d ule of Assess me nts – M ai nte n a nce P h ase a n d F oll o w -u p – A vel u m a b
A vel u m a b Tre at me nt ( -4/ + 2 d a ys) a
E n d of 
Tre at me nt
F oll o w -u p b
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7
E n d -of -
Tre at me nt 
Visit
S afet y F oll o w -u p Visit
L o n g -ter m 
F oll o w -u p
Re -b aseli ne 
( D a y -1 0 t o 
D a y -1) c
W 1
D a y 1
W 3
D a y 
1 5
W 5
D a y 2 9
W 7
D a y 4 3
W 9
D a y 5 7
W 1 1
D a y 7 1
W 1 3
D a y 
8 5
U ntil 
Pr o gres -
si o n
Wit hi n 7 
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit
3 0 D a ys 
after L ast 
Tre at me n
t ( ± 5 
d a ys) e
P h o ne C all
9 0 D a ys 
after L ast 
Tre at me nt 
( ± 1 w e e k)
E ver y   
1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
St u d y Pr oce d ures
Eli gi bilit y criteria f
X
P h ysical e xa mi nati o n g
X
X  
X  
X  
X  
X  
X  
X
6 wee ks
X
X
Vi tal si g ns
X
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
We i g hth
X
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
E C O G P S i
X
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
1 2 -lea d E C G
X
X
S u bject -re p orte d o utc o mes / 
q ualit y of life assess me nts j
X
X j
X
X
X
6 wee ks
X
X
A nti -ca ncer t hera p y b
X
X
X
C o nc o mita nt me dicati o ns a n d 
pr oce d ures
C ollecte d t hr o u g h t he 3 0- da y Safet y F oll o w -u p Visit
A E c ollecti o n
A Es are c ollecte d t hr o u g h t he Safet y F oll o w -u p Visit
Treat me nt -relate d n o n-seri o us A Es are c ollecte d u ntil t he 9 0-da y Safet y F oll o w -u p P h o ne Call b
X
S A E c ollecti o n
All S A Es are d oc u me nte d u ntil t he 9 0- da y Safet y F oll o w -u p P h o ne Call,
O n g oi n g S A Es at t he 9 0 -da y Safet y F oll o w -u p Call will be f oll o we d b
X
S a m ples a n d L a b or at or y Assess me nts
He mat ol o g y a n d 
he m ostase ol o g y k
X
X  
X  
X  
X  
X  
X  
X
2 wee ks
X
X
F u ll ser u m c he mistr yl
X
X
X
C ore ser u m c he mistr y l
X  
X  
X  
X  
X  
X  
X
2 wee ks
Uri nal ysis m
X
X
X
X
1 2 wee ks
X
X
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 7 / 1 5 0
A vel u m a b Tre at me nt ( -4/ + 2 d a ys) a
E n d of 
Tre at me nt
F oll o w -u p b
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7
E n d -of -
Tre at me nt 
Visit
S afet y F oll o w -u p Visit
L o n g -ter m 
F oll o w -u p
Re -b aseli ne 
( D a y -1 0 t o 
D a y -1) c
W 1
D a y 1
W 3
D a y 
1 5
W 5
D a y 2 9
W 7
D a y 4 3
W 9
D a y 5 7
W 1 1
D a y 7 1
W 1 3
D a y 
8 5
U ntil 
Pr o gres -
si o n
Wit hi n 7 
D a ys of 
Decisi o n t o 
Disc o nti n ue 
Tre at me nt d
Visit
3 0 D a ys 
after L ast 
Tre at me n
t ( ± 5 
d a ys) e
P h o ne C all
9 0 D a ys 
after L ast 
Tre at me nt 
( ± 1 w e e k)
E ver y   
1 2 Wee ks 
after L ast 
Tre at me nt 
( ± 2 w e e k)
β- h C G pre g na nc y test n
X
X
X
X
X
4 wee ks
X
X
T 4 a n d T S H
X
X
X
6 wee ks
X
X
Car diac tr o p o ni n o
X
X  
X  
X  
X  
X  
X  
X
Res p o nse Assess me nts
Ra n d o mizati o n r
X
D osi n g
Pretreat me nt s
X  
X  
X  
X  
X  
X  
X
2 wee ks
A v el u ma b s,t
X  
X  
X  
X  
X  
X  
X
2 wee ks
A E = a d verse e ve nt; β - hC G = β -h u ma n c h ori o nic g o na d otr o pi n; C R = c o m plete res p o nse; C T = c o m p ute d t o m o gra p h y; E C G = electr ocar di o gra m, E C O G P S = Easter n C o o perati ve O nc ol o g y 
Gr o u p Perf or ma nce Stat us; E O T = e n d of treat me nt; I M P = i n vesti gati o nal me dici nal pr o d uct;
; P D = pr o gressi ve disease; P R = partial res p o nse; R E CI S T = 
Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1; S A E = seri o us a d verse e ve nt; T 4 = free t h yr o xi ne; T S H = t h yr oi d-sti m ulati n g h or m o ne; W = wee k.
a
A ti me wi n d o w of u p t o 4 da ys bef ore or 2 da ys after t he sc he d ule d Da y 1 visit (-4 / + 2 da ys) will be per mitte d f or all trial pr oce d ures f or t he Da y 1 visit of eac h c ycle.  Su bjects s h o ul d als o 
ret ur n t o t he trial site as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y.
b
All s u bjects will ha ve a n E O T visit wit hi n 7 da ys after t he decisi o n t o disc o nti n ue st u d y treat me nt.  All A Es will be d oc u me nte d u ntil t he 3 0-da y Safet y F oll o w - up visit.  S u bjects wit h a n o n g oi n g 
S A E at t he 3 0 -da y Safet y F oll o w - u p visit m ust be m o nit ore d a n d f oll o we d u p u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n.  Aft er t his visit, all S A Es a n d all treat me nt-relate d n o n-seri o us 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 8 / 1 5 0
A Es nee d t o be d oc u me nte d u ntil t he 9 0 -da y Safet y F oll o w -u p P h o ne Call.  Su bjects wit h a n o n g oi n g S A E at t he 9 0- da y Safet y F oll o w -u p Call m ust be m o nit ore d a n d f oll o we d b y t he I n vesti gat or 
u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”.  At 9 0 da ys f oll o wi n g t he last treat me nt, s u bjects will be c o ntacte d b y tele p h o ne t o 
c ollect i nf or mati o n o n ne w or o n g oi n g S A Es a n d treat me nt -relate d n o n-seri o us A Es.  A n y S A E assesse d as relate d t o I M P m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d 
si nce t he last a d mi nistrati o n of I M P.  S u bjects wit h o ut pr o gressi ve disease at E n d-of -Treat me nt visit will be f oll o we d u p f or disease pr o gressi o n ( C T / M RI sca ns e ver y 6 wee ks [ ± 1 wee k] , a n d 
after 1 2 m o nt hs, e ver y 1 2 wee ks [ ± 1 wee k] ) u ntil P D.  I n a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks f or s ur vi val (i ncl u di n g assess me nt of a n y f urt her a nti-ca ncer t hera p y).  T he s ur vi val 
f oll o w-u p will c o nti n ue u ntil 5 years after t he last s u bject recei ves t he last d ose of trial dr u g (see Secti o n  7. 1. 5 f or details).
c
S u bjects w h o disc o nti n ue treat me nt d ue t o a n y reas o n d uri n g t he R e- baseli ne peri o d a n d bef ore ra n d o mizati o n will ha ve a n E O T visit wit hi n 7 da ys of t he decisi o n t o disc o nti n ue c he m ot hera p y 
a n d a 3 0 -da y Safet y F oll o w -u p visit i n acc or da nce wit h t he I n d ucti o n P hase S c he d ule of A ssess me nts.
d
T u m or e val uati o n at t he E n d -of -Treat me nt visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .
e
If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore t he e n d of t he 3 0- da y peri o d, t he 3 0- da y Safet y F oll o w -u p visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y.
f
E nr oll me nt a n d ra n d o mizati o n i nt o t he Mai nte na nce P hase will be d o ne aft er t he c o nfir mati o n of f ulfilli n g all i ncl usi o n criteria ( Secti o n  5. 3. 1 ) wit h o ut matc hi n g a n y e xcl usi o n criteria ( Secti o n 
5. 3. 2 ).
g 
T he p h ysical e xa mi nati o n will occ ur e ver y 2 wee ks u ntil Wee k 1 3, a n d e ver y 6 wee ks t hereafter.
h
T he d ose of a vel u ma b will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he da y of  dr u g a d mi nistrati o n. T he d ose of a vel u ma b use d f or t he pre vi o us 
a d mi nistrati o n ca n be re peate d if t he c ha n ge i n t he s u bject’s wei g ht is 1 0 % or less t ha n t he wei g ht use d f or t he last d ose ca lc ulati o n.
i
If t he Re-baseli ne E C O G P S was perf or me d wit hi n 3 da ys pri or t o Da y 1, it d o es n ot ha ve t o be re peate d at Da y 1.
j
S u bject -re p orte d o utc o mes / q ualit y of life assess me nts s h o ul d be c o m plete d b y s u bjects pri or t o a n y st u d y-relate d pr oce d ures at t he i n dicate d visits.  T he assess me nt s s h o ul d be c o n d ucte d at Re-
baseli ne; i n t he e ve nt t h at t his d oes n’t occ ur, it ca n be d o ne at Visit 1 ( Da y 1) pri or t o treat me nt. 
k
He mat ol o g y (i ncl u di n g C o m plete Bl o o d C o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 2 .  Follicle -sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble ( Secti o n 7. 1. 1 ).  Co m plete 
bl o o d c o u nt res ults m ust als o be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.  
l
F ull c he mistr y a n d c ore ser u m c he mistr y sa m ples are detaile d i n  Ta ble 1 2 .  Sa m ples f or c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
m
A f ull uri nal ysis is re q uire d at t he E n d-of -Treat me nt visit a n d t he Re -basel i ne visit a n d a basic uri nal ysis at all ot her i n dicate d visits (see Ta ble 1 2   f or details).
n 
β- h C G s h o ul d be deter mi ne d fr o m eit her u ri ne or ser u m sa m ple.  Res ults of t he m ost rece nt pre g na nc y test nee ds t o be a vaila ble pri or t o ne xt d osi n g.
o
Car diac tr o p o ni n le vels wil l be c ollecte d fr o m R e- baseli ne u p t o 1 2 wee ks i n t he M ai nte na nce P hase. ( See Ta ble 1 1 )  
s
Pre me dicat e patie nts wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) pri or t o t he first 4 i nf usi o ns of a vel u ma b.   Pre me dicati o n s h o ul d be a d mi nistere d f or s u bse q ue nt a vel u ma b 
d oses base d u p o n cli nical j u d g me nt a n d prese nce/se verit y of pri or i nf usi o n reacti o ns.  T his re gi me n ma y be m o difie d base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate pr o vi de d 
it d oes n ot i ncl u de s yste mic c ortic oster oi ds a n d has t o be rec or de d as c o nc o mita nt me dicati o n.
t
S u bjects will recei ve a vel u ma b as l o n g as E C O G P S re mai ns sta ble, a n d if i n t he o pi ni o n of t he I n vesti gat or, t he s u bject will be nefit fr o m c o nti n ue d treat me nt, a n d if t here are n o ne w s y m pt o ms 
or w orse ni n g of e xisti n g s y m pt o ms.  S u bjects recei vi n g a vel u ma b will re mai n o n -treat me nt u ntil P D.   S u bjects w h o ha ve e x perie nce d i nitial disease pr o gressi o n ma y c o nti n ue treat me nt wit h 
a vel u ma b if t he f oll o wi n g criteria are met: In vesti gat or belie ves t hat t he s u bject will e x perie nce cli nical be nefit fr o m t he treat me nt; t here is n o u nacce pta ble t o xicit y res ulti n g fr o m t he treat me nt; 
t he s u bject’s E C O G P S is sta ble ( P S = 0 or 1); a n d treat me nt be y o n d pr o gressi o n will n ot dela y a n i m mi ne nt i nter ve nti o n t o pre ve nt seri o us c o m plicati o ns of disease pr o gressi o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
3 9 / 1 5 0
T a ble 7
Sc he d ule of Assess me nts –
, 
, a n d  
 S a m pli n g d uri n g 
M ai nte n a nce a n d O pe n -l a bel Tre at me nt P h ases ( A vel u m a b ar m o nl y)
; E O T = e n d of treat me nt; Hrs = h o urs; 
; P K = p har mac o ki netics; V = visit; W = Wee k.
a.
S u bjects c o m pleti n g t he last cycle of t he I n d ucti o n P hase will e nter t he Re- baseli ne peri o d pri or t o Da y 1 of t he Mai nte na nce P hase.  
b.
If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore t he e n d of t h e 3 0 -da y peri o d, t he 3 0 -Da y Safet y F oll o w - up visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y.
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 0 / 1 5 0
2
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure
T he S p o ns or of t his cli nical trial wit h a vel u ma b is E M D Ser o n o Researc h & De vel o p me nt 
I nstit ute, I nc. ( E M D Ser o n o R & D), Billerica, M A, i n t he U nite d States of A merica (U S A ) a n d 
Merc k K G a A, Dar msta dt, Ger ma n y, i n rest of w orl d.
A c o ntract researc h or ga nizati o n ( C R O),
 (f or merl y 
 
 
U S A, will u n derta ke t he o pe rati o nal as pects of t his trial. Details of s uc h str uct ures a n d ass ociate d 
pr oce d ures will be defi ne d i n a se parate I nte grate d Pr oject Ma na ge me nt Pla n (I P M P) mai ntai ne d 
b y
.  The I PM P will be pre pare d b y  the 
Cli nical Pr oject Ma na ger i n c o o perati o n 
wit h ot her
 O perati o nal Tea m Lea ds .
2. 1
I n vesti g ati o n al Sites
T he trial will be c o n d ucte d at a p pr o xi matel y 2 3 0 sites i n N ort h A merica, S o ut h A merica, Asia 
Pacific , a n d E ur o pe, wit h a p pr o xi matel y 4 7 sites i n t he U S A.
2. 2
Tri al C o or di n ati o n / M o nit ori n g
T he S p o ns or will c o or di nate t he trial a n d will utilize t he s u p p ort of C R Os f or s o me acti vities of 
t he trial.  S p o ns or will perf or m o versi g ht of t he acti vities perf or me d by t he C R Os.
T he Cli nical Trial S u p plies de part me nt of t he S p o ns or will s u p pl y the trial me dicati o n of 
a vel u ma b.  Pac ka gi n g a n d distri b uti o n of cli nical s u p p lies will be perf or me d b y t he Cli nical Trial 
S u p plies de part me nt of t he S p o ns or.   First -li ne c he m ot hera p y will be s u p plie d b y  t he st u d y ce nter 
or b y  t he Sp o ns or, acc or di n g t o l ocal la ws a n d re g ulati o ns.
S u bject e nr ollme nt
will be ma na ge d b y  an i nteracti ve we b res p o nse s yste m (I W R S).  T he 
C o or di nati n g I n vesti gat or 
 
e prese nts all I nvesti gat ors f or decisi o ns a n d disc ussi o ns 
re gar di n g t his trial, c o nsiste nt wit h t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 
G o o d Cli nical Practice ( G C P, hereafter referre d t o as I C H G C P).  The C o or di nati n g I n vesti gat or 
will pr o vi de e x pert me dical i n p ut a n d a d vice relati n g t o trial desi g n a n d e xec uti o n a n d is 
res p o nsi ble f or t he re vie w a n d si g n-off of t he cli nical trial pr ot oc ol.
Safet y  la b orat or y assess me nts will be perf or me d ce ntrally .  L o cal la b orat ories ma y be use d at t he 
discreti o n of t he I n vesti gat or as cli nicall y n ee de d f or safet y ma na ge me nt of t he s u bject, a n d res ults 
fr o m t he l ocal la b orat ories will be e ntere d i n t he electr o nic case re p ort f or ms (e C R Fs) per t he e C R F 
C o m pleti o n G ui deli nes; h o we ver, ce ntral la b orat or y res ults m ust als o be c ollecte d.  Uri nal ys is a n d 
uri ne pre g na nc y  testi n g will be d o ne l ocally o nl y .
 
 a n d 
 assess me nts will b e 
perf or me d u n der t he res p o nsi bilit y a n d / or s u per visi o n of t he S p o ns or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 1 / 1 5 0
T he Gl o bal Dr u g Safet y De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y, or t heir desi g nate d 
re prese ntati ves will s u per vise dr u g safety a n d t he ti mel y re p orti n g of a d verse e ve nts ( A Es) a n d 
seri o us a d verse e ve nts (S A Es ).
Q ualit y  ass ura nce of t he trial c o n d uct will be perf or me d b y t he Researc h & De vel o p me nt Q ualit y 
De part me nt , Merc k K Ga A, Dar msta dt, Ger ma n y.
T he de part me nt of Gl o bal Bi ostatistics will s u per vise t he statistical a nal yses ( wit h t he e xce pti o n 
of t he 
 data a nal yses), w hic h will be o uts o urce d t o a C R O.   T he trial will a p pear i n t he f oll o wi n g 
cli nical trial re gistr y: Cli nical Trials.g o v
2. 3
Re vie w C o m mittees
2. 3. 1
I n de pe n de nt D at a M o nit ori n g C o m mittee
A n I n de pe n de nt Data M o nit ori n g 
C o m mittee (I D M C) will be c o m p ose d of a mi ni m u m of 
3 me m bers w h o d o n ot ha ve a n y  c o nflict of i nterests wit h t he trial S p o ns or, i ncl u di n g 2 cli nicia ns 
a n d a bi ostatisticia n.  The I D M C will peri o dicall y  re vie w safety data.  The f ull me m bers hi p, 
ma n date, a n d pr ocesses of t he I D M C will be detaile d i n t he I D M C c harter.
2. 3. 2
I n de pe n de nt R a di ol o gist
A n i n de pe n de nt ra di ol o gist verifies a n d c o nfir m s eli gi bilit y t o e nter t he Mai nte na nce P hase.
3
B ac k gr o u n d I nf or m ati o n
3. 1
G astric C a ncer
Gl o ball y , gastric ca ncer is t he fift h m ost c o m m o n ca ncer a n d t he t hir d lea di n g ca use of ca ncer 
deat h .  I n 2 0 1 2, t here were a p pr o xi matel y 95 0, 0 0 0 ne w cases a n d 7 2 3, 0 0 0 deat hs w orl d wi de 
(Ste wart 2 0 1 4 ). Of t hese ca ncers, a p pr o xi matel y 9 0 % t o 9 5 % were a de n ocarci n o mas wit h t he 
re mai ni n g 5 % t o 1 0 % c o m prisi n g of ne ur oe n d ocri ne t u m ors, l ym p h o mas, s q ua m o us cell ca ncer, 
a n d sarc o mas.
T he i nci de nce of gastric ca ncer varies wi del y  by c o u ntr y, wit h n o tr ue gl o bal sta n dar d treat me nt 
esta blis he d. Hi g her i nci de nce rates are o bser ve d i n Asia, C osta Rica, Per u, a n d Easter n E ur o pe, 
w hile Wester n E ur o pe a n d t he U S A ha ve l o wer i nci de nce rates (Gl o b oca n 2 0 1 2 ).
C he m ot hera p y is r o uti nel y use d t o treat metastatic gastric ca ncer; h o we ver, t here is n o si n gle 
sta n dar d re gi me n t hat is use d gl o ball y . C o m m o n che m ot hera p y a ge nts use d t o treat gastric ca ncer, 
eit her as m o n ot hera p y  or i n c o m bi nati o n, i ncl u de t he f oll o wi n g: fl u or o uracil ( 5-F U) a n d ot her 
fl u or o p yrimi di nes (e g, ca pecita bi ne, S 1), car m usti ne, se m usti ne a n d d o x or u bici n, mit o m y ci n C, 
cis plati n, o xali plati n, ta xa nes, a n d iri n oteca n. T he relati ve be nefits of t hese differe nt dr u gs, al o ne 
a n d i n c o m bi nati o n, are u nclear (N C C N 2 0 1 5 ). Rece ntl y , trast uz u ma b has bec o me a vaila ble f or 
use wit h c he m ot hera p y f or t he treat me nt of patie nts w h ose t u m ors o vere x press t he h u ma n 
e pi der mal gr o wt h fact or rece pt or 2 ge ne (H u dis 2 0 0 7 ). Des pite t he a vaila bilit y of t hese a ge nts,
ad va nce d, u nresecta ble, a n d/ or metastatic gastric ca ncer re mai ns a si g nifica nt u n met me dical nee d.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 2 / 1 5 0
3. 2
Pr o gr a m me d De at h Rece pt or a n d Li g a n ds
T he pr o gra m me d deat h 1 ( P D -1) rece pt or a n d P D -1 li ga n ds 1 a n d 2 ( P D -L 1 , P D-L 2 ) pla y i nte gral 
r oles i n i m m u ne re g ulati o n.  E x presse d o n acti vate d T- cells, P D - 1 is acti vate d b y  PD- L 1 a n d 
P D -L 2  ex presse d b y  str o mal cells, t u m or cells, or b ot h, i nitiati n g T- cell deat h a n d l ocalize d 
i m m u ne s u p pressi o n (D o n g 1 9 9 9 ; D o n g 2 0 0 2 ; Free ma n 2 0 0 0 ; T o palia n 2 0 1 2a ), p ote ntiall y 
pr o vi di n g a n i m m u ne-t olera nt e n vir o n me nt f or t u m or de vel o p me nt a n d gr o wt h. 
 
 
I n t he cli nical setti n g, treat me nt wit h a nti b o dies t hat bl oc k t he P D- 1 – a nti-P D -L 1  interacti o n ha ve 
bee n re p orte d t o pr o d uce o bjecti ve res p o nse rates ( O R R) of 7 % t o 3 8 % i n patie nts wit h a d va nce d 
or metastatic s oli d t u m ors, wit h t olera ble safety pr ofiles (Ha mi d 2 0 1 3 ; Bra h mer 2 0 1 2 ; T o palia n 
2 0 1 2 b ). N ota bl y , res p o nses a p peare d pr ol o n ge d, wit h d urati o ns of 1 year or m ore f or t he maj ority 
of patie nts. Rece nt st u dies ha ve d oc u me nte d t he acti vit y of a nti-P D -L 1 a nti b o dies i n s u bjects wit h 
a d va nc e d gastric ca ncer (M ur o 2 0 1 4 ; L u tz k y 2 0 1 4).
3. 3
A vel u m a b
T he i n vesti gati o nal me dici nal pr o d uct (I M P) f or t he prese nt trial is a vel u ma b.  Avel u ma b is a f ull y 
h u ma n m o n ocl o nal a nti b o d y of t he i m m u n o gl o b uli n (I g) G 1 is ot y pe.  A vel u ma b selecti vel y bi n ds 
t o P D -L 1  an d c o m petiti vel y bl oc ks its i nteracti o n wit h P D - 1.  C o m pare d wit h a nti-P D -1 a nti b o dies 
t hat tar get T- cells, a vel u ma b tar gets t u m or cells a n d is t heref ore e x pecte d t o ha ve fe wer si de 
effects, i ncl u di n g a l o wer ris k of a ut oi m m u ne -relate d safety iss ues, as bl oc ka de of P D -L 1  lea ves 
t he P D -L 2 / P D-1 pat h wa y  intact t o pr o m ote peri p heral self-t olera nce (Latc h ma n 2 0 0 1 ).  For 
c o m plete details of t he i n vitr o a n d n o ncli nical trials, please refer t o t he I n vesti gat or’s Br oc h ure 
(I B).
I n li g ht of t he rece nt data de m o nstrati n g t he cli nical efficac y of a n a nti-P D -L 1  anti b o d y  in 
a d va nce d gastric ca ncer, a n d gi ve n t he cli nical i m p orta nce of P D-L 1 e x pressi o n i n gastric ca ncer 
t u m or cells ( O ki 2 0 1 4) a n d t he m o de of acti o n of a vel u ma b, a vel u ma b is bei n g de vel o pe d as a 
p ote ntial t hera py f or patie nts wit h vari o us a d va nce d s oli d t u m ors, i ncl u di n g gastric ca ncer.  T his 
a nti-P D -L 1 t hera pe utic a ntib o d y  co nce pt is i nte n de d t o be de vel o pe d i n o nc ol o gical setti n gs b y  
Merc k K Ga A, Dar msta dt, Ger ma n y, a n d b y its s u bsi diar y, E M D Ser o n o R & D.
T he o n g oi n g trials f or a vel u ma b are descri be d i n t he I B.  A vel u ma b is c urre ntl y in cli nical 
de vel o p me nt wit h 2 o n g oi n g P hase I trials i n s u bjects wit h s oli d t u m ors, o ne o n g oi n g P hase II trial 
i n Mer kel cell carci n o ma ( M C C), a n d 2 P hase III trials i n n o n- s mall cell l u n g ca ncer ( N S C L C).  
Of t he o n g oi n g st u dies, 2 of t hese st u dies ha ve c o h orts of patie nts wit h a d va nce d gast ric ca ncer:

Trial E M R 1 0 0 0 7 0 - 0 0 1 is “a P hase I, o pe n -la bel, m ulti ple -asce n di n g d ose trial t o i n vesti gate t he 
safety, t olera bilit y, P K, bi ol o gical, a n d cli nical acti vit y of a vel u ma b i n s u bjects wit h metastatic 
or l ocall y  a d va nce d s oli d t u m ors.”

Trial E M R 1 0 0 0 7 0- 0 0 2 is “a P hase I trial t o i n vesti gate t he t olera bilit y, safet y, P K, bi ol o gical, 
a n d cli nical acti vit y of a vel u ma b i n Ja pa nese s u bjects wit h metastatic or l ocall y a d va nce d s oli d 
t u m ors, wit h e x pa nsi o n part i n Asia n s u bjects wit h gastric ca ncer.”
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 3 / 1 5 0
I n a d diti o n t o t he trial descri be d i n t his pr ot oc ol, E M R 1 0 0 0 7 0 - 0 0 7, a n ot her P hase III st u d y in 
patie nts wit h a d va nce d gastric ca ncer ( E M R 1 0 0 0 7 0 - 0 0 8) is o n g oi n g f or t hir d-li ne treat me nt.  
3. 3. 1
S afet y
A vaila ble safet y a n d efficac y data f or t he a vel u ma b pr o gra m are disc usse d i n t he I B a n d esta blis h 
a p ositi ve be nefit ris k f or c o n d ucti n g P hase III st u dies wit h 1 0 m g/ k g (t he d osi n g use d i n t his trial).  
T he safety pr ofile of a vel u ma b has bee n e val uate d fro m data of m ore t ha n 1, 7 5 0 s u bjects, i ncl u di n g 
all
s u bjects treate d wit h 
1 0 m g/ k g 
fr o m st u dies E M R 1 0 0 0 7 0 - 0 0 1 ( 1, 6 5 0 s u bjects) a n d 
E M R 1 0 0 0 7 0 -0 0 3 Part A ( 8 8 s u bjects as p o ole d safet y dataset wit h a data c ut -off of 0 9 J u ne 2 0 1 6) 
a n d s u bjects i n t he o n g oi n g l ocal Ja pa nese P hase I E M R 1 0 0 0 7 0 - 0 0 2.  T he se safety data fr o m 
s u bjects wit h differe nt t u m or t ypes treate d wit h a vel u ma b s u g gests a n acce pta ble safet y pr ofile of 
t he c o m p o u n d.  M ost of t he o bser ve d e ve nts were eit her i n li ne wit h t h ose e x pecte d i n s u bjects 
wi t h a d va nce d s oli d t u m ors or wit h si milar class effects of m o n ocl o nal a nti b o dies bl oc ki n g t he 
P D -1/ P D -L 1  axis .  I nf usi o n-relate d reacti o ns i ncl u di n g dr u g h y perse nsiti vit y  reacti o ns, a n d 
i m m u ne-me diate d 
a d verse reacti o ns (i m m u ne-relate d p ne u m o nitis, i m m u ne-relate d c olitis, 
i m m u ne-relate d he patitis, 
i m m u ne-relate d e n d ocri n o pat hies 
[t h yr oi d dis or ders, 
a dre nal 
i ns ufficie nc y, ne w o nset T y pe I dia betes mellit us, pit uitar y  dis or ders], i m m u ne-relate d ne p hritis, 
a n d re nal d y sf u ncti o n a n d ot her i m m u ne-relate d A Es [ m yo sitis, m y ocar ditis, G uillai n -Barre 
s yn dr o me, u veitis] ) ha ve bee n i de ntifie d as i m p orta nt ris ks f or a vel u ma b ( please see c urre nt I B f or 
details).  Detaile d g ui deli nes f or t he ma na ge me nt of i m m u ne-relate d A Es a n d i nf usi o n-relate d 
reacti o ns ha ve bee n i m ple me nte d i n t he st u d y pr ot oc ols, i ncl u di n g t his o ne ( please see Secti o n 3. 5 , 
Secti o n 5. 1. 2. 2. 1,  Secti o n 5. 1. 3. 2,  Secti o n 6. 2. 1,  Secti o n 6. 4,  Secti o n 6. 5. 4 , Secti o n 6. 5. 5,  a n d 
Secti o n 6. 1 2 ).
3. 3. 2
P h ar m ac o k i netic Res ults
Draft 
P K 
assess me nts ha ve bee n perf or me d i n o n g oi n g Trials 
E M R 1 0 0 0 7 0 - 0 0 1 a n d 
E M R 1 0 0 0 7 0- 0 0 2. T he preli mi nar y  res ults base d o n t he data a vaila ble as of 1 9 Dece m ber 2 0 1 4 
are prese nte d u n der t he i n di vi d ual trial hea di n gs.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 4 / 1 5 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 5 / 1 5 0
3. 4
R ati o n ale f or t he C urre nt Cli nic al Tri al
T he safet y an d cli nical efficac y of a vel u ma b ha ve bee n deter mi n e d i n m ulti ple t u m or t ypes 
(N S C L C, o varia n ca ncer, mes ot heli o ma, mela n o ma, t h ym o ma, a n d a dre n oc ortic ocarci n o ma) 
(Disis 2 0 1 5 , G ulle y  2 0 1 5).  T he rati o nale t o e nr oll s u bjects wit h u nresecta ble l ocall y  ad va nce d or 
metastatic a de n ocarci n o ma of t he st o mac h or gastr oes o p ha geal j u ncti o n ( G EJ) is s u p p orte d b y  data 
re p orte d fr o m ot her P D -1/ P D -L 1  age nts a n d fr o m 2 e x pa nsi o n c o h orts i n 2 a vel u ma b P hase I 
st u dies.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 6 / 1 5 0
3. 4. 1
D at a fr o m A nti -P D -1/ P D -L 1 T her a pies i n G astric C a ncer
Data fr o m ot her a nti -P D -1/ P D -L 1  t hera pies i n gastric ca ncer are as f oll o ws:

Data prese nte d at t he A merica n S ociet y f or Cli nical O nc ol o g y  An n ual Meeti n g 2 0 1 4 fr o m a 
P hase I e x pa nsi o n c o h ort of 1 6 s u bjects wit h gastr oes o p ha geal ca ncer treate d wit h M E DI 4 7 3 6 
(a nti-P D -L 1), w hic h re p orte d 4 o u t of 1 6 res p o n ders (L utz k y  2 0 1 4).

Data prese nte d at t he E ur o pea n S ociet y f or Me dical O nc ol o g y  An n ual Meeti n g 2 0 1 4 fr o m a 
P hase I c o h ort of 3 9 P D -L 1 + s u bjects wit h a d va nce d gastric ca ncer treate d wit h a nti-P D -1 
( Ke yn ote 0 1 2), w hic h re p orte d 1 2 o ut of 3 9 res p o n ders (M ur o 2 0 1 4 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 7 / 1 5 0
3. 5
S u m m ar y of t he O ver all Be nefit a n d Ris k
Base d o n t he n o ncli nical a n d P hase I data a vaila ble t o date, t he c o n d uct of t he trial is c o nsi dere d 
j ustifia ble usi n g t he d ose a n d d ose re gi me n of t he a vel u ma b as s pecifie d i n t his cli nical trial 
pr ot oc ol. A n I D M C ( see Secti o n  2. 3. 1) will assess t he ris k-be nefit rati o o n a n o n g oi n g basis. T he 
trial will be disc o nti n ue d i n t he e ve nt of a n y ne w fi n di n gs t hat i n dicate a rele va nt deteri orati o n of 
t he ris k-be nefit relati o ns hi p t hat w o ul d re n der c o nti n uati o n of t he trial u nj ustifia ble.
T he pri mar y  k n o w n i de ntifie d ris ks of e x p os ure t o a vel u ma b i ncl u de:

I nf usi o n-relate d reacti o ns

I m m u ne-relate d a d verse e ve nts (ir A Es).
T o miti gate t he ris k of i nf usi o n-relate d reacti o ns, p re me dicate patie nts wit h a n a nti hista mi ne a n d 
wit h paraceta m ol (aceta mi n o p he n) pri or t o t he first 4 i nf usi o ns of a vel u ma b. Pre me dicati o n s h o ul d 
be 
a d mi nistere d f or s u bse q ue nt a vel u ma b d oses 
base d 
u p o n 
cli nical j u d g me nt a n d 
pre se nce/se verit y of pri or i nf usi o n reacti o ns.  T his re gi me n m a y  be m o difie d base d o n l ocal 
treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate pr o vi de d it d oes n ot i ncl u de s yste mic 
c ortic oster oi ds .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 8 / 1 5 0
I n a d diti o n, si nce a vel u ma b ca n i n d uce a nti b o d y-de pe n de nt cell-me diate d c yt ot o xicit y ( A D C C), 
t here is a p ote ntial ris k of t u m or l ysis s yn dr o me (see Secti o n  6. 5. 4. 3) .  
As n ote d i n Secti o n  3. 2 , trials wit h a nti b o dies t hat bl oc k t he P D- 1 – P D -L 1 i nteracti o n ha ve bee n 
re p orte d t o pr o d uce O R R of 7 % t o 3 8 % i n patie nts wit h a d va nce d or metastatic s oli d t u m o rs, wit h 
res p o nse d urati o ns of 1 year or m ore f or t he maj orit y of patie nts.
T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he cli nical trial pr ot oc ol, I CH G C P, a n d 
t he a p plica ble nati o nal re g ulat or y re q uire me nts.
4
Tri al O bjecti ves
4. 1
Pri m ar y O bjecti ves

T he pri mar y  o bjecti ves of t his trial are t o de m o nstrate s u peri orit y of mai nte na nce t hera p y wit h 
a vel u ma b vers us c o nti n uati o n of first -li ne c he m ot hera p y wit h re gar d t o O verall S ur vi val (O S )
i n all ra n d o mize d s u bjects or i n P D -L 1 + s u bjects w h o ha ve n ot pr o gresse d o n first-li ne 
c he m ot hera p y.
4. 2
Sec o n d ar y O bjecti ves
Sec o n dar y  o bjecti ves are as f oll o ws:

T o de m o nstrate s u peri orit y of mai nte na nce t hera p y wit h a vel u ma b vers us c o nti n uati o n of 
first-li ne c he m ot hera p y wit h re gar d t o P F S as per R E CI S T v 1. 1 acc or di n g t o I n vesti gat or 
assess me nt.

T o de m o nstrate s u peri orit y of mai nte na nce t hera p y wit h a vel u ma b vers us c o nti n uati o n of 
first-li ne c he m ot hera p y wit h re gar d t o t he O R R as per R E CI S T v 1. 1 a n d per I nvesti gat or 
assess me nt

T o c o m pare t he s u bject-re p orte d o utc o mes / q ualit y of life ( Q o L) of s u bjects w he n treate d wit h 
a vel u ma b vers us c o nti n uati o n of first-li ne c he m ot hera p y as assesse d b y  t he E ur o pea n Q o L
5- di me nsi o ns 5 Le vel Q uesti o n naire (E Q - 5 D-5 L ), a n d 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 ( E O R T C) Q L Q -C 3 0 a n d m o d ule Q L Q -S T O 2 2

T o deter mi ne t he safe t y a n d t olera bilit y of a vel u ma b.
D oc u me nt N o. 
O bject N o.
C CI
C CIC CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
4 9 / 1 5 0
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a m ultice nter, i nter nati o nal, ra n d o mize d, o pe n -la bel P hase III trial c o m pari n g mai nte na nce 
t hera py wit h a vel u ma b wit h c o nti n uati o n of first -li ne c he m ot hera py i n s u bjects wit h u nresecta ble, 
l ocall y ad va nce d or met astatic, a de n ocarci n o ma of t he st o mac h, or of t he G EJ ( See Secti o ns 5. 1. 2. 1
a n d 5. 1. 2. 2 f or details).
T he me dici nal pr o d ucts o xali plati n, 5- F U a n d ca pecita bi ne are use d as c he m ot hera p y age nts i n t he 
I n d ucti o n P hase a n d t he Mai nte na nce P hase of t his trial.  All t hree s u bsta nces are acce pte d as 
sta n dar d of treat me nt f or t he i n dicati o n u n der st u d y. Bef ore a d mi nisteri n g a n y of t hese s u bsta nces, 
t he In vesti gat or is re q uire d t o refer t o w hat is state d i n t he c urre nt pr o d uct i nf or mati o n (l ocal la bel, 
S u m mar y  of Pr o d uct C haracteristics [ S m P C]), partic ularl y i n re gar d t o c o ntrai n dicati o ns, war ni n gs 
a n d preca uti o ns f or use, d osa ge a dj ust me nts i n t he e ve nt of t o xicit y, pat ie nt m o nit ori n g pr o visi o ns, 
t he d urati o n of t he nee d f or c o ntrace pti o n, a n d me dici nal pr o d ucts t hat are pr o hi bite d or t hat m ust 
be use d wit h ca uti o n.  In case of a p ote ntial c o ntra dicti o n bet wee n t he s pecificati o ns o utli ne d i n 
t his cli nical trial pr ot oc ol a n d t he i nf or mati o n c o ntai ne d i n t he pr o d uct i nf or mati o n (l ocal la bel, 
S m P C) of o xali plati n, 5 -F U, or ca pecita bi ne, t he l ocal la bel al wa ys pre vails.  I n vesti gat ors s h o ul d 
c hec k u p date d la beli n g via rele va nt we bsites bef ore e nr oll me nt, ra n d o mizati o n, a n d c h e m ot hera p y 
a d mi nistrati o n i n t he In d ucti o n P hase a n d t he Mai nte na nce P hase.  
T his st u d y  is c o n d ucte d wit h a S cree ni n g peri o d a n d a n I n d ucti o n P hase, Mai nte na nce P hase, a n d 
F oll o w -u p P hase.
5. 1. 1
O ver all Desi g n
A p pr o xi matel y  46 6 s u bjects are pla n ne d t o be e nr olle d i n t he M ai nte na nce P hase. T he act ual 
n u m ber of s u bjects e nr olle d i n t he I n d ucti o n P hase will be dri ve n b y  obser ve d i n d ucti o n fail ure 
rates a n d will be s uc h t o all o w f or a p pr o xi matel y 4 6 6 patie nts t o be ra n d o mize d i n t he M ai nte na nce 
P hase.   At t he ti me of t his pr ot oc ol a me n d me nt, s u bject e nr oll me nt i n t he Mai nte na nce P hase is 
c o m plete, wit h 4 9 9 s u bjects ra n d o mize d i nt o t he Mai nte na nce P hase.
S u bjects e nr olle d i n t he 
In d ucti o n P hase will recei ve a first-li ne t hera p y c o m prise d of o xali plati n a n d eit her 5- F U or 
ca pecita bi ne (I n d ucti o n P hase) f or 1 2 wee ks (see Secti o n 5. 1. 2. 1). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 0 / 1 5 0
F oll o wi n g t he I n d ucti o n P hase, s u bjects w h o e x perie nce a C R, P R, or S D after 1 2 wee ks 
(a p pr o xi matel y 4 6 6 s u bjects) will be ra n d o ml y assi g ne d ( Mai nte na nce P hase) t o recei ve eit her 
avel u ma b (see Secti o n  5. 1. 2. 2. 1) or c o nti n uati o n of t he sa me re gi me n of c he m othera p y fr o m t he 
I n d ucti o n P hase (see Secti o n  5. 1. 2. 2. 2 ). S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her 
c he m ot hera p y will recei ve best s u p p orti ve care ( B S C) al o ne wit h n o acti ve t hera p y.
Pri or t o ra n d o mizati o n, In vesti gat ors m ust s pecif y w hic h of treat me nts (c o nti n uati o n of t he sa me 
re gi me n of c he m ot hera p y fr o m the I n d ucti o n P hase vers us B S C) will be selecte d f or s u bjects i n 
c he m ot hera p y c o ntr ol ar m.  
 
 
 
 
After t he I n d ucti o n P hase, all s u bjects will b e 
e val uate d f or eli gi bilit y i nt o t he Mai nte na nce P hase b y an i n d e pe n de nt ra di ol o gist usi n g R E CI S T 
v 1. 1.  
St u d y  treat me nt will c o nti n ue u ntil:

Disease pr o gressi o n (see Secti o n 5. 5. 1)

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n) b y  In vesti gat or’s o pi ni o n

U nacce pta ble t o xicit y per I n vesti gat or o pi ni o n, or

A n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d (see Secti o n 5. 5).
S u bjects recei vi n g a vel u ma b ma y  co nti n ue treat me nt past t he i nitial deter mi nati o n of disease 
pr o gressi o n per R E CI S T v 1. 1 as l o n g t he f oll o wi n g criteria are met:

I n vesti gat or-assesse d cli nical be nefit, wit h o ut a n y ra pi d disease pr o gressi o n

T olera nce of trial treat me nt

Sta ble 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 (P S ) ( P S = 0 or 1)

Treat me nt b e y o n d pr o gressi o n will n ot dela y a n i m mi ne nt i nter ve nti o n t o pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n (f or e xa m ple, ce ntral ner v o us s ys te m metastases).
T he decisi o n t o c o nti n ue a vel u ma b treat me nt be y o n d pr o gressi o n s h o ul d be disc usse d wit h t he 
M e dical M o nit or a n d d oc u me nte d i n t he st u d y rec or ds.
F or s u bjects c o nti n ui n g a vel u ma b after i nitial pr o gressi ve disease (P D ), a ra di o gra p hic assess me nt 
s h o ul d be perf or me d wit hi n 6 wee ks of ori gi nal P D t o deter mi ne w het her t here has bee n a decrease 
i n t he t u m or size, or c o nti n ue d P D.  The assess me nt of cli nical be nefit s h o ul d be bala nce d b y  
cli nical j u d g me nt as t o w het her t he s u bject is cli nicall y deteri orati n g a n d u nli kel y  to recei ve a n y 
be nefit fr o m c o nti n ue d treat me nt wit h a vel u ma b.
F or s u bjects recei vi n g a vel u mab, if disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve 
dia g n osis/ra di o gra p hic c o nfir mati o n is n ot ma de at t he ti me of disc o nti n uati o n, a sec o n d i ma gi n g 
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 1 / 1 5 0
sca n m a y  be all o we d f or c o nfir mati o n of pr o gressi o n.  If pr o gressi o n at t he sec o n d i ma gi n g scan 
is n ot c o nfir me d a n d t he s u bject wis hes t o restart, t he s u bject will be all o we d t o c o nti n ue recei vi n g 
a vel u ma b as l o n g as t he y meet t he criteria f or c o nti n uati o n of treat me nt be y o n d pr o gressi o n. 
If t he I n vesti gat or feels t hat t he s u bject c o nti n ues t o achie ve cli nical be nefit b y  co nti n ui n g 
treat me nt, t he s u bject s h o ul d re mai n o n t he trial a n d c o nti n ue t o recei ve m o nit ori n g acc or di n g t o 
t he Sc he d ule of Assess me nts (Ta ble 3 ).
A n y  a d diti o nal c o nti n uati o n of a vel u ma b pl us B S C be y o n d f urt her pr o gressi o n m ust be disc usse d 
a n d a gree d u p o n wit h t he M e dical M o nit or.  Furt her disease pr o gressi o n is defi ne d as a n a d diti o nal 
i ncrease i n t u m or b ur de n of 2 0 % a n d ≥ 5 m m a bs ol ute i ncrease i n t u m or b ur de n fr o m ti me of i nitial 
P D.   T his i ncl u des a n i ncrease i n t he s u m of all tar get lesi o ns a n d/ or t he de vel o p me nt of ne w 
meas ura ble lesi o ns.
S u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a mi ni m u m of 
1 2 m o nt hs or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after c o nfir mati o n of res p o nse. I n 
case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, b ut pri or t o t he e n d of t he 
trial, 1 re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t he I n vesti gat or a n d after a gree me nt 
wit h t he Me dical M o nit or. 
T o be eli gi ble f or retreat me nt, t he s u bject m ust n ot ha ve e x perie nce d 
a n y to xicit y  that le d t o treat me nt disc o nti n uati o n of t he i nitial a vel u ma b t hera py. S u bjects w h o 
re-i nitiate treat me nt will sta y o n trial a n d will be treate d a n d m o nit ore d acc or di n g t o t he pr ot oc ol 
a n d f oll o w t he Sc he d ule of Assess me nts u ntil disease pr o gressi o n (see Ta ble 3 ).
S u bjects recei vi n g mai nte na nce
c he m ot hera p y will recei ve trial treat me nt u ntil P D per R E CI S T 
v ersi o n 1. 1, f or t he acce pte d ma xi mal d urati o n of t he a ge nt(s) selecte d, si g nifica nt cli nical 
deteri orati o n (cli nical pr o gressi o n), u nac ce pta ble t o xicit y, wit h dra wal of c o nse nt, or if a n y 
criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d.   
O n -st u d y su bject ma na ge me nt a n d st u d y en d p oi nt e val uati o n will be base d o n I n vesti gat or 
assess me nts (see Secti o n 7. 3).
S u bjects will atte n d cli nic visits at re g ular i nter vals t o recei ve trial treat me nt a n d f or efficac y  an d 
safety assess me nts (see Secti o n  7. 1 ).
T he pri mar y e n d p oi nt of t he trial is O S , defi ne d as t he ti me (i n m o nt hs) fr o m ra n d o mizati o n t o t he 
date of deat h, re gar dless of t he act ual ca use of t he s u bject’s deat h. T he pri mar y  e n d p oi nt O S will 
be teste d i n all ra n d o mize d s u bjects (i nte nt-t o-treat [I T T] A nal y sis Set ) a n d i n P D -L 1 + s u bjects 
( P D-L 1 + A nal y sis Set) .
T he P D -L 1 e x pressi o n stat us will be deter mi ne d acc or di n g t o t he 
c o n ve nti o nal t u m or-cell (cell n u m ber -base d perce nta ge) sc ori n g met h o d w here s u bjects wit h 
P D -L 1  t u m or e x pressi o n ≥1 % are c o nsi dere d t o be P D -L 1 +.
Safet y  e n d p oi nts i ncl u de A Es, assesse d t hr o u g h o ut t he trial a n d e val uate d usi n g t he N CI-C T C A E 
v 4. 0 3; p h y sical e xa mi nati o ns; cli nical la b orat or y assess me nts; c o nc o mita nt me dicati o ns ; vital 
si g ns; electr ocar di o gra m ( E C G) para meters; a n d E C O G P S .
T he trial desi g n sc he matic is prese nte d i n  Fi g ure 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 2 / 1 5 0
Fi g ure 1 
Sc he m atic of Tri al Desi g n
All s u bjects i n b ot h ar ms will recei ve B S C as bac k gr o u n d t hera p y as s pecifie d i n Secti o n  6. 1. 4 .
B S C = best s u p p orti ve care; 5- F U = 5-f l u or o uracil; n = n u m ber of s u bjects; P D = pr o gressi ve disease .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 3 / 1 5 0
5. 1. 2
Tri al tre at me nt A d mi nistr ati o n a n d Sc he d ule
T he trial Sc he d ule of Assess me nts are prese nte d i n Ta ble 1 t o Ta ble 7.
5. 1. 2. 1
I n d ucti o n C he m ot her a p y
S u bjects e nr olle d i n t his trial will start wit h a 1 2 -wee k c he m ot hera p y I n d ucti o n P hase c o m prise d 
of o xali plati n a n d eit her 5- F U or ca pecita bi ne (acc or di n g t o t he d osi n g sc he d ule i n S ecti o n 6. 2. 2
a n d Ta ble 1 a n d Ta ble 2 or i n acc or da nce t o t he la bel i nstr ucti o ns a n d per l ocal g ui deli nes ).

O xali plati n at 8 5 m g/ m 2 I V on D a y  1 wit h le uc o v ori n 2 0 0 m g/ m 2 I V o n Da y  1 ( or e q ui vale nt 
le v ole uc o v ori n d ose ) f oll o we d b y  5-F U at 2 6 0 0 m g/ m 2 I V c o nti n u o us i nf usi o n o ver 2 4 h o urs 
o n Da y  1, gi ve n e ver y 2 wee ks (f or u p t o 1 2 wee ks, Ta ble 2) .
O R
O xali plati n at 8 5 m g/ m 2 I V on D a y  1 wit h le uc o v ori n 4 0 0 m g / m2 I V on Da y 1 ( or e q ui vale nt 
le v ole uc o v ori n d ose) f oll o we d b y  5-F U at 4 0 0 m g/ m 2 I V pus h o n Da y  1 an d 2 4 0 0 m g/ m 2 I V 
c o nti n u o us i nf usi o n o ver 4 6- 4 8 h o urs ( Da ys 1 a n d 2) gi ve n e ver y 2 wee ks (f or u p t o 1 2 wee ks)
O R

O xali plati n at 1 3 0 m g/ m 2 IV o n D a y 1 wit h ca pecita bi ne at 1 0 0 0 m g / m2, t wice dail y  for 2 wee ks 
f oll o we d by a 1 -wee k rest peri o d gi ve n e ver y  3 wee ks (f or u p t o 1 2 wee ks, Ta ble 1 ).
L ocal la bel a n d g ui deli nes s h o ul d be f oll o we d f or s pecific starti n g d oses d ue t o re nal or he patic 
i m pair me nts a n d f or s u bse q ue nt d ose m o dificati o ns d ue t o differe nt t o xicities.
S u bjects w h o e x perie nce a C R, P R , or S D after 1 2 wee ks will be ra n d o ml y assi g ne d t o eit her 
avel u ma b or c o nti n ue t he sa me re gi me n of c he m ot hera p y fr o m t he I n d ucti o n P hase .  S u bjects w h o 
de m o nstrate a res p o nse d uri n g t he I n d ucti o n P hase t hat re n ders t heir meas ura ble disease n o l o n ger 
meas ura ble at t he ti me of t he Mai nte na nce P ha se ca n be ra n d o mize d .
5. 1. 2. 2
M ai nte n a nce T her a p y
5. 1. 2. 2. 1
A vel u m a b Ar m
S u bjects ra n d o ml y  assi g ne d t o t he a vel u ma b ar m will recei ve I V i nf usi o n of a vel u ma b ( 1 0 m g/ k g 
o ver 1 h o ur) o nce e ver y  2 wee ks (see Ta ble 6) . 
T o miti gate i nf usi o n-relate d reacti o ns, pre me dicate patie nts wit h a n a nti hista mi ne a n d wit h 
paraceta m ol (aceta mi n o p he n) pri or t o t he first 4 i nf usi o ns of a vel u ma b. Pre me dicati o n s h o ul d be 
a d mi nistere d f or s u bse q ue nt a vel u ma b d oses base d u p o n cli nical j u d g me nt a n d prese nce/se verit y 
of pri or i nf usi o n reacti o ns.  T his re gi me n ma y be m o difie d base d o n l ocal treat me nt sta n dar ds a n d 
g ui deli nes as a p pr o priate pr o vi de d it d o es n ot i ncl u de s yste mic c ortic oster oi ds.
T he f or m ulati o n a n d pac ka gi n g i nf or mati o n of a vel u ma b is pr o vi de d i n Secti o n  6. 1. 2, Secti o n 6. 1. 1
a n d Secti o n 6. 6, res pecti vel y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 4 / 1 5 0
5. 1. 2. 2. 2
C he m ot her a p y Ar m
S u bjects ra n d o ml y assi g ne d t o t he m ai nte na nce c he m ot hera p y ar m will recei ve first-li ne 
c he m ot hera p y acc or di n g t o t he d osi n g sc he d ule (see Secti o n 6. 2 a n d Ta ble 3 t o Ta ble 4) or i n 
acc or da nce t o t he la bel i nstr ucti o ns a n d p er l ocal g ui deli nes ) u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y, f or t he acce pte d ma xi mal d urati o n of t he a ge nt(s) selecte d, or a n y of t he 
criteria f or wit h dra wal fr o m trial treat me nt is f ulfille d ( Secti o n  5. 5 ).
T he d ose a n d sc he d ule d uri n g t he Mai nte na nce P hase are as f oll o ws:
S u bjects 
ra n d o ml y 
assi g ne d t o c he m ot hera p y 
will c o nti n ue 
t he sa me re gi me n of 
o xali plati n -fl u or o p yri mi di ne d o u blet as t he y recei ve d d uri n g t he I n d ucti o n P hase u ntil disease 
pr o gressi o n.

S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her c he m ot hera p y will recei ve B S C 
al o ne wit h n o acti ve t hera p y.  Pri or t o ra n d o mizati o n, I n vesti gat ors m ust s pecif y BS C 
treat me nt f or t hese s u bjects (see Ta ble 5)

F or s u bjects recei vi n g c he m ot hera p y ( o xali plati n + 5- F U or o xali plati n + ca pecita bi ne), 
d ose m o dificati o ns after t he starti n g d ose are all o we d if t he c o nti n uati o n of t he o xali plati n -
fl u or o p yri mi di ne d o u blet , or a c o m p o ne nt t here of, is pr o hi bite d b y  to xicit y .  F or s u bjects 
i nt olera nt t o f urt her o xali plati n, si n gle-a ge nt ca pecita bi ne or 5 -F U + le uc o v ori n will be a n 
o pti o n f or d ose m o dificati o n.
A d diti o nall y , i n or der t o re d uce t he i nci de nce a n d se verity of na usea a n d v o miti n g as well as t he 
se verity of h y perse nsiti vit y  reacti o ns, s u bjects will be a d mi nistere d pretreat me nt pri or t o eac h 
t hera py i nf usi o n per l ocal i nstit uti o nal practice.
5. 1. 3
D ose M o dific ati o n 
a n d A d verse Dr u g Re acti o ns Re q uiri n g 
Tre at me nt Disc o nti n u ati o n
5. 1. 3. 1
D ose M o dific ati o n f or A vel u m a b
T he d ose of a vel u ma b will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d wit hi n 
7 2 h o urs pri or t o t he da y of dr u g a d mi nis trati o n. T he d ose of a vel u ma b use d f or t he pre vi o us 
a d mi nistrati o n ca n be re peate d if t he c ha n ge i n t he s u bject’s wei g ht is 1 0 % or less t ha n t he wei g ht 
use d f or t he last d ose calc ulati o n.
Eac h s u bject will sta y on t he a vel u ma b-assi g ne d d ose of 1 0 m g/ k g u n less treat me nt nee ds t o be 
st o p pe d. D osi n g m o dificati o ns (c ha n ges i n i nf usi o n rate) a n d d ose dela y s are descri be d i n 
Secti o n 5. 1. 3. 2 a n d Secti o n  6. 5. 4. 1. T here will be n o d ose re d ucti o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 5 / 1 5 0
5. 1. 3. 2
A d verse 
Dr u g 
Re acti o ns 
Re q uiri n g 
A vel u m a b 
Disc o nti n u ati o n or M o dific ati o ns
T he f oll o wi n g a d verse dr u g reacti o ns ( A D Rs, see Secti o n 7. 4. 1. 1 ) re q uire per ma ne nt treat me nt 
disc o nti n uati o n of a vel u ma b:

A n y  Gra de 4 A D Rs re q uire treat me nt disc o nti n uati o n wit h a vel u ma b e xce pt f or si n gle 
la b orat or y val ues o ut of n or mal ra n ge t hat are u nli kel y relate d t o trial treat me nt as assesse d b y 
t he I nvesti gat or, d o n ot ha ve a n y cli nical c orrelate, a n d res ol ve wit hi n 7 da y s wit h a de q uate 
me dica l ma na ge me nt.

A n y  Gra de 3 A D Rs re q uire treat me nt disc o nti n uati o n wit h a vel u ma b e xce pt f or a n y of t he 
f oll o wi n g: 

Tra nsie nt (≤ 6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver, w hic h are c o ntr olle d wit h me dical 
ma na ge me nt

Tra nsie nt (≤ 2 4 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, or e mesis t hat 
res ol ve t o Gra de ≤ 1 

Si n gle la b orat or y val ues o ut of n or mal ra n ge (e xcl u di n g Gra de ≥ 3 li ver f u ncti o n test 
i ncrease) t hat are u nli kel y  relate d t o trial treat me nt acc or di n g t o t he I n vesti gat or, d o n ot ha ve 
a n y cli nical c orrelate

Gra de 3 s ki n t o xicit y

T u m or flare p he n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites of k n o w n 
or s us pecte d t u m or

C ha n ge i n E C O G P S t o ≥ 3 t hat res ol ves t o ≤ 2 wit hi n 1 4 da y s (i nf usi o ns s h o ul d n ot be gi ve n 
o n t he f oll o wi n g c ycle, if t he E C O G P S is ≥ 3 o n t he da y  of trial treat me nt a d mi nistrati o n).

As y m pt o matic 
Gra de 
≥ 3 li pase or a m ylase ele vati o n n ot ass ociate d wit h 
cli nical 
ma nifestati o ns of pa ncreatitis. Me dical M o nit or m ust be c o ns ulte d f or s uc h li pase a n d 
a m yl ase a b n or malities .

A n y  Gra de 2 A D R s h o ul d be ma na ge d as f oll o ws:

If a Gra de 2 A D R res ol ves t o Gra de ≤ 1 b y  t he last da y of t he c urre nt c ycle, treat me nt ma y 
c o nti n ue.

If a Gra de 2 A D R d oes n ot res ol ve t o Gra de ≤ 1 b y  the last d a y  of t he c urre nt c ycle, i nf usi o ns 
s h o ul d n ot be gi ve n o n t he f oll o wi n g c ycle.  If at t he e n d of t he f oll o wi n g c ycle t he e ve nt 
has n ot res ol ve d t o Gra de 1, t he s u bject s h o ul d per ma ne ntl y disc o nti n ue treat me nt wit h a n 
a vel u ma b A D R (e xce pt f or h or m o ne i ns ufficie ncies, t hat ca n be ma na ge d b y  re place me nt 
t hera py;  f or t hese h or m o ne i ns ufficie ncies, u p t o 2 s u bse q ue nt d oses ma y be o mitte d).

U p o n t he sec o n d occ urre nce of t he sa me Gra de 2 A D R (e xce pt f or h or m o ne i ns ufficie ncies 
t hat ca n be ma na ge d b y re place me nt t hera p y) i n t he sa me s u bject, treat me nt wit h a vel u ma b 
has t o be per ma ne ntl y  disc o nti n ue d.
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 6 / 1 5 0
I nf usi o n-relate d reacti o ns, h y perse nsiti vit y  reacti o ns , a n d fl u-li ke s ym pt o ms ( Gra des 1 t o 4), t u m or 
l ysis s yn dr o me, a n d ir A Es s h o ul d be ha n dle d acc or di n g t o g ui deli nes i n Secti o n  6. 5. 4. 1, Secti o n
6. 5. 4. 2,  Secti o n 6. 5. 4. 3, a n d Secti o n  6. 5. 4. 4.
5. 1. 3. 3
D ose M o dific ati o n f or C he m ot her a p y
D uri n g t he I n d ucti o n P hase, d ose m o dificati o ns ( d ose dela y s a n d d ose c ha n ges) f or t o xicit y after 
t he starti n g d ose are all o we d a n d s h o ul d be ma de i n acc or da nce wit h la beli n g i nstr ucti o ns a n d l ocal 
i nstit uti o nal g ui deli nes.  Su bjects o n c he m ot hera p y i n t he Mai nte na nce P hase will c o nti n ue wit h 
t he sa me d ose t he y ha d at t he e n d of t he I n d ucti o n P hase (starti n g d ose or re d uce d d ose).  D uri n g 
t he Mai nte na nce P hase, d ose m o dificati o ns are als o all o we d f or t o xicit y.
T he d ose of c he m ot hera p y will be calc ulate d base d o n t he wei g ht or b o d y  surface area, as 
a p plica ble, of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or t o t he d a y  of dr u g a d mi nistrati o n (see 
Ta ble 9 ).  
D ose m o dificati o n g ui deli nes 
( d ose dela y s a n d d ose c ha n ges) after t he starti n g d ose f or 
c he m ot hera py are pr o vi de d i n Ta ble 8.   F or s pecific starti n g d oses d ue t o re nal or he patic 
i m pair me nt a n d f or s u bse q ue nt d ose m o dificati o ns d ue t o differe nt t o xicities, please f oll o w t he 
l ocal la bel a n d g ui deli nes.
F or s u bjects i nt olera nt t o f urt her o xali plati n, si n gle-a ge nt ca pecita bi ne or 5- F U + le uc o v ori n will 
be a n o pti o n f or d ose m o dificati o n.
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 7 / 1 5 0
T a ble 8
D ose M o dific ati o n Ge ner al G ui deli nes f or C he m ot her a p y
M ai nt e n a n c e T h er a p y
Fir st D o s e R e d u cti o n
S e c o n d D o s e R e d u cti o n
T hir d D o s e R e d u cti o n
5- F U ( 2 6 0 0 m g/ m2 d o s e
o v er 2 4 h o ur s )
1 9 5 0 m g/ m 2 - 2 0 8 0 m g/ m
2
o v er 2 4 h o ur s
1 3 0 0 m g/ m 2 (1 5 6 0 m g/ m 2
o v er 2 4 h o ur s )
Di s c o nti n u e
5- F U ( 2 4 0 0 m g/ m 2 d o s e)
o v er 4 6 -4 8 h o ur s
1 8 0 0 m g/ m 2 - 1 9 2 0 m g/ m 2
o v er 4 6 -4 8 h o ur s
1 2 0 0 m g/ m 2 -1 4 4 0 m g/ m 2
o v er 4 6 -4 8 h o ur s
Di s c o nti n u e
C a p e cit a bi n e
7 5 % of st arti n g d o s e 
5 0 % of st arti n g d o s e
Di s c o nti n u e
O x ali pl ati n ( 8 5 m g/ m
2
d o s e)
6 4 t o 6 8 m g/ m
2 i n 
a c c or d a n c e wit h l o c al 
l a b el/i n stit uti o n al 
g ui d eli n e s
4 2. 5 m g/ m 2 i n a c c or d a n c e 
wit h l o c al l a b el/i n stit uti o n al 
g ui d eli n e s
Di s c o nti n u e
O x ali pl ati n ( 1 3 0 m g/ m 2
d o s e)
9 8 t o 1 0 4 m g/ m 2 i n 
a c c or d a n c e wit h l o c al 
l a b el/i n stit uti o n al 
g ui d eli n e s
6 5
m g/ m 2 i n a c c or d a n c e 
wit h l o c al l a b el/i n stit uti o n al 
g ui d eli n e s
Di s c o nti n u e
5- F U = 5 -fl u or o ur a cil
5. 2
Disc ussi o n of Tri al Desi g n
5. 2. 1
R ati o n ale 
S u p p ort i n g 
t he 
C h oice 
of 
t he 
F irst-li ne 
C he m ot her a p y
T here is n o c o nse ns us o n w hat s h o ul d be t he o pti mal first -li ne c he m ot hera p y f or t he ma na ge me nt 
of a d va nce d gastric ca ncer. A plati n u m fl u or o pyri mi di ne d o u blet is c o nsi dere d as a n acce pta ble 
o pti o n b y  the Nati o nal C o m pre he nsi ve Ca ncer Net w or k (N C C N ), E S M O , a n d Ja pa nese g ui deli nes 
f or t he ma na ge me nt of t hat disease (Wa d dell
2 0 1 3 ). I n the pr o p ose d st u d y, all s u bjects will recei ve 
a plati n u m fl u or o p yri mi di ne d o u blet c o nsisti n g of ca pecita bi ne or 5 -F U a n d o xali plati n .  S u bjects
w h ose disease is at least sta ble will be ra n d o mly assi g ne d t o recei ve eit her a vel u ma b (acti ve ar m) 
or will, per t he j u d g me nt of t he In vesti gat or, recei ve s u bse q ue nt c ycles of t he i nitial c he m ot hera p y 
re gi me n u ntil u nacce pta ble t o xicities or disease pr o gressi o n.
T he a d mi nistrati o n of o xali plati n a n d ca pecita bi ne or 5- F U as a first-li ne re gi me n f or t he treat me nt 
of a d va nce d gastric ca ncer is acce pta ble f or t he f oll o wi n g reas o ns: 

St u d y  RE A L - 2 (C u n ni n g ha m 2 0 0 8 ) de m o nstrate d t hat ca pecita bi ne a n d o xali plati n are as 
effecti ve as fl u or o uracil a n d cis plati n, res pecti vel y i n patie nts wit h pre vi o usl y u ntreate d gastric 
ca ncer. I n ter ms of safet y, o xali plati n a d mi nistrati o n res ulte d i n l o wer i nci de nce of Gra de 3 
a n d 4 ne utr o pe nia, re nal t o xicit y an d t hr o m b oe m b olis m b ut t o sli g htl y hi g her i nci de nce of 
Gra de 3 a n d 4 diarr hea a n d ne ur o pat h y . T he safet y pr ofiles of 5- F U a n d ca pecitabi ne were 
si milar.

Ca pecita bi ne or 5- F U i n c o m bi nati o n wit h a plati n u m -base d a nti ne o plastic a ge nt (cis plati n) was 
t he c he m ot hera p y bac k b o ne use d i n t he T O G A st u d y that s u p p orte d t he a p pr o val of trast uz u ma b 
f or patie nts wit h gastric ca ncer w it h h u ma n e pi der mal gr o wt h fact or rece pt or 2 p ositi ve 
( HE R 2 +) disease .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 8 / 1 5 0

O xali plati n tri g gers a partic ular t y pe of a p o pt otic deat hs t hat is c o nsi dere d t o be i m m u n o ge nic 
a n d was preferre d t o cis plati n f or t he plati n u m c o m p o ne nt of t he re q uire d c he m ot hera p y d o u blet
(Tes niere 2 0 1 0 ).

T o ha ve o nl y o xali plati n as t he plati n u m salt will li mit t he ris k of ha vi n g a c o nf o u n di n g fact or 
o n t he pri mar y  en d p oi nt s as R E A L - 2 di d n ot c o m pletel y  rule -o ut t hat cis plati n a n d o xali plati n 
ha d e xactl y t he sa me cli nical efficac y.
5. 2. 2
R ati o n ale f or E xcl usi o n of H E R 2 P ositi ve P o p ul ati o n 
S u bjects wit h h u ma n e pi der mal gr o wt h fact or rece pt or 2- p ositi ve disease are e xcl u de d fr o m t his 
trial.  This rati o nale f or e xcl u di n g t hese s u bjects is t hat t he c urre nt sta n dar d of care (S O C ) f or 
H E R 2 p ositi ve s u bjects is differe nt t ha n H E R 2 ne gati ve s u bjects a n d w o ul d re q uire a d diti o n of
trast uz u ma b t o t he i n d ucti o n c he m ot hera p y c h oices.  I ncl usi o n of H E R 2 p ositi ve s u bjects w o ul d 
als o res ult i n a n a d diti o nal o pti o n f or m ai nte na nce t hera py a n d t h us res ult i n greater s u bject 
heter o ge neit y .  
5. 2. 3
R ati o n ale f or S witc hi n g S u bjects
fr o m C he m ot her a p y t o 
A vel u m a b
T he pr o p osal t o s witc h s u bjects assi g ne d t o t he e x peri me ntal ar m after t he y ha ve c o m plete d 
1 2 wee ks of c he m ot hera p y  is a ppr o priate f or t he f oll o wi n g reas o ns:

T here is n o data s u p p orti n g t hat a d diti o nal c he m ot hera p y b e yo n d 4 t o 6 c yc les ( u p t o 1 2 wee ks 
of treat me nt) will res ult i n i m pr o ve d s ur vi val i n t he c o nte xt of a disease w here it is c o m m o n 
practice t o re-i n d uce patie nts at t he ti me of disease pr o gressi o n. 
Patie nts w h o ha ve n ot 
res p o n de d t o or w h o will cease t o res p o n d t o a vel u ma b will be re-i n d uce d eit her wit h 
plati n u m -base d d o u blets or wit h dr u gs t hat ha ve s h o w n cli nical be nefit as a sec o n d-li ne t hera p y. 
S u bjects will be m o nit ore d e ver y 6 wee ks a n d resc ue t hera p y m a y be a d mi nistere d o nce disease 
pr o gressi o n is esta blis he d .

Treat me nt of patie nts wit h a vel u ma b has res ulte d i n a n O R R of 1 5 % i n patie nts wit h gastric 
ca ncer fr o m Asia n a n d n o n -Asia n re gi o ns.  So me of t hese res p o nses were l o n g lasti n g a n d a 
n u m ber of s u bjects wit h pr ol o n ge d S D were als o o bser ve d.  Base d o n t hese data , it is reas o na ble 
t o i nterr u pt c he m ot hera p y after 1 2 wee ks t o i nitiate a n i m m u n ot hera p y that has bee n re p orte d 
t o i n d uce pr ol o n ge d res p o nses i n a d va nce d gastric ca ncer patie nts w h o will ulti matel y pr o gress 
after i nitial c he m ot hera p y re gi me ns. 

F or s u bjects ra n d o mly assi g ne d t o recei ve a d diti o nal c he m ot hera p y i n t he Mai nte na nce P hase, 
it is rec o m me n de d t hat t he c he m ot hera p y re gi me n d o es n ot t o e xcee d 6 c ycles.  This is 
s u p p orte d b y  the pre vi o usl y  esta blis he d re gi me n i n t he re gistrati o n st u d y for trast uz u ma b 
( T O G A).  In c o ncl usi o n, s witc hi n g s u bjects after 1 2 wee ks
of c he m ot hera p y t o recei ve 
a vel u ma b treat me nt is c o nsi dere d a p pr o priate.
5. 2. 4
J ustific ati o n of O pe n -l a bel St u d y Desi g n
T he o pe n -la bel st u d y desi g n is j ustifie d base d o n t he f oll o wi n g:
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
5 9 / 1 5 0
D o u ble- bli n d c o ntr olle d st u d y wo ul d be i m p ossi ble d ue t o differe nces i n treat me nt sc he d ule a n d 
t o xicit y pr ofile t hat w o ul d u n mas k treat me nt assi g n me nt.
5. 2. 5
R ati o n ale f or t he Pri m ar y E n d p oi nt
O verall s ur vi val was c h ose n as t he pri mar y  e n d p oi nt beca use t his is a n u ne q ui v ocal meas ure me nt 
of cli nical be nefit t hat will n ot be c o nf o u n de d b y t he o pe n -la bel nat ure of t he st u d y.
O verall s ur vi val i n P D -L 1 + s u bjects was c h ose n as o ne of t he pri mar y  o bjecti ves base d o n res ults 
fr o m t he E M R 1 0 0 0 7 0 -0 0 1, P hase I b, gastric pri mar y  co h ort. I n t he gr o u p of G C/ G EJ C s u bjects 
w h o di d n ot pr o gress o n or after first-li ne c he m ot hera py, a differe nce i n me dia n O S of 4. 3 m o nt hs 
was o bser ve d i n s u bjects wit h P D -L 1  t u m or cells ≥1 % c o m pare d t o t he o verall s u bjects.
5. 2. 6
Tri al Peri o ds
T he st u d y will c o nsist of (i) Scree ni n g / baseli ne e val uati o n, (ii) i n d ucti o n, (iii) mai nte na nce , a n d 
(i v) p ost -treat me nt f oll o w-u p peri o d.
i) D uri n g Scree ni n g / baseli ne ( Da y - 2 8 t o D a y 1), i nf or me d c o nse nt will be o btai ne d a n d s u bject 
c o m plia nce wit h t he i ncl usi o n/e xcl usi o n criteria will be ascertai ne d.
ii) D uri n g t he I n d ucti o n P hase, s u bjects will recei ve 4 c ycles of c he m ot hera p y c o m prise d of
o xali plati n a n d ca pecita bi ne e ver y 3 wee ks O R 6 c ycles of c he m ot hera p y c o m prise d of o xali plati n 
a n d 5-F U e ver y 2 wee ks.  
I n d ucti o n C he m ot hera py:
S u bjects e nr olle d i n t his trial will recei ve c he m ot hera p y c o m prise d of o xali plati n a n d eit her 
5- F U or ca pecita bi ne.  Su bjects w h o e x perie nce a C R, P R, or S D after 1 2 wee ks will be 
ra n d o ml y assi g ne d t o eit her a vel u ma b or c o nti n uati o n of t he sa me first-li ne c he m ot hera p y t he y 
recei ve d d uri n g t he I n d ucti o n P hase.   S u bjects w h o de m o nstrate a res p o nse d uri n g t he 
I n d ucti o n P hase t hat re n ders t heir meas ura ble disease n o l o n ger meas ura ble at t he ti me of t he 
Mai nte na nce P hase ca n be ra n d o miz e d.
iii) D uri n g t he Mai nte na nce P hase , s u bjects will be ra n d o ml y assi g ne d t o recei ve eit her avel u ma b 
or c o nti n uati o n of t he sa me c he m ot hera p y re gi me n fr o m t he I nd ucti o n P hase, u ntil disease 
pr o gressi o n , u nacce pta ble t o xicit y , or f or t he acce pte d ma xi mal d urati o n of t he a ge nt(s) selecte d.
Mai nte na nce A vel u ma b A r m:
S u bjects recei vi n g avel u ma b will 
c o nti n ue o n -treat me nt u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y. S u bjects recei vi n g a vel u ma b d uri n g t he Mai nte na nce 
P hase ma y 
c o nti n ue treat me nt past t he i nitial deter mi nati o n of disease pr o gressi o n acc or di n g t o 
R E CI S T v 1. 1 if t h e y meet t he criteria prese nte d i n Secti o n  6. 2. 1 (I n vesti gat or-assesse d be nefit; 
t olera nce of treat me nt; sta ble E C O G P S; a n d d oes n ot dela y ot her i m mi ne nt i nter ve nti o n).
S u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a mi ni m u m of 
1 2 m o nt hs or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after c o nfir mati o n of res p o nse.  
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 0 / 1 5 0
I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, b ut pri or t o t he e n d of 
t he trial, 1 re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t he I nvesti gat or a n d after 
a gree me nt wit h t he Me dical M o nit or.  I n or der t o be eli gi ble f or retreat me nt, t he s u bject m ust 
n ot ha ve e x perie nce d a n y t o xicit y  t hat le d t o treat me nt disc o nti n uati o n of t he i nitial a vel u ma b 
t hera py.  S u bjects w h o re -i nitiate treat me nt will sta y o n trial a n d will be t reate d a n d m o nit ore d 
acc or di n g t o t he pr ot oc ol.
Mai nte na nce C he m o t hera p y A r m:
Mai nte na nce c he m ot hera p y will c o nti n ue u ntil disease pr o gressi o n or u nacce pta ble t o xicit y or 
u ntil t he ma xi m u m acce pta ble d osi n g is ac hie ve d at t he discreti o n of t he I nvesti gat or.
S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her c he m ot hera p y will recei ve B S C al o ne 
wit h n o acti ve t hera p y until disease pr o gressi o n.   Pri or t o ra n d o mizati o n, I n vesti gat ors m ust 
s pecif y B S C treat me nt f or t hese s u bjects.
i v) T he F oll o w - u p P hase will i ncl u de a p ost -treatme nt peri o d a n d l o n g-ter m f oll o w- u p visits. 
D uri n g t he p ost -treat me nt peri o d (fr o m treat me nt disc o nti n uati o n t o S afet y F oll o w -u p), a S afet y
F oll o w -u p visit will be sc he d ule d 3 0 da y s after last treat me nt a n d a p h o ne call will occ ur 9 0 da ys 
after treat me nt disc o nti n uati o n.
A l o n g-ter m f oll o w- u p visit will occ ur e ver y 1 2 wee ks f or 5 years after t he last s u bject recei ves 
t he last d ose of st u d y dr u g (see Secti o n 7. 1. 7 f or details).
D uri n g Scree ni n g , i n d ucti o n, mai nte na nce a n d p ost-treat me nt peri o ds, s u bject will u n der g o visits 
a n d assess me nt pr oce d ures as per descri be d i n t he Sc he d ule of Assess me nts (Ta ble 1 t o Ta ble 7) .
5. 2. 7
I ncl usi o n of S peci al P o p ul ati o ns
N ot a p plica ble.
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y  pers o ns meeti n g all i ncl usi o n criteria a n d n o e xcl usi o n criteria ma y be e nr olle d i nt o t he trial 
as s u bjects. Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical 
care, t he I n vesti gat or will e ns ure t hat t he s u bject or t he s u bject’s le gal re prese ntati ve has pr o vi de d 
writte n i nf or me d c o nse nt f oll o wi n g t he pr oce d ure descri be d i n Secti o n  9. 2.
5. 3. 1
I ncl usi o n Criteri a
F or i ncl usi o n i n t he trial, all of t he f oll o wi n g i ncl usi o n criteria m ust be f ulfille d:
1.
Has rea d, u n derst o o d a n d si g ne d writte n i nf or me d c o nse nt bef ore a n y trial-relate d pr oce d ure 
is u n derta ke n t hat is n ot part of t he sta n dar d s u bject ma na ge me nt
2.
Male or fe male s u bjects a ge d ≥1 8 y ears
3.
A vaila bilit y  of a rece ntl y-o btai ne d ( wit hi n 6 m o nt hs)
bi o ps y  fr o m a n o n -irra diate d area, 
f or mali n-fi xe d, paraffi n -e m be d de d ( F F P E) bl oc k c o ntai ni n g t u m or tiss ue or a mi ni m u m 
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 1 / 1 5 0
n u m ber of 1 0 ( prefera bly 2 5) u nstai ne d t u m or sli des (c ut wit hi n 1 wee k) s uita ble f or P D -L 1  
e x pressi o n assess me nt . 
4.
Disease m ust be meas ura ble per R E CI S T v 1. 1
5.
S u bjects 
wit h 
hist ol o gicall y  co nfir me d u nresecta ble l ocall y ad va nce d or metastatic 
a de n ocarci n o ma of t he st o mac h or G EJ
6.
E C O G P S of 0 t o 1 at trial e ntr y
7.
Esti mate d life e x pecta nc y  of m ore t ha n 1 2 wee ks
8.
A de q uate he mat ol o gical f u ncti o n defi ne d b y  w hite bl o o d cell (W B C ) c o u nt ≥ 2. 5 × 1 0 9/ L wit h 
a bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥ 0. 5 × 1 0 9/ L, platelet c o u nt 
≥1 0 0 × 1 0 9/ L, a n d he m o gl o bi n ≥9 g/ d L ( ma y  ha ve bee n tra nsf use d). 
9.
A de q uate he patic f u ncti o n defi ne d b y a t otal bilir u bi n le vel ≤ 1. 5 × t he u p per li mit of n or mal 
( U L N) ra n ge a n d as partate a mi n otra nsferase (A S T ) a n d ala ni ne a mi n otra nsferase ( AL T) le vels 
≤ 2. 5 × U L N f or all s u bjects
1 0. A de q uate re nal f u ncti o n defi ne d b y  a n esti mate d creati ni ne cleara nce ≥3 0 m L / mi n acc or di n g 
t o t he C oc kcr oft-Ga ult f or m ula ( or l ocal i nstit uti o nal sta n dar d met h o d)
1 1. Ne gati ve bl o o d pre g na nc y  test at Scree ni n g f or w o me n of c hil d beari n g p ote ntial .  F or t he 
p ur p oses of t his trial, w o me n of c hil d beari n g p ote ntial are defi ne d as: “ All fe male s u bjects 
after p u bert y  unless t he y are p ost me n o pa usal f or at least 2 years, are s ur gicall y sterile, or are 
se x uall y i nacti ve.”
1 2. Hi g hl y effecti ve c o ntrace pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % per ye ar) f or 
b ot h male a n d fe male s u bjects if t he ris k of c o nce pti o n e xists ( N ote: T he effects of t he trial 
treat me nt o n the de vel o pi n g h u ma n fet us are u n k n o w n; t h us, w o me n of c hil d beari n g p ote ntial 
a n d me n m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n, defi ne d i n  A p pe n di x II
G ui da nce 
o n C o ntrace pti o n
or as sti p ulate d i n nati o nal or l ocal g ui deli nes.  
Hi g hly effecti ve 
c o ntrace pti o n m ust be use d 1 5 d a y s pri or t o first trial treat me nt a d mi nistrati o n, a n d f or t he 
d urati o n of trial treat me nt for all s u bjects.  Hi g hl y effecti ve c o ntrace pti o n m ust be use d at least 
f or 6 0 d a y s after st o p pi n g a vel u ma b treat me nt a n d as i n dicate d i n t he res pecti ve la bel [ S m P C] 
f or o xali plati n, 5- F U or ca pecita bi ne f or s u bjects recei vi n g c he m ot hera p y [i n t he I nd ucti o n
P hase a n d t he Mai nte na nce P hase], or as per la bel of a n y  ot her t hera p y use d as B S C .  S h o ul d 
a w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile s he or her part ner is partici pati n g 
i n t his trial, t he treati n g p h ysicia n s h o ul d be i nf or me d i m me diatel y).
5. 3. 2
E xcl usi o n Criteri a
S u bjects are n ot eli gi ble f or t his trial if t he y  f ulfill a n y of t he f oll o wi n g e xcl usi o n criteria:
1.
Pri or t hera py wit h a n y a nti b o d y or dr u g tar geti n g T- cell c ore g ulat or y pr otei ns (i m m u ne 
c hec k p oi nts) s uc h as P D- 1, P D -L 1 , or c yt ot o xic T-ly m p h oc y te a nti ge n-4 ( C T L A -4)  
2.
C o nc urre nt a ntica ncer treat me nt (f or e xa m ple, c yt ore d ucti ve t hera p y, ra di ot hera py [ wit h t he 
e xce pti o n of palliati ve b o ne - directe d ra di ot hera p y], i m m u ne t hera p y, or c yt o ki ne t hera py,  
e xce pt f or er yt hr o p oieti n)
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 2 / 1 5 0
3.
Pri or c he m ot hera p y  for u nresecta ble l ocally a d va nce d or metastatic a de n ocarci n o ma of t he 
st o mac h or G EJ
4.
T u m or s h o w n t o be H E R 2 + b y  im m u n o hist oc he mistr y  (I H C > 3 +) a n d/ or b y  fl u oresce nce i n 
sit u h ybri dizati o n ( FI S H) (I H C 2 +, FI S H + )
5.
Maj or s ur ger y f or a n y reas o n, e xce pt dia g n ostic bi o ps y , wit hi n 4 wee ks of e nr ollme nt a n d/ or 
if t he s u bject has n ot f ull y rec o vere d fr o m t he s ur ger y wit hi n 4 wee ks of e nr ollme nt
6.
S u bjects recei vi n g i m m u n os u p pressi ve a ge nts (s uc h as ster oi ds) f or a n y reas o n s h o ul d be 
ta pere d off t hese dr u gs bef ore i nitiati o n of t he trial treat me nt ( wit h t he e xce pti o n of s u bjects 
wit h a dre nal i ns ufficie nc y, w h o m a y  co nti n ue c ortic oster oi ds at p h y si ol o gic re place me nt d ose, 
e q ui vale nt t o ≤1 0 m g pre d nis o ne dail y ).  N ote: Pre vi o us or o n g oi n g a d mi nistrati o n of s yste mic 
ster oi ds f or t he ma na ge me nt of a n ac ute aller gic p he n o me n o n is acce pta ble as l o n g as it is 
a ntici pate d t hat t he a d mi nistrati o n of ster oi ds will be c o m plete d i n 1 4 d a y s, or t hat t he daily 
d ose after 1 4 da y s will be ≤ 1 0 m g per da y  of e q ui vale nt pre d nis o ne
7.
All s u bjects wit h brai n metastases, e xce pt t h ose meeti n g t he f oll o wi n g criteria:
a.
Brai n metastases ha ve bee n treate d l ocally, ha ve n ot bee n pr o gressi n g at least 2 m o nt hs 
after c o m pleti o n of t hera p y, a n d n o ster oi d mai nte na nce t hera p y is re q uire d, a n d
b.
N o o n g oi n g ne ur ol o gical s y m pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he disease 
(se q uelae t hat are a c o nse q ue nce of t he treat me nt of t he brai n metastases are acce pta ble)
8.
Pre vi o us mali g na nt disease ( ot her t ha n gastric ca ncer) wit hi n t he last 5 ye ars wit h t he 
e xce pti o n of basal or s q ua m o us cell carci n o ma of t he s ki n or carci n o ma i n sit u (e g, bla d der, 
cer vical, c ol orectal, breast)
9.
Pri or or ga n tra ns pla ntati o n, i ncl u di n g all o ge neic ste m -cell tra ns pla ntati o n
1 0. Si g nifica nt ac ute or c hr o ni c i nfecti o ns i ncl u di n g, a m o n g ot hers:
a.
K n o w n hist or y  of testi n g p ositi ve f or h u ma n i m m u n o deficie nc y vir us ( HIV) or k n o w n 
ac q uire d i m m u n o deficie nc y  sy n dr o me ( AI D S)
b.
P ositi ve test f or H B V s urface a nti ge n a n d / or c o nfir mat or y HC V ri b o n ucleic aci d (R N A ) 
test if t he a nti-H C V a nti b o d y  test is p ositi ve.
c.
Acti ve t u berc ul osis ( T B) ( hist or y of e x p os ure or hist or y of p ositi ve T B test; pl us prese nce 
of cli nical s y m pt o ms, p h y sical or ra di o gra p hic fi n di n gs)
1 1. Acti ve a ut oi m m u ne disease t hat mi g ht deteri orate w he n recei vi n g a n i m m u n osti m ulat or y 
a ge nt:
a.
S u bjects wit h dia betes t ype I, vitili g o, ps oriasis, h y p o- or h y pert h yr oi d disease n ot 
re q uiri n g i m m u n os u p pressi ve treat me nt are eli gi ble
b.
S u bjects re q uiri n g h or m o ne re place me nt wit h c ortic oster oi ds are eli gi ble if t he ster oi ds are 
a d mi nistere d o nl y f or t he p ur p ose of h or m o nal re place me nt a n d at d oses ≤1 0 m g or 1 0 m g 
e q ui vale nt pre d nis o ne per da y
c.
A d mi nistrati o n of ster oi ds t hr o u g h a r o ute k n o w n t o res ult i n a mi ni mal s ys te mic e x p os ure 
(t o pical, i ntra nasal, i ntr o- oc ular, or i n halati o n) are acce pta ble
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 3 / 1 5 0
1 2. K n o w n se vere h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies ( Gra de ≥3 N CI -C T C A E 
v 4. 0 3), a n y hist or y of a na p h yla xis, or u nc o ntr olle d ast h ma (t hat is, 3 or m ore feat ures of 
partiall y  c o ntr olle d ast h ma)
1 3. Persisti n g t o xicit y  relate d t o pri or t hera p y of Gra de > 2 N CI -C T C A E v 4. 0 3 e xce pt al o pecia
1 4. Ne ur o pat h y Gra de > 3.
1 5. Pre g na nc y  or lactati o n
1 6. K n o w n alc o h ol or dr u g a b use
1 7. Hist or y  of u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g b ut n ot li mite d t o:
a.
H y perte nsi o n u nc o ntr olle d b y  sta n dar d t hera pies ( n ot sta bilize d t o 1 5 0/ 9 0 m m H g or l o wer), 
or
b.
U nc o ntr olle d acti ve i nfecti o n, or 
c.
U nc o ntr olle d dia betes (e g, he m o gl o bi n A 1c ≥ 8 %)
1 8. Cli nicall y  si gnifica nt (ie, acti ve) car di o vasc ular disease: cere bral vasc ular acci de nt / str o ke 
( < 6 m o nt hs pri or t o e nr ollme nt ), m y ocar dial i nfarcti o n ( < 6 m o nt hs pri or t o e nr ollme nt ), 
u nsta ble a n gi na pect oris, c o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n Classificati o n 
Class ≥ II), or seri o us car diac arr h yt h mia re q uiri n g me dicati o n (i ncl u di n g c orrecte d Q T 
i nter val [Q Tc ] pr ol o n gati o n of > 4 7 0 ms a n d/ or pace ma ker) or pri or dia g n osis of c o n ge nital 
l o n g Q T sy n dr o me
1 9. All ot her si g nifica nt diseases (f or e xa m ple, i nfla m mat or y bo wel disease), w hic h, i n t he 
o pi ni o n of t he I n vesti gat or, mi g ht i m pair t he s u bject’s t olera nce of trial treat me nt
2 0. A n y  ps yc hiatric c o n diti o n t hat w o ul d pr o hi bit t he u n dersta n di n g or re n deri n g of i nf or me d 
c o nse nt a n d t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts
2 1. Vacci nati o n wit h li ve or li ve/atte n uate d vir uses wit hi n 5 5 da y s ( 5 half -li ves x 1 2 7 h o urs 
+ 3 0 d a y s) of first d ose of a vel u ma b a n d w hile o n trial is pr o hi bite d e xce pt f or a d mi nistrati o n
of i nacti vate d vacci nes (f or e xa m ple, i nacti vate d i nfl ue nza vacci nes)
2 2. Le gal i nca pacit y or li mite d le gal ca pacit y
2 3. Patie nts will 
be e xcl u de d fr o m t he I n d ucti o n P hase a n d t he Mai nte na nce 
P hase if 
a d mi nistrati o n of t heir c he m ot hera p y w o ul d be i nc o nsiste nt wit h t he c urre nt l ocal la beli n g 
( S m P C) (e g, i n re gar d t o c o ntrai n dicati o ns, war ni n gs/ preca uti o ns or s pecial pr o visi o ns) f or 
t hat c he m ot hera p y.  In vesti gat ors s h o ul d c hec k u p date d la beli n g via rele va nt we bsites at t he 
ti me of e ntr y i nt o t he I n d ucti o n P hase a n d t he Mai nte na nce P hase.
5. 4
Criteri a f or I niti ati o n of Tri al Tre at me nt
T he i ncl usi o n a n d e xcl usi o n criteria will be c hec ke d at t he Scree ni n g visit .  Eli gi ble s u bjects will 
be e nr olle d bef ore treat me nt start after verificati o n of f ulfilli n g all i ncl usi o n criteria wit h o ut 
matc hi n g a n y e xcl usi o n criteri o n.
D oc u me nt N o.
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 4 / 1 5 0
5. 5
Criteri a f or S u bject Wit h dr a w al
5. 5. 1
Wit h dr a w al fr o m Tri al T her a p y
S u bjects will be wit h dra w n fr o m trial treat me nt d uri n g t he I n d ucti o n a n d/ or Mai nte na nce P hase 
f or a ny of t he f oll o wi n g reas o ns:

S u bjects meeti n g t he defi niti o n of P D w hile o n -treat me nt base d o n R E CI S T v 1. 1 . Su bjects i n 
t he Mai nte na nce P hase recei vi n g a vel u ma b w h o e x perie nce disease pr o gressi o n ma y  co nti n ue 
treat me nt wit h a vel u ma b if t hey meet t he criteria prese nte d i n Secti o n 6. 2. 1 (In vesti gat or 
belie ves t he s u bject will e x perie nce cli nical be nefit fr o m t he treat me nt a n d t here is n o 
u nacce pta ble t o xicity res ulti n g fr o m t he treat me nt [ See Secti o n  6. 2. 1]. S uc h s u bjects will be 
wit h dra w n fr o m t he treat me nt if t here is a s u bse q ue nt sca n/assess me nt of P D base d o n R E CI S T 
v 1. 1).

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w s ym pt o ms t hat are 
dee me d b y  the I n vesti gat or t o be cli nicall y si g nifica nt or si g nifica nt w orse ni n g of e xisti n g 
s ym pt o ms

U nacce pta ble t o xicit y

Wit h dra wal of c o nse nt

Occ urre nce of a n e xcl usi o n criteri o n, w hic h is cli nicall y rele va nt a n d affects t he s u bject’s 
safety, if disc o nti n uati o n is c o nsi dere d necessar y  b y t he I n vesti gat or a n d / or S p o ns or

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal dr u g (if a p plica ble )

Occ urre nce of a n y Gra de ≥ 3 A D Rs or re petiti ve Gra de 2 A D Rs as defi ne d i n Secti o n  5. 1. 3. 2
f or s u bjects recei vi n g a vel u ma b.

Occ urre nce of A Es, res ulti n g i n t he disc o nti n uati o n of t he trial dr u g bei n g d e sire d or c o nsi dere d 
necessar y  b y t he I n vesti gat or a n d / or t he s u bject 

Occ urre nce of pre g na nc y 

Use of a n o n per mitte d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 5. 2,  w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he trial dr u g

N o nc o m plia nce (see Secti o n 6. 9) .
F or s u bjects recei vi n g a vel u ma b, if disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve 
dia g n osis/ra di o gra p hic c o nfir mati o n is n ot ma de at t he ti me of disc o nti n uati o n, a sec o n d i ma gi n g 
sca n m a y  be all o we d f or c o nfir mati o n of pr o gressi o n.  If pr o gressi o n at t he sec o n d i ma gi n g sca n 
is n ot c o nfir me d a n d t he s u bject wis hes t o restart, t he s u bject will be all o we d t o c o nti n ue recei vi n g
a vel u ma b as l o n g as t he y meet t he criteria f or c o nti n uati o n of treat me nt be y o n d pr o gressi o n.   F or 
m ore i nf or mati o n, see Secti o n  6. 2. 1.  
S u bjects w h o wit h dra w fr o m trial t hera p y  will c o nti n ue t o be f oll o we d f or s ur vi val a n d ne w a nti-
ca ncer t hera pies.  The s ur vi val f oll o w- u p of all s u bjects wil l c o nti n ue u ntil 5 ye ars after t he last 
s u bject recei ves t he last d ose of a vel u ma b.  Un der s o me circ u msta nces, t he s u bjects ma y  not be 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 5 / 1 5 0
f oll o we d f or 5 years f or s ur vi val i n t his st u d y, e g, t he s u bjects ma y be offere d t o e nr oll i nt o a r oll-
o ver st u d y , or t he S p o ns or ma y  ter mi nate t he st u d y early.
5. 5. 2
Wit h dr a w al fr o m t he Tri al
S u bjects ma y wit h dra w fr o m t he trial at a n y ti me wit h o ut gi vi n g a reas o n .  Wit h dra wal of c o nse nt 
will be c o nsi dere d wit h dra wal fr o m t he trial.  I n case of wit h dra wal fr o m t he trial, t he assess me nts 
sc he d ule d f or t he last visit ( E n d of Treat me nt visit) s h o ul d be perf or me d (see Secti o n 7. 1. 5 ), if 
p ossi ble, wit h f oc us o n t he m ost rele va nt assess me nts.  I n a n y  case, t he a p pr o priate E n d of Safety 
F oll o w - u p e C R F pa ge m ust be c o m plete d.  In case of wit h dra wal, s u bjects will be as ke d to 
c o nti n ue safety a n d s ur vi val f oll o w- u p, w hic h i ncl u des t he c ollecti o n of data o n s ur vi val, 
s u bject-re p orte d o utc o mes/ Q o L q uesti o n naires, a n d s u bse q ue nt a ntica ncer t hera p y.
A s u bject m ust be wit h dra w n if a n y of t he f oll o wi n g occ ur d uri n g t he trial:

Wit h dr a wal of t he s u bject’s c o nse nt

Partici pati o n i n a n y ot her t hera pe utic trial d uri n g t he treat me nt d urati o n of t his trial; h o we ver, 
s u bjects will c o nti n ue t o be f oll o we d f or s ur vi val (see Secti o n 7. 1. 7).
If a s u bject fails t o atte n d sc he d ule d trial assess me nts, t he In vesti gat or m ust deter mi ne t he reas o ns 
a n d t he circ u msta nces as c o m pletel y a n d acc uratel y as p ossi ble .
If a s u bject is wit h dra w n pri or t o pro gressi o n f or a n y  reas o n, t he s u bject will n ot be re place d.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he w h ole trial ma y  be disc o nti n ue d pre mat urely i n t he e ve nt of a n y of t he f oll o wi n g:

Ne w i nf or mati o n lea di n g t o u nfa v ora ble ris k-be nefit j u d g me nt of t he trial dr u g, f or e xa m ple, 
d ue t o:

E vi de nce of i nefficac y  of t he trial dr u g

Occ urre nce of si g nifica nt pre vi o usl y  un k n o w n a d verse reacti o ns or u ne x pecte dl y  hi gh 
i nte nsit y or i nci de nce of k n o w n a d verse reacti o ns

Ot her u nfa v ora ble safet y fi n di n gs.
( N ote: Evi de nce of i neffic acy m ay arise fr o m t his tri al or fr o m ot her tri als; u nf av or a ble s afety 
fi n di n gs m ay arise fr o m cli nic al or  
 ex a mi n ati o ns, f or ex a m ple, t oxic ol o gy.)

S p o ns or’s decisi o n t hat c o nti n uati o n of t he trial is u nj ustifia ble f or me dical or et hical reas o ns

P o or e nr ollme nt
of s u bjects ma ki n g c o m pleti o n of t he trial wit hi n a n acce pta ble ti me fra me 
u nli kel y

Disc o nti n uati o n of de vel o p me nt of t he S p o ns or’s I M P

After t he i nteri m a nal y sis, t he ID M C declares s u peri or efficac y  i n t he a vel u ma b treat me nt ar m 
c om pare d 
wit h 
t h ose ra n d o ml y assi g ne d t o c o nti n ue o n first-li ne c he m ot hera p y a n d 
rec o m me n ds t hat t he trial be st o p pe d earl y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 6 / 1 5 0
Healt h A ut h orities a n d I nde pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs) 
will be i nf or me d a b o ut t he disc o nti n ua ti o n of t he trial i n acc or da nce wit h a p plica ble re g ulati o ns.
T he w h ole trial ma y  be ter mi nate d or s us pe n de d u p o n re q uest of Healt h A ut h orities.
5. 7
Defi niti o n of E n d of Tri al
If t he trial is n ot ter mi nate d f or a reas o n gi ve n i n Secti o n  5. 6, t he s ur vi val f oll o w-u p will c o nti n ue 
u ntil 5 y ears after t he last s u bject recei ves t he last d ose of a vel u ma b.
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he Tri al
T he ter m I MP refers t o t he i n vesti gati o nal dr u g u n der g oi n g a cli nical trial, as well as t o a n y 
c o m parat or dr u g or place b o (as a p plica ble).  I n t his trial, t he i n vesti gati o nal dr u g is a vel u ma b a n d 
t he c o m parat or is a c he m ot hera p y re gi me n a d mi nistere d after ra n d o mizati o n.  
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
6. 1. 1
I n d ucti o n C he m ot her a p y
S u bjects will recei ve a n o xali plati n -fl u or o p yri mi di ne d o u blet c o m prise d of o xali plati n a n d eit her 
5- F U or ca pecita bi ne d uri n g t he I n d ucti o n P hase , w hic he ver is a p pr o ve d a n d us e d as t he S O C at 
t he In vesti gat or’s i nstit uti o n.

O xali plati n is a sterile l y o p hilize d p o w der or c o nce ntrate f or s ol uti o n f or i nf usi o n i nte n de d f or 
i nf usi o n, a n d is sli g htl y sol u ble i n water .  T he m olec ular wei g ht of o xali plati n is 3 9 7. 2 8 5 8 g/ m o l

5- F U is a sterile s ol uti o n i nte n de d f or I V ad mi nistrati o n.  It is a w hite t o practicall y w hite 
cr ys talli ne p o w der w hic h is s pari n gl y s ol u ble i n water.  T he m olec ular wei g ht of fl u or o uracil is 
1 3 0. 0 8 k Da.

Ca pecita bi ne is a w hite t o off -w hite cr ys talli ne p o w der s u p plie d as a ta blet f or m ulati o n i nte n de d 
f or oral a d mi nistrati o n .  Ta blets s h o ul d be s wall o we d wit h water wit hi n 3 0 mi n utes after a meal .  
T he m olec ular wei g ht of ca pecita bi ne is 3 5 9. 3 5 g/ m ol.
6. 1. 2
A vel u m a b
A vel u ma b is a sterile, clear, a n d c ol orless s ol uti o n i nte n d e d f or I V a d mi nistrati o n .  It is prese nte d 
at a c o nce ntrati o n of 2 0 m g/ m L  in si n gle-use glass vials cl ose d wit h a r u b ber st o p per a n d seale d 
wit h a n al u mi n u m p ol y pr o p y le ne fli p-off seal.
6. 1. 3
M ai nte n a nce C he m ot her a p y
S u bjects will c o nti n ue t he sa me re gi me n of o x ali plati n-fl u or o p yri mi di ne d o u blet as i n t he 
I n d ucti o n P hase (see Secti o n 6. 1. 1) .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 7 / 1 5 0
6. 1. 4
Best S u p p orti ve C are
All s u bjects i n b ot h ar ms will recei ve B S C as bac k gr o u n d t hera p y .  S u bjects w h o are n ot dee me d 
eli gi ble t o recei ve f urt her c he m ot hera p y will recei ve B S C al o ne wit h n o acti ve t hera p y .  T here is 
n o u ni versal defi niti o n of B S C t hat ca n be a p plie d acr oss i nstit uti o ns, c o u ntries, or re gi o ns 
(Zafar 2 0 0 8 ).  Best s u p p orti ve care is defi ne d as “treat me nt a d mi nistere d wit h t he i nte nt t o 
ma xi mize Q o L wit h o ut a s pecific a nti ne o plastic re gi me n, w hic h i ncl u de a nti bi otics, a nal gesics, 
a ntie metics, t h orace ntesis, parace ntesis, bl o o d tra nsf usi o ns, n utriti o nal s u p p ort (i ncl u di n g 
jej u n ost o m y), ste nts f or d y s p ha gia, a n d f ocal e xter nal-bea m ra diati o n f or c o ntr ol of pai n, c o u g h, 
d y s p nea, or blee di n g” (Jasse m 2 0 0 8 ).  Best s u p p orti ve care will be a d mi nistere d per i nstit uti o nal 
g ui deli nes a n d ca n be a d mi nistere d wit h o ut a n y  a d diti o nal t hera p y.
6. 2
D os a ge a n d A d mi nistr ati o n
6. 2. 1
A vel u m a b D os a ge a n d A d mi nistr ati o n
S u bjects will recei ve a n I V i nf usi o n of a vel u ma b at a d ose of 1 0 m g / k g ( o ver t he d urati o n of 
1 h o ur) f oll o wi n g pretreat me nt as descri be d i n Secti o n 5. 1. 2. 2. 1 (Ta ble 3 ). M o dificati o ns of t he 
i nf usi o n rate d ue t o i nf usi o n-relate d reacti o ns are descri be d i n Secti o n 6. 5. 4. 1.  T he d ose of 
a vel u ma b will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d wit hi n 7 2 h o urs pri or 
t o t he da y  of dr u g a d mi nistrati o n. T he d ose of a vel u ma b use d f or t he pre vi o us a d mi nistrati o n ca n 
be re peate d if t he c ha n ge i n t he s u bject’s wei g ht is 1 0 % or less t ha n t he wei g ht use d f or t he last 
d ose calc ulati o n.  S u bjects will recei ve a vel u ma b o nce e ver y 2 wee ks u ntil t he criteria i n 
Secti o ns 5. 5 t hr o u g h 5. 7 are met.
S u bjects recei vi n g a vel u ma b ma y  co nti n ue treat me nt past t he i nitial deter mi nati o n of disease 
pr o gressi o n per R E CI S T v 1. 1 as l o n g t he f oll o wi n g criteria are met:

I n vesti gat or-assesse d cli nical be nefit, wit h o ut a n y r a pi d disease pr o gressi o n

T olera nce of a vel u ma b

Sta ble E C O G P S

Treat me nt b e y o n d pr o gressi o n will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n (f or e xa m ple, ce ntral ner v o us s ys te m metastases).
T he decisi o n t o c o nti n ue a vel u ma b treat me nt be y o n d pr o gressi o n s h o ul d be disc usse d wit h t he 
M e dical M o nit or a n d d oc u me nte d i n t he trial rec or ds.
F or s u bjects c o nti n ui n g a vel u ma b after i nitial P D, a ra di o gra p hic assess me nt s h o ul d be perf or me d 
wit hi n 6 wee ks of ori gi nal P D t o deter mi ne w het her t here has bee n a decrease i n t he t u m or size, 
or c o nti n ue d P D. T he assess me nt of cli nical be nefit s h o ul d be bala nce d b y c li nical j u d g me nt as t o 
w het her t he s u bject is cli nicall y deteri orati n g a n d u nli kel y  to recei ve a n y be nefit fr o m c o ntin ue d 
treat me nt wit h a vel u ma b.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 8 / 1 5 0
F or s u bjects recei vi n g a vel u ma b, if disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve 
dia g n osis/ra di o gra p hic c o nfir mati o n is n ot ma de at t he ti me of disc o nti n uati o n, a sec o n d i ma gi n g 
sca n m a y  be all o we d f or c o nfir mati o n of pr o gressi o n.  If pr o gressi o n at t he sec o n d i ma gi n g sca n 
is n ot c o nfir me d a n d t he s u bject wis hes t o restart, t he s u bject will be all o we d t o c o nti n ue recei vi n g 
a vel u ma b as l o n g as t he y meet t he criteria f or c o nti n uati o n of treat me nt be y o n d pr o gressi o n.
If t he I n vesti gat or feels t hat t he s u bject c o nti n ues t o ac hie ve cli nical be nefit b y  co nti n ui n g 
treat me nt, t he s u bject s h o ul d re mai n o n t he trial a n d c o nti n ue t o recei ve m o nit ori n g acc or di n g t o 
t he Sc he d ule of Assess me nts (Ta ble 3 ).
A n y  a d diti o nal c o nti n uati o n of a vel u ma b pl us B SC be y o n d f urt her pr o gressi o n m ust be disc usse d 
a n d a gree d u p o n wit h t he Me dical M o nit or. F urt her disease pr o gressi o n is defi ne d as a n a d diti o nal 
i ncrease i n t u m or b ur de n of 2 0 % a n d ≥ 5 m m a bs ol ute i ncrease i n t u m or b ur de n fr o m ti me of i nitial 
P D . T his i ncl u des a n i ncrease i n t he s u m of all tar get lesi o ns or t he de vel o p me nt of ne w 
meas ura ble lesi o ns.
Ne w lesio ns are c o nsi dere d meas urea ble at t he ti me of i nitial pr o gressi o n if t he l o n gest dia meter 
is at least 1 0 m m (e xce pt f or pat h ol o gical l ym p h n o des, w hic h m ust ha ve a s h ort a xis of at least 
1 5 m m). A n y  ne w lesi o n c o nsi dere d n o n meas ura ble at t he ti me of i nitial pr o gressi o n ma y  bec o me 
meas urea ble a n d t heref ore i ncl u de d i n t he t u m or b ur de n v ol u me if t he l o n gest dia meter i ncreases 
t o at least 1 0 m m (e xce pt f or pat h ol o gical l ym p h n o des, w hic h m ust ha ve a s h ort a xis of at least 
1 5 m m).
A d diti o nall y , s u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a 
mi ni m u m 
of 1 2 m o nt hs a n d/ or 
u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after 
c o nfir mati o n of res p o nse. I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, 
b ut pri or t o t he e n d of t he trial, 1 re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t he 
I n vesti gat or a n d after a gree me nt wit h t he Me dical M o nit or. 
T o be eli gi ble f or retreat me nt, t he 
s u bject m ust n ot ha ve e x perie nce d a n y t o xicit y that le d t o treat me nt disc o nti n uati o n of t he i nitial 
a vel u ma b t hera py. S u bjects w h o re-i nitiate treat me nt will sta y on trial a n d will be treate d a n d 
m o nit ore d acc or di n g t o t he pr ot oc ol a n d f oll o w t he Sc he d ule of Assess me nts
u ntil disease 
pr o gressi o n (see Ta ble 3 ).
6. 2. 2
C he m ot her a p y D os a ge a n d A d mi nistr ati o n
I n d ucti o n c he m ot her a p y will be a d mi nistere d acc or di n g t o t he f oll o wi n g r ules.
T hera p y will be a d mi nistere d at t he d ose a n d sc he d ule s h o w n i n Ta ble 1 a n d Ta ble 2 or i n 
acc or da nce t o t he la bel i nstr ucti o ns a n d per l ocal g ui deli nes.  T he d osi n g fre q ue nc y is s u m marize d 
bel o w:

O xali plati n at 8 5 m g/ m 2 I V on D a y 1 wit h le uc o v ori n 2 0 0 m g/ m 2 I V o n Da y  1 ( or e q ui vale nt 
le v ole uc o v ori n d ose ) f oll o we d b y  5-F U at 2 6 0 0 m g/ m 2 I V c o nti n u o us i nf usi o n o ver 2 4 h o urs 
o n Da y  1, give n e ver y  2 wee ks (f or u p t o 1 2 wee ks) ,
O R
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
6 9 / 1 5 0
O xali plati n at 8 5 m g/ m 2 I V on D a y  1 wit h le uc o v ori n 4 0 0 m g / m2 I V on Da y 1 ( or e q ui vale nt 
le v ole uc o v ori n d ose) f oll o we d b y  5-F U at 4 0 0 m g/ m 2 I V pus h o n Da y  1 an d 2 4 0 0 m g/ m 2 I V 
c o nti n u o us i nf usi o n o ver 4 6- 4 8 h o urs ( Da ys 1 a n d 2) gi ve n e ver y 2 wee ks (f or u p t o 1 2 wee ks)
O R

O xali plati n at 1 3 0 m g/ m 2 I V on D a y 1 wit h ca pecita bi ne at 1 0 0 0 m g/ m 2 t wice dail y  for 2 wee ks 
f oll o we d by a 1 -wee k rest peri o d gi ve n e ver y  3 wee ks (f or u p t o 1 2 wee ks).  
L ocal la bel a n d g ui deli nes s h o ul d be f oll o we d f or s pecific starti n g d oses d ue t o re nal or he patic 
i m pair me nts a n d f or s u bse q ue nt d ose m o dificati o ns d ue t o differe nt t o xicities .
C he m ot hera p y d uri n g Mai nte na nce P hase will be a d mi nistere d acc or di n g t o t he f oll o wi n g r ules:

S u bjects will recei ve c o nti n uati o n of t he sa me re gi me n of o xali plati n -fl u or o p yri mi di ne 
d o u blet as i n t he I n d ucti o n P hase .

S u bjects w h o are n ot dee me d eli gi ble t o recei ve f urt her c he m ot hera p y will recei ve B S C 
al o ne wit h n o acti ve t hera p y.  Pri or t o ra n d o mizati o n, I n vesti gat ors m ust s pecif y BS C 
treat me nt f or t hese s u bjects.  

F or s u bjects recei vi n g c he m ot hera p y ( o xali plati n + 5- F U or o xali plati n + ca pecita bi ne) ,
d ose m o dificati o ns after t he starti n g d ose are all o we d if t he c o nti n uati o n of t he o xali plati n -
fl u or o p yri mi di ne d o u blet , or a c o m p o ne nt t here of, is pr o hi bite d b y  to xicit y .  F or s u bjects 
i nt olera nt t o f urt her o xali plati n, si n gle-a ge nt ca pecita bi ne or 5 -F U + le uc o v ori n will be a n 
o pti o n f or d ose m o dificati o n.
T hera p y will be a d mi nistere d u ntil disease pr o gressi o n, or u nacce pta ble t o xicit y, or f or t he 
acce pte d ma xi mal d urati o n of t he a ge nt(s) selecte d.
T hera p y  will be st o p pe d after t he first o n -treat me nt ra di ol o gical e val uati o n of disease pr o gressi o n.
S u bjects will recei ve trial treat me nt u ntil P D per R E CI S T v 1. 1, si g nifica nt cli nical deteri orati o n 
(cli nical pr o gressi o n), u nacce pta ble t o xicit y, f or t he acce pte d ma xi mal d urati o n of t he a ge nt(s) 
selecte d, wit h dra wal of c o nse nt, or if a n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt 
is f ulfille d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 0 / 1 5 0
T a ble 9
All o we d T her a p y Re gi me ns
Pr o d u ct 
D e s cri pti o n
D o s a g e 
F or m
D o s e
D o si n g Fr e q u e n c y
5- fl u or o ur a cil 
( 5-F U )
I ntr a v e n o u s
(I V)
L e u c o v ori n 2 0 0 m g/ m 2 f oll o w e d b y 
5- F U 2 6 0 0 m g/ m
2
L e u c o v ori n 4 0 0 m g/ m 2 f oll o w e d b y 
5- F U 4 0 0 m g/ m
2 i ntr a v e n o u s p u s h 
(I V P) f oll o w e d b y 2 4 0 0 m g/ m
2 I V
O n D a y 1 e v er y 2 w e e k s.
L e u c o v ori n o n D a y 1 
5- F U I V P o n D a y 1
5- F U I V o v er 4 6 -4 8 h o ur s o n D a y 1 a n d 
D a y 2
C a p e cit a bi n e 
T a bl et
1 0 0 0 m g/ m 2
T wi c e d ail y f or 2 w e e k s f oll o w e d b y a 1 -w e e k 
r e st p eri o d, gi v e n i n 3-w e e k c y cl e s
O x ali pl ati n
I ntr a v e n o u s
(I V)
8 5 m g/ m 2 wit h 5 -F U
1 3 0 m g/ m
2 wit h c a p e cit a bi n e
O n D a y 1 e v er y 2 w e e k s 
O n D a y 1 e v er y 3 w e e k s .  C a p e cit a bi n e 
t a bl et s s h o ul d b e s w all o w e d wit h w at er wit hi n 
3 0 mi n ut e s aft er a m e al .
6. 3
Assi g n me nt t o Tre at me nt Gr o u ps
O nce t he s u bject has pr o vi de d a si g ne d i nf or me d c o nse nt f or m (IC F) a n d meets i ncl usi o n a n d
e xcl usi o n criteria, a n d has c o m plete d t he In d ucti o n P hase as s pecifie d i n t his pr ot oc ol, t he 
I n vesti gat or or dele gate will re q uest t he trial treat me nt assi g n me nt usi n g t he I WR S. 
Q uali fie d 
s u bjects will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o recei ve eit her a vel u ma b or mai nte na nce 
c he m ot hera py. T he trial is f ull y co ntr olle d b y  the I WR S, w hic h assi g ns treat me nt i n di vi d ual 
( u ni q ue) kit n u m bers f or eac h s u bject. T he kit n u m ber is li n ke d via t he G o o d Ma n ufact uri n g 
Practice q ual ifie d sys te m t o t he c orres p o n di n g treat me nt as well as t o t he s u bject.
S u bject i de ntifiers will c o m prise 1 7 di gits, t he first 1 0 di gits re prese nti n g t he trial n u m ber, t he 
f oll o wi n g 3 di gits re prese nti n g t he site n u m ber, a n d t he last 4 di gits re prese nti n g the s u bject 
n u m ber, w hic h is all ocate d s e q ue ntiall y starti n g wit h 0 0 0 1.
6. 4
N o n- i n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
S u bjects ra n d o ml y assi g ne d t o recei ve a vel u ma b will recei ve pretreat me nt as descri be d i n 
Secti o n 5. 1. 2. 2. 1.
S u bjects ra n d o ml y  assi g ne d t o recei ve mai nte na nce c he m o t hera p y will recei ve pretreat me nt pri or 
t o eac h i nf usi o n per l ocal i nstit uti o nal practice.
I m me diate access t o a n i nte nsi ve care u nit or e q ui vale nt e n vir o n me nt a n d a p pr o priate me dical 
t hera py (i ncl u di n g e pi ne p hri ne, c ortic oster oi ds, I V a nti hista mi nes, br o nc h o dilat ors, a n d o x y ge n) 
m ust be a vaila ble f or use i n t he treat me nt of i nf usi o n -relate d reacti o ns. I nf usi o n of a vel u mab will 
be st o p pe d i n case of Gra de ≥ 2 i nf usi o n -relate d, aller gic, or a na p h ylactic reacti o ns.
As wit h all m o n ocl o n al a nti b o d y t her a pies, t here is a ris k of aller gic re acti o n .  A vel u m a b 
s h o ul d be a d mi nistere d i n a setti n g t h at all o ws f or i m me di ate access a n d a d mi nistr ati o n of 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 1 / 1 5 0
t her a p y f or se vere aller gic/ h y perse nsiti vit y re acti o ns, s uc h as t he a bilit y t o i m ple me nt 
i m me di ate res uscit ati o n me as ures .  Ster oi ds ( de x a met h as o ne 1 0 m g), e pi ne p hri ne ( 1: 1 0 0 0 
dil uti o n), aller g y me dic ati o ns 
( a nti hist a mi nes), or e q ui v ale nts s h o ul d be a v ail a ble f or 
i m me di ate access.
If h y perse nsiti vit y  reacti o n occ urs, t he s u bject m ust be treate d acc or di n g t o t he best a vaila ble 
me dical 
practice. 
G ui deli nes 
f or ma na ge me nt 
of i nf usi o n-relate d reacti o ns a n d se vere 
h y perse nsiti vit y  an d fl u-li ke s ym pt o ms acc or di n g t o t he N CI are f o u n d i n Secti o ns 6. 5. 4. 1 a n d 
6. 5. 4. 2 , res pecti vel y.  A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h yl actic reacti o ns 
acc or di n g t o t he W or ki n g Gr o u p of t he Res uscitati on C o u ncil ( U nite d Ki n g d o m) ca n be f o u n d at 
htt ps:// w w w.res us. or g. u k/ pa ges/reacti o n. p df .  S u bjects s h o ul d be i nstr ucte d t o re p ort a n y  dela ye d 
reacti o ns t o t he I n vesti gat or i m me diatel y.
6. 5
C o nc o mit a nt Me dic ati o ns a n d T her a pies
All c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he eC R F, n oti n g t he na me, d ose, 
d urati o n, a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y c ha n ges t o a c o nc o mita nt 
me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he e C R F.
6. 5. 1
Per mitte d Me dici nes
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y  the cli nical trial pr ot oc ol) t hat are c o nsi dere d 
necessar y  t o pr otect s u bject welfare a n d will n ot i nterfere wit h t he trial treat me nt ma y be gi ve n at 
t he In vesti gat or’s discreti o n.
Ot her dr u gs t o be use d f or pr o p h yl a xis, treat me nt of h y perse nsiti vit y  reacti o ns, a n d treat me nt of 
fe ver or fl u-li ke sy m pt o ms are descri be d i n Secti o n  6. 5. 4. 2.
T he I n vesti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m 
t he date of si g nat ure of i nf or me d c o nse nt, i n t he a p pr o priate secti o n of t he e C R F.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he trial a n d a n y cha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n, a n d i n dicati o n of eac h dr u g.
Palliati ve b o ne -directe d ra di ot hera p y m a y be a d mi nistere d d uri n g t he trial.  T he assess me nt of P D 
will be ma de acc or di n g 
t o R E CI S T v 1. 1 a n d n ot base d o n t he necessit y f or palliati ve 
b o ne- directe d- ra di ot hera p y. Resc ue me dica ti o ns m a y  be a d mi nistere d t o a d dress i neffecti ve 
treat me nt, a ntici pate d a d verse reacti o ns, or a ntici pate d e mer ge nc y sit uati o ns.
Me dici nal pr o d ucts k n o w n t o pr ol o n g t he Q Tc m ust be use d wit h ca uti o n i n s u bjects recei vi n g 
o xali plati n.  
Bis p h os p h o nate or de n os u ma b treat me nt is all o we d d uri n g t he st u d y pr o vi de d t hat t he y are 
a d mi nistere d as c o nc o mita nt palliati ve a n d s u p p orti ve care f or disease -relate d s ym pt o ms.  Disease 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 2 / 1 5 0
pr o gressi o n s h o ul d be c o m pletel y rule d o ut a n d t he e xact reas o n f or t he use of t hese t herapies m ust 
clearl y be d oc u me nt e d.  
6. 5. 2
Pr o hi bite d Me dici nes
As state d f or t he e xcl usi o n criteria i n Secti o n  5. 3. 2 , s u bjects m ust n ot ha ve ha d pri or t hera p y wit h 
a n y anti b o d y  or dr u g tar geti n g T- cell c ore g ulat or y pr otei ns (i m m u ne c hec k p oi nts) s uc h as 
a nti-P D - 1, a nti-P D -L 1, or a nti-c yt ot o xic T -l ym p h oc y te a nti ge n -4 a nti b o d y or c o nc urre nt 
a ntica ncer treat me nt (f or e xa m ple, c yt ore d ucti ve t hera py, ra di ot hera p y [ wit h t he e xce pti o n of 
palliati ve b o ne- directe d ra di ot hera py, * or ra di ot hera py a d mi nistere d o n s u perficial lesi o ns], 
i m m u ne t hera py, or c yt o ki ne t hera py e xce pt f or er yt hr o p oieti n), maj or s ur ger y (e xcl u di n g pri or 
dia g n ostic bi o ps y ), or c o nc urre nt s yste mic t hera p y wit h ster oi ds or ot her i m m u n os u p pressi ve 
a ge nts or use of a n y i n vesti gati o nal dr u g wit hi n 2 8 da y s bef ore starti n g st u d y treat me nt.
* Palliati ve b o ne -directe d ra di ot hera p y s h o ul d be w it hi n a li mite d fiel d of ra diati o n a n d f or palliati o n o nl y.  It s h o ul d 
be a s h ort c o urse, acc or di n g t o l ocal i nstit uti o nal rec o m me n dati o n, a n d s h o ul d be c o m plete d at least 7 da ys pri or t o 
t he first a d mi nistrati o n of a vel u ma b.
I n a d diti o n, t he f oll o wi n g treat me nts m ust n ot be a d mi nistere d d uri n g t he trial:

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs (t hat is, c he m ot hera p y or s yste mic c ortic oster oi ds 
e xce pt f or s h ort-ter m treat me nt of aller gic reacti o ns or f or t he treat me nt of ir A Es), or ot her 
e x peri me ntal p har mace utical pr o d ucts. S h ort -ter m a d mi nistrati o n of s yste mic ster oids (t hat is, 
f or aller gic reacti o ns or t he ma na ge me nt of ir A Es is all o we d)

Gr o wt h
fact ors f or s u bjects ra n d o ml y assi g ne d t o recei ve a vel u ma b ( gra n ul oc yte c ol o n y 
sti m ulati n g fact or or gra n ul oc y te macr o p ha ge 
c ol o n y sti m ulati n g fact or). 
E xce pti o n: 
er yt hr o p oieti n a n d dar be p oeti n al p ha ma y be prescri be d at t he I n vesti gat or’s discreti o n.
If t he a d mi nistrati o n of a n o n-per mitte d c o nc o mita nt dr u g bec o mes necessar y  d uri n g t he trial, t he 
s u bject will be wit h dra w n fr o m trial treat me nt (t he S p o ns or ma y  be c o ntacte d t o disc uss w het her 
t he trial treat me nt m ust be disc o nti n ue d). T he s u bject s h o ul d c o m plete t he E n d of Treat me nt visit 
( Secti o n 7. 1. 5)  a n d be f oll o we d f or s ur vi val acc or di n g t o Secti o n 7. 1. 6.
Me dicati o ns ot her t ha n th ose s pecifically e xcl u de d i n t his trial (see a b o ve) ma y  be a d mi nistere d 
f or t he ma na ge me nt of s ym pt o ms ass ociate d wit h t he a d mi nistrati o n of a vel u ma b or mai nte na nce
c he m ot hera py as re q uire d. 
T hese 
mi g ht 
i ncl u de a nal gesics, a nti-na usea me dicati o ns, 
a nti hista mi nes, di uretics, a ntia n xiet y me dicati o ns, a n d me dicati o n f or pai n ma na ge me nt, i ncl u di n g 
narc otic a ge nts.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he trial a n d a n y cha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n, a n d i n dicati o n of eac h dr u g.
6. 5. 3
Ot her I nter ve nti o ns
T he f oll o wi n g n o n dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he trial ( or wit hi n 2 8 da y s 
bef ore ra n d o mizati o n):
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 3 / 1 5 0

Maj or s ur ger y  (e xcl u di n g pri or dia gn ostic bi o ps y )

Her bal re me dies wit h i m m u n osti m ulati n g pr o perties (f or e xa m ple, mistlet oe e xtract) or k n o w n 
t o p ote ntiall y i nterfere wit h maj or or ga n f u ncti o n (f or e xa m ple, h yperici n)

S u bjects s h o ul d n ot a b use alc o h ol or ot her dr u gs d uri n g t he trial.
6. 5. 4
S peci al Prec a uti o ns
As a r o uti ne preca uti o n, s u bjects ra n d o ml y assi g ne d t o t he a vel u ma b ar m m ust be o bser ve d i n a n 
area wit h res uscitati o n e q ui p me nt a n d e mer ge nc y age nts. 
At all ti mes d uri n g a vel u ma b or 
mai nte na nce
c he m ot hera p y treat me nt, i m me diate e mer gen c y  treat me nt of a n i nf usi o n-relate d 
reacti o n or a se vere hy perse nsiti vit y  reacti o n acc or di n g t o i nstit uti o nal sta n dar ds m ust be ass ure d. 
I n or der t o treat p ossi ble h y perse nsiti vit y  reacti o ns, f or i nsta nce, de xa met has o ne 1 0 m g  an d 
e pi ne p hri ne i n a 1: 1 0 0 0 dil uti o n or e q ui vale nts s h o ul d al wa y s be a vaila ble al o n g wit h e q ui p me nt 
f or assiste d ve ntilati o n.
I nf usi o n of a vel u ma b will be st o p pe d i n case of Gra de ≥ 2 h y perse nsiti vit y , i nfla m mat or y res p o nse, 
or i nf usi o n-relate d reacti o n. T he treat me nt rec o m me n dati o ns f or i nf usi o n-relate d reacti o ns, se vere 
h y perse nsiti vit y  reacti o ns, a n d t u m or l ysis s yn dr o me acc or di n g t o t he N CI  are as o utli ne d i n 
Secti o n  6. 5. 4. 1, Secti o n 6. 5. 4. 2, a n d Secti o n  6. 5. 4. 3, res pecti vely.
I n vesti gat ors s h o ul d als o m o nit or s u bjects cl osel y f or p ote ntial ir A Es, w hic h m a y  first ma nifest 
after wee ks of treat me nt. S uc h e ve nts m a y  co nsist of persiste nt ras h, diarr hea a n d c olitis, 
a ut oi m m u ne he patitis, art hritis, gl o mer ul o ne p hritis, car di o m yo pat h y, or u veitis a n d ot her 
i nfla m mat or y eye  co n diti o ns. T he s pectr u m of h y p ot hetical ir A Es als o i ncl u des f or mati o n of a ut o-
a nti b o dies li ke a nti n uclear a nti b o dies or a nti ne utr o p hil c yt o plas mic a nti b o dies.  See Secti o n 
6. 5. 4. 4 f or details o n t he ma na ge me nt of ir A Es.
6. 5. 4. 1
I nf usi o n-rel ate d Re acti o ns
S y m pt o ms of i nf usi o n -relate d reacti o ns are fe ver, c hills, ri g ors, dia p h oresis, a n d hea dac he.  T hese 
s ym pt o ms ca n be ma na ge d acc or di n g t o  Ta ble 1 0.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 4 / 1 5 0
T a ble 1 0
Tre at me nt M o dific ati o n 
f or S y m pt o ms of I nf usi o n-rel ate d Re acti o ns 
Ass oci ate d wit h A vel u m a b
N CI - C T C A E Gr a d e v 4. 0 3
Tr e at m e nt M o difi c ati o n f or A v el u m a b
Gr a d e 1 – mil d

Mil d tr a n si e nt r e a cti o n; i nf u si o n i nt err u pti o n n ot 
i n di c at e d; i nt er v e nti o n n ot i n di c at e d.

D e cr e a s e t h e a v el u m a b i nf u si o n r at e b y 5 0 % 
a n d m o nit or cl o s el y f or a n y w or s e ni n g.
Gr a d e 2 – m o d er at e

T h er a p y or i nf u si o n i nt err u pti o n i n di c at e d b ut 
r e s p o n d s pr o m ptl y t o s y m pt o m ati c tr e at m e nt 
(f or e x a m pl e, a nti hi st a mi n e s, N S AI D s, 
n ar c oti c s, I V fl ui d s); pr o p h yl a cti c m e di c ati o n s 
i n di c at e d f or 2 4 h o ur s.

St o p a v el u m a b i nf u si o n.

R e s u m e i nf u si o n at 5 0 % of pr e vi o u s r at e o n c e 
i nf u si o n-r el at e d r e a cti o n h a s r e s ol v e d or 
d e cr e a s e d t o at l e a st Gr a d e 1 i n s e v erit y, a n d 
m o nit or cl o s el y f or a n y w or s e ni n g.
Gr a d e 3 or Gr a d e 4 – s e v er e or lif e- t hr e at e ni n g

Gr a d e 3: Pr ol o n g e d (f or e x a m pl e, n ot r a pi dl y 
r e s p o n si v e t o s y m pt o m ati c m e di c ati o n a n d/ or 
bri ef i nt err u pti o n of i nf u si o n); r e c urr e n c e of 
s y m pt o m s f oll o wi n g i niti al i m pr o v e m e nt; 
h o s pit ali z ati o n i n di c at e d f or cli ni c al s e q u el a e.

Gr a d e 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; 
ur g e nt i nt er v e nti o n i n di c at e d.

St o p t h e a v el u m a b i nf u si o n i m m e di at el y a n d 
di s c o n n e ct i nf u si o n t u bi n g fr o m t h e s u bj e ct.

S u bj e ct s h a v e t o b e wit h dr a w n i m m e di at el y 
fr o m a v el u m a b tr e at m e nt a n d m u st n ot r e c ei v e 
a n y f urt h er a v el u m a b tr e at m e nt.
I V =i ntr a v e n o u s, N CI-C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y Cri t eri a f or A d v er s e E v e nt, 
N S AI D s = n o n st er oi d al a nti -i nfl a m m at or y dr u g s.
O nce t he a vel u ma b i nf usi o n rate has bee n decrease d b y  50 % or i nterr u pte d d ue t o a n 
i nf usi o n-relate d reacti o n, it m ust re mai n decrease d f or all s u bse q ue nt i nf usi o ns. If t he s u bject has 
a sec o n d i nf usi o n-relate d reacti o n Gra de ≥ 2 o n t he sl o wer i nf usi o n rate, t he i nf usi o n s h o ul d b e 
st o p pe d, a n d t he s u bject s h o ul d disc o nti n ue a vel u ma b treat me nt. If a s u bject e x perie nces a Gra de 3 
or 4 i nf usi o n-relate d reacti o n at a n y time, t he s u bject m ust disc o nti n ue a vel u ma b. If a n i nf usi o n 
reacti o n occ urs, all details a b o ut dr u g pre parati o n a n d i nf usi o n m ust be rec or de d.
6. 5. 4. 2
Se vere H y perse nsiti vit y Re acti o ns a n d Fl u -li ke S y m pt o ms
If h y perse nsiti vit y  reacti o n occ urs, t he s u bject m ust be treate d acc or di n g t o t he best a vaila ble 
me dical practice. A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h ylactic reacti o ns 
acc or di n g t o t he W or ki n g Gr o u p of t he Res uscitati o n C o u ncil ( U nite d Ki n g d o m) ca n be f o u n d at 
htt ps:// w w w.res us. or g. u k/ pa ges/reacti o n. p df. S u bjects s h o ul d be i nstr ucte d t o re p ort a n y  dela ye d 
reacti o ns t o t he I n vesti gat or i m me diatel y.
S y m pt o ms i ncl u de i m paire d air wa y, decrease d o x y ge n sat urati o n ( < 9 2 %), c o nf usi o n, let har g y, 
h y p ote nsi o n, pale or cla m m y ski n, a n d c ya n osis. 
T hese s ym pt o ms ca n be ma na ge d wit h 
e pi ne p hri ne i njecti o n a n d de xa met has o ne. S u bjects s h o ul d be place d o n m o nit or i m me diatel y, a n d 
t he i nte nsi ve care u nit s h o ul d be alerte d f or p ossi ble tra nsfer if re q uire d.
F or pr o p h y la xis of fl u-li ke s ym pt o ms, 2 5 m g i n d o met haci n or c o m para ble n o nster oi dal a nti-
i nfla m mat or y dr u g d ose (e g, 6 0 0 m g i b u pr ofe n, 5 0 0 m g na pr o xe n s o di u m) ma y be a d mi nistere d 2 
h o urs bef ore a n d 8 h o urs after t he start of eac h d ose of a vel u ma b I V i nf usi o n. Alter nati ve 
treat me nts f or fe ver (e g, paraceta m ol/aceta mi n o p he n) may b e gi ve n t o s u bjects at t he discreti o n of 
t he In vesti gat or.
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 5 / 1 5 0
6. 5. 4. 3
T u m or L ysis S y n dr o me
I n a d diti o n, beca use a vel u ma b ca n i n d uce A D C C , t here is a p ote ntial ris k of t u m or l ysis s yn dr o m e. 
S h o ul d t his occ ur, s u bjects s h o ul d be treate d per t he l ocal g ui deli nes a n d t he ma na ge me nt 
al g orit h m (Fi g ure 2 ) p u blis he d b y H o war d ( 2 0 1 1).
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 -0 0 7
7 6 /1 5 0
Fi g ure 2
Assess me nt a n d I niti al M a n a ge me nt of T u m or L ysis S y n dr o me
T L S =t u m or l ysis s y n dr o me.
D oc u me nt N o. 
O bject N o.
M e a s ur e s er u m p ot a s s iu m, p h o s p h or u s , c al c iu m , cr e ati ni n e, ur i c a ci d , a n d ur in e o ut p ut 
J 
! 
L a b or at or y T L S 
Cli ni c a iT L S 
N o T L S at d i a g n o si s 
2: 2 a b n or m a l l a b or at or y 
A c ut e ki d n e y i nj ur y 
t e st v a lu e s 
S y m pt o m ati c h y p o -
! 
N o s y m pt o m s 
c a lc e mi a 
D y sr h yt h m i a 
A s s e s s c a n c er m a s s 
I 
1 
1 
S m a ll or r e s e ct e d 
M e d iu m- s iz e 
L ar g e c a n c er m a s s 
l o c aliz e d t u m or 
c a n c er m a s s 
B ul k y t u m or or or g a n 
i nfiltr atio n 
B o n e m arr o w r e pl a c e d 
w it h c a n c er 
+ 
A s s e s s c ell- ly s i s p ot e nt i al 
A s s e s s c ell- ly s i s p ot e nti al 
I 
I 
! 
! 
! 
r 
L o w II M e di u m or I 
u n k n o w n 
Hi g h 
L o w II M e d iu m or II 
u n k n o w n 
Hi g h I 
! 
A s s e s s p at ie nt 
pr e s e nt at io n 
Pr e e x isti n g n e p hr o p at h y 
D e h y dr at io n 
H y p ot e n s io n 
N e p h r ot o x i n e x p o s ur e 
I 
j_ c p 
j_ c: p 
N e g ligi bl e Ri s k 
L o w Ri s k or 
Hi g h Ri s k of 
Hi g h Ri s k of 
E st a b lis h e d 
of C lin i c a l T L S 
of Cl i ni c al T L S 
C lini c ai T L S 
Cli n ic a iT L S 
Cli n ic a iT L S 
N o pr o p h y la xi s 
lntr a v e n o u s fl uid s 
l ntr a v e n o u s fl uid s 
Intr a v e n o u s fl uid s 
Intr a v e n o u s fl ui d s 
N o m o n it orin g 
All o p ur in o l 
A llo p ur in o l or r a s-
R a s b ur ic a s e 
R a s b ur ic a s e 
D a ily la b or at or y t e st s 
b uri c a s e 
C ar d ia c m o n it orin g 
C ar d ia c m o n it orin g 
I n p ati e nt m o n it orin g 
L a b or at or y t e st s e v er y 
Int e n s iv e c ar e u n it 
L a b or at or y t e st s e v er y 
6- 8 hr 
L a b or at or y t e st s e v er y 
8- 1 2 h r 
4- 6 hr 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 7 / 1 5 0
6. 5. 4. 4
I m m u ne-rel ate d A d verse E ve nts
Beca use i n hi biti o n of P D -L 1  sti m ulates t he i m m u ne s yste m, ir A Es m a y  occ ur. Treat me nt of ir A Es 
is mai nl y de pe n de nt u p o n se verity ( N CI -C T C A E gra de):

Gra des 1 t o 2: treat s y m pt o maticall y  or wit h m o derate d ose ster oi ds, m ore fre q ue nt m o nit ori n g

Gra des 1 t o 2 ( persiste nt): ma na ge si milar t o hi g h gra de A E ( Gra des 3 t o 4)

Gra des 3 t o 4 : treat wit h hi g h d ose c ortic oster oi ds.
Treat me nt of ir A Es s h o ul d f oll o w t he g ui deli nes i n  Ta ble 1 1.
T a ble 1 1
M a n a ge me nt of I m m u ne -rel ate d A d verse E ve nts
G a str oi nt e sti n al ir A E s
S e v erit y of Di arr h e a / C oliti s
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
Gr a d e 1
Di arr h e a: < 4 st o ol s/ d a y o v er 
B a s eli n e
C oliti s: a s y m pt o m ati c
C o nti n u e a v el u m a b t h er a p y .
S y m pt o m ati c tr e at m e nt ( e g, 
l o p er a mi d e)
Cl o s e m o nit ori n g f or w or s e ni n g 
s y m pt o m s
E d u c at e s u bj e ct t o r e p ort 
w or s e ni n g i m m e di at el y
If w or s e n s:
Tr e at a s Gr a d e 2 , 3 or 4
Gr a d e 2
Di arr h e a: 4 t o 6 st o ol s p er d a y o v er 
B a s eli n e; I V fl ui d s i n di c at e d 
< 2 4 h o ur s; n ot i nt erf eri n g wit h 
a cti viti e s of d ail y li vi n g (A D L )
C oliti s: a b d o mi n al p ai n; bl o o d i n 
st o ol
Wi t h h ol d a v el u m a b t h er a p y .
S y m pt o m ati c tr e at m e nt
If i m pr o v e s t o Gr a d e ≤1: 
R e s u m e a v el u m a b t h er a p y
If p er si st s > 5-7 d a y s or r e c ur s:
Tr e at a s Gr a d e 3 o r 4
Gr a d e 3 t o 4
Di arr h e a ( Gr a d e 3): ≥ 7 st o ol s p er 
d a y o v er B a s eli n e; i n c o nti n e n c e; I V 
fl ui d s ≥2 4 h; i nt erf eri n g wit h A D L
C oliti s ( Gr a d e 3): s e v er e a b d o mi n al 
p ai n, m e di c al i nt er v e nti o n i n di c at e d, 
p erit o n e al si g n s
Gr a d e 4: lif e -t hr e at e ni n g, p erf or ati o n
Wi t h h ol d a v el u m a b f or Gr a de 3 .
P er m a n e ntl y di s c o nti n u e a v el u m a b f or 
Gr a d e 4 or r e c urr e nt Gr a d e 3.
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e I V or 
e q ui v al e nt .
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s .
C o n si d er l o w er e n d o s c o p y
If i m pr o v e s: 
C o nti n u e st er oi d s u ntil Gr a d e ≤1, 
t h e n t a p er o v er at l e a st 1 m o nt h; 
r e s u m e a v el u m a b t h er a p y 
f oll o wi n g st er oi d s t a p er (f or i niti al 
Gr a d e 3).
If w or s e n s, p er si st s > 3 t o 5 d a y s, 
or r e c ur s aft er i m pr o v e m e nt :
A d d i nfli xi m a b 5 m g/ k g (if n o 
c o ntr ai n di c ati o n).
N ot e: I nfli xi m a b s h o ul d n ot b e 
u s e d i n c a s e s of p erf or ati o n or 
s e p si s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 8 / 1 5 0
D er m at ol o gi c al ir A E s
Gr a d e of R a s h
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
Gr a d e 1 t o 2 
C o v eri n g ≤ 3 0 % b o d y s urf a c e ar e a 
C o nti n u e a v el u m a b t h er a p y .
S y m pt o m ati c t h er a p y (f or e x a m pl e, 
a nti hi st a mi n e s, t o pi c al st er oi d s).
If Gr a d e 2 p er si st s > 1 t o 2 w e e k s 
or r e c ur s: 
Wi t h h ol d a v el u m a b t h er a p y
C o n si d er s ki n bi o p s y 
C o n si d er 0. 5 t o 1. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt . O n c e 
i m pr o vi n g, t a p er st er oi d s o v er at 
l e a st 1 m o nt h, c o n si d er 
pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s, a n d 
r e s u m e a v el u m a b t h er a p y
f oll o wi n g st er oi d s t a p er.
If w or s e n s: 
Tr e at a s Gr a d e s 3 t o 4 
Gr a d e s 3 t o 4
Gr a d e 3: C o v eri n g > 3 0 % b o d y 
s urf a c e ar e a 
Gr a d e 4: Lif e -t hr e at e ni n g 
c o n s e q u e n c e s
Wi t h h ol d a v el u m a b f or Gr a d e 3.
P er m a n e ntl y di s c o nti n u e f or Gr a d e 4 or 
r e c urr e nt Gr a d e 3.
C o n si d er s ki n bi o p s y .
D er m at ol o g y c o n s ult .
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt .
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s
If i m pr o v e s t o Gr a d e ≤1: 
T a p er st er o i d s o v er at l e a st 1 
m o nt h ; r e s u m e a v el u m a b t h er a p y 
f oll o wi n g st er oi d s t a p er (f or i niti al 
Gr a d e 3)
P ul m o n ar y  ir A E s
Gr a d e of P n e u m o niti s
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
Gr a d e 1
R a di o gr a p hi c c h a n g e s o nl y 
C o n si d er wit h h ol di n g a v el u m a b 
t h er a p y 
M o nit or f or s y m pt o m s e v er y 2
t o 3 
d a y s 
C o n si d er P ul m o n ar y a n d I nf e cti o u s 
Di s e a s e c o n s ult s 
R e -a s s e s s at l e a st e v er y 3 w e e k s
If w or s e n s: 
Tr e at a s Gr a d e 2 or Gr a d e 3 t o 4 
Gr a d e 2
Mil d t o m o d er at e n e w s y m pt o m s 
Wi t hh ol d a v el u m a b t h er a p y
P ul m o n ar y a n d I nf e cti o u s Di s e a s e 
c o n s ult s
M o nit or s y m pt o m s d ail y, c o n si d er 
h o s pit ali z ati o n 
R e -a s s e s s e v er y 1 t o 3 d a y s 
If i m pr o v e s: 
W h e n s y m pt o m s r et ur n t o 
Gr a d e ≤1, t a p er st er oi d s o v er at 
l e a st 1 m o nt h, a n d t h e n r e s u m e 
a v el u m a b t h er a p y f oll o wi n g 
st er oi d s t a p er
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
7 9 / 1 5 0
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt 
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s
C o n si d er br o n c h o s c o p y, l u n g bi o p s y 
If n ot i m pr o vi n g aft er 2 w e e k s or 
w or s e ni n g or f or r e c urr e nt 
Gr a d e 2 : 
Tr e at a s Gr a d e 3 t o 4 
Gr a d e 3 t o 4
Gr a d e 3: S e v er e n e w s y m pt o m s; 
N e w/ w or s e ni n g h y p o xi a;
Gr a d e 4: Lif e -t hr e at e ni n g 
P er m a n e ntl y di s c o nti n u e a v el u m a b 
t h er a p y
H o s pit ali z e
P ul m o n ar y a n d I nf e cti o u s Di s e a s e 
c o n s ult s
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt 
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s 
C o n si d er br o n c h o s c o p y, l u n g bi o p s y 
If i m pr o v e s t o Gr a d e ≤ 1: 
T a p er st er oi d s o v er at l e a st 1 
m o nt h 
If n ot i m pr o vi n g aft er 4 8 h o ur s or 
w or s e ni n g: 
A d d a d diti o n al 
i m m u n o s u p pr e s si o n (f or e x a m pl e, 
i nfli xi m a b, c y cl o p h o s p h a mi d e, I V 
i m m u n o gl o b uli n, or 
m y c o p h e n ol at e m of etil) 
H e p ati c ir A E s
Gr a d e of Li v er T e st El e v ati o n
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
Gr a d e 1
Gr a d e 1 A S T or A L T > U L N t o 3. 0 ×
U L N a n d/ or t ot al bilir u bi n > U L N t o 
1. 5 × U L N 
C o nti n u e a v el u m a b t h er a p y
C o nti n u e li v er f u n cti o n m o nit ori n g 
If w or s e n s: 
Tr e at a s Gr a d e s 2 or 3 t o 4 
Gr a d e 2
A S T or A L T > 3. 0 t o ≤ 5 × U L N 
a n d/ or t ot al bilir u bi n > 1. 5 t o ≤ 3 ×
U L N 
Wi t h h ol d a v el u m a b t h er a p y .
I n cr e a s e fr e q u e n c y of m o nit ori n g t o 
e v er y 3 d a y s 
If r et ur n s t o Gr a d e ≤1 : 
R e s u m e r o uti n e m o nit ori n g, 
r e s u m e a v el u m a b t h er a p y
If el e v ati o n p er si sts > 5 t o 7 d a y s 
or w or s e n s : Tr e at a s Gr a d e 3 t o 4
Gr a d e 3 t o 4
A S T or A L T > 5 × U L N a n d/ or t ot al 
bilir u bi n > 3 × U L N 
P er m a n e ntl y d i s c o nti n u e a v el u m a b 
t h er a p y 
I n cr e a s e fr e q u e n c y of m o nit ori n g t o 
e v er y 1 t o 2 d a y s .
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt .
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s .
C o n s ult g a st r o e nt er ol o gi st/ 
h e p at ol o gi st.
C o n si d er o bt ai ni n g M RI/ C T s c a n of 
li v er a n d li v er bi o p s y if cli ni c all y 
w arr a nt e d .
If r et ur n s t o Gr a d e ≤1 : 
T a p er st er oi d s o v er at l e a st 1 
m o nt h 
If d o e s n ot i m pr o v e i n > 3 t o 5 
d a y s, w or s e n s or r e b o u n d s: 
A d d m y c o p h e n ol at e m of etil 1 
gr a m ( g) t wi c e d ail y 
If n o r e s p o n s e wit hi n a n a d diti o n al 
3 t o 5 d a y s, c o n si d er ot h er 
i m m u n o s u p pr e s s a nt s p er l o c al 
g ui d eli n e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 0 / 1 5 0
R e n al ir A E s
Gr a d e of Cr e ati ni n e I n cr e a s e d 
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w - u p M a n a g e m e nt
Gr a d e 1
Cr e ati ni n e i n cr e a s e 1. 5 x b a s eli n e or 
Cr e ati ni n e i n cr e a s e d > U L N t o 1. 5 ×
U L N
C o nti n u e a v el u m a b t h er a p y
C o nti n u e r e n al f u n cti o n m o nit ori n g
If w or s e n s:
Tr e at a s Gr a d e 2 t o 3 or 4
Gr a d e 2 t o 3
Cr e ati ni n e i n cr e a s e d > 1. 5 x 
b a s eli n e a n d ≤ 6 × U L N or 
Cr e ati ni n e > 1. 5 a n d ≤6 x U L N
Wi t h h ol d a v el u m a b t h er a p y
I n cr e a s e fr e q u e n c y of m o nit ori n g t o 
e v er y 3 d a y s
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s
C o n si d er r e n al bi o p s y
If r et ur n s t o G r a d e ≤1:
T a p er st er oi d s o v er at l e a st 1 
m o nt h, a n d r e s u m e a v el u m a b 
t h er a p y f oll o wi n g st er oi d s t a p er
If w or s e n s: 
Tr e at a s Gr a d e 4
Gr a d e 4
Cr e ati ni n e i n cr e a s e d > 6 × U L N
P er m a n e ntl y di s c o nti n u e a v el u m a b 
t h er a p y
M o nit or cr e ati ni n e d ail y
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt.
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s
C o n si d er r e n al bi o p s y
N e p hr ol o g y c o n s ult
If r et ur n s t o Gr a d e ≤1:
T a p er st er oi d s o v er at l e a st 1 
m o nt h
C ar di a c ir A E s
M y o c ar diti s
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
N e w o n s et of c ar di a c si g n s or 
s y m pt o m s a n d / or n e w l a b or at or y 
c ar di a c bi o m ar k er el e v ati o n s ( e g,
tr o p o ni n, C K-m u s cl e/ br ai n , B N P) or 
c ar di a c i m a gi n g a b n or m aliti e s 
s u g g e sti v e of m y o c ar diti s
Wi t h h ol d a v el u m a b t h er a p y.
H o s pit ali z e .
I n t h e pr e s e n c e of lif e- t hr e at e ni n g 
c ar di a c d e c o m p e n s ati o n, c o n si d er 
tr a n sf er t o a f a cilit y e x p eri e n c e d i n 
a d v a n c e d h e art f ail ur e a n d arr h yt h mi a 
m a n a g e m e nt .
C ar di ol o g y c o n s ult t o e st a bli s h eti ol o g y 
a n d r ul e -o ut i m m u n e -r el at e d m y o c ar diti s.
G ui d eli n e b a s e d s u p p ort i v e tr e at m e nt a s 
p er c ar di ol o g y c o n s ult. *
C o n si d er m y o c ar di al bi o p s y if 
r e c o m m e n d e d p er c ar di ol o g y c o n s ult.
If s y m pt o m s i m pr o v e a n d i m m u n e-
r el at e d eti ol o g y i s r ul e d o ut, r e st art 
a v el u m a b t h er a p y.
If s y m pt o m s d o n ot i m pr o v e/ w or s e n, 
vir al m y o c ar diti s i s e x cl u d e d, a n d 
i m m u n e-r el at e d eti ol o g y i s 
s u s p e ct e d or c o nfir m e d f oll o wi n g 
c ar di ol o g y c o n s ult, m a n a g e a s 
i m m u n e-m e di at e d m y o c ar diti s.
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 1 / 1 5 0
I m m u n e-r el at e d m y o c ar diti s
P er m a n e ntl y di s c o nti n u e a v el u m a b.
G ui d eli n e b a s e d s u p p orti v e tr e at m e nt a s 
a p pr o pri at e a s p er c ar di ol o g y c o n s ult. *
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s.
O n c e i m pr o vi n g, t a p er st er oi d s o v er 
at l e a st 1 m o nt h.
If n o i m pr o v e m e nt or w or s e ni n g, 
c o n si d er a d diti o n al 
i m m u n o s u p pr e s s a nt s ( e g,
a z at hi o pri n e, c y cl o s p ori n e A)
* L o c al g ui d eli n e s, or e g , E ur o p e a n S o ci et y of C ar di ol o g y or A m eri c a n H e art A s s o ci ati o n g ui d eli n e s
E ur o p e a n S o ci et y of C ar di ol o g y g ui d eli n e s w e b sit e: htt p s:// w w w. e s c ar di o. or g/ G ui d eli n e s/ Cli ni c al- Pr a cti c e -
G ui d eli n e s
A m eri c a n H e art A s s o ci ati o n g ui d eli n e s w e b sit e:
htt p:// pr of e s si o n al. h e art. or g/ pr of e s si o n al/ G ui d eli n e s St at e m e nt s/ s e ar c hr e s ult s.j s p ? q = & y = &t = 1 0 0 1
E n d o cri n e ir A E s
E n d o cri n e Di s or d er
I niti al M a n a g e m e nt
F oll o w -u p M a n a g e m e nt
Gr a d e 1 or Gr a d e 2 
e n d o cri n o p at hi e s ( h y p ot h yr oi di s m, 
h y p ert h yr oi di s m, a dr e n al 
i n s uffi ci e n c y, T y p e I di a b et e s 
m ellit u s)
C o nti n u e a v el u m a b t h er a p y
E n d o cri n ol o g y c o n s ult if n e e d e d
St art t h yr oi d h or m o n e r e pl a c e m e nt 
t h er a p y (f or h y p ot h yr oi di s m), 
a nti -t h yr oi d tr e at m e nt (f or 
h y p ert h yr oi di s m), c orti c o st er oi d s (f or 
a dr e n al i n s uffi ci e n c y) or i n s uli n (f or 
T y p e I di a b et e s m ellit u s) a s 
a p pr o pri at e.  
R ul e -o ut s e c o n d ar y e n d o cri n o p at hi e s 
(i e, h y p o pit uit ari s m / h y p o p h y siti s)
C o nti n u e h or m o n e 
r e pl a c e m e nt/ s u p pr e s si o n a n d 
m o nit ori n g of e n d o cri n e f u n cti o n a s 
a p pr o pri at e.
Gr a d e 3 or Gr a d e 4 
e n d o cri n o p at hi e s ( h y p ot h yr oi di s m, 
h y p ert h yr oi di s m, a dr e n al 
i n s uffi ci e n c y, T y p e I di a b et e s 
m ellit u s)
Wi t h h ol d a v el u m a b t h er a p y
C o n si d er h o s pit ali z ati o n
E n d o cri n ol o g y c o n s ult
St art t h yr oi d h or m o n e r e pl a c e m e nt 
t h er a p y (f or h y p ot h yr oi di s m), 
a nti -t h yr oi d tr e at m e nt (f or 
h y p ert h yr oi di s m), c orti c o st er oi d s (f or 
a dr e n al i n s uffi ci e n c y) or i n s uli n (f or 
T y p e I di a b et e s m ellit u s) a s 
a p pr o pri at e.  
R ul e -o ut s e c o n d ar y e n d o cri n o p at hi e s 
(i e, h y p o pit uit ari s m / h y p o p h y siti s)
R e s u m e a v el u m a b o n c e 
s y m pt o m s a n d/ or l a b or at or y t e st s 
i m pr o v e t o Gr a d e ≤ 1 ( wit h or 
wit h o ut h or m o n e 
r e pl a c e m e nt/ s u p pr e s si o n).
C o nti n u e h or m o n e 
r e pl a c e m e nt/ s u p pr e s si o n a n d 
m o nit ori n g of e n d o cri n e f u n cti o n 
a s a p pr o pri at e. 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 2 / 1 5 0
H y p o pit uit ari s m/ H y p o p h y siti s 
( s e c o n d ar y e n d o cri n o p at hi e s)
If s e c o n d ar y t h yr oi d a n d/ or a dr e n al 
i n s uffi ci e n c y i s c o nfir m e d (i e,
s u b n or m al s er u m t h yr o xi n e wit h 
i n a p pr o pri at el y l o w t h yr oi d-sti m ul ati n g 
h or m o n e a n d/ or l o w s er u m c orti s ol wit h 
i n a p pr o pri at el y l o w a dr e n o c orti c otr o pi c
h or m o n e ):

R ef er t o e n d o cri n ol o gi st f or 
d y n a mi c t e sti n g a s i n di c at e d a n d 
m e a s ur e m e nt of ot h er h or m o n e s 
( F S H, L H, G H/I G F-1, P R L, 
t e st o st er o n e i n m e n, e str o g e n s i n 
w o m e n) 

H or m o n e 
r e pl a c e m e nt/ s u p pr e s si v e t h er a p y 
a s a p pr o pri at e 

P erf or m pit uit ar y M RI a n d vi s u al 
fi el d e x a mi n ati o n a s i n di c at e d
If h yp o p h y siti s c o nfir m e d:

C o nti n u e a v el u m a b if mil d 
s y m pt o m s wit h n or m al M RI. 
R e p e at t h e M RI i n 1 m o nt h

Wi t h h ol d a v el um a b if m o d er at e, 
s e v er e or lif e -t hr e at e ni n g 
s y m pt o m s of h y p o p h y siti s a n d/ or 
a b n or m al M RI. C o n si d er 
h o s pit ali z ati o n. Initi at e 
c orti c o st er oi d s ( 1 t o 2 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt) f oll o w e d 
b y c orti c o st er oi d s t a p er d uri n g at 
l e a st 1 m o nt h. 
•
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u n i sti c i nf e cti o n s.
R e s u m e a v el u m a b o n c e s y m pt o m s 
a n d h or m o n e t e st s i m pr o v e t o 
Gr a d e ≤ 1 ( wit h or wit h o ut h or m o n e 
r e pl a c e m e nt).
I n a d diti o n, f or h y p o p h y siti s wit h 
a b n or m al M RI, r e s u m e a v el u m a b 
o nl y o n c e s hri n k a g e of t h e pit uit ar y 
gl a n d o n M RI/ C T s c a n i s 
d o c u m e nt e d. 
C o nti n u e h or m o n e 
r e pl a c e m e nt/ s u p pr e s si o n t h er a p y a s 
a p pr o pri at e.
Ot h er ir A E s ( n ot d e s cri b e d a b o v e)
Gr a d e of ot h er ir A E s
( N CI-C T C A E v 4)
I niti al M a n a g e m e nt
F oll o w - u p M a n a g e m e nt
Gr a d e 2 or Gr a d e 3 cli ni c al si g n s or 
s y m pt o m s s u g g e sti v e of a p ot e nti al 
ir A E
Wi t h h ol d a v el u m a b t h er a p y p e n di n g 
cli ni c al i n v e sti g ati o n
If ir A E i s r ul e d o ut, m a n a g e a s 
a p pr o pri at e a c c or di n g t o t h e
di a g n o si s a n d c o n si d er r e st arti n g 
a v el u m a b t h er a p y
If ir A E i s c o nfir m e d, tr e at a s 
Gr a d e 2 or 3 ir A E
Gr a d e 2 ir A E or fir st o c c urr e n c e of 
Gr a d e 3 ir A E
Wi t h h ol d a v el u m a b t h er a p y
1. 0 t o 2. 0 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt  
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult a s a p pr o pri at e
If i m pr o v e s t o Gr a d e ≤ 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h 
a n d r e s u m e a v el u m a b t h er a p y 
f oll o wi n g st er oi d s t a p er.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 3 / 1 5 0
R e c urr e n c e of s a m e Gr a d e 3 ir A E s
P er m a n e ntl y di s c o nti n u e a v el u m a b 
t h er a p y
1. 0 t o 2. 0 m g/ k g/ d a y
pr e d ni s o n e or e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult a s a p pr o pri at e
If i m pr o v e s t o Gr a d e ≤ 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h
Gr a d e 4 
P er m a n e ntl y di s c o nti n u e a v el u m a b 
t h er a p y
1. 0 t o 2. 0 m g/ k g/ d a y
pr e d ni s o n e or e q ui v al e nt a n d/ or ot h er 
i m m u n o s u p pr e s s a nt a s n e e d e d
A d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult
If i m pr o v e s t o Gr a d e ≤ 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h
R e q uir e m e nt f or 1 0 m g p er d a y or 
gr e at er pr e d ni s o n e or e q ui v al e nt f or 
m or e t h a n 1 2 w e e k s f or r e a s o n s 
ot h er t h a n h or m o n al r e pl a c e m e nt f or 
a dr e n al i n s uffi ci e n c y
P er si st e nt Gr a d e 2 or 3 ir A E l a sti n g 
1 2 w e e k s or l o n g er
P er m a n e ntl y di s c o nti n u e a v el u m a b 
t h er a p y
S p e ci alt y c o n s ult
A D L = a cti viti e s of d ail y li vi n g , A L T = al a ni n e a mi n otr a n sf er a s e, A S T = a s p art at e a mi n otr a n sf er a s e, B N P = B- t y p e 
n atri ur eti c p e pti d e , C K = cr e ati n e ki n a s e , C T = c o m p ut e d t o m o gr a p h y , F S H =f olli cl e-sti m ul ati n g h or m o n e, G H = gr o wt h 
h or m o n e, I G F -1 =i n s uli n -li k e gr o wt h f a ct or 1, ir A E =i m m u n e-r el at e d a d v er s e e v e nt, I V =i ntr a v e n o u s, L H =l ut ei ni zi n g 
h or m o n e , M RI = m a g n eti c r e s o n a n c e i m a gi n g, N CI-C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y Crit eri a 
f or A d v er s e E v e nt, P R L = pr ol a cti n, U L N = u p p er li mit of n or m al.
6. 5. 5
M a n a ge me nt 
of S pecific A d verse E ve nts or A d verse Dr u g 
Re acti o ns
T he ma na ge me nt of ir A Es is descri be d i n Secti o n 6. 5. 4. 4.
6. 6
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
A vel u ma b is f or m ulate d as a 2 0 m g/ m L s ol uti o n a n d is s u p plie d b y  the S p o ns or i n si n gle-use glass 
vials, st o p pere d wit h a r u b be r se pt u m a n d seale d wit h a n al u mi n u m p ol ypr o p y le ne fli p-off seal.
All I MPs will be pac ka ge d a n d la bele d i n acc or da nce wit h all a p plica ble re g ulat or y  re q uire me nts 
a n d G o o d Ma n ufact uri n g Practice G ui deli nes. A vel u ma b will be pac ke d i n b o xes eac h c o ntai ni n g 
1 vial. T he i nf or mati o n o n t he trial treat me nt will be i n acc or da nce wit h a p pr o ve d s u b missi o n 
d oc u me nts .  
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 4 / 1 5 0
O xali plati n, 5 -F U, a n d ca pecita bi ne, will be s u p plie d b y  the st u d y ce nter or b y  the S p o ns or, 
acc or di n g t o l ocal la ws a n d re g ulati o ns.
6. 7
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
T he c o nte nts of t he a vel u ma b vials are sterile a n d n o n p yr o ge nic, a n d d o n ot c o ntai n bacteri ostatic 
preser vati ves. A n y s pills t hat occ ur s h o ul d be clea ne d u p usi n g t he facilit y’s sta n dar d clea n u p 
pr oce d ures f or bi ol o gic pr o d ucts.
A vel u ma b m ust be st ore d at 
 t o 
 u ntil use, wit h a te m perat ure l o g mai ntai ne d dail y . All 
me dicati o n b o xes s u p plie d t o eac h trial site m ust be st ore d caref ull y, safel y, a n d se parately fr o m 
ot her dr u gs.
A vel u ma b st ore d at r o o m te m perat ure 
 or at ele vate d te m perat ures 
 
f or e xte n de d peri o ds is s u bject t o de gra dati o n. A vel u ma b m ust n ot be fr oze n. R o u g h s ha ki n g of 
a vel u ma b m ust be a v oi de d.
F or a p plicati o n i n t his trial, a vel u ma b m ust be dil ute d wit h 0. 9 % sali ne s ol uti o n (s o di u m c hl ori de 
i njecti o n). Detaile d i nf or mati o n o n i nf usi o n ba gs a n d me dical de vices t o be use d f or t he 
pre parati o n of t he dil uti o ns a n d s u bse q ue nt a d mi nistrati o n will be pr o vi de d i n t he I P M P.
A vel u ma b m ust n ot be use d f or a n y  p ur p ose ot her t ha n t he trial. T he a d mi nistrati o n of a vel u ma b 
t o s u bjects w h o ha ve n ot bee n e nr olle d i nt o t he trial is n ot c o vere d by t he trial i ns ura nce.
A n y  un use d p orti o n of t he s ol uti o n s h o ul d be discar de d i n bi o hazar d waste dis p osal wit h fi nal 
dis p osal b y  acce pte d l ocal a n d nati o nal sta n dar ds of i nci nerati o n.
St ora ge, ha n dli n g, pre parati o n, a n d dis p osal of I M P s h o ul d be acc ordi n g t o l ocal i nstit uti o nal 
g ui deli nes.
6. 8
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he I n vesti gat or is res p o nsi ble f or e ns uri n g acc o u nta bilit y for a vel u ma b a n d mai nte na nce 
c he m ot hera p y, i ncl u di n g rec o nciliati o n a n d mai nte na nce of dr u g rec or ds.

U p o n recei pt of trial treat me nt, t he I nvesti gat or ( or desi g nee) will c hec k f or acc urate deli ver y 
a n d ac k n o wle d ge recei pt b y  si gni n g ( or i nitiali n g) a n d dati n g t he d oc u me ntati o n pr o vi de d b y  
t he S p o ns or a n d ret ur ni n g it t o t he S p o ns or. A c o p y will be retai ne d f or t he I nvesti gat or Site 
File.

T he dis pe nsi n g of t he trial treat me nt will be caref ull y rec or de d o n t he a p pr o priate dr u g 
acc o u nta bilit y for ms pr o vi de d b y  t he S p o ns or a n d a n acc urate acc o u nti n g will be a vaila ble f or 
verificati o n b y t he cli nical researc h ass oci ate ( C R A) at eac h m o nit ori n g visit.

Trial treat me nt acc o u nta bilit y  rec or ds will i ncl u de:
1.
C o nfir mati o n of trial treat me nt deli ver y  t o t he trial site
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 5 / 1 5 0
2.
T he i n ve nt or y at t he site of trial treat me nt pr o vi de d b y  the S p o ns or a n d pre pare d at 
t he site
3.
T he use of eac h d ose b y  eac h s u bject
4.
T he dis p ositi o n of u n use d trial treat me nt
5.
Dates, q ua ntities, batc h n u m bers, e x pir y  dates a n d (f or trial treat me nt pre pare d at t he 
site) f or m ulati o n, as well as t he s u bjects’ trial n u m bers.

T he I n vesti gat or s h o ul d mai ntai n rec or ds t ha t a de q uatel y d oc u me nt:
1.
T hat t he s u bjects were 
pr o vi de d t he d oses s pecifie d b y  the cli nical trial 
pr ot oc ol/a me n d me nt(s)
2.
T hat all trial treat me nt pr o vi de d b y  t he S p o ns or was f ull y rec o ncile d.
U n use d trial treat me nt m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he prese nt trial. 
A n y  trial treat me nt t hat has bee n dis pe nse d t o a s u bject m ust n ot be re-dis pe nse d t o a differe nt 
s u bject.
T he C R A will peri o dicall y  collect t he trial treat me nt acc o u nta bilit y for ms a n d will c hec k all ret ur ns 
( b ot h u n use d an d use d c o ntai ners) bef ore a ut h orizi n g t heir destr ucti o n b y  t he trial site.
At t he c o ncl usi o n or ter mi nati o n of t his trial, trial site pers o n nel a n d t he C R A will c o n d uct a fi nal 
pr o d uct s u p pl y in ve nt or y  on t he i n vesti gati o nal dr u g acc o u nta bilit y for ms a n d all u n use d 
c o ntai ners will be destr o y e d. I nstr ucti o ns f or destr ucti o n of pr o d uct will be pr o vi de d t o t he site. 
T he C li nical T rial M o nit or will be s u p plie d wit h a c o p y f or fili n g of t he i n vesti gati o nal dr u g 
acc o u nta bilit y f or ms. T his d oc u me ntati o n m ust c o ntai n a rec or d of cli nical s u p plies use d, u n use d, 
a n d destr o ye d a n d s hall i ncl u de i nf or mati o n o n:

All a d mi nistere d u nits

All u n use d u nits

All destr o y e d u nits ( d uri n g t he trial)

All destr o y e d u nits at t he e n d of t he trial

Date of destr ucti o n(s)

Na me a n d si g nat ure of t he I n vesti gat or/ p har macist.
It m ust be e ns ure d at eac h trial site t hat t he trial treat me nt is n ot use d:

After t he e x pir y  date

After t he retest date u nless t he trial treat me nt is re- a nal yz e d a n d its retest date e xte n de d.
T his is t o be cl osel y  m o nit ore d b y t he Cli nical Trial M o nit or.
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 6 / 1 5 0
6. 9
Assess me nt of I n vesti g ati o n al Me di ci n al Pr o d uct C o m pli a nce
I n t his trial, s u bjects will recei ve trial treat me nt at t he i n vesti gati o nal site. Well -trai ne d me dical 
staff will m o nit or a n d perf or m t he trial treat me nt a d mi nistrati o n. T he i nf or mati o n of eac h trial 
treat me nt a d mi nistrati o n i nclu di n g t he date, ti me, a n d d ose of trial treat me nt will be rec or de d o n 
t he e C R F. T he I nvesti gat or will ma ke s ure t hat t he i nf or mati o n e ntere d i nt o t he e C R F re gar di n g 
dr u g a d mi nistrati o n is acc urate f or eac h s u bject. A n y  reas o n f or n o nc o m plia nce s h o ul d be 
d oc u me nte d.
N o nc o m plia nce is defi ne d as a s u bject missi n g > 1 st u d y treat me nt a d mi nistrati o n f or n o n me dical 
reas o ns (see Secti o n 5. 5. 1 ). If 1 st u d y treat me nt a d mi nistrati o n is misse d a n d t he i nter val bet wee n 
t he s u bse q ue nt treat me nt a n d t he last st u d y treat me nt visit is l o n ger t ha n 4 wee ks f or n o n me dical 
reas o ns, t he criteria of i ns ufficie nt c o m plia nce are met as well.
6. 1 0
Bli n di n g
T his is a n o pe n -la bel trial; t h us, trial treat me nt is n ot bli n de d.
6. 1 1
E mer ge nc y U n bli n di n g
N ot a p plica ble.
6. 1 2
Tre at me nt of O ver d ose
A n o ver d ose is defi ne d as a n y dose ≥ 1 0 % 
o ver t he calc ulate d d ose f or t hat partic ular 
a d mi nistrati o n as descri be d i n t his cli nical trial pr ot oc ol. A n y  o ver d ose m ust be rec or de d i n t he 
trial treat me nt secti o n of t he e C R F.
F or m o nit ori n g p ur p oses, a n y  case of o ver d ose, w het her or n ot ass ociate d wit h a n A E (seri o us or 
n o nseri o us), m ust be re p orte d t o t he S p o ns or’s Gl o bal Dr u g Safet y D e part me nt i n a n e x pe dite d 
ma n ner usi n g t he a p pr o priate re p orti n g f or m (see Secti o n 7. 4. 1. 4 ).
T here are n o k n o w n s y m pt o ms of a vel u ma b o ver d ose t o date. T he I nvesti gat or sh o ul d use his or 
her cli nical j u d g me nt w he n treati n g a n o ver d ose of t he trial treat me nt.
F or all mai nte na nce
c he m ot hera py, I n vesti gat ors m ust f oll o w l ocal i nstit uti o nal g ui deli nes f or 
o ver d ose treat me nt.
6. 1 3
Me dic al C are of S u bjects after E n d of Tri al
After a s u bject has st o p pe d trial treat me nt, us ual treat me nt will be a d mi nistere d, if re q uire d, i n 
acc or da nce wit h t he trial site’s S O C a n d ge nerall y acce pte d me dical practice a n d de pe n di n g o n t he 
s u bject’s i n di vi d ual me dical nee ds.
U p o n wit h dra wal fr o m trial treat me nt, s u bjects ma y  recei ve t he t ype of care t he y an d t heir 
p h y sicia ns a gree u p o n. 
S u bjects will be f oll o we d f or s ur vi val a n d A Es as s pecifie d i n 
Secti o n 7. 1. 6.   
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 7 / 1 5 0
7
Tri al Pr oce d ures a n d Assess me nts
7. 1
Sc he d ule of Assess me nts
A c o m plete Sc he d ule of Assess me nts f or t he Scree ni n g peri o d a n d t he I n d ucti o n P hase is pr o vi de d 
i n Ta ble 1 a n d Ta ble 2,  f or t he Mai nte na nce a n d F oll o w - u p P hase i n Ta ble 3 t o Ta ble 6,  a n d f or 
Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical care, t he 
I n vesti gat or will e ns ure t hat t he s u bject or t he s u bject’s le gal re prese ntati ve has pr o vi de d writte n 
i nf or me d c o nse nt acc or di n g t o t he pr oce d ure descri be d i n Secti o n 9. 2.
7. 1. 1
Scree ni n g a n d B aseli ne P r oce d ures a n d Assess me nts
T he Scree ni n g pr oce d ures a n d B aseli ne assess me nts will be c o m plete d wit hi n 2 8 da ys bef ore trial 
treat me nt starts.
D uri n g t he Scree ni n g peri o d a n d bef ore a n y trial-relate d i n vesti gati o ns a n d assess me nts are starte d, 
s u bjects will be as ke d t o si g n t he I C F. T he Scree ni n g pr oce d ures a n d Baseli ne assess me nts will 
be c o m plete d wit hi n 2 8 da y s of si g ni n g t he I CF. Fail ure t o esta blis h eli gi bilit y wit hi n 2 8 d a y s 
w o ul d res ult i n scree ni n g fail ure a n d t he s u bject will be e xcl u de d fr o m t he trial; h o we ver, s u bjects 
ca n be re-e ntere d i n t he trial base d o n t he I nvesti gat or’s j u d g me nt a n d f oll o wi n g S p o ns or a p pr o val .  
I n t his case, a ne w I C F will be re q uire d t o be si g ne d b y t he s u bject.
T he s u bjects’ i nf or mati o n t hat will be d oc u me nte d d uri n g Scree ni n g i ncl u des t he de m o gra p hic 
i nf or mati o n ( birt h date, se x, a n d et h nicit y) a n d t he c o m plete me dical hist or y, i ncl u di n g t he hist or y 
of gastric ca ncer, pre vi o us a n d o n g oi n g me dicati o ns, a n d baseli ne me dical c o n diti o n (t he 
i nf or mati o n of c o nc o mita nt me dicati o ns a n d A Es a n d S A Es will be m o nit ore d t hr o u g h o ut t he trial 
treat me nt peri o d). M ore o ver, a n E mer ge nc y  Me dical S u p p ort car d will be ha n de d o ut at t he 
Baseli ne as sess me nts visit.
D uri n g Scree ni n g , s u bjects will u n der g o a c o m plete p h y sical e xa mi nati o n, i ncl u di n g rec or di n g 
b o d y  hei g ht a n d wei g ht, vital si g ns, 1 2 -lea d E C G, a n d a deter mi nati o n of t he E C O G P S (Ta ble 1
a n d Ta ble 2) . T he Q o L q uesti o n naires will be a d mi nistere d a n d c o m plete d b y  the s u bjects at 
baseli ne t o c ollect baseli ne data a b o ut t heir healt h -relate d Q o L.
T he Scree ni n g
la b orat or y exa mi nati o n i ncl u des he mat ol o g y , he m ostase ol o g y , f ull ser u m 
c he mistr y, a n d f ull uri nal y sis ( di pstic k pl us micr osc o pic e val uati o n). F ree t h yr o xi ne ( T4) a n d 
t h yr oi d-sti m ulati n g h or m o ne ( T S H) will als o be assesse d at Scree ni n g f or all s u bjects. T he 
baseli ne
 
D uri n g Scree ni n g, a ser u m β- h u ma n c h ori o nic g o na d otr o pi n ( β-h C G ) pre g na nc y  test will be 
perf or me d f or fe males of c hil d beari n g p ote ntial ( ma y be a nal yz e d l ocall y). H E R 2 testi n g ( per 
l ocal g ui deli nes) , bl o o d H B V a n d H C V m a y  be a nal yze d l ocally f or all Scree ni n g s u bjects as t hese 
c o n diti o ns are trial e ntr y excl usi o n criteria (see Secti o n 5. 3. 2) .  H B V s urface a nti ge n a n d a nti-H C V 
tests m ust be perf or me d at Scree ni n g t o e xcl u de s u bjects wit h he patitis i nfecti o n.  If t he a nti-H C V 
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 8 / 1 5 0
test is p ositi ve, t he i nfecti o n m ust be c o nfir me d b y  an H C V R N A test.  Fe males w h o are 
p ost me n o pa usal (a ge-relate d a me n orr hea ≥ 1 2 c o nsec uti ve m o nt hs 
a n d i ncrease d f ollicle-
sti m ulati n g h or m o ne [ F S H] > 4 0 mI U/ m L), or w h o ha ve u n der g o ne h ysterect o m y or bilateral 
o o p h orect o m y a re e xe m pt fr o m pre g na nc y  testi n g.  If necessar y  to c o nfir m p ost me n o pa usal stat us, 
F S H will be dra w n at Scree ni n g.
T he t u m or e val uati o n (t y pe a n d sta gi n g, etc .) will be perf or me d usi n g C T sca n or M RI (if M RI is 
use d, C T of c hest is ma n dat or y ) as well as t u m or mar kers or an y  ot her esta blis he d met h o ds (see
Secti o n  7. 2. 5 f or details). A brai n C T/ M RI  sca n is re q uire d at Scree ni n g if n ot perf or me d wit hi n 
6 wee ks pri or t o e nteri n g t he I n d ucti o n P hase .  A b o ne sca n s h o ul d be d o ne at Scree ni n g as 
cli nicall y i n dicate d.
S u bjects are re q uire d t o pr o vi de t u m or tiss ue sa m ples; see Secti o n  7. 6. 1 f or details. T u m or tiss ue 
collecti o n will be d o ne of a rece ntl y -o btai ne d bi o ps y  wit hi n 6 m o nt hs fr o m a n o n- irra diate d area, 
F F P E bl oc k c o ntai ni n g t u m or tiss ue or a mi ni m u m n u m ber of 1 0 ( prefera bl y  2 5) u nstai ne d t u m or 
sli des s uita ble f or P D-L 1  e x pressi o n assess me nt (c ut wit hi n 1 wee k). Criteria f or deter mi ni n g t he 
a de q uac y of t u m or tiss ue are descri be d i n t he St u d y Ma n ual. 
S u bjects w h o u n der g o a bi o ps y  s pecifically as part of t he Scree ni n g assess me nts f or t his pr ot oc ol 
s hall be per mitte d t o part ici pate i n t he pr ot oc ol pr o vi de d t he y meet all ot her i ncl usi o n criteria a n d 
n o e xcl usi o n criteria.  It is rec o m me n de d t hat m ulti ple bi o ps y  sa m ples s h o ul d be c ollecte d, as 
feasi ble, f or bi o mar ker assess me nt t o mi ni mize 
i nacc uracies i n assess me nt d ue t o t u m or 
heter o ge neit y . T he site pat h ol o gist s hall re vie w t he H e mat o x yl i n a n d E osi n stai ns w he n m ore t ha n 
o ne F F P E bl oc k fr o m a s u bject has bee n recei ve d. If fr o m a resecti o n s peci me n, t he bl oc k t hat 
ma xi mizes t u m or c o nte nt a n d t u m or cell preser vati o n s h o ul d be teste d b y  the ce ntral la b orat or y.
If fr o m bi o ps y s peci me n(s), all a vaila ble t u m or-c o ntai ni n g bl oc ks re prese nti n g u p t o a ma xi m u m 
of 6 disti nct bi o psies, s h o ul d be se nt t o t he ce ntral la b orat or y  as feasi ble.  
T he bl o o d sa m ples f or baseli ne 
, a n d 
 as well as f or 
 
assess me nts ( o pti o nal) will be c ollecte d bef ore or o n Da y  1 bef ore trial treat me nt starts f or s u bjects 
ra n d o ml y assi g ne d t o recei ve a vel u ma b. 
7. 1. 2
I n d ucti o n P h ase Tre at me nt Peri o d
I n t his trial, t he treat me nt will be gi ve n u ntil P D, si g nifica nt cli nical deteri orati o n (cli nical 
pr o gressi o n), u nacce pta ble t o xicit y, or a n y c riteri o n f or wit h dra wal fr o m t he trial or trial treat me nt 
is f ulfille d (see Secti o n 5. 5. 1 ). 
Treat me nt d uri n g t he I n d ucti o n P hase will c o nsist of: 

6 c y cles of o xali plati n ( 8 5 m g/ m2 I V o n Da y 1 e ver y 2 wee ks) + le uc o v ori n ( 2 0 0 m g/ m2 I V o n 
D a y  1 ev er y  2 wee ks or e q ui vale nt le v ole uc o v ori n d ose ) f oll o we d b y  5-F U ( 2 6 0 0 m g/ m 2 I V 
c o nti n u o us i nf usi o n o ver 2 4 h o urs o n Da y 1 e ver y  2 wee ks,
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
8 9 / 1 5 0
O R
O xali plati n at 8 5 m g/ m 2 I V on D a y  1 wit h le uc o v ori n 4 0 0 m g / m2 I V on Da y 1 ( or e q ui vale nt 
le v ole uc o v ori n d ose) f oll o we d b y  5-F U at 4 0 0 m g/ m 2 I V pus h o n Da y  1 an d 2 4 0 0 m g/ m 2 I V 
c o nti n u o us i nf usi o n o ver 4 6- 4 8 h o urs ( Da ys  1 a n d 2) gi ve n e very 2 wee ks (f or u p t o 1 2 wee ks) .
O R

4 c ycles of O xali plati n ( 1 3 0 m g/ m 2 I V on Da y  1 ever y  3 wee ks ) + Ca pecita bi ne ( 1 0 0 0 m g / m2
P O t wice daily o n Da y s 1-1 4). Ca pecita bi ne ta blets s h o ul d be s wall o we d wit h water wit hi n 3 0 
mi n utes after a meal.
All t he l a b or at or y s a m ples a n d vit al si g ns will be c ollecte d pri or t o e ac h dr u g a d mi ni str ati o n.  
A d mi nistr ati o n of c he m ot her a p y will t a ke pl ace o nl y after rele v a nt res ults h a ve bee n 
c hec ke d b y a me dic all y q u alifie d pers o n a n d criteri a f or d osi n g h a ve bee n met.  
D uri n g t he treat me nt peri o d, t he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d (see 
Ta ble 1 a n d Ta ble 2 f or t he detaile d sc he d ule):

S A Es, A Es a n d c o nc o mita nt me dicati o ns a n d pr oce d ures will be d oc u me nte d at eac h trial visit.

E C O G P S will be assesse d at Da y  1 of eac h treat me nt c ycle (Scree ni n g E C O G P S ma y  be use d 
f or C ycle 1 Da y 1 if it was perf or me d wit hi n 3 da ys pri or t o Da y 1).

P h y sical e xa mi nati o ns will be perf or me d o n D a y  1 of eac h treat me nt c ycle.  S uc h e xa mi nati o ns 
will i ncl u de a c o m pre he nsi ve s ki n e xa mi nati o n f or t u m or.

Vital si g ns a n d b o d y  wei g ht will be assesse d at eac h visit.

B o d y wei g ht will be assesse d at Da y 1 of eac h c ycle.

T he la b orat or y he mat ol o g y a n d he m ostase ol o g y , will be assesse d o n Da y  1 of eac h c ycle.  C ore 
ser u m c he mistr y tests will be assesse d at Da y  1 of eac h c ycle.  A f ull uri nal y sis will be 
perf or me d at Scree ni n g a n d t he E n d - of-treat me nt visit.  S u bjects s h o ul d als o ret ur n t o t he site 
as per l ocal i nstit uti o nal practice f or a n y a d diti o nal r o uti ne assess me nts d uri n g c he m ot hera p y.

A uri ne or ser u m β - hC G pre g na nc y test will be perf or me d e ver y 4 wee ks d uri n g t he treat me nt 
c ycle ( bef ore c he m ot hera p y a d mi nistrati o n) f or fe males of c hil d beari n g p ote ntial.
D oc u me nt N o.
O bject N o.
C CI
C CIC CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 0 / 1 5 0
7. 1. 3
R a n d o miz ati o n/ Re -b aseli ne
At t he e n d of 1 2 wee ks of I nd ucti o n P hase, s u bjects e nter a 1 0- d a y  Re-baseli ne peri o d a n d t he 
f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d (see Ta ble 3 t o Ta ble 6 f or detaile d 
sc he d ule):

Re vie w of eli gi bilit y  criteria

T he s u bject-re p orte d o utc o mes / Q o L assess me nts will be c o m plete d b y  su bjects pri or t o 
a n y ot her trial-relate d pr oce d ures.

A Es a n d c o nc o mita nt me dicati o ns a n d pr oce d ures

E C O G P S

1 2- lea d E C G

P h y sical e xa mi nati o n, i ncl u di n g a c o m pre he nsi ve s ki n e xa mi nati o n f or t u m or

Vital si g ns a n d b o d y wei g ht

La b orat or y  he mat ol o g y, he m ostase ol o g y, f ull ser u m c he mistr y (i ncl u di n g c ore c he mistr y) 
a n d f ull uri nalys is

Uri ne or ser u m β - hC G pre g na nc y  test f or fe males of c hil d beari n g p ote ntial

Free T 4 a n d T S H

Car diac tr o p o ni n le vels will be c ollecte d fr om Re- baseli ne u p t o 1 2 wee ks i n t he 
M ai nte na nce P hase.  
Car diac tr o p o ni n le vels will be e val uate d ce ntrall y.  Local la b orat ories ma y  be use d at t he 
discreti o n of t he I n vesti gat or as cli nicall y nee de d f or safet y m a na ge me nt/treat me nt decisi o n of t he 
s u bject. Meas ure me nt of car diac tr o p o ni n T (c T n T) is preferre d, h o we ver car diac tr o p o ni n I (c T nI) 
ma y  be s u bstit ute d w here c T n T is n ot a vaila ble at t he l ocal la b orat or y.  The sa me s u b u nit (c T n T 
or c T nI) meas ure d at t he R e-baseli ne visit s h o ul d be meas ure d c o nsiste ntl y thr o u g h o ut t he st u d y 
i n eac h patie nt.  At t he R e-baseli ne visit , cli nicall y si gnifica nt p ositi ve res ults s h o ul d be f urt her 
assesse d as per l ocal S O C t o r ule-o ut c o nc urre nt car diac c o n diti o ns w hic h w o ul d ma ke t he patie nt 
i neli gi ble f or t he st u d y as p er e xcl usi o n criteria.  Duri n g t he st u d y, cli nicall y si gnifica nt ne w 
ele vati o ns s u g gesti ve of m y ocar ditis s h o ul d be assesse d as per  Ta ble 1 1 .  Ad diti o nal tests s h o ul d 
als o be perf or me d w he n cli nicall y i n dicate d.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 1 / 1 5 0
S u bjects w h o pr o gress d uri n g t he I n d ucti o n P hase or w h o are deter mi ne d t o ha ve P D d uri n g t he 
Re - baseli ne peri o d will be disc o nti n ue d fr o m t he trial.
S u bjec ts wit h o ut P D will be ra n d o mly assi g ne d t o recei ve mai nte na nce treat me nt wit h eit her 
a vel u ma b or c o nti n uati o n of t he sa me re gi me n of c he m ot hera p y fr o m t he I nd ucti o n P hase .  
S u bjects w h o de m o nstrate a res p o nse d uri n g t he I n d ucti o n P hase t hat re n ders t heir meas ura ble 
disease n o l o n ger meas ura ble at t he ti me of t he Mai nte na nce P hase ca n be ra n d o mize d.
S u bjects w h o disc o nti n ue treat me nt d ue t o a n y reas o n d uri n g t he Re -baseli ne peri o d a n d bef ore 
ra n d o mizati o n will ha ve a n e n d o f treat me nt (E O T ) visit wit hi n 7 da y s of t he decisi o n t o 
disc o nti n ue c he m ot hera p y an d a 3 0- d a y  Safet y Foll o w - u p visit i n acc or da nce wit h t he I n d uctio n 
P hase S c he d ule of A ssess me nts.
7. 1. 4
M ai nte n a nce P h ase Tre at me nt Peri o d
I n t he Mai nte na nce P hase, s u bjects will recei ve trial treat me nt (a vel u ma b or c o nti n uati o n of t he 
re gi me n of c he m ot hera p y fr o m t he I n d ucti o n P hase ) u ntil P D, f or t he acce pte d ma xi mal d urati o n 
of t he a ge nt(s) selecte d, u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m trial dr u g is 
f ulfille d (see Secti o n 5. 5).
T he C T/ M RI  sca ns will be c ollecte d u ntil P D is assesse d b y  the In vesti gat or acc or di n g t o 
R E CI S T v 1. 1.  S u bjects recei vi n g a vel u ma b ma y c o nti n ue treat me nt past t he i nitial deter mi nati o n 
of disease pr o gressi o n acc or di n g t o R E CI S T v 1. 1 if t he y 
meet t he criteria prese nte d i n 
Secti o n 6. 2. 1 (I n vesti gat or-assesse d be nefit; t olera nce of treat me nt; sta ble E C O G P S; a n d d oes n ot 
dela y  ot her i m mi ne nt i nter ve nti o n).
T he decisi o n t o c o nti n ue a vel u ma b treat me nt be y o n d pr o gressi o n s h o ul d be disc usse d wit h t he 
M e dical M o nit or a n d d oc u me nte d i n t he st u d y rec or ds.
F or s u bjects c o nti n ui n g a vel u ma b after i nitial P D, a ra di o gra p hic assess me nt s h o ul d be perf or me d 
wit hi n 6 wee ks of ori gi nal P D t o deter mi ne w het her t here has bee n a decrease i n t he t u m or size, 
or c o nti n ue d P D.  T he assess me nt of cli nical be nefit s h o ul d be bala nce d b y c li nical j u d g me nt as t o 
w het her t he s u bject is cli nicall y deteri orati n g a n d u nli kel y  to recei ve a n y be nefit fr o m c o nti n ue d 
treat me nt wit h a vel u ma b.
F or s u bjects recei vi ng a vel u ma b, if disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve 
dia g n osis/ra di o gra p hic c o nfir mati o n is n ot ma de at t he ti me of disc o nti n uati o n, a sec o n d i ma gi n g 
sca n m a y  be all o we d f or c o nfir mati o n of pr o gressi o n.  If pr o gressi o n at t he sec o n d i ma gi n g sca n 
is n ot c o nfir me d a n d t he s u bject wis hes t o restart, t he s u bject will be all o we d t o c o nti n ue recei vi n g 
a vel u ma b as l o n g as t he y meet t he criteria f or c o nti n uati o n of treat me nt be y o n d pr o gressi o n. 
If t he I n vesti gat or feels t hat t he s u bject c o nti nues t o ac hie ve cli nical be nefit b y  co nti n ui n g 
treat me nt, t he s u bject s h o ul d re mai n o n t he trial a n d c o nti n ue t o recei ve m o nit ori n g acc or di n g t o 
t he Sc he d ule of Assess me nts (Ta ble 3 ).
A n y  a d diti o nal c o nti n uati o n of a vel u ma b pl us B S C be y o n d f urt her pr o gressi o n m ust be disc usse d 
a n d a gree d u p o n wit h t he M e dical M o nit or.  Furt her disease pr o gressi o n is defi ne d as a n a d diti o nal 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 2 / 1 5 0
i ncrease i n t u m or b ur de n of 2 0 % a n d ≥ 5 m m a bs ol ute i ncrease i n t u m or b ur de n fr o m ti me of i nitial 
P D.   T his i ncl u des a n i ncrease i n t he s u m of all tar get lesi o ns or t he de vel o p me nt of ne w 
meas ura ble lesi o ns.  
A d diti o nall y , s u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a 
mi ni m u m of 1 2 m o nt hs or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y, after c o nfir mati o n of 
res p o nse. I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, b ut pri or t o t he 
e n d of t he trial, 1 re-i nitiati o n of tr eat me nt is all o we d at t he discreti o n of t he I n vesti gat or a n d after 
a gree me nt wit h t he Me dical M o nit or. I n or der t o be eli gi ble f or retreat me nt, t he s u bject m ust n ot 
ha ve e x perie nce d a n y t o xicit y  that le d t o treat me nt disc o nti n uati o n of t he i nitial a vel u mab t hera py.  
S u bjects w h o re -i nitiate treat me nt will sta y o n trial a n d will be treate d a n d m o nit ore d acc or di n g t o 
t he pr ot oc ol a n d f oll o w t he Sc he d ule of Assess me nts u ntil disease pr o gressi o n (see Ta ble 3 ).
T he treat me nt s h o ul d start wit hi n 4 d a y s after ra n d o mizati o n.  W hile o n trial treat me nt, s u bjects 
will be as ke d t o visit t he trial site as s pecifie d i n t he S c he d ule of A ssess me nts (see Ta ble 3, Ta ble 
4, Ta ble 5 , a n d Ta ble 6) .
F or b ot h a vel u ma b a n d mai nte na nce c he m o t hera py, a ti me wi n d o w of u p t o 4 d a y s bef ore or 2 d a y  
after t he sc he d ule d visit da y  (-4/ + 2 da y s) will be per mitte d f or all trial pr oce d ures . Su bjec ts s h o ul d 
ret ur n t o t he tar get date e ve n if t he pre vi o us visit was off sc he d ule.
T he t u m or e val uati o n (see Secti o n  7. 3) will be perf or me d e ver y 6 wee ks (f or t he first 1 2 m o nt hs 
a n d e ver y 1 2 wee ks t hereafter ) wit h a ti me wi n d o w of -5 da y s f or b ot h a vel u ma b a n d mai nte na nce
c he m ot hera py.
S u bjects will recei ve eit her:

A vel u ma b b y  IV i nf usi o n f oll o wi n g pretreat me nt (see Secti o n 5. 1. 2. 2. 1) o nce e ver y 2 wee ks 
(see Secti o n 6. 2. 1 ), or

Mai nte na nce c he m ot hera p y foll o wi n g pretreat me nt as a p plica ble pri or t o eac h i nf usi o n (see 
Secti o n  6. 2. 2).
Assess me nts t o be perf or me d d uri n g t he M a i nte na nce P hase are prese nte d i n Ta ble 3 t o Ta ble 6.
D uri n g t he treat me nt peri o d, t he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d (see 
Ta ble 3 t o Ta ble 6 f or t he detaile d sc he d ule):

T he s u bject-re p orte d o utc o mes/ Q o L  assess me nts will be c o m plete d b y  su bjects pri or t o 
a n y trial-relate d pr oce d ures (ti me p oi nts o utli ne d i n Ta ble 3 t o Ta ble 6) a n d t he n e ver y 
6 wee ks t hereafter.

A Es a n d c o nc o mita nt me dicati o ns a n d pr o ce d ures will be d oc u me nte d at eac h visit.

E C O G P S will be assesse d at eac h treat me nt visit.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 3 / 1 5 0

P h y sical e xa mi nati o ns will be perf or me d t hr o u g h Wee k 
1 3 or w hile t he s u bject is 
o n- treat me nt.
After Wee k 1 3, t he p h y sical e xa mi nati o n will occ ur e ver y 6 wee ks.  Su c h 
e xa mi nati o ns will i ncl u de a c o m pre he nsi ve s ki n e xa mi nati o n f or t u m or .

Vital si g ns a n d b o d y wei g ht will be assesse d i n eac h treat me nt visit.

T he la b orat or y  he mat ol o g y, he m ostase ol o g y will be assesse d at eac h visit.

S er u m c he mistr y tests will be assesse d as f oll o ws:
o
F ull ser u m c he mistr y  at Re-baseli ne f or all s u bjects
o
C ore ser u m c he mistr y :

S u bjects o n t he a vel u ma b ar m: Wee k 1, Wee k 3, Wee k 5, W ee k 7, W ee k 9, 
W ee k 1 1, Wee k 1 3, a n d e ver y 2 wee ks t hereafter.

S u bjects o n B S C -o nl y  wit h n o acti ve t hera p y: W ee k 1 , Wee k 4, Wee k
7, 
W ee k 1 0, Wee k 1 3, a n d e ver y 3 wee ks t hereafter.

S u bjects o n t he c he m ot hera p y d o u blet ar m recei vi n g o xali plati n + 
ca pecita bi ne o n W ee k 1, Wee k 4, Wee k 7, W ee k 1 0, W ee k 1 3 a n d e ver y 
3 wee ks t hereafter.

S u bjects o n t he c he m ot hera p y d o u blet ar m recei vi n g o xali plati n + 5 -F U o n 
W ee k 1, W ee k 3, Wee k 5, Wee k 7, W ee k 9, W ee k 1 1, W ee k 1 3, a n d e ver y 
2 wee ks t hereafter.

A basic uri nal y sis ( di pstic k) will be at Wee k 1, Wee k 7, Wee k 1 3, a n d e ver y 1 2 wee ks 
t hereafter.  If t he basic uri nal ysis is a b n or mal, a f ull uri nal ysis s h o ul d be perf or me d.

A uri ne or ser u m β - hC G pre g na nc y  test will be perf or me d at t he visits i n dicate d i n t he 
Assess me nt Sc he d ules (f or fe males of c hil d beari n g p ote ntial).  

Bl o o d sa m ples f or P K deter mi nati o ns will be c ollecte d fr o m all s u bjects i n t he a vel u ma b 
ar m o n or bef ore D a y 1 ( Wee k 1) pri or t o t he first a d mi nistrati o n of st u d y dr u g, wit hi n 
2 h o urs pri or t o eac h trial dr u g a d mi nistrati o n at Wee ks 
3, 5, 7 (e ver y 2 wee ks), at 
Wee ks
1 3, 1 9, a n d 2 5 (e ver y 6 wee ks), a n d t he n at 1 2- wee k i nter vals w hile o n- treat me nt
u p t o Wee k 1 0 9 ( 2 years fr o m ra n d o mizati o n) .  P ost-trial dr u g a d mi nistrati o n sa m ples will 
be c ollecte d at t he e n d of i nf usi o n ( wit hi n 1 5 mi n utes) at Wee ks 1, 7, a n d 2 5.  Sa m ples will 
be c ollecte d at t he E n d -of -Treat me nt visit a n d t he 3 0- d a y  Safet y F oll o w -u p visit , e x ce pt 
f or s u bjects still o n trial treat me nt be yo n d Wee k 1 0 9 .
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 4 / 1 5 0

T rial dr u g i nf usi o n at eac h trial visit ( o nce e ver y 2 or 3 wee ks).  

Pre me dicati o n as descri be d i n Secti o n 5. 1. 2. 2. 1

Car diac tr o p o ni n le vels will be c ollecte d fr o m Re- baseli ne u p t o 1 2 wee ks i n t he 
M ai nte na nce P hase.  
Car diac tr o p o ni n le vels will be e va l uate d ce ntrall y.  Local la b orat ories ma y  be use d at t he 
discreti o n of t he I n vesti gat or as cli nicall y nee de d f or safet y m a na ge me nt/treat me nt decisi o n of t he 
s u bject. Meas ure me nt of c T n T is preferre d, h o we ver c T nI ma y  be s u bstit ute d w here c T n T is n ot 
a vaila ble at t he l ocal la b orat or y. T he sa me s u b u nit (c T n T or c T nI) meas ure d at t he Re- baseli ne
visit s h o ul d be meas ure d c o nsiste ntl y thr o u g h o ut t he st u d y in eac h patie nt.
At t he Re- baseli ne
visit , cli nicall y si g nifica nt p ositi ve res ults s h o ul d be f urt her assesse d as per l ocal S O C t o r ule-o ut 
c o nc urre nt car diac c o n diti o ns w hic h w o ul d ma ke t he patie nt i neli gi ble f or t he st u d y as per 
e xcl usi o n criteria.
D uri n g 
t he st u d y, cli nicall y si g nifica nt ne w ele vati o ns s u g gesti ve of 
m y ocar ditis s h o ul d be assesse d as per  Ta ble 1 1. A d diti o nal tests s h o ul d als o be perf or me d w he n 
cli nicall y i n dicate d.
7. 1. 5
E n d of T re at me nt
S u bjects m ust u n der g o a n E n d - of-Treat me nt visit after disc o nti n uati o n of I MP f or a n y reas o n.  
T his visit s h o ul d be perf or me d wit hi n 7 da y s of t he decisi o n t o disc o nti n ue treat me nt b ut bef ore 
a n y ne w a nti ne o plastic t hera py is starte d (if p ossi ble), w hic he ver occ urs earlier.  See Ta ble 1
t hr o u g h Ta ble 7 f or t he assess me nts t o be perf or me d.
All A Es will be c ollecte d u p u nt il t he 3 0-Da y  Safet y F oll o w- up visit. 
At t he E n d - of-Treat me nt visit, t he f oll o wi n g assess me nts will be perf or me d:
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 5 / 1 5 0

D oc u me ntati o n of A Es a n d c o nc o mita nt me dicati o n a n d pr oce d ures

P h y sical e xa mi nati o n, i ncl u di n g vital si g ns, a n d b o d y wei g ht

1 2- lea d E C Gs

La b o rat or y he mat ol o g y, he m ostase ol o g y , f ull ser u m c he mistr y, pre g na nc y  test, a n d f ull
uri nal y sis.

T 4 a n d T S H

E C O G P S
7. 1. 6
S afet y F oll o w -u p Visit
A ll s u bjects will ha ve a s u bse q ue nt visit sc he d ule d 3 0 da y s ( ± 5 d a y s) after t he last a d mi nistrati o n 
of trial dr u g, a n d will be c o ntacte d b y  ph o ne 9 0 da y s ( ± 1 wee k) after t he last a d mi nistrati o n of 
trial dr u g.  
T he visit will i ncl u de t he f oll o wi n g f ull assess me nt of safet y para meters ( see Ta ble 3 t o Ta ble 6 ):

T he s u bject-re p orte d o utc o mes / Q o L assess me nts will be c o m plete d b y  su bjects pri or t o a n y 
trial-relate d pr oce d ures

D oc u me ntati o n of A Es a n d c o nc o mita nt me dicati o n a n d pr oce d ures

E C O G P S

P h y sical e xa mi nati o n i ncl u di n g vital si g ns, b o dy wei g ht, a n d s ki n t u m or e xte nt

T he la b orat or y he mat ol o g y, he m ostase ol o g y , f ull ser u m c he mistr y, a n d basic uri nal y sis 
( di pstic k pl us micr osc o pic e val uati o n) .  If t he basic uri nal y sis is a b n or mal, a f ull uri nal y sis 
s h o ul d be perf or me d.

A uri ne β - hC G pre g na nc y test (i n fe males of c hil d beari n g p ote ntial) will be c o n d ucte d.

T 4 a n d T S H le vels
All A Es will be d oc u me nte d u ntil t he 3 0- d a y  Safet y Foll o w -u p visit. S u bjects wit h a n o n g oi n g 
S A E at t he 3 0 -d a y  Safet y F oll o w-u p visit m ust be m o nit ore d a n d f oll o we d u p b y  t he I n vesti gat or 
u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 6 / 1 5 0
f oll o w- u p”.
After t his vi sit, all S A Es a n d all treat me nt-relate d n o n-seri o us A Es nee d t o be 
d oc u me nte d u ntil t he 9 0- da y  Safet y F oll o w - u p P h o ne Call.   All s u bjects will be c o ntacte d b y  ph o ne 
9 0 da y s after t he last a d mi nistrati o n of trial dr u g t o c ollect i nf or mati o n o n ne w or o n g oi n g S A Es 
a n d treat me nt-relate d n o n-seri o us A Es.  
If a n ot her a nti ne o plastic t hera py is a d mi nistere d bef ore t he e n d of t his 3 0- d a y  p eri o d, t he 3 0- da y 
Safet y  F oll o w-u p visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y .
7. 1. 7
L o n g -ter m F oll o w-u p
All S A E s o n g oi n g at t he Safet y  Foll o w - u p Ph o ne C all m ust be m o nit ore d a n d f oll o we d u p b y  t he 
I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as 
“l ost t o f oll o w -u p.”
A n y  S A E assesse d as relate d t o I M P m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me 
ela pse d si nce t he last a d mi nistrati o n of t he I M Ps.
S u bjects wit h o ut P D acc or di n g t o R E CIS T v 1. 1 at t he E n d- of-Treat me nt visit will be f oll o we d u p 
f or disease pr o gressi o n ( C T / M RI  sca ns e ver y 6 wee ks [ ± 1 wee k ], a n d after 1 2 m o nt hs, e ver y 
1 2 wee ks [± 1 wee k ] usi n g t he sa me pr oce d ures a n d re vie w as w hile o n-treat me nt) u ntil P D.  
S u bjects will be f oll o we d q uarterl y (t hat is, e ver y 1 2 w ee ks, ± 2 wee ks) f or s ur vi val (i ncl u di n g 
assess me nt of a n y ne w t u m or t hera py) .  The s ur vi val f oll o w- u p of s u bjects will c o nti n ue u ntil 5 
ye ars after t he last s u bject recei ves t he last d ose of a vel u ma b.  U n der s o me circ u msta nces, t he 
s u bjects ma y n ot be f oll o we d f or 5 years f or s ur vi val i n t his st u d y, e g, t he s u bjects ma y be offere d 
t o e nr oll i nt o a r oll-o ver st u d y , or t he S p o ns or ma y  ter mi nate t he st u d y earl y.
7. 1. 8
Bl o o d Dr a ws f or Cli nic al Assess me nts
T he o verall a m o u nt of bl o o d t o be dra w n fr o m a si n gle s u bject wit h a b o d y  wei g ht ≥7 0 k g ( 1 5 4 l bs) 
m ust n ot e xcee d 6 0 m L/ da y a n d 2 0 0 m L  in a n 8- wee k peri o d f or safet y la b orat or y testi n g, 
pre g na nc y  testi n g, 
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
7. 2. 1
De m o gr a p hic D at a
At Scree ni n g , t he f oll o wi n g de m o gra p hic data will be c ollecte d: date of birt h, se x ( ge n der), race, 
a n d et h nicit y.
7. 2. 2
Di a g n osis of G astric C a ncer
T he t u m or disease i nf or mati o n t hat will be d oc u me nte d a n d verifie d at t he Scree ni n g visit f or eac h 
s u bject i ncl u des
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 7 / 1 5 0

Detaile d hist or y  of t he t u m or, i ncl u din g hist o pat h ol o gical dia g n osis, gra di n g, a n d sta gi n g i n 
acc or da nce wit h t he I nter nati o nal U ni o n A gai nst Ca ncer T u m or N o de Metastasis Classificati o n 
of Mali g na nt T u m ors at dia g n osis;

All t hera py use d f or pri or treat me nt of t he t u m or (i ncl u di n g s ur ger y, ra diot hera p y  an d 
c he m ot hera p y, i m m u n ot hera p y);

A n y  ot her c o n diti o ns t hat were 
treate d wit h 
c he m ot hera p y, ra diati o n t hera py, or 
i m m u n ot hera p y;

S m o ki n g hist or y ;

C urre nt ca ncer si g ns a n d s ym pt o ms a n d si de effects fr o m c urre nt a n d pre vi o us a ntica ncer 
treat me nts; an d

C urre nt ca ncer disease stat us.
7. 2. 3
Me dic al Hist or y
I n or der t o deter mi ne t he s u bject’s eli gi bilit y to t he trial, a c o m plete me dical hist or y  of eac h s u bject 
will be c ollecte d a n d d oc u me nte d d uri n g Scree ni n g , w hic h will i ncl u de, b ut ma y n ot be li mite d t o, 
t he f oll o wi n g:

Past a n d c o nc o mita nt n o n mali g na nt diseases a n d treat me nts

All me dicati o ns (i ncl u di n g her bal me dicati o ns) ta ke n a n d pr oce d ures carrie d o ut wit hi n 2 8 da y s 
pri or t o Scree ni n g .
F or t he trial e ntr y, all of t he s u bjects m ust f ulfill all i ncl usi o n criteria descri be d i n Secti o n 5. 3. 1 , 
a n d n o ne of t he s u bjects s h o ul d ha ve a n y e xcl usi o n criteri o n fr o m t he list descri be d i n 
Secti o n 5. 3. 2.
7. 2. 4
Vit al Si g ns a n d P h ysic al E x a mi n ati o n
Vital si g ns i ncl u di n g b o d y  te m perat ure, res pirat or y rate, heart rate (after 5- mi n ute rest), a n d arterial 
bl o o d press u re (after 5- mi n ute rest) will be rec or de d at trial e ntr y .
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g, i n ge neral, a p peara nce, der mat ol o gical, hea d/ nec k, 
p ul m o nar y , car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, m usc ul os keletal s yste m, 
e xtre mities, e yes [i ns pecti o n a n d visi o n c o ntr ol], n ose, t hr oat, a n d ne ur ol o gic stat us) will be 
perf or me d a n d t he res ults d oc u me nte d.
T he E C O G P S will be d oc u me nte d d uri n g t he Scree ni n g P hase a n d at eac h sc he d ule d visit (if t he 
Scree ni n g E C O G P S was perf or me d wit hi n 3 da y s pri or t o Da y 1, it d oes n ot ha ve t o be re peate d 
at Da y 1).
B o d y wei g ht a n d hei g ht will be rec or de d.
D oc u me nt N o.
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 8 / 1 5 0
7. 2. 6
Ot her B aseli ne Assess me nts
All ot her baseli ne meas ure me nts, s uc h as vital si g ns, a c o m plete p h ysical e xa mi nati o n, E C O G P S, 
cli nical la b orat or y para meters, a n d 1 2-lea d E C G, will be assesse d.
7. 3
Effic ac y Assess me nts
Ra di o gra p hic i ma ges a n d p h y sical fi n di n gs ( p hys ical assess me nts) use d f or t he deter mi nati o n of 
disease pr o gressi o n will be e val uate d per I n vesti gat or assess me nt, w hic h will deter mi ne w het her 
t he criteria f or t u m or res p o nse or pr o gressi o n acc or di n g t o R E CI S T v 1. 1 ha ve bee n met , as well 
as deter mi ne t he ti me p oi nt o verall res p o nse a n d date of disease pr o gressi o n acc or di n g t o R E CI S T 
v 1. 1 f or eac h s u bject .
F or eac h s u bject, t u m or res p o nse assess me nt will be perf or me d b y  CT sca n or M RI  (if M RI is 
use d, c hest C T is ma n dat or y ) i ma gi n g of t he c hest/a b d o me n/ pel vis ( pl us ot her re gi o ns as 
s pecifically re q uire d) a n d ot her esta blis he d assess me nts of t u m or b ur de n if C T / M RI i ma gi n g is 
i ns ufficie nt f or t he i n di vi d ual s u bject. A ll t he sca ns perf or me d at baseli ne a n d ot her i ma gi n g 
perf or me d as cli nicall y re q uire d ( ot her s u p p orti ve i ma gi n g) nee d t o be re peate d at s u bse q ue nt visits 
(e xce pt f or brai n sca ns, u nless cli nicall y in dicate d). I n ge neral, lesi o ns detecte d at baseli ne nee d 
t o be f oll o we d usi n g t he sa me i ma gi n g met h o d ol o g y an d prefera bl y t he sa me i ma gi n g e q ui p me nt 
at s u bse q ue nt t u m or e val uati o n visits.
A brai n C T/ M RI sca n is re q uire d at Scree ni n g if n ot perf or me d wit hi n 6 wee ks pri or t o e nteri n g 
t he I n d ucti o n P hase . Brai n C T / M RI  sca ns s h o ul d be perf or me d after Scree ni n g , if cli nicall y 
i n dicate d b y  de vel o p me nt of ne w s pecific s ym pt o ms. 
A b o ne sca n s h o ul d be d o ne as cli nicall y 
i n dicate d at Scree ni n g a n d be yo n d. F or eac h s u bject, t he I n vesti gat or will desi g nate 1 or m ore of 
t he f oll o wi n g meas ures of t u m or stat us t o f oll o w f or deter mi ni n g res p o nse: C T or M RI i ma ges of 
pri mar y  an d/ or metastatic t u m or masses, p h y sical e xa mi nati o n fi n di n gs, a n d t he res ults of ot her 
assess me nts. All a vaila ble i ma ges c ollecte d d uri n g t he trial per i o d will be c o nsi dere d. T he m ost 
a p pr o priate meas ures t o e val uate t he t u m or stat us of a s u bject s h o ul d be use d .  T he meas ure(s) t o 
be c h ose n f or se q ue ntial e val uati o n d uri n g t he trial m ust c orres p o n d t o t he meas ures use d t o 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
9 9 / 1 5 0
d oc u me nt t he pr o gressi ve t u m or stat us t hat q ualifies t he s u bject f or e nr ollme nt . T he t u m or 
res p o nse assess me nt will be assesse d a n d liste d acc or di n g t o t he Sc he d ule of Assess me nts (see
Ta ble 1 ).
Treat me nt decisi o ns will be ma de b y  the I n vesti gat or base d o n t he I nvesti gat or’s assess me nt of 
t u m or stat us.
T he C T/ M RI  sca ns will be c ollecte d u ntil P D is assesse d b y  the In vesti gat or acc or di n g t o 
R E CI S T v 1. 1.  
F or efficac y deter mi nati o n, t u m or res p o nses t o treat me nt will be base d o n t he e val uati o n of t he 
res p o nse of tar get, n o n- tar get, a n d ne w lesi o ns acc or di n g t o R E CI S T v 1. 1 (all meas ure me nts 
s h o ul d be rec or de d i n metric n otati o n, as descri be d i n R E CI S T v 1. 1) as per I n vesti gat or 
assess me n t.

T o assess O R R , t he t u m or b ur de n at baseli ne will be esti mate d a n d use d f or c o m paris o n 
wit h s u bse q ue nt meas ure me nts. 
At baseli ne, t u m or lesi o ns will be cate g orize d i n tar get 
a n d n o n -tar get lesi o ns as descri be d i n R E CIS T v 1. 1.
Res ults f or t hese e val uati ons will be rec or de d wit h as m uc h s pecificit y as p ossi ble s o t hat pre - a n d 
p ost -treat me nt res ults will pr o vi de t he best o p p ort u nit y f or e val uati n g t u m or res p o nse.
A n y  CR or P R s h o ul d be c o nfir me d, prefera bl y at t he sc he d ule d 6- wee k i nter val, b ut n o s o o ner 
tha n 4 wee ks after t he i nitial d oc u me ntati o n of C R or P R. C o nfir mati o n of P R ca n be c o nfir me d 
at a n assess me nt later t ha n t he ne xt assess me nt after t he i nitial d oc u me ntati o n of P R.
T he I n vesti gat or ma y perf or m sca ns i n a d diti o n t o a sc he d ule d trial sca n f or me dical reas o ns or if 
t he I n vesti gat or s us pects P D. S u bjects w h o wit h dra w fr o m t he trial f or cli nical or s ym pt o matic 
deteri orati o n bef ore o bjecti ve d oc u me ntati o n of P D will be re q ueste d t o u n der g o a p pr o priate 
i ma gi n g t o c o nfir m P D. E ver y  eff ort s h o ul d be ma de t o c o nfir m a cli nical dia g n osis of P D b y  
i ma gi n g.  If disc o nti n uati o n occ urs d ue t o pr o gressi o n a n d a defi niti ve dia g n osis/ra di o gra p hic 
c o nfir mati o n is n ot ma de at t he ti me of disc o nti n uati o n, a sec o n d i ma gi n g sca n m a y  be all o we d 
f or c o nfir mati o n o f pr o gressi o n.  If pr o gressi o n at t he sec o n d i ma gi n g sca n is n ot c o nfir me d a n d 
t he s u bject wis hes t o restart, t he s u bject will be all o we d t o c o nti n ue recei vi n g a vel u ma b as l o n g as 
t he y meet t he criteria f or c o nti n uati o n of treat me nt be y o n d pr o gressi o n.
7. 4
Ass ess me nt of S afet y
T he safet y pr ofile of t he trial treat me nts will be assesse d t hr o u g h t he rec or di n g, re p orti n g, a n d 
a nal yz i n g of baseli ne me dical c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, i ncl u di n g vital 
si g ns, a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y a p pare nt t o xicit y  e x perie nce d b y t he s u bject will be perf or me d 
t hr o u g h o ut t he c o urse of t he trial, fr o m t he ti me of t he s u bject’s si g nat ure of i nf or me d c o nse nt. 
Trial site pers o n nel will re p ort a n y A E, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  th e 
s u bject (see Secti o n 7. 4. 1. 2 ). Gi ve n t he i nte n de d mec ha nis m of acti o n of a vel u ma b, partic ular 
atte nti o n will be gi ve n t o A Es t hat ma y  f oll o w t he e n ha nce d T-cell acti vati o n, s uc h as der matitis, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 0 / 1 5 0
c olitis, he patitis, u veitis, or ot her i m m u ne-relate d reacti o ns. O p ht hal m ol o gic e xa mi nati o ns s h o ul d 
be c o nsi dere d, w he n cli nicall y  i n dicate d, f or si g ns or s ym pt o ms of u veitis .
T he re p orti n g peri o d f or A Es is descri be d i n Secti o n  7. 4. 1. 3.
T he safet y assess me nts will be perf or me d acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 1 a n d 
Ta ble 5 ).
7. 4. 1
A d verse E ve nts
7. 4. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. A n 
A E ca n t heref ore be a n y unfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y  of eac h A E.
I n vesti gat ors will refere nce t he N CI-C T C A E v 4. 0 3 ( p u blicati o n date: 1 4 J u ne 2 0 1 0), a descri pti ve 
ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If a partic ular A E’s se verit y is n ot s pecifically gra de d b y t he g ui da nce d oc u me nt, t he I n vesti gat or 
is t o use t he ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5 f oll o wi n g his or her best 
me dical j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g

Gra de 5 or Deat h
Acc or di n g t o S p o ns or c o n ve nti o n, a n y cli nical A E wit h se verity of Gra de 4 or 5 m ust als o be 
re p orte d as a n S A E. H o we ver, a la b orat or y ab n or malit y  of Gra de 4, s uc h as a ne mia or ne utr o pe nia, 
is c o nsi dere d seri o us o nl y if t he c o n diti o n meets o ne of t he seri o us criteria descri be d bel o w.
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 1 / 1 5 0
If deat h occ urs, t he pri mar y  ca use of deat h or e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be rec or de d as t he o utc o me of t his s pecific e ve nt a n d deat h will 
n ot be rec or de d as se parate e ve nt. O nl y , if n o ca use of deat h ca n be re p orte d (f or e xa m ple, s u d de n 
deat h, u ne x plai ne d de at h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o trial treat me nt usi n g 
t he f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o 
t he trial treat me nt i ncl u de, b ut m a y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d 
t he trial treat me nt, k n o w n si de effects of trial treat me nt, me dical hist or y, c o nc o mita nt me dicati o n, 
c o urse of t he u n derl yi n g disease, trial pr oce d ures.
U nrel ate d:
N ot 
reas o na bly 
relate d t o t he I M P.  T he 
A E 
c o ul d 
n ot 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he trial treat me nt u n der st u d y i n t his 
cli nical trial pr ot oc ol.  A reas o na ble alter nati ve e x pla nati o n m ust be a vaila ble.
Rel ate d:
Reas o na bl y 
relate d 
t o 
t he 
I MP.  
 
T he  
A E 
c o ul d 
me dicall y  
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he trial treat me nt u n der st u d y i n t his 
cli nical trial pr ot oc ol.
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (f or e xa m ple, o n a n 
E C G trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o treatme nt disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  
t he I n vesti gat or. If a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n 
(f or e xa m ple, a ne mia, i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue 
itself.
A d verse Dr u g Re acti o n 
A d verse Dr u g Reacti o ns are defi ne d i n t his st u d y as a n y A E s us pecte d t o be relate d t o st u d y 
treat me nt b y t he I n vesti gat or a n d/ or S p o ns or.
S eri o us A d verse E ve nts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a ny d ose:

Res ults i n deat h.

Is life-t hreate ni n g.  ( N ote: T he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is 
at ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca use d deat h 
if it was m ore se vere).

Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n.

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity.

Is a c o n ge nital a n o maly or birt h defect.

Is ot her wise c o nsi dere d t o be me dicall y i m p orta nt.
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 2 / 1 5 0
N ote: 
I m p orta nt me dical e ve nts t hat m a y  not res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y  be c o nsi dere d as S A Es w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y 
ma y  je o par dize t he s u bject or m a y  re q uire 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. 
E xa m ples of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n I M P  is als o 
c o nsi dere d a n S A E, as descri be d i n Secti o n  7. 4. 1. 4.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y trial treat me nt or trial pr oce d ures (f or 
e xa m ple, a n o ver ni g ht sta y t o facilitate t hera p y an d relate d h y drati o n t hera p y  ap plicati o n) are n ot 
c o nsi dere d S A Es. 
H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (f or e xa m ple, u n desira ble effects of a n y ad mi nistere d 
treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es.
Pr o gressi o n of t he disease/ dis or der bei n g st u die d assesse d b y  
meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n (S) A E, u nless t he patie nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d a n d/ or u nless t he o utc o me is fatal wit hi n t he a d verse e ve nt 
re p orti n g peri o d (as defi ne d i n Secti o n 7. 4. 1. 3 ).
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or fre q ue nc y duri n g 
t he trial are defi ne d as b aseli ne m e dical co n diti o ns, a n d are n ot t o be c o nsi dere d A Es.   H o we ver, 
if a d verse si g ns or s ym pt o ms occ ur i n ass ociati o n wit h disease pr o gressi o n, t he n t hese s h o ul d b e 
rec or de d as A Es.
A E/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n
Disease pr o gressi o n rec or de d i n t he c o urse of efficac y  assess me nts o nl y, b ut wit h o ut a n y a d verse 
si g ns or sy m pt o ms s h o ul d n ot be re p orte d as A Es.
H o we ver, if a d verse si g ns or s ym pt o ms occ ur i n ass ociati o n wit h disease pr o gressi o n t he n t hese 
s h o ul d be rec or de d as A Es or re p orte d as S A Es, if t he y meet criteria f or seri o us ness.
A d verse E ve nts of S peci al I nterest
A n y  AE t hat is s us pecte d t o be a p ote ntial ir A E a n d i nf usi o n -relate d reacti o ns will be c o nsi dere d 
a n a d verse e ve nt of s pecial i nterest ( A E SI). 
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 3 / 1 5 0
7. 4. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts
At eac h trial v isit, t he s u bject will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, 
w het her re p orte d b y t he s u bject o r o bser ve d b y t he In vesti gat or.
C o m plete, acc ur ate, a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d i n Secti o n 7. 4. 1. 3 ) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n 
of t he e C R F. All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o priate re p ort
f or m as descri be d i n Secti o n 7. 4. 1. 4.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates [a n d ti mes w he n it is i m p orta nt t o assess t he ti me of A E o nset relati ve t o t he 
rec or de d treat me nt a d mi nistrati o n ti me]), its se verit y, its ca usal relati o ns hi p wit h t he trial 
treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or ot her acti o n ta ke n, i ncl u di n g 
d ose m o dificati o n or disc o nti n uati o n of t he trial treat me nt, a n d its o utc o me. I n ad diti o n, seri o us 
cases s h o ul d be i de ntifie d a n d t he a p pr o priate s eri o us ness criteria d oc u me nte d.
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns.
7. 4. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he s u bject is i nitiall y  incl u de d i n t he 
trial ( date of first si g nat ure of i nf or me d c o nse nt) a n d c o nti n ues f or all S A Es a n d treat me nt-relate d 
n o n- seri o us A Es t hr o u g h t he st u d y’s Safet y F oll o w -u p P h o ne Call, defi ne d as 9 0 da y s ( ± 1 wee k) 
after t he last IM P .
A n y  SA E assesse d as relate d t o t he trial treat me nt m ust be re p orte d w he ne ver it occ urs, irres pecti ve 
of t he ti me ela pse d si nce t he last a d mi nistrati o n.
7. 4. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest a n d D ose -L i miti n g T o xicities
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y ( wit hi n a ma xi m u m 2 4 h o urs after bec o mi n g a ware of t he e ve nt) i nf or m t he S p o ns or 
or its des i g nee usi n g t he S A E Re p ort F or m f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns .
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a S A E R e p ort F or m m ust be pr o vi de d i m me diatel y  t hereafter.  
Rele va nt pa ges fr o m t he eC R F m a y  be pr o vi de d i n parallel (f or e xa m ple, me dical hist or y , 
c o nc o mita nt dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  t he I n vesti gat or, if a vaila ble (f or 
e xa m ple, la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t he i nf or mati o n pr o vi de d 
o n t he S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he e C R F.
T he I n vesti gat or m ust res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (f or e xa m ple, a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 4 / 1 5 0
S p o ns or/ desi g nee m a y  h ave o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee 
a n d (as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h 
e x pe dite d safet y re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us uall y  be ma de via t he res p o nsi ble m o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he Gl o bal Dr u g Safe t y De part me nt of t he S p o ns or m a y  co ntact t he I n vesti gat or 
directl y  t o o btai n clarificati o n or t o o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
7. 4. 1. 5
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics 
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n ve sti g at ors
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularly deat hs) i n v ol vi n g trial s u bjects t o t he I EC/I R B t hat a p pr o ve d t he 
trial.
I n acc or da nce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of “fi n di n gs t hat 
c o ul d a d versel y affect t he safety o f s u bjects, i m pact t he c o n d uct of t he trial or alter t he I EC’s/I R B’s 
a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he trial”.
I n partic ular a n d i n li ne wit h res pecti ve 
re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are b ot h seri o us a n d 
u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (sus pecte d u ne x pecte d 
seri o us ad verse reacti o ns [S U S A Rs ]). T he I nvesti gat or s h o ul d place c o pies of Safet y  Re p orts i n 
t he I n vesti gat or Site File .  Nati o nal re g ulati o ns wit h re gar d t o Safet y Re p ort n otificati o ns t o 
I n vesti gat ors will be ta ke n i nt o acc o u nt.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. 
W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I n vesti gat or Site File.
F or trials c o vere d b y t he E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities re gar di n g 
t he re p orti n g of S A Es/ S U S A Rs/ Safet y Iss ues will be carrie d o ut i n acc or da nce wit h t hat Directi ve 
a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
7. 4. 1. 6
M o nit ori n g of S u bjects wit h A d verse E ve nts
A d verse e ve nts are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he trial (see Secti o n 7. 4. 1. 3 ) 
a n d are assesse d f or fi nal o utc o me at t he 3 0- da y  Safet y F oll o w- u p visit. After t h is visit, S A Es a n d 
treat me nt-relate d n o n-seri o us A Es are rec or de d a n d assesse d c o nti n u o usl y u ntil t he 9 0-d a y Safet y 
F oll o w -u p P h o ne Call . 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 5 / 1 5 0
All S A Es o n g oi n g at t he 9 0 -d a y  Safet y F oll o w - u p Ph o ne C all m ust be m o nit ore d a n d f oll o we d u p 
b y  the I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is 
d oc u me nte d as “l ost t o f oll o w -u p”. Re as o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de 
a n d d oc u me nte d. It is als o t he res p o nsi bilit y of t he I nvesti gat or t o e ns ure t hat a n y necessar y 
a d diti o nal t hera pe utic meas ures a n d f oll o w- u p pr oce d ures are perf or me d.
7. 4. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure
O nl y  pre g na ncies c o nsi dere d by t he I n vesti gat or t o be relate d t o trial treat me nt ( e g, res ulti n g fr o m 
a dr u g i nteracti o n wit h a c o ntrace pti ve me dicati o n) are c o nsi dere d t o be A Es. 
H o we ver, all 
pre g na ncies wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n 7. 4. 1. 3 m ust 
be rec or de d b y  co n ve nti o n i n t he A E pa ge/secti o n of t he e C R F. 
T he sa me r ule a p plies t o 
pre g na ncies i n fe male s u bjects a n d t o pre g na ncies i n fe male part ners of male s u bjects. T he 
I n vesti gat or m ust n otif y t he S p o ns or/ desi g nee i n a n e x pe dite d ma n ner of a n y pre g na nc y usi n g t he 
Pre g na nc y  Re p ort F or m , w hic h m ust be tra ns mitte d acc or di n g t o t he sa me pr ocess as descri be d 
f or S A E re p orti n g i n Secti o n 7. 4. 1. 4.
I n vesti gat ors m ust 
acti vel y foll o w - u p, d oc u me nt, a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he s u bjects are wit h dra w n fr o m t he trial.
T he I nvesti gat or m ust n otif y  the S p o ns or/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y  For m. 
If a n a b n or mal o utc o me occ urs, t he S A E Re p ort F or m will be use d if t h e s u bject s ustai ns a n e ve nt 
a n d t he Pare nt -C hil d/ Fet us A E Re p ort F or m if t he c hil d/fet us s ustai ns a n e ve nt.
A n y  ab n or mal o utc o me m ust be re p orte d i n a n e x pe dite d ma n ner as descri be d i n Secti o n  7. 4. 1. 4,  
w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da y s after deli ver y.
I n the e ve nt of a pre g na nc y  in a s u bject occ urri n g d uri n g t he c o urse of t he trial, t he s u bject m ust 
be disc o nti n ue d fr o m trial treat me nt i m me diatel y . T he S p o ns or/ desi g nee m ust be n otifie d wit h o ut 
dela y  a n d t he s u bject m ust be f oll o we d as me nti o ne d a b o ve.
7. 4. 3
Cli nic al L a b or at or y Assess me nts
All la b orat or y sa m ples t hat are detaile d i n t he Sc he d ule of Assess me nts (see Ta ble 1 t o Ta ble 7 ) 
m ust be c ollecte d, a n d se nt t o t he ce ntral la b orat or y for a nal ys is.  Ser u m β- h C G pre g na nc y  tests 
ma y  be a nalyz e d l ocall y.
Sa m ple f or c o m plete bl o o d c o u nt a n d c ore c he mistr y m ust be a vaila ble a n d re vie we d pri or t o d ose 
a d mi nistrati o n.  Res ults of all ce ntral la b orat or y testi n g will be tra nsferre d t o t he cli nical data base.
Uri nal y sis a n d u ri ne p re g na nc y testi n g will be d o ne l ocall y.
L ocal la b orat or y  sa m ples ma y be dra w n a n d if c ollecte d are re q uire d t o be rec or de d i n t he e C R Fs.
I n t he case of li ver f u ncti o n test (L F T ) ele vati o ns ( A S T, A L T a n d/ or t otal bilir u bi n) re q uiri n g 
a d diti o nal la b dra ws (acc or di n g t o g ui deli nes set f ort h i n Ta ble 1 1 Ma na ge me nt of ir A Es), a n 
u nsc he d ule d la b dra w s h o ul d be se nt t o t he ce ntral la b orat or y  f or a nalys is.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 6 / 1 5 0
Car diac tr o p o ni n le vels will be c ollecte d fr o m R e- baseli ne u p t o 1 2 wee ks i n t he M ai nte na nce 
P hase.  Car diac tr o p o ni n le vels will be e val uate d ce ntrall y .  Local la b orat ories ma y  be use d at t he 
discreti o n of t he I n vesti gat or as cli nicall y nee de d f or safet y m a na ge me nt/treat me nt decisi o n of t he 
s u bject. Meas ure me nt of c T n T is preferre d, h o we ver c T nI m a y  be s u bstit ute d w here c T n T is n ot 
a vaila ble at t he l ocal la b orat or y. T he sa me s u b u nit (c T n T or c T nI) meas ure d at t he Re- baseli ne
visit s h o ul d be meas ure d c o nsiste ntl y thr o u g h o ut t he st u d y in eac h patie nt . 
At t he Re -baseli ne 
visit , cli nicall y si g nifica nt p ositi ve res ults s h o ul d be f urt her assesse d as per l ocal S O C t o r ule-o ut 
c o nc urre nt car diac c o n diti o ns w hic h w o ul d ma ke t he patie nt i neli gi ble f or t he st u d y as per 
e xcl usi o n criteria.
D uri n g 
t he st u d y, cli nicall y si g nifica nt ne w ele vati o ns s u g gesti ve of 
m y ocar ditis s h o ul d be assesse d as per  Ta ble 1 1. A d diti o nal tests s h o ul d als o be perf or me d w he n 
cli nicall y i n dicate d.
T he re p ort of t he res ults m ust be retai ne d as a part of t he s u bject’s me dical rec or d or s o urce 
d oc u me nts.  Bl o o d sa m ples f or t he f ull safet y t ests liste d i n Ta ble 1 2 will be ta ke n fr o m n o nfaste d 
s u bjects d uri n g t he Scree ni n g P hase ( 2 8 d a y s pri or t o e nteri n g t he I n d ucti o n P hase ); d uri n g t he 
T reat me nt P hase as s pecifie d i n Ta ble 1,  Ta ble 2,  Ta ble 3,  Ta ble 4,  Ta ble 5, Ta ble 6 ; at t he 
E n d - of-Treat me nt visit ; a n d at t he Safet y  Foll o w - u p visit.  T he T 4, T S H, a n d uri nal y sis will o nl y  
be assesse d at t he ti me p oi nts defi ne d i n Ta ble 1, Ta ble 2, Ta ble 3, Ta ble 4, Ta ble 5 , a n d Ta ble 6.   
If c o nfir mati o n of a s u bject’s p ost me n o pa usal stat us is necessar y , a n F S H le vel will als o be 
perf or me d at Scree ni n g , see Secti o n 7. 1.
T a ble 1 2
Cli nic al L a b or at or y Assess me nts
F ull C h e mi str y
C or e C h e mi str y a
H e m at ol o g y
Al b u mi n
Al k ali n e p h o s p h at a s e
A b s ol ut e l y m p h o c yt e c o u nt
Al k ali n e p h o s p h at a s e
A L T
A b s ol ut e n e utr o p hil c o u nt
A L T
A m yl a s e
H e m at o crit
A m yl a s e
A S T
H e m o gl o bi n
A S T
B U N/t ot al ur e a
Pl at el et c o u nt
G G T
C al ci u m
R B C c o u nt
B U N/t ot al ur e a
C hl ori d e
W h it e bl o o d c ell c o u nt a n d diff er e nti al c o u nt
C al ci u m
Cr e ati n e ki n a s e
R eti c ul o c yt e s
C hl ori d e
Cr e ati ni n e
M C H
C h ol e st er ol
Gl u c o s e
M e a n c or p u s c ul ar v ol u m e
Cr e ati n e ki n a s e
L D H
M C H C
Cr e ati ni n e
Li p a s e
C R P
P h o s p h or u s/ P h o s p h at e s
Gl u c o s e
M a g n e si u m
H e m o st a s e ol o g y
L D H
P ot a s si u m
a P T T
Li p a s e
S o di u m
Pr ot hr o m bi n ti m e/I N R
P h o s p h or u s/ P h o s p h at e s
T ot al bilir u bi n
M a g n e si u m
B a si c Uri n al y si s ( di p sti c k, i n cl u di n g m a cr o s c o pi c 
a p p e ar a n c e, bilir u bi n, bl o o d, c ol or, gl u c o s e, 
k et o n e s, l e u k o c yt e e st er a s e, nitrit e, p H, pr ot ei n, 
s p e cifi c gr a vit y, ur o bili n o g e n)
P ot a s si u m
S o di u m
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 7 / 1 5 0
F ull C h e mi str y
C or e C h e mi str y a
H e m at ol o g y
T ot al bilir u bi n
F ull uri n al y si s ( di p sti c k pl u s mi cr o s c o pi c e v al u ati o n) 
t o b e p erf or m e d o nl y at t h e S cr e e ni n g, 
R e -b a s eli n e, a n d E n d of Tr e at m e nt vi sit s a n d a 
b a si c uri n al y si s pri or t o e a c h a d mi ni str ati o n of t h e 
tri al tr e at m e nt at We e k 1, W e e k 7, W e e k 1 3, e v er y 
1 2 w e e k s t h er e aft er, a n d at 3 0 -d a y S af et y 
F oll o w -u p vi sit.
T ot al pr ot ei n
Uri c a ci d
T ot alit y of bi n di n g 
Tri gl y c eri d e s
T S H a n d T 4
H or m o n e
F S H ( y e s/ n o if a p pli c a bl e)
, A L T = al a ni n e a mi n otr a n sf er a s e, a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e, 
A S T = a s p art at e a mi n otr a n sf er a s e, B U N = bl o o d ur e a nitr o g e n, C R P = C-r e a cti v e pr ot ei n, F S H =f olli cl e- sti m ul ati n g 
h or m o n e, G G T = g a m m a -gl ut a m yltr a n sf er a s e, I N R =i nt er n ati o n al n or m ali z e d r ati o, L D H =l a ct at e d e h y dr o g e n a s e, 
M C H = m e a n c or p u s c ul ar h e m o gl o bi n, M C H C = m e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n, R B C =r e d bl o o d c ell, 
T S H =t h yr oi d -sti m ul ati n g h or m o n e, T 4 =fr e e t h yr o xi n e.
a.
C or e s er u m c h e mi stri e s.
If a s u bject has a cli nicall y si gnifica nt a b n or mal la b orat or y test val ue t hat is n ot prese nt at baseli ne, 
t he test will be re peate d wee kl y a n d t he s u bject will be f oll o we d u ntil t he test val ue has ret ur ne d 
t o t he n or mal ra n ge or t he I n vesti gat or has deter mi ne d t hat t he a b n or mality is c hr o nic or sta ble.
7. 4. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
Vital si g ns i ncl udi n g b o d y  te m perat ure, res pirat or y rate, heart rate (after 5- mi n ute rest), a n d arterial 
bl o o d press ure (after 5 -mi n ute rest) w ill be rec or de d at trial e ntr y.
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g ge neral a p peara nce, der mat ol o gical, hea d/ nec k, 
p ul m o nar y , car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, m usc ul os keletal s yste m, 
e xtre mities, e yes [i ns pecti o n a n d visi o n c o ntr ol], n ose, t hr oat, a n d ne ur ol o gic stat us) will be 
perf or me d at Scree ni n g a n d at s u bse q ue nt visits as d oc u me nte d i n t he Sc he d ule of Assess me nts 
a n d t he res ults d oc u me nte d i n t he e C R F.  A b n or mal fi n di n gs are t o be reassesse d at s u bse q ue nt 
visits.
T he E C O G P S will be d oc u me nte d d uri n g t he Scree ni n g P hase a n d at eac h sc he d ule d visit (if t he 
Scree ni n g E C O G P S was perf or me d wit hi n 3 da y s pri or t o Da y 1, it d oes n ot ha ve t o be re peate d 
at Da y 1) a n d d oc u me nte d i n t he e C R F.
B o d y wei g ht will be rec or de d at Scree ni n g a n d at s u bse q ue nt visits as i n dicate d i n t he Sc he d ule of 
Assess me nts a n d d oc u me nte d i n t he e C R F. Hei g ht will be meas ure d at Scree ni n g o nl y .
A 1 2 -lea d E C G will be rec or de d as i n dicate d i n t he Sc he d ule of Assess me nts.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 8 / 1 5 0
All ne wl y  dia g n ose d or w orse ni n g c o n diti o ns, si g ns, a n d s ym pt o m s o bser ve d fr o m Scree ni n g , 
w het her relate d t o trial treat me nt or n ot, are t o be re p orte d as A Es.
F or fe male s u bjects of c hil d beari n g p ote ntial, a ser u m β- h C G pre g na nc y  test will be carrie d o ut 
d uri n g t he Scree ni n g P hase . A uri ne or ser u m β- h C G test will b e perf or me d at t he visits as 
i n dicate d i n t he Sc he d ules of Assess me nts . Res ults of t he m ost rece nt pre g na nc y  test has t o be 
a vaila ble pri or t o t he ne xt d osi n g of trial treat me nt. S u bjects w h o are p ost me n o pa usal (a ge-relate d 
a me n orr hea ≥ 1 2 c o nsec uti ve m o nt hs a n d F S H > 4 0 mI U/ m L), or w h o ha ve u n der g o ne 
h y sterect o my or bilateral o o p h orect o m y are e xe m pt fr o m pre g na nc y testi n g.
7. 5. 1
B o d y Fl ui d(s)
W h ole bl o o d s ufficie nt t o pr o vi de 0. 2 m L  of ser u m will be c ollecte d f or 
.  F urt her 
details will be s u m marize d i n t he La b orat or y  Ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 0 9 / 1 5 0
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 0 / 1 5 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 1 / 1 5 0
7. 7
Ot her Assess me nts
7. 7. 1
S u bject- re p orte d O utc o mes / Q u alit y of Life
S u bject -re p orte d o utc o mes / Q o L  will be assesse d b y t he E Q- 5 D-5 L , a n d E O R T C Q LQ- C 3 0, a n d  
m o d ule Q L Q -S T O 2 2. 
Q uesti o n naires will be c o m plete d b y  the s u bject at Scree ni n g a n d as 
i n dicate d w hile o n trial treat me nt (see Ta ble 1 t o Ta ble 6 f or detaile d sc he d ule f or eac h re gi me n). 
S u bject -re p orte d o utc o mes will als o be assesse d at t he Disc o nti n uati o n/ E n d of Treat me nt visit a n d 
t he Safety F oll o w -u p visit ( details will be pr o vi de d i n t he St u d y  Ma n ual).  
T he s u bject-re p orte d o utc o mes / Q o L q uesti o n naires s h o ul d be c o m plete d b y  the s u bject pri or t o 
a n y of t he ot her trial-relate d assess me nts bei n g perf or me d, t hat is, p h y sical e xa mi nati o ns, bl o o d 
dra ws, trial treat me nt a d mi nistrati o n, etc.  S u bjects will use a vali date d electr o nic ta blet or 
vali date d site pa d t o rec or d t heir res p o nses t o t hese q uesti o n naires.  In rare a nd e xte n uati n g 
circ u msta nces w he n a n electr o nic ta blet or site pa d is n ot a vaila ble or n ot w or ki n g pr o perl y, 
c ollecti o n o n vali date d pa per q uesti o n naires m a y  be all o we d t o e ns ure data are c ollecte d a n d n ot 
l ost.
Data will be c ollecte d b y t he C R O a n d h o use d i n a data base. A nal ys is of t he q uesti o n naires will 
be descri be d i n t he statistical a nal ys is pla n (S A P ).
8
St atistics
8. 1
S a m ple Size
T he sa m ple size of t his st u d y is base d o n c o m pari n g mai nte na nce t hera p y a vel u ma b vers us 
c o nti n uati o n of first-li ne c he m ot hera p y i n ter ms of t he t w o pri mar y  h yp ot heses (for hierarc h y  of 
m ulti ple testi n g pr oce d ure, see Secti o n 8. 5. 1 ) of O S i n all ra n d o mize d s u bjects a n d i n P D -L 1 + 
s u bjects.
T he st u d y  will be c o nsi dere d s uccessf ul if at least o ne of t he t w o n ull h y p ot heses f or O S i n eit her 
all ra n d o mize d s u bjects or i n P D -L 1 + s u bjects, c o ul d be rejecte d as statisticall y si g nifica nt. A n 
i m bala nce d t ype I err or all ocati o n will be use d f or t he t w o pri mar y h y p ot heses a n d c o ntr ol o verall 
fa mil y wise t ype I err or rate at 2. 5 % ( 1-si de d) wit h 0. 5 % ( 1-si de d) all ocate d t o P D -L 1 + s u bjects
a n d 2 % (1- si de d) all ocate d t o all ra n d o mize d s u bjects . T he sa m ple size f or t his st u d y is dri ve n b y 
t he f oll o wi n g ass u m pti o ns f or t he pri mar y e n d p oi nt of O S:

E x p o ne ntial distri b uti o n of O S ;

1: 1 ra n d o mizati o n;

Dr o p -o ut rate = 5 %;

U nif or m accr ual o ver a peri o d of 1 8 m o nt hs;

A f oll o w - u p ti me of 1 8 m o nt hs after ra n d o mizati o n of t he last s u bject;
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 2 / 1 5 0

F or all ra n d o mize d s u bjects recei vi n g a vel u ma b, me dia n O S is 1 5 m o nt hs;

F or P D -L 1 + s u bjects recei vi n g a vel u ma b, t he me dia n O S is 1 9. 3 m o nt hs;

F or all ra n d o mize d s u bjects a n d P D -L 1 + s u bjects recei vi n g first-li ne c he m ot hera p y, t he 
me dia n O S is 1 0. 5 m o nt hs.
T his c orres p o n ds t o a h azar d rati o ( H R) of 0. 7 f or O S i n all ra n d o mize d s u bjects a n d 0. 5 4 f or O S 
i n P D-L 1 + s u bjects. At pla n ni n g sta ge, it wa s ass u me d t hat t he pre vale nce of P D-L 1 + s u bjects i n 
all ra n d o mize d s u bjects is 3 5 %.  D ue t o a l o wer pre vale nce of P D-L 1 + s u bjects i n t he st u d y t ha n 
i nitiall y e xpecte d, t he tar gete d 1 1 2 O S e ve nts i n P D -L 1 + s u bjects f or t he pri mar y a nal ys is will n ot 
be reac he d d uri n g t he st u d y.  T he pri mar y a nal ys is of O S i n P D-L 1 + s u bjects will be c o n d ucte d at 
t he ti me of t he pri mar y a nal ysis of O S i n all ra n d o mize d s u bjects wit h p o wer less t ha n 8 0 %.
T he ass u me d dr o p - o ut rate f or O S is base d o n res pecti ve e x perie nce i n pre vi o us cli nical st u dies.
T he act ual n u m ber of s u bjects e nr olle d i n t he I nd ucti o n P hase will be dr i ve n b y  the o bser ve d 
i n d ucti o n fail ure rates, a n d will be s uc h t o all o w f or a p pr o xi matel y 4 6 6 s u bjects t o be ra n d o mize d 
i nt o t he treat me nt ar m i n t he Mai nte na nce P hase.  At t he ti me of t his pr ot oc ol a me n d me nt, s u bject 
e nr oll me nt i nt o t he Mai nte na nce P hase is c o m plete, wit h a t otal of 4 9 9 s u bjects ra n d o mize d i nt o 
t he Mai nte na nce P hase .
T he data c ut -off f or t he pri mar y a nal ysis wil l ta ke place o n a pr os pecti vely -deter mi ne d date, u p o n 
w hic h t he tar get n u m ber of 3 5 6 O S e ve nts i n all ra n d o mize d s u bjects are pr ojecte d t o ha ve bee n 
reac he d, a n d t he last s u bject ra n d o mize d i n t he Mai nte na nce P hase has bee n f oll o we d f or at least 
1 8 m o nt hs fr o m ra n d o mizati o n.
F or O S
i n all ra n d o mize d s u bjects, 3 5 6 O S e ve nts are re q uire d t o ac hie ve 9 0 % p o wer of t he 
l o g-ra n k test at a 1- si de d o verall 2 % al p ha le vel. T his calc ulati o n i ncl u des o ne i nteri m efficac y 
a nal ys is a n d ass u mes it will be perf or me d after 7 5 % of e ve nts ha ve bee n o bser ve d. T he i nteri m 
a n d pri mar y  a nal ys es will f oll o w a se q ue ntial al p ha s pe n di n g f u ncti o n a p pr oac h de vel o pe d b y  Lan 
a n d De Mets, usi n g a n O’ Brie n a n d Fle mi n g b o u n dar y  fu ncti o n. A p pl y i n g t his a p pr oac h wit h a n 
ass u me d 2 6 7 a n d 3 5 6 o bser ve d e ve nts res pecti vel y, a 1- si de d si g nifica nce le vel of 0. 0 0 7 2 f or t he 
i nteri m a nal ysis a n d 0. 0 1 7 8 f or t he fi nal a nal ys is w ill preser ve a n o verall t ype I err or rate of 2 % 
f or t he O S i n all ra n d o mize d s u bjects.
T he si m ulati o ns wit h t he a b o ve ass u m pti o ns ha ve bee n perf or me d t o assess t he o verall p o wer f or 
t he tar get n u m ber of O S e ve nts a n d ti mi n g of i nteri m a n d pri mar y  anal yses. T he c orrelati o n 
bet wee n test statistics f or O S i n all ra n d o mize d s u bjects a n d O S i n P D -L 1 + s u bjects (s q uare r o ot 
of pre vale nce = √0. 3 5 ) has bee n c o nsi dere d. T he c o m plete m ulti ple testi n g pr oce d ure f or t he t w o 
O S h y p ot heses ( details of m ulti ple testi n g pr oce d ure are i n Secti o n 8. 5. 1 ) usi n g t he i nteri m test 
statistics f or all ra n d o mize d s u bjects a n d test statistics f or all ra n d o mize d s u bjects a n d P D -L 1 + 
s u bjects at pri mar y anal ysis ha ve bee n a p plie d i n t he si m ulati o ns. If e xactl y 3 5 6 O S e ve nts i n all 
ra n d o mize d s u bjects a n d 1 1 2 O S e ve nts i n P D -L 1 + s u bjects are reac he d, the si m ulati o ns s h o we d 
a pr o ba bilit y  of rejecti o n at least o ne h y p ot hesis of 9 3. 5 %. 
T he n ull h y p ot hesis of O S i n all 
ra n d o mize d s u bjects is rejecte d i n ar o u n d 9 0. 9 % of t he si m ulati o ns, t he n ull h y p ot hesis of O S i n 
P D -L 1 + s u bjects is rejecte d i n ar o u n d 8 0. 3 % of t he si m ulati o ns.
Calc ulati o ns were perf or me d usi n g E A S T ® versi o n 6. 3, C y tel I nc a n d R s oft ware .
D oc u me nt N o.
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 3 / 1 5 0
8. 2
R a n d o miz ati o n
T he st u d y is a ra n d o mize d, acti ve -c o ntr olle d, a n d o pe n -la bel st u d y.  Eli gi ble s u bjects will be 
ra n d o ml y assi g ne d i nt o eit her t he a vel u ma b ar m or c o ntr ol gr o u p i n a 1: 1 rati o after 1 2- wee k
c he m ot hera p y i n t he In d ucti o n P hase. T he ra n d o mizati o n will be stratifie d b y re gi o n (Asia vers us 
n o n- Asia) . T he p ur p ose of t he stratificati o n is t o e ns ure a bala nce of t he treat me nt ar ms wit hi n 
eac h re gi o n. Ra n d o mizati o n will occ ur usi n g t he I WR S as descri be d i n Secti o n  2 u p o n c o m pleti o n 
of t he I n d ucti o n P hase a n d deter mi nati o n of s u bject eli gi bilit y .  
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nt
T he pri mar y  e n d p oi nt of t he trial is O S, defi ne d as t he ti me (i n m o nt hs) fr o m ra n d o mizati o n t o t he 
date of deat h, re gar dless of t he act ual ca use of t he s u bject’s deat h .
T he s ur vi val f oll o w- u p will c o nti n ue u ntil 5 ye ars after t he last s u bject recei ves t he last d ose of 
a vel u ma b.  F or s u bjects w h o are still ali ve at t he ti me of data a nal ys is or w h o are l ost t o f oll o w-u p, 
O S will be ce ns ore d at t he last rec or de d date t hat t he s u bject is k n o w n t o be ali ve ( date of last 
c o ntact, last visit date, date of last ra n d o mize d treat me nt a d mi nistrati o n, or date of last sca n, 
w hic he ver is t he latest) as of t he data c ut -off date f or t he a nal y sis.  
8. 3. 2
Sec o n d ar y E n d p oi nts
T he sec o n dar y e n d p oi nts , w hic h c orres p o n d t o t he Mai nte na nce 
P hase i n t his trial, are t he 
f oll o wi n g:

P F S i n all ra n d o mize d s u bjects accor di n g t o R E CI S T v 1. 1, per I n vesti gat or assess me nt

B O R i n all ra n d o mize d s u bjects acc or di n g t o R E CIS T v 1. 1 , per I n vesti gat or assess me nt

S u bject -re p orte d o utc o mes / Q o L

Safet y  a n d t olera bilit y i n all s u bjects.
8. 3. 2. 1
Pr o gressi o n -Free S ur vi v al
Pr o gressi o n -Free S ur v i val, defi ne d as t he ti me (i n m o nt hs) fr o m ra n d o mizati o n t o t he date of t he 
first d oc u me ntati o n of o bjecti ve P D or deat h d ue t o a n y ca use ( w hic he ver occ urs first), is t he first 
ke y  sec o n dar y en d p oi nt of t he st u d y. T he date of t he first d oc u me nte d o bjecti ve P D will be 
deter mi ne d acc or di n g t o R E CI S T v 1. 1 base d o n In vesti gat or res p o nse assess me nt.
T he P F S data will be ce ns ore d o n t he date of t he last a de q uate t u m or assess me nt f or s u bjects w h o 
d o n ot ha ve a n e ve nt ( P D or deat h), f or s u bjects w h o start ne w a ntica ncer treat me nt pri or t o a n 
e ve nt, or f or s u bjects wit h a n e ve nt after 2 or m ore missi n g t u m or assess me nts.  S u bjects w h o d o 
n ot ha ve a baseli ne t u m or assess me nt or w h o d o n ot ha ve a n y p ost -baseli ne t u m or assess ments 
will be ce ns ore d o n t he date of ra n d o mizati o n u nless deat h occ urre d o n or bef ore t he ti me of t he 
sec o n d pla n ne d t u m or assess me nt, i n w hic h case t he deat h will be c o nsi dere d a n e ve nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 4 / 1 5 0
8. 3. 2. 2
Best O ver all Res p o nse
Best O verall Res p o nse i n Mai nte na nce P hase is t he ke y sec o n dar y en d p oi nt f or t he st u d y.  T he 
c o nfir me d B O R will be deter mi ne d acc or di n g t o R E CI S T v 1. 1, per I n vesti gat or assess me nt, a n d 
statisticall y e val uate d as t he O R R.  B O R is defi ne d as t he best res p o nse o btai ne d a m o n g all t u m or 
assess me nt visits after t he date of ra n d o mizati o n u ntil d oc u me nte d disease pr o gressi o n.
F or a B O R of P R or C R, c o nfir mati o n of t he res p o nse acc or di n g t o R E CI S T v 1. 1 will be re q uire d, 
prefera bl y at t he re g ularl y sc he d ule d 6 -wee k assess me nt i nter val b ut n o s o o ner t ha n 4 wee ks a fter 
t he i nitial d oc u me ntati o n of C R or P R.  Co nfir mati o n of P R ca n be c o nfir me d at a n assess me nt 
later t ha n t he ne xt assess me nt after t he i nitial d oc u me ntati o n of P R.  A BO R of S D re q uires t hat 
a n o verall res p o nse of S D has bee n deter m i ne d at a ti me p oi nt at least 6 wee ks after ra n d o mizati o n.
T he O R R is defi ne d as t he pr o p orti o n of all ra n d o mize d s u bjects wit h a c o nfir me d B O R of P R or 
C R acc or di n g t o R E CI S T v 1. 1 , as per I n vesti gat or assess me nt.
8. 3. 2. 3
S u bject- Re p orte d O utc o mes / Q u alit y of Life
T he f oll o wi n g s u bject-re p orte d o utc o mes are f urt her sec o n dar y en d p oi nts f or m ai nte na nce 
t hera py :

E Q - 5 D-5 L

E O R T C Q L Q- C 3 0

E O R T C Gastric Ca ncer M o d ule Q L Q- S T O 2 2 .
8. 3. 3
S afet y E n d p oi nts
Safet y  en d p oi nts i ncl u de A Es, 
p h y sical e xa mi nati o ns, cli nical la b orat or y assess me nts, 
c o nc o mita nt me dicati o ns, vital si g ns, E C G para meters, a n d E C O G P S .
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 5 / 1 5 0
8. 4
A n al ysis Sets
Scree ni n g A n al ysis Set
T he Scree ni n g A nal ys is Set i ncl u des all s u bjects w h o si g ne d t he I C F.
I nte nti o n-t o-Tre at (I T T) A n al ysis Set
T he I T T A nal ys is Set will i ncl u de all s u bjects w h o were ra n d o ml y assi g ne d t o Mai nte na nce P hase 
st u d y treat me nt. A nal ys es perf or me d o n t he I TT A nal y sis Set will be perf or me d acc or di n g t o
s u bjects’ treat me nt ar ms, as ra n d o mize d. T he I TT A nal ys is Set will be t he pri mar y  an al y sis set 
f or all pri mar y a n d sec o n dar y efficac y e n d p oi nts.
Per -Pr ot oc ol A n al ysis Set
T he Per- Pr ot oc ol ( P P) A nal y sis Set will i ncl u de all I TT s u bjects w h o di d n ot ha ve cli nicall y 
i m p orta nt pr ot oc ol de viati o ns . Cli nicall y  i m p orta nt pr ot oc ol de viati o ns will be s pecifie d i n t he 
trial S A P.  
P D -L 1 + A n al ysis Set
T he P D -L 1 + A nal ys is Set is a s u bset of t he I TT A nal y sis Set c o nsisti n g of all P D -L 1 + s u bjects 
deter mi ne d b y t he P D -L 1  I H C 7 3-1 0 p har m D x c o m pa ni o n dia g n ostic assa y.  A nal yses perf or me d 
o n t he P D -L 1 +
A nal ys is Set will be perf or me d acc or di n g t o s u bjects’ treat me nt ar ms as 
ra n d o mize d.  One of t w o pri mar y  hy p ot heses f or O S s u bjects will be teste d i n t he P D -L 1 + A nal ys is 
Set.
He alt h -Rel ate d Q u alit y of Life A n al ysis Set 
T he H R Q o L A nal ys is Set is a s u bset o f t he I T T A nal y sis Set a n d i ncl u des all I T T s u bjects w h o 
meet b ot h of t he f oll o wi n g criteria:

Re -baseli ne H R Q o L assess me nt c o m plete d

At least o ne M ai nte na nce P hase H R Q o L assess me nt c o m plete d .
Re -baseli ne H R Q o L assess me nt occ urs f oll o wi n g c o m pleti o n of I n d ucti o n P hase c he m ot hera p y 
treat me nt at t he Re-baseli ne visit, w hic h s h o ul d occ ur wit hi n t he 1 0 -d a y  Re- baseli ne peri o d. 
Mai nte na nce P hase H R Q o L assess me nt is defi ne d as H R Q o L q uesti o n naires c o mplete d after t he 
first d ose of Mai nte na nce 
P hase st u d y treat me nt f or s u bjects w h o recei ve d a vel u ma b or 
c o nti n uati o n of I n d ucti o n P hase c he m ot hera p y treat me nt, a n d H R Q o L q uesti o n naires c o m plete d 
after date of ra n d o mizati o n f or s u bjects o n B S C- o nl y . 
S afet y f or I n d ucti o n P h ase ( S afet y-I n d ucti o n) A n al ysis Set
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 6 / 1 5 0
T he Safet y- I n d ucti o n A nal y sis Set will i ncl u de all s u bjects w h o were e nr olle d i nt o t he st u d y (ie, 
si g ne d i nf or me d c o nse nt) a n d recei ve d at least 1 d ose of I n d ucti o n P hase c he m ot hera p y.  A n al ysis 
f or t he Safet y- I n d ucti o n A nal ysis Set will be s u m marize d f or all s u bjects as o ne si n gle gr o u p.
S afet y f or M ai nte n a nce P h ase ( S afet y -M ai nte n a nce) A n al ysis Set
T he Safet y- Mai nte na nce A nal ys is Set will i ncl u de all s u bjects w h o recei ve d at least 1 d ose of 
ra n d o mize d treat me nt or w h o were assi g ne d t o recei ve B S C - o nl y i n t he Mai nte na nce P hase .  
A nal y ses perf or me d o n t he Safet y- Mai nte na nce A nal y sis Set will c o nsi der s u bjects as treate d.
8. 5
Descri pti o n of St atistic al A n al yses
8. 5. 1
Ge ner al C o nsi der ati o ns
F ull details of all pla n ne d a nal yses will be descri be d i n t he trial S A P.   T he S A P ma y  mo dif y  the 
pla ns o utli ne d i n t he pr ot oc ol; h o we ver, a n y maj or m o dificati o ns of pla n ne d a nal ys es will be 
reflecte d i n a pr ot oc ol a me n d me nt if it is m o difie d bef ore data u n bli n di n g.  If, after t he trial is 
u n bli n de d, c ha n ges are ma de t o t he S A P, t he n t hese de viati o ns t o t he pla n will be d oc u me nte d i n 
t he Cli nical Trial Re p ort.
All safety a n d efficac y en d p oi nts will be s u m marize d b y  treat me nt ar m wit h t he e xce pti o n of 
e n d p oi nts c orres p o n di n g t o t he I n d ucti o n P hase w hic h will be s u m marize d b y  total n u m ber of 
s u bjects.  
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss trial ce nters.  
T he “ce nter” fact or will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal ys es d ue t o t he 
hi g h n u m ber of partici pati n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of s u bjects 
ra n d o mize d at eac h ce nter.
I n ge neral, c o nti n u o us varia bles will be s u m marize d usi n g n u m ber ( n), mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m, a n d ma x i m u m. Cate g orical varia bles will be s u m marize d usi n g fre q ue nc y 
c o u nts a n d perce nta ges.
T he calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of s u bjects i n t he A nal y sis S et of 
i nterest, u nless ot her wise s pecifie d i n t he trial S A P.
B aseli ne
F or t he I n d ucti o n P hase, baseli ne is defi ne d as t he last meas ure me nt ta ke n pri or t o t he first d ose of 
treat me nt d uri n g t he I n d ucti o n P hase. F or t he Mai nte na nce P hase , baseli ne is defi ne d as t he last 
meas ure me nt ta ke n pri or t o t he first d ose of ra n d o mize d treat me nt f or safet y e n d p oi nts a n d t he last 
meas ure me nt ta ke n pri or t o ra n d o mizati o n f or efficac y en d p oi nts .  If s uc h a val ue is missi n g, t he 
last meas ure me nt pri or t o t he first d ose of ra n d o mize d treat me nt will be use d as t he baseli ne 
meas ure me nt
f or t he efficac y anal ys is e xce pt f or a nal ys es of t u m or assess me nts data w here t he 
B aseli ne assess me nt w o ul d be c o nsi dere d missi n g . F or s u bjects w h o recei ve d B S C -o nl y , baseli ne 
is defi ne d as t he last meas ure me nt ta ke n pri or t o ra n d o mizati o n f or b ot h safety a n d efficac y 
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 7 / 1 5 0
e n d p oi nts. B aseli ne f or heart rate a n d Q Tc assess me nts will be deri ve d fr o m t he visit w here b ot h
heart rate a n d Q T are n ot missi n g.
O n -Tre at me nt
F or t he I n d ucti o n P hase, t he o n- treat me nt peri o d is defi ne d as t he ti me fr o m t he first a d mi nistrati o n 
of c he m ot hera p y t o t he last a d mi nistrati o n of c he m ot hera p y + 3 0 d a y s, t he earliest date of 
s u bse q ue nt a ntica ncer dr u g t hera p y - 1 d a y , or t he date of ra n do mizati o n i nt o t he Mai nte na nce 
P hase - 1 da y , w hic he ver occ urs first.
F or s u bjects ra n d o mize d t o acti ve Mai nte na nce P hase st u d y me dicati o n, the o n- treat me nt peri o d 
is defi ne d as t he ti me fr o m t he first st u d y treat me nt a d mi nistrati o n t o t he last st u d y treatme nt 
a d mi nistrati o n date + 3 0 da y s or t he earliest date of s u bse q ue nt a ntica ncer dr u g t hera py mi n us 1 
da y, w hic he ver occ urs first, u nless ot her wise state d. F or s u bjects w h o recei ve d B S C -o nl y , st u d y 
treat me nt is c o nsi dere d t o start o n t he da y  of ra n d o mizati o n a n d e n d o n t he earliest date fr o m 
a m o n g t he f oll o wi n g: t he date gi ve n o n t he E n d of Assess me nt a n d St u d y  Ter mi nati o n e C R F pa ges, 
date of deat h .
M ulti ple C o m p aris o n Str ate g y
A hierarc h ical test strate g y will be use d t o c o ntr ol t he o verall t ype I err or rate f or t he pri mar y 
e n d p oi nt O S a n d ke y sec o n dar y e n d p oi nts of P F S a n d B O R i n t he f oll o wi n g hierarc hical or der:
1: O S i n t he IT T A nal y sis Set a n d t he P D -L 1 + A nal y sis Set i n t he Mai nte na nce P hase
2: P F S i n t he IT T A nal ysis Set i n t he Mai nte na nce P hase
3 : B O R i n t he I T T A nal ysis Set i n t he Mai nte na nce P hase
T he o verall 2. 5 % ( 1-si de d) t ype I err or will be s plit bet wee n O S i n all ra n d o mize d s u bjects a n d 
P D -L 1 + s u bjects wit h 2. 0 % ( 1-si de d) a n d 0. 5 % ( 1-si de d), res pecti vely.
O ne i nteri m a nal ysis is 
pla n ne d f or O S i n all ra n d o mize d s u bjects.  OS i n P D -L 1 + s u bjects will be teste d at t he pri mar y 
a nal ys is o nl y .  A La n -De Mets al p ha s pe n di n g f u ncti o n f or O’ Brie n -Fle mi n g b o u n daries will b e 
us e d t o c o ntr ol t he o verall t ype I err or rate of O S i n all ra n d o mize d s u bjects at 2 % bet wee n t he 
i nteri m a n d pri mar y a nal ysis (see Secti o n 8. 6 ).
F or t he pri mar y e n d p oi nt, a cl ose d testi n g pr oce d ure wit h wei g hte d B o nferr o ni tests , descri be d by 
H o m mel 2 0 0 7 will be use d f or deter mi ni n g si g nifica nce of t he d ual h y p ot hesis pri mar y  testi n g.
T he s u m mar y  is briefly descri b e d as f oll o ws (detaile d pr ocess is i n t he st u d y S A P ).
If a n y of t he t w o n ull h y p ot heses of O S (e val uate d i n all ra n d o mize d s u bjects a n d i n P D -L 1 + 
s u bjects) is rejecte d, t he c orres p o n di n g al p ha le vel will be rec ycle d bet wee n b ot h p o p ulati o ns. T he 
al p ha re c ycli n g a p pr oac h is as f oll o ws :
1.
If t he n ull hy p ot hesis of O S i n all ra n d o mize d s u bjects is rejecte d at eit her t he i nteri m or 
t he pri mar y  anal ys is, t he 2 % ( 1-si de d) al p ha all ocate d t o O S i n all ra n d o mize d s u bjects 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 8 / 15 0
will be rec y cle d t o O S i n P D-L 1 + s u bjects, t he n 2. 5 % ( 1 -si de d) al p ha le vel will be use d 
f or O S i n P D-L 1 + s u bjects.
2.
If t he n ull h y p ot hesis of O S i n P D -L 1 + s u bjects at t he pri mar y  anal ys is is rejecte d, t he 
0. 5 % al p ha all ocate d t o O S i n P D -L 1 + s u bjects will be rec ycle d t o O S i n all ra n d o mize d 
s u bjects. I n this case, t he si g nifica nce will be base d o n a l ocal 2. 5 % ( 1-si de d) al p ha le vel 
f or O S i n all ra n d o mize d s u bjects. Ass u mi n g t he pla n ne d n u m ber of e ve nts are o bser ve d 
at eac h a nal ys is, t he 1-si de d b o u n daries w o ul d t he n be 0. 0 2 3 3 f or O S i n all ra n d o mize d 
s u bjects at pri mar y  anal ysis.  This has bee n recalc ulate d b y  kee pi n g t he al p ha le vel of 
0. 0 0 7 2 at i nteri m a nal ys is u nc ha n ge d.
P F S , f oll o we d b y B O R, will be teste d if a n d o nl y  if b ot h n ull h yp ot heses f or O S i n all ra n d o mize d 
s u bjects a n d P D -L 1 + s u bjects are rejecte d. I n t hat case, P F S will be teste d wit h f ull 2. 5 % ( 1-si de d) 
t ype I err or at t he pri mar y a nal ys is. B O R will be teste d wit h f ull 2. 5 % ( 1 -si de d) t y pe I err or at t he 
pri mar y  anal ys is after t he n ull h y p ot hesis of P F S is rejecte d. All a nal ys es i ncl u di n g O S i n P D -L 1 + 
s u bjects, P F S a n d B O R will be e x pl orat or y if t he st u d y is st o p pe d at i nteri m base d o n rejecti o n of 
n ull h y p ot hesis of O S i n all ra n d o mize d s u bjects.
N o f or mal a dj ust me nt f or m ulti plicit y  will be u n derta ke n f or n o n- ke y sec o n dar y en d p oi nts, 
se nsiti vit y a nalys es, or e x pl orat or y a nalys es.
Statistical a nal y ses will be perf or me d usi n g S A S ® versi o n 9.4 or hi g her.
8. 5. 2
A n al ysis of Pri m ar y E n d p oi nt
Pri m ar y A n al ysis
T he pri mar y  en d p oi nt f or mai nte na nce t hera py is O S . T he t w o pri mar y  anal y sis sets will be t he 
I T T A nal ys is Set a n d t he P D -L 1 + A nal y sis Set.
T he f oll o wi n g a nal ys is will be c o n d ucte d i n t he 
sa me ma n ner f or b ot h I TT a n d P D -L 1 + A nal y sis sets.
T he differe nce bet wee n t he t w o treat me nt 
ar ms will be c o m pare d usi n g a stratifie d, 1- si de d, l o g-ra n k test. T he stratificati o n fact or will be 
re gi o n ( Asia vers us n o n- Asia).
C o ntr ol of t ype I err or a n d statistical si g nifica nce is disc usse d i n 
S ecti o n 8. 5. 1. T he f oll o wi n g n ull h y p ot hes is will be teste d:
H 0: A (t)/ B (t) ≥ 1, vers us H 1: A (t)/ B (t) < 1
w here (t) re prese nts t he hazar d rate (c orres p o n di n g t o eac h e n d p oi nt) at ti me t f or treat me nt ar ms 
A ( a vel u ma b ) a n d B (c o nti n uati o n of t he sa me c he m ot hera p y re gi me n / B S C).
A stratifie d C o x pr o p orti o nal hazar ds m o del will be use d t o assess treat me nt effect bet wee n t he 
t w o treat me nt ar ms a n d t o e x pl ore t he r o b ust ness of t he pri mar y  en d p oi nt c o nfir mat or y anal ys is.  
T he nat ural para meter of t his m o del is t he l o g hazar d rati o.  Eac h strat u m will defi ne a se parate 
baseli ne hazar d f u ncti o n.  Ties will be ha n dle d b y re placi n g t he pr o p orti o nal hazar ds m o del b y t he 
discrete l o gistic m o del.   T he hazar d rati o of a vel u ma b vers us mai nte na nce c he m ot hera p y/ B S C
( with mai nte na nce c he m ot hera p y / B S C as refere nce) t o get her wit h t he c orres p o n di n g Wal d 2- si de d 
9 5 % CI s will be prese nte d. 
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 1 9 / 1 5 0
Ka pla n -Meier (ie, pr o d uct -li mit) esti mates of me dia n O S
will be prese nte d b y  treat me nt ar m 
t o get her wit h 2-si de d 9 5 % CIs calc ulate d acc or di n g t o  Br o o k me y er a n d Cr o wle y ( 1 9 8 2). Fi nall y,  
t he n u m ber of s u bjects at ris k vs. faile d al o n g wit h Ka pla n-Meier esti mates of s ur vi val pr o ba bilit y 
( ofte n referre d t o as “s ur vi val rate”) at 3, 6, 9 a n d 1 2 m o nt hs will be esti mate d wit h c orres p o n di n g 
2- si de d 9 5 % CI s deri ve d usi n g t he l o g-l o g tra nsf or mati o n acc or di n g t o Kal bfleisc h a n d Pre ntice 
( 1 9 8 0).
T he n u m ber a n d perce nta ge of s u bjects wit h o bser ve d O S e ve nts will be prese nte d b y  treat me nt 
ar m (a vel u ma b or mai nte na nce c he m ot hera p y/ B S C). I n a d diti o n, fre q ue nc y c o u nts f or ce ns ori n g 
reas o n will be prese nte d b y treat me nt gr o u p.
Se nsiti vit y A n al yses
T he f oll o wi n g se nsiti vit y anal ys es f or O S will be perf or me d t o e x pl ore t he r o b ust ness of t he 
pri mar y  c o nfir mat or y a nal yses. T hese se nsiti vit y  anal ys es will be perf or me d i n t he sa me ma n ner 
f or b ot h I TT a n d P D -L 1 + a nal ys is sets. A d diti o nal se nsiti vit y anal y ses ma y  be s pecifie d i n t he 
trial S A P.

T he pri ma r y e n d p oi nt a nal ysis will be re peate d base d o n t he P P A nalys is Set if t his a nalys is set 
i ncl u des less t ha n 9 0 % of s u bjects i n t he I T T A nal ysis Set.

A n u nstrati fie d a nalys is will be perf or me d c o m pari n g O S bet wee n t he treat me nt ar ms.

If t he act ual n u m ber of e ve nts is 1 0 % m ore t ha n t he pla n ne d n u m ber at t he pri mar y  anal ys is, 
t he pri mar y a nalys is of O S will be re peate d b y usi n g t he date at w hic h e xactl y  3 5 6 e ve nts i n all 
ra n d o mize d s u bjects were o bser ve d, or after a mi ni m u m f oll o w-u p of at least 1 8 m o nt hs after
ra n d o mizati o n, w hic he ver occ urs last.
T he f oll o wi n g a nal ys es will als o be perf or me d:

T he vali dit y  of t he pr o p orti o nal hazar ds ass u m pti o n will be assesse d vis uall y  by pl otti n g 
l o g(-l o g(s ur vi val)) vers us l o g(ti me) b y treat me nt ar m.

A Ka pla n -Meier pl ot f or O S f oll o w-u p d urati o n will als o be ge nerate d t o assess t he f oll o w-u p 
ti me i n t he treat me nt ar ms b y re versi n g t he O S ce ns ori n g a n d e ve nt i n dicat ors.
8. 5. 3
A n al ysis of Sec o n d ar y E n d p oi nts
Base d o n t he hierarc hical testi n g strate g y  descri be d i n Secti o n 8. 5. 1,  P F S a n d B O R will be teste d 
at t he pri mar y  an al y sis, if, a n d o nl y  if, b ot h of h y p ot hes es testi n g O S (i n all ra n d o mize d s u bjects 
a n d P D-L 1 + s u bjects ) reach statistical si g nifica nce.
8. 5. 3. 1
Ke y Sec o n d ar y E n d p oi nt – Pr o gressi o n -Free S ur vi v al
T he statistical a nal ysis of P F S per In vesti gat or assess me nt will be t he sa me as descri be d f or t he 
pri mar y  a nalys is of O S. 
I n a d diti o n, t he f oll o wi n g se nsiti vit y a nalys es of P F S will be perf or me d:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 0 / 1 5 0

E ve nts ( P Ds/ deat hs) after t he start of ne w a ntica ncer treat me nt will be c o nsi dere d as e ve nts

Cli nical pr o gressi o n will be c o nsi dere d as a n e ve nt

C o u nti n g all P D a n d deat hs as e ve nts re gar dless of missi n g assess me nts or ti mi n g of t he 
e ve nt.
8. 5. 3. 2
Ke y Sec o n d ar y E n d p oi nt – Best O ver all Res p o nse
F or t he a nal ys is of B O R i n t he Mai nte na nce P hase (see Secti o n 8. 5. 3 ) acc or di n g t o R E CI S T v 1. 1 
a n d per I n vesti gat or assess me nt, t he O R R ( defi ne d as ha vi n g a c o nfir me d B O R of C R or P R ) will 
be calc ulate d al o n g wit h
c orres p o n di n g 2- si de d e xact Cl o p per -Pears o n 9 5 % CI s f or t he t w o
treat me nt ar ms. T he C oc hra n -Ma ntel -Hae nszel test will be stratifie d b y re gi o n ( Asia vers us 
n o n- Asia) t o c o m pare t he O R R bet wee n t he t w o treat me nt ar ms. I n case t he ass u m pti o ns of t he 
C oc hra n -Ma ntel -Hae nszel test are vi olate d d ue t o a s mall n u m ber of s u bjects i n s o me strata, a 
Fis her’s e xact test will be use d.  T his a nal ys is will be base d o n t he I T T A nal ysis Set.
8. 5. 3. 3
Ot her Sec o n d ar y E n d p oi nts
8. 5. 3. 3. 1
E ur o pe a n Q u alit y of Li fe - 5 Di me nsi o ns - 5 Le vels 
O bser ve d a n d c ha n ge fr o m baseli ne val ues f or t he E Q -5 D- 5 L  in de x sc ore will be s u m marize d 
descri pti vel y at pla n ne d visits d uri n g t he Mai nte na nce 
P hase, t he Disc o nti n uati o n Visit, a n d 
E n d - of-Treat me nt Visit b y  treat me nt ar m. T his a nal ys is will be base d o n t he H R Q o L A nal ys is 
Set. T he E Q - 5 D-5 L  Vis ual A nal o g Scale sc ores will be prese nte d by data listi n g o nl y .
8. 5. 3. 3. 2
E ur o pe a n 
Or g a niz ati o n 
f or Re se arc h a n d Tre at me nt 
of 
C a ncer Q L Q -C 3 0
O bser ve d a n d c ha n ge fr o m baseli ne val ues f or t he Gl o bal healt h stat us / Q o L scale a n d eac h of t he 
fi ve Q L Q -C 3 0 f u ncti o nal scales (ie, P h y sical, R ole, E m oti o nal, C o g niti ve, a n d S ocial) will be 
s u m marize d descri pti vel y at pla n ne d visits d uri n g t he Mai nte na nce P hase, t he Disc o nti n uati o n 
Visit, a n d E n d - of-Treat me nt Visit b y  treat me nt ar m. I n a d diti o n, t he best (lar gest p ositi ve c ha n ge), 
w orst (lar gest ne gati ve c ha n ge), a n d last-o bser ve d o n -treat me nt c ha n ge fr o m baseli ne val ues will 
be s u m marize d. 
Eac h meas ure will be c o m pare d bet wee n t he t w o treat me nt ar ms usi n g a 
mi xe d -effect s m o del re peate d meas ures ( M M R M) a nal ys is t o e val uate l o n git u di nal c ha n ge fr o m 
baseli ne usi n g re gi o n a n d baseli ne val ue as c o variates. T his a nal y sis will be base d o n t he H R Q o L
A nal y sis Set.
8. 5. 3. 3. 3
E ur o pe a n 
Or g a niz ati o n 
f or Re se arc h a n d Tre at me nt 
of 
C a ncer G astric C a ncer M o d ule Q L Q -S T O 2 2
O bser ve d a n d c ha n ge fr o m baseli ne val ues f or eac h of t he fi ve Q L Q -S T O 2 2 gastric ca ncer m o d ule 
s ym pt o m scales (ie, d ys p ha gi a, pai n, refl u x , eati n g, a n d an xiet y ) will be s u m marize d descri pti vel y 
at pla n ne d visits d uri n g t he Mai nte na nce P hase, t he Disc o nti n uati o n Visit, a n d E n d - of-Treat me nt 
Visit b y  treat me nt ar m. I n a d diti o n, t he best (lar gest ne gati ve c ha n ge), w orst (lar gest p ositi ve 
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 1 / 1 5 0
c ha n ge), a n d last- o bser ve d o n-treat me nt c ha n ge fr o m baseli ne val ues will be s u m marize d. Eac h 
meas ure will be c o m pare d bet wee n t he t w o treat me nt ar ms usi n g a M M R M a nal ysis t o e val uate 
l o n git u di nal c ha n ge fr o m baseli ne usi n g re gi o n a n d baseli ne val ue as c o variates. T his a nal ysis 
will be base d o n t he H R Q o L A nal ys is Set.
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 2 / 1 5 0
8. 5. 5
A n al ysis of S afet y E n d p oi nts
All Safet y  anal ys es will be perf or me d o n t he Safet y -Mai nte na nce A nal ys is Set u nless ot her wise 
n ote d. Safet y e n d p oi nts will be ta b ulate d usi n g descri pti ve statistics o nl y.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 3 / 1 5 0
Safet y  assess me nts will be base d o n re vie w of A Es , c o nc o mita nt me dicati o ns, l ocal la b orat or y 
meas ure me nts (ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis), E C O G P S , p h ysical e xa mi nati o ns, 
b o d y  wei g ht, vital si g ns, a n d 1 2-lea d E C Gs.
A d verse E ve nts
All A Es will be c o de d acc or di n g t o t he Me dical Dicti o nar y  for Re g ulat or y  Acti vities (Me d D R A )
dicti o nar y ( Versi o n 2 0. 1) .  Se verit y  of A Es will be gra de d usi n g t he N CI -C T C A E v 4. 0 3 t o xicit y 
gra di n g s cale. 
T reat me nt- e mer ge nt A Es ( T E A Es) are defi ne d as e ve nts wit h o nset dates occ urri n g o n -treat me nt 
or e ve nts w hic h w orse n o n -treat me nt (see Secti o n 7. 4. 1. 2 ).  T E A Es are defi ne d se paratel y f or t he 
I n d ucti o n a n d Mai nte na nce P hases. U nless ot her wise s pecifie d, s u m maries will be perf or me d o n 
Mai nte na nce
P hase T E A Es.
T he i nci de nce of T E A Es, re gar dless of relate d ness t o treat me nt, will be s u m marize d b y  Sys te m 
Or ga n Class a n d Preferre d Ter m f or eac h treat me nt ar m. Si milar s u m maries will als o be pr o vi de d 
f or treat me nt- e mer ge nt seri o us a d verse e ve nts ( T E S A Es), T E A Es lea din g t o per ma ne nt 
disc o nti n uati o n of treat me nt, T E A Es b y  ma xi m u m se verit y, T E A Es b y  hi g hest relati o ns hi p t o 
treat me nt, T E A Es wit h fatal o utc o me, a n d T E A Es of s pecial i nterest ( A E SIs) s uc h as ir A Es.
T he i nci de nce of T E A Es a n d T E S A Es d uri n g t he I n d ucti o n P hase will be s u m marize d b y  s yste m 
or ga n class/ preferre d ter m b y  t otal n u m ber of s u bjects.
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures
C o nc o mita nt me dicati o ns (ie, me dicati o ns ot her t ha n trial treat me nt ta ke n at a n y ti me o n-
treat me nt) will be s u m marize d f or t he Mai n te na nce P hase usi n g fre q ue ncies a n d perce nta ges 
wit hi n a gi ve n dr u g class a n d preferre d na me b y  treat me nt ar m a n d o verall. 
C o nc o mita nt 
pr oce d ures (ie , pr oce d ures u n derta ke n at a n y  ti me o n-treat me nt) will be liste d o nl y.
L a b or at or y V al ues
O bser ve d a n d c ha n ge fr o m baseli ne val ues d uri n g t he Mai nte na nce P hase will be s u m marize d b y 
visit, test, a n d treat me nt ar m f or c he mistr y  an d he mat ol o g y  la b orat or y res ults.  La b orat or y res ults 
will be classifie d b y  gra de acc or di n g t o N CI -C T C A E .  T he w orst o n- treat me nt gra de s d uri n g t he 
Mai nte na nce P hase f or c he mistr y an d he mat ol o g y  la b orat or y res ults b y treat me nt ar m will be 
s u m marize d. S hifts i n t o xicit y gra di n g fr o m baseli ne t o hi g hest gra de d uri n g t he Mai nte na nce 
P hase b y  treat me nt ar m will be dis pla y e d. Res ults d uri n g t he Mai nte na nce P hase f or la b orat or y 
tests t hat are n ot part of N CI-C T C A E will be prese nte d cate g oricall y (e g, bel o w, wit hi n, or a b o ve 
n or mal li mits) b y  treat me nt ar m. O nl y  su bjects wit h p ost -baseli ne la b orat or y val ues will be 
i ncl u de d i n t hese a nal yses. Uri nal y sis res ults will be liste d o nl y . F urt her details of a nal yses f or 
t he la b orat or y para meters will be pr o vi de d i n t he trial S A P.
E C O G Perf or m a nce St at us
D oc u me nt N o.
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 4 / 1 5 0
S hifts fr o m Re- baseli ne (e n d of I n d ucti o n P hase) i n E C O G P S sc ore will be prese nte d at pla n ne d 
visits d uri n g t he Mai nte na nce P hase, t he Disc o nti n uati o n Visit, a n d E n d - of-Treat me nt Visit b y  
n u m ber a n d perce nta ge f or eac h treat me nt ar m. S hifts fr o m Re- baseli ne t o hi g hest o n- treat me nt 
E C O G P S sc ore will be s u m marize d i n a si milar fas hi o n.
P h ysic al E x a mi n ati o ns
Cli nicall y  si gnifica nt, a b n or mal fi n di n gs fr o m p h y sical e xa mi nati o ns bef ore I CF si g nat ure are t o 
be re p orte d as pre -e xisti n g me dical c o n diti o ns a n d will be i ncl u de d i n s u m maries of me dical 
hist or y . O n t he ot her ha n d, cli nicall y si gnifica nt, a b n or mal fi n di n gs fr o m p h y sical e xa mi nati o ns 
after I C F si g nat ure are t o be re p orte d as A Es a n d will b e i ncl u de d i n s u m maries of A Es.
Vit al Si g ns
Ma xi m u m o n- treat me nt i ncrease a n d ma xi m u m o n- treat me nt decrease fr o m baseli ne val ues d uri n g 
t he Mai nte na nce P hase will be s u m marize d b y  para meter (e g, b o d y te m perat ure, res pirat or y rate, 
heart rate, a n d bl o o d press ure) usi n g descri pti ve statistics b y  treatme nt ar m. A si milar s u m mar y 
will be pr o vi de d f or t he I n d ucti o n P hase b y t otal n u m ber of s u bjects.
1 2- Le a d E C Gs
O bser ve d a n d c ha n ge fr o m baseli ne val ues d uri n g t he Mai nte na nce P hase base d o n 1 2 -lea d E C Gs 
will be s u m marize d at t he Disc o nti n uati o n Visit a n d E n d - of-Treat me nt Visit b y  para meter (e g, 
Heart Rate, P R I nter val, Q R S I nter val, R R I nter val, Q T I nter val, Q T c orrecte d b y  Bazzett’s 
f or m ula [Q Tc B ] I nter val, or Q T c orrecte d b y  Fri dericia’s f or m ula [Q Tc F ] I nter val) a n d treat me nt 
ar m. I n ad diti o n, s hifts fr o m baseli ne i n E C G res ults (e g , n or mal, a b n or mal) will be prese nte d at 
t he Disc o nti n uati o n Visit a n d E n d-of- Treat me nt Visit b y  para meter a n d treat me nt ar m.
F urt her details of safet y a nal yses will be pr o vi de d i n t he trial S A P.
8. 5. 6
Re p orti n g of Ot her Cli nic al D a t a of I nterest
S u bject C h ar acteristics
Pre -i n d ucti o n s u bject c haracteristics will be o btai ne d d uri n g t he Scree ni n g / Baseli ne pr oce d ures 
a n d will be s u m marize d b y  total n u m ber of s u bjects f or t he I T T A nal y sis Set. 
S u bject 
c haracteristics m a y  incl u de, b ut are n ot li mite d t o, a ge, se x, race/et h nicity,  hei g ht, wei g ht, b o d y 
mass i n de x, re gi o n c orres p o n di n g t o t he site at w hic h t he s u bject is e nr olle d, a n d E C O G P S.  A 
si milar s u m mar y of pre -mai nte na nce Re- baseli ne c haracteristics will be pr o vi de d b y  treat me nt ar m
a n d o verall f or t he I T T A nal y sis Set.
Dise ase C h ar acteristics
I nf or mati o n o n baseli ne disease c haracteristics c ollecte d o n t he e C R F will be s u m marize d b y 
treat me nt ar m a n d o verall f or t he I T T A nal ys is Set. Disease c haracteristics ma y  incl u de, b ut are 
n ot li mite d t o, site of pri mar y  tu m or (ie , st o mac h, G EJ), o verall t u m or res p o nse stat us (ie, C R, P R, 
or S D) f oll o wi n g t he I n d ucti o n P hase, a n d P D -L 1  assa y stat us (ie, p ositi ve, ne gati ve).
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 5 / 1 5 0
E nr ol lme nt a n d Dis p ositi o n
T he n u m ber a n d perce nta ge of s u bjects scree ne d ( n u m ber o nl y), scree n-faile d ( n u m ber o nl y) , 
disc o nti n ue d d uri n g t he I n d ucti o n P hase ( n u m ber o nl y ), ra n d o mize d, ra n d o mize d b ut n ot treate d 
d uri n g t he Mai nte na nce 
P hase, treate d d uri n g t he Mai nte na nce 
P hase, a n d pre mat urel y 
disc o nti n ue d d uri n g t he Mai nte n a nce P hase will be s u m marize d b y  treat me nt ar m a n d o verall.
Pri mar y  reas o ns f or scree n-fail ure, ra n d o mizati o n fail ure, a n d pre mat ure wit h dra wal d uri n g t he 
Mai nte na nce P hase will be s u m marize d. T he n u m ber a n d perce nta ge of s u bjects i n t he A nal ys is 
Set wit h maj or pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he P P A nal y sis Set will be prese nte d 
b y  treat me nt ar m a n d reas o n f or e xcl usi o n. All maj or pr ot oc ol de viati o ns will be liste d.
Me dic al Hist or y
Pre -e xisti n g me dical c o n diti o ns re p orte d at t he ti me of t h e Scree ni n g / Baseli ne pr oce d ures will be 
s u m marize d usi n g fre q ue nc y ta bles b y  treat me nt ar m a n d o verall f or t he Safet y- Mai nte na nce 
A nal y sis Set.   A si milar s u m mar y will be pr o vi de d b y  total s u bjects f or t he Safet y- I n d ucti o n 
A nal y sis Set.
Tre at me nt E x p os ure a n d C o m pli a nce
T he e xte nt of e x p os ure t o treat me nt d uri n g t he I n d ucti o n P hase will be s u m marize d f or t otal 
n u m ber of s u bjects i n t he Safet y -I n d ucti o n A nal y sis Set.
T he e xte nt of e x p os ure t o ra n d o mize d treat me nt (ie, a vel u ma b or mai nte na nce c he m ot hera py) wi ll 
be c haracterize d b y  durati o n ( wee ks), n u m ber of a d mi nistrati o ns, c u m ulati ve d ose (e g, m g / k g or 
m g/ m 2), d ose i nte nsity ( m g/ k g/ wee k or m g / m2/ wee k), relati ve d ose i nte nsit y (act ual d ose gi ve n / 
pla n ne d d ose), n u m ber of d ose dela y s, a n d n u m ber of i nf usi o n rate re d ucti o ns (a vel u ma b ar m 
o nl y ), f or t he Safet y- Mai nte na nce A nal ys is Set. T he n u m ber a n d perce nta ge of n o n- c o m plia nt 
s u bjects (see Secti o n 6. 9 ) wit h re gar d t o ra n d o mize d treat me nt will be prese nte d b y treat me nt ar m 
base d o n t he Safet y -Mai nte na nce A nal ys is Set.
Pri or A nti -C a ncer T her a pies a n d Pr oce d ures
Pri or a nti -ca ncer t hera pies (ie, a nti -ca ncer me dicati o ns ot her t ha n trial tr eat me nt ta ke n at a n y ti me 
pri or t o I CF si g nat ure) will be s u m marize d usi n g fre q ue ncies a n d perce nta ges b y  dr u g class a n d 
preferre d na me wit hi n treat me nt ar m a n d o verall f or t he Safet y -I n d ucti o n A nal y sis S et a n d 
Safet y -Mai nte na nce A nal y sis Set. A si milar su m mar y  will be pr o vi de d b y  dr u g class, preferre d 
na me, a n d t otal s u bjects f or t he Safet y- I n d ucti o n A nal y sis Set.  Pri or a nti-ca ncer pr oce d ures (ie, 
pr oce d ures u n derta ke n at a n y  ti me pri or t o IC F si g nat ure) will be liste d o nl y .
8. 6
I nteri m a n d A d diti o n al Pl a n ned A n al yses
N o i nteri m a nal ysis is pla n ne d f or O S i n P D -L 1 + s u bjects. T here is o ne i nteri m a nal ys is pla n ne d 
f or o ver w hel mi n g efficac y of O S i n all ra n d o mize d s u bjects w he n a p pr o xi matel y 7 5 % of O S
e ve nts, ie, 2 6 7 O S e ve nts ha ve bee n o bser ve d. 
A La n -De Mets al p ha s pe n di n g f u ncti o n f or 
O’ Brie n -Fle mi n g b o u n daries will be use d t o c o ntr ol t he o verall t ype I err or rate of 2 % ( 1-si de d) 
f or O S. T he b o u n dar ies f or declari n g s u peri orit y for t he i nteri m a nal y sis a n d t he fi nal a nal ysis of 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 6 / 1 5 0
O S i n all ra n d o mize d s u bjects will be u p date d base d o n t he act ual n u m ber of e ve nts o bser ve d at 
t he ti me of t he data c ut f or eac h a nal ys is.  If t he pla n ne d n u m ber of e ve nts are o bser ve d at eac h 
a nal ys is, 1- si de d b o u n daries of 0. 0 0 7 2 a n d 0. 0 1 7 8, res pecti vely will be use d f or e val uati n g 
statistical si g nifica nce. Si nce f or mal efficac y bo u n daries will be use d at t he i nteri m a nal ysis f or 
t he statistical testi n g of O S i n all ra n d o mize d s u bjects, a statisticall y si g nifica nt fi n di n g at t he 
i nteri m will be i nte n de d t o clai m t he s u peri ority. If O S i n all ra n d o mize d s u bjects is statisticall y 
si g nifica nt at t he i nteri m a nal ys is, o nl y  descri pti ve a nal ys is of O S i n P D -L 1 + s u bjects will be 
perf or me d at t his i nteri m a nal ys is ti me p oi nt. If t he st u d y pr ocee ds t o t he fi nal a nal ys is a n d n ull 
h y p ot hesi s of O S i n P D -L 1 + is rejecte d at al p ha le vel 0. 0 0 5 t he n t he b o u n dar y  for t he fi nal 
h y p ot hesis of O S i n ra n d o mize d s u bjects will be base d o n a l ocal si g nifica nce le vel of 0. 0 2 5. 
Ass u mi n g t he pla n ne d n u m ber of e ve nts are o bser ve d at eac h a nal ys is, t he 1- si de d b o u n daries 
w o ul d t he n be 0. 0 2 3 3 f or O S i n all ra n d o mize d s u bjects at pri mar y  anal y sis. T his has bee n 
recalc ulate d by kee pi n g t he al p ha le vel of 0. 0 0 7 2 at i nteri m a nal ys is u nc ha n ge d.
T he Ta ble 1 3 s u m marizes t he o perati n g c haracteristics a n d efficac y bo u n daries, i n t he case t hat 
pla n ne d n u m ber of e ve nts are o bser ve d f or O S i n ra n d o mize d s u bjects i n b ot h a nal yses.  T he
O’ Brie n -Fle mi n g efficac y bo u n daries b ase d o n a La n -De Mets s pe n di n g f u ncti o n will be u p date d 
pri or t o t he ti me of a nal ysis of O S base d o n t he act ual n u m ber of e ve nts a n d t he i nf or mati o n 
fracti o n f or t ype I err or c o ntr ol.  I nf or mati o n fracti o n at t he i nteri m a nal ysis will be calc ulate d 
ass u mi n g t he pla n ne d 3 5 6 e ve nts will be o bser ve d at t he ti me of t he pri mar y a nal ys is. At t he 
pri mar y  a nalys is, t he b o u n daries will be u p date d base d o n t he tr ue n u m ber of e ve nts o bser ve d a n d 
i nf or mati o n fracti o n use d at eac h a nalys is.
T a ble 1 3
Pl a n ne d L a n -De Mets ( O’ Brie n-Fl e mi n g) Effic ac y B o u n d aries of O S
i n 
All R a n d o mize d S u bjects
L o o k
I nf o 
Fr acti o n 
A p pr o x. 
C u m. E ve nts 
of O S
C u m ul ati ve T y pe 
I Err or 
( 1-si de d)
Effic ac y B o u n d aries
Z- sc ale
P- sc ale
( 1-si de d)
I nteri m
~ 7 5 %
2 6 7
0. 0 0 7 2
2. 4 5
0. 0 0 7 2
Fi nal
1 0 0 % 
3 5 6
0. 0 2 0 0
2. 1 0
0. 0 1 7 8
O S = O verall S ur vi val.
La n -De Mets al p ha s pe n di n g f u ncti o n f or O’ Brie n -Fle mi n g b o u n daries
T he o verall t y pe I err or rate = 0. 0 2 0 ( 1 -si de d) f or pri mar y e n d p oi nt of O S i n all ra n d o mize d s u bjects.
T he e xact efficac y b o u n daries ma y be u p date d pri or t o t he ti me of a nal ysis base d o n t he act ual n u m ber of 
e ve nts a n d t he i nf or mati o n fracti o n.
F urt her details re gar di n g t he i nteri m a nal ys is will be pr o vi de d i n t he trial S A P.
A n I D M C will be f or me d a n d will be res p o nsi ble f or peri o dic e val uati o ns of t he trial as well as t he 
e val uati o n of t he i nteri m a nal ysis. T he I D M C (see Secti o n 2. 3. 1 ) will c o n ve ne t o perf or m t he 
e val uati o n at t he i nteri m a nal ys is i n or der t o safe g uar d t he S p o ns or’s pers o n nel fr o m u n bli n de d 
trial res ults. T he pri mar y  en d p oi nt of O S , t he ke y  sec o n dar y en d p oi nt s of P F S, B O R , a n d ot her 
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 7 / 1 5 0
sec o n dar y efficac y e n d p oi nt (re p orte d o utc o mes / Q o L
assesse d b y  th e E Q - 5 D-5 L , E O R T C 
Q L Q -C 3 0, a n d E O R T C m o d ule Q L Q- S T O 2 2 q uesti o n naires) a nal ys es will be c o n d ucte d i n t his 
i nteri m a nal ys is. See Secti o n s 8. 5. 1 a n d 8. 5. 3 f or details re gar di n g t he hierarc hical testi n g strate g y 
t o be use d. If at t he ti me of t his i nteri m a nal ysis, t he a nal ys is is perf or me d wit h e xactl y 2 6 7 deat h s 
o bser ve d ( 7 5 % pla n ne d i nf or mati o n fracti o n), t he O S i n all ra n d o mize d s u bjects of a vel u ma b-
assi g ne d s u bjects is s h o w n t o be s u peri or t o t hat of s u bjects ra n d o ml y assi g ned t o t he mai nte na nce 
c he m ot hera p y / B S C ar m wit h a p- val ue of < 0. 0 0 7 2 t he I D M C ma y  declare s u peri or efficac y in t he 
a vel u ma b treat me nt ar m c o m pare d wit h t he mai nte na nce c he m ot hera p y / B S C ar m a n d rec o m me n d 
t hat t he trial be st o p pe d earl y. 
T he I D M C will als o be prese nte d wit h s u bject dis p ositi o n, 
de m o gra p hic i nf or mati o n, baseli ne disease c haracteristics, a n d safet y inf or mati o n. 
A n 
i n de pe n de nt statistical pr o vi der will perf or m t he i nteri m a nal yses t o s u p p ort t he I DM C. 
Details 
will be d oc u me n te d i n a se parate S A P or I D M C c harter.  Res ults fr o m t he i nteri m a nalys es will be 
tra ns mitte d fr o m t his gr o u p t o t he I DM C 
o nl y . Trial staff i n v ol ve d wit h t he da y  to d a y  
ma na ge me nt of t he trial as well as a n y Sp o ns or staff will n ot ha ve access t o t his i nteri m 
i nf or mati o n. Details of t he I D M C missi o n, c o m p ositi o n, a n d o perati o ns will be pr o vi de d i n t he 
I D M C c harter.
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he I n vesti g at or
T he I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he trial at his / her site.  He / s he will e ns ure t hat 
t he trial is perf or me d i n acc or da nce wit h t he cli nical trial pr ot oc ol a n d wit h t he et hical pri nci ples 
t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, as well as wit h t he I C H N ote f or G ui da nce o n 
G C P (IC H T o pic E 6, 1 9 9 6) a n d a p plica ble re g ulat or y re q uire me nts.  I n partic ular, t he I n vesti gat or 
m ust e ns ure t hat o nl y  s u bjects w h o ha ve gi ve n t heir i nf or me d c o nse nt are i ncl u de d i n t he trial.
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or trials c o n d ucte d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F D A f or mar keti n g a p pr o val 
a n d c o ul d c o ntri b ute si g nifica ntl y to t he de m o nstrati o n of efficac y an d safet y of a n I M P ( w hic h 
are c o nsi dere d “c o vere d cli nical trials” b y  t he F D A), t he I n vesti gat or a n d all s u bi n vesti gat ors are 
o bli ge d t o discl ose a n y f i na ncial i nterest w hic h t he y, t heir s p o uses or t heir de pe n de nt c hil dre n m a y  
ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der st u d y. T his i nf or mati o n is re q uire d d uri n g t he 
trial a n d f or 1 2 m o nt hs f oll o wi n g c o m pleti o n of t he trial.
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or a s u bject’s partici pati o n i n t he trial is his / her writte n i nf or me d 
c o nse nt.  The s u bject’s writte n i nf or me d c o nse nt t o partici pate i n t he trial m ust be gi ve n bef ore 
a n y trial-relate d acti vities are carrie d o ut.   
 
 
A de q uate i nf or mati o n m ust t heref ore be gi ve n t o t he s u bject b y  the I n vesti gat or bef ore i nf or me d 
c o nse nt is o btai ne d (a pers o n desi g nate d b y  the I n vesti gat or m a y  gi ve the i nf or mati o n, if per mitte d 
b y  local re g ulati o ns).  A su bject i nf or mati o n s heet i n t he l ocal la n g ua ge a n d pre pare d i n acc or da nce 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 8 / 1 5 0
wit h t he N ote f or G ui da nce o n G C P (I C H T o pic E 6, 1 9 9 6) will be pr o vi de d b y t he S p o ns or f or t he 
p ur p ose of o btai ni n g i nf or me d co nse nt.  In a d diti o n t o pr o vi di n g t his writte n i nf or mati o n t o a 
p ote ntial s u bject, t he I nvesti gat or or his / her desi g nate will i nf or m t he s u bject ver ball y  of all 
perti ne nt as pects of t he trial.  The la n g ua ge use d i n d oi n g s o m ust be c h ose n s o t hat t he i nfor mati o n 
ca n be f ull y a n d rea dil y  u n derst o o d b y l a y pers o ns.
De pe n di n g o n nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or m a y  inf or m t he s u bject 
a n d si g n t he I CF, as a b o ve.
W here t he i nf or mati o n is pr o vi de d b y  the I n vesti gat or, t he I C F m ust be si g ne d a n d pers o nall y 
date d b y t h e s u bject a n d t he I n vesti gat or.
T he si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d b y  the I n vesti gat or s o t hat t he f or ms ca n be retrie ve d at a n y ti me f or
m o nit ori n g, a u diti n g, a n d i ns pecti o n p ur p oses.  A co p y  of t he si g ne d a n d date d i nf or mati o n a n d 
I CF s h o ul d be pr o vi de d t o t he s u bject pri or t o partici pati o n.  Whe ne ver i m p orta nt ne w i nf or mati o n 
bec o mes a vaila ble t hat ma y  be rele va nt t o t he s u bject’s c o nse nt, t he writte n s u bject i nf or mati o n 
s heet a n d a n y ot her writte n i nf or mati o n pr o vi de d t o s u bjects will be re vise d b y  the S p o ns or or 
desi g nee a n d be s u b mitte d a gai n t o t he I E C / I RB f or re vie w a n d fa v ora ble o pi ni o n.  T he a gree d, 
re vise d i nf or mati o n will be pro vi de d t o eac h s u bject i n t he trial f or si g ni n g a n d dati n g , w hic h will 
be d oc u me nte d .  S ufficie nt ti me will be pr o vi de d t o s u bjects t o rea d t he i nf or mati o n a n d t he 
o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d clarificati o n a b o ut the 
c ha n ges.  T he I n vesti gat or will e x plai n t he c ha n ges t o t he pre vi o us versi o n .
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n b y  the I WR S s yste m, 
i m me diatel y after i nf or me d c o nse nt has bee n o btai ne d.  This n u m ber will ser ve as t he s u bject’s 
i de ntifier i n t he trial as well as i n t he cli nical trial data base.
T he s u bject’s data c ollecte d i n t he trial will be st ore d u n der t his n u m ber.  Onl y  the I n vesti gat or 
will be a ble t o li n k t he s u bject’s trial data t o t he s u bject via a n i de ntificati o n list ke pt at t he site.  
T he s u bject’s ori gi nal me dical data t hat are re vie we d at t he site d uri n g s o urce data verificati o n b y 
t he Cli nical Trial M o nit or, 
a u dits, a n d Healt h A ut h orit y  ins pecti o ns will be ke pt strictly 
c o nfi de ntial.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g s u bject data.  Su bjects will be i nf or me d acc or di n gl y a n d will be re q ueste d t o gi ve t heir 
c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns (see Secti o n 7. 6) .  
Details re gar di n g s u bjects’ ri g ht t o pri vac y  will be descri be d i n t he I C F.
9. 4
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d
S u bjects e nr olle d i n t his cli nical trial will be pr o vi de d wit h E mer ge nc y  Me dical S u p p ort car ds 
d uri n g t heir trial partici pati o n, w hic h will be f ur nis he d b y  the S p o ns or or desi g nee.  Th e 
E mer ge nc y  Me dical S u p p ort car d is base d o n t he nee d t o pr o vi de cli nical trial s u bjects wit h a wa y 
of i de ntif yi n g t he msel ves as partici pati n g i n a cli nical trial, a n d s u bse q ue ntl y to gi ve healt h care 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 2 9 / 1 5 0
pr o vi ders access t o t he i nf or mati o n a b o ut t his partici pati o n t hat m a y  be nee de d t o deter mi ne t he 
c o urse of t h e s u bject’s me dical treat me nt.
T his ser vice is desi g ne d t o pr o vi de i nf or mati o n t o healt h care pr o vi ders w h o are n ot part of t he 
cli nical trial.
Cli nical trial In vesti gat ors, w h o are alrea d y a ware of t he cli nical trial pr ot oc ol a n d treat me nt, ha ve 
ot her mea ns of accessi n g t he necessar y  me dical i nf or mati o n f or t he ma na ge me nt of e mer ge ncies 
occ urri n g i n t heir s u bjects.
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n vesti gat or cari n g f or t he 
affecte d s u bject.  The I nvesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact i nf or mati o n o n 
t he car d f or t his p ur p ose.  If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, s he or he will 
a ns wer a n y q uesti o ns.  An y  su bse q ue nt acti o n will f oll o w t he sta n dar d pr ocesses esta blis he d f or 
t he In vesti gat ors.
I n cases w here t he I n vesti gat or is n ot a vaila ble, Merc k K Ga A / E M D Ser o n o R & D or desi g nee 
will pr o vi de t he a p pr o priate mea ns t o c o ntact a S p o ns or p h ys icia n. T his i ncl u des t he pr o visi o n of 
a 2 4- h o ur c o ntact n u m ber at a call ce nter, w here b y  t he healt h care pr o vi ders will be gi ve n access 
t o t he a p pr o priate S p o ns or p h ysicia n t o assist wit h t he me dical e mer ge nc y a n d t o pr o vi de s u p p ort 
f or t he s u bject c o ncer ne d.
9. 5
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects
I ns ura nce c o vera ge wi ll be pr o v i de d f or eac h c o u ntr y partici pati n g t o t he trial.  I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t his cli nical trial pr ot o c ol will be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts (s uc h as t he I CF) t o t he res p o nsi ble I EC or I RB f or its 
fa v ora ble o pi ni o n or a p pr o val, w hic h will be file d i n t he I n vesti gat or Site File. A c o p y will be 
file d i n t he S p o ns or Trial Master File at t he C R O.
T he I E C or I R B will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n 
or a p pr o val was gi ve n a n d t he me m bers a n d v oti n g me m bers prese nt. 
Writte n 
e vi de nce of 
fa v ora ble o pi ni o n or a p pr o val t hat clearly i de ntifies t he trial, t he cli nical trial pr ot oc ol versi o n a n d 
t he S u bject I nf or mati o n a n d I CF versi o n re vie we d s h o ul d be pr o vi de d. 
W here p ossi ble, c o pies of 
t he meeti n g mi n utes s h o ul d be o btaine d.
A me n d me nts t o t his cli nical trial pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d I E C or I R B, 
bef ore i m ple me ntati o n of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ). Rele va nt safety i nf or mati o n will 
be s u b mitte d t o t he I EC or I RB d uri n g t he c o urse of t he trial i n acc or da nce wit h nati o nal 
re g ulati o ns a n d re q uire me nts.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 0 / 1 5 0
9. 7
He alt h A ut h orities
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (e g, I M P D ossier, 
S u bject 
I nf or mati o n, a n d t he I C F) will be s u b mitte d or n otifie d t o t he Healt h A ut h orities i n acc or da nce 
wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
1 0
Tri al M a n a ge me nt
1 0. 1
C ase Re p ort F or m H a n dli n g
T he I n vesti gat or or desi g nee will be res p o nsi ble f or e nteri n g trial data i n t he e C R F pr o vi de d b y  
t he C R O a n d f oll o w t he data e ntr y gui deli nes.  It is t he I nvesti gat or’s res p o nsi bilit y  t o e ns ure t he 
acc urac y of t he data e ntere d i n t he e C R Fs a n d t o si g n t he case re p ort f or ms.  Please refer t o the 
Ma n ual of O perati o ns f or e C R F ha n dli n g g ui deli nes.
T he data will be e ntere d i nt o a vali date d data base.  The C R O will f oll o w t he sta n dar ds of t he 
S p o ns or i n t he data base desi g n a n d data str uct ure.  The C R O will be res p o nsi ble f or data re vie w 
a n d pr ocessi n g, i n acc or da nce wit h t he C R O’s data ma na ge me nt pr oce d ures.  Data base l oc k will 
occ ur o nce q ualit y  co ntr ol pr oce d ures a n d q ualit y ass ura nce pr oce d ures (if a p plica ble) ha ve bee n 
c o m plete d.  Co pies of t he e C R Fs will be pr o vi de d t o t he I n vesti gat ors at t he co m pleti o n of t he 
trial.
1 0. 2
S o urce D at a a n d S u bject Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y s u bject i n t he trial.  It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g t his s u bject file.  
T his file will c o ntai n t he de m o gra p hic a n d me dical i nf or mati o n f or t he s u bject liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 

S u bject’s f ull na me, date of birt h, se x, hei g ht, wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita n t t hera pies (i ncl u di n g c ha n ges d uri n g t he trial)

Trial i de ntificati o n, ie, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d s u bject n u m ber

Dates f or e ntr y  i nt o t he trial (i nf or me d c o nse nt) a n d visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t his cli nical trial pr ot oc ol

All A Es

Date t hat t he s u bject left t he trial i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he trial or 
I M P (if a p plica ble).

It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g t his s u bject file.
A d diti o nall y , a n y ot her d oc u me nts c o ntai ni n g s o urce data m ust be file d.  This i ncl u des ori gi nal 
pri nt o uts of data rec or de d or ge nerate d b y  aut o mate d i nstr u me nts, p h ot o gra p hic ne gati ves, X- ra ys, 
C T or M RI  sca n i ma ges, E C G rec or di n gs, la b orat or y val ue listi n gs, etc.  Suc h d oc u me nts m ust 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 1 / 1 5 0
i ncl u de at least t he s u bject n u m ber a n d t he date w he n t he pr oce d ure was perf or me d.  I nf or mati o n 
s h o ul d be pri nte d b y  the i nstr u me nt use d t o perf or m t he assess me nt or meas ure me nt, if p ossi ble.  
I nf or mati o n t hat ca n n ot be pri nte d by a n a ut o mate d i nstr u me nt will be e ntere d ma n uall y.  Me dical 
e val uati o n of s uc h rec or ds s h o ul d be d oc u me nte d as necessar y  a n d t he d oc u me ntati o n si g ne d a n d 
date d b y t he I n vesti gat or.
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
T he I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File u p o n i nitiati o n of t he trial.  This 
file will c o ntai n all d oc u me nts necessar y  for t he c o n d uct of t he trial a n d will be u p date d a n d 
c o m plete d t hr o u g h o ut t he trial.  It m ust be a vaila ble f or re vie w by t he M o nit or, a n d m ust be rea d y 
for S p o ns or a u dit as well as f or i ns pecti o n b y  Healt h A ut h orities d uri n g a n d after t he trial, a n d 
m ust be safel y arc hi ve d f or at least 1 5 y ears ( or per l ocal re q uire me nts or as ot her wise n otifie d b y 
t he S p o ns or) after t he e n d of t he trial.  The d oc u me nts t o be arc hi ve d i ncl u de t he S u bject 
I de ntificati o n Li st a n d t he si g ne d s u bject I C Fs.  If arc hi vi n g of t he I n vesti gat or Site File is n o 
l o n ger p ossi ble at t he site, t he In vesti gat or m ust n otif y  t he S p o ns or.
All ori gi nal s u bject files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble re g ulati o ns, a n d / or as per 
I C H G C P g ui deli nes, w hic he ver is l o n ger.  In a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
1 0. 4
M o nit ori n g, 
Q u alit y Ass ur a nce 
a n d I ns pecti o n b y He alt h 
A ut h orities
T his trial will be m o nit ore d i n acc or da nce wit h t he I CH N ote f or G ui da nce o n G C P (IC H T o pic 
E 6, 1 9 9 6).  T he Cli nical Trial M o nit or will perf or m visits t o t he trial site at re g ular i nter vals.
Re prese ntati ves of t he S p o ns or’s Q ualit y  Ass ura nce u nit or a desi g nate d or ga nizati o n, as well as 
Healt h A ut h orities, m ust be per mitte d t o i ns pect all trial -relate d d oc u me nts a n d ot her materials at 
t he site, i ncl u di n g t he I n vesti gat or Site File, t he c o m plete d e C R Fs, t he trial dr u g, a n d t he s u bjects’ 
ori gi nal me dical rec or ds / files.
T he cli nical trial pr ot oc ol, eac h ste p of t he data ca pt ure pr oce d ure, a n d t he ha n dli n g of t he d ata, 
i ncl u di n g t he fi nal C li nical T rial R e p ort, will be s u bject t o i n de pe n de nt q ualit y  ass ura nce acti vities.  
A u dits ma y  be c o n d ucte d at a n y t i me d uri n g or after t he trial t o e ns ure t he vali dit y a n d i nte grit y of 
t he trial data.
1 0. 5
C h a n ges t o t he Cli nic al Tri al Pr ot oc ol
C ha n ges t o t he cli nical trial pr ot oc ol will be d oc u me nte d i n writte n pr ot oc ol a me n d me nts.  Maj or 
(s u bsta ntial, si g nifica nt) a me n d me nts will us uall y  re q uire s u b missi o n t o t he Healt h A ut h orities a n d 
t o t he rele va nt IE C / I R B f or a p pr o val or fa v ora ble o pi ni o n.  I n s uc h cases, t he a me n d me nt will be 
i m ple me nte d o nl y after a p pr o val or fa v ora ble o pi ni o n has bee n o btai ne d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 2 / 1 5 0
Mi n or ( n o ns u bsta ntial) pr ot oc ol a me n d me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y  
t he S p o ns or a n d at t he site.  The y will be s u b mitte d t o t he rele va nt I E C / I RB or t o Healt h 
A ut h orities o nl y  w here re q ueste d by perti ne nt re g ulati o ns .
A n y  ame n d me nt t hat c o ul d affect t he s u bject’s a gree me nt t o partici pate i n t he trial re q uires
a d diti o nal i nf or me d c o nse nt pri or t o i m ple me ntati o n (see Secti o n  9. 2).
1 0. 6
Cli nic al Tri al Re p ort a n d P u blic ati o n P olic y
1 0. 6. 1
Cli nic al Tri al Re p ort
After c o m pleti o n of t he trial, a C li nical T rial R e p ort w ill be writte n b y t he S p o ns or i n c o ns ultati o n 
wit h t he C o or di nati n g I n vesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3.
1 0. 6. 2 
P u blic ati o n
T he first p u blicati o n will be a p u blicati o n of t he res ults of t he a nal ys is of t he pri mar y  en d p oi nts 
t hat will i ncl u de data fr o m all trial sites.
T he I n vesti gat or will i nf or m t he S p o ns or i n a d va nce a b o ut a n y pla ns t o p u blis h or prese nt data 
fr o m t he trial.  An y  pu blicati o ns a n d prese ntati o ns of t he res ults (a bstracts i n j o ur nals or 
ne ws pa pers, oral prese ntati o ns, etc.), eit her i n w h ole or i n part, b y  In vesti gat ors or t heir 
re prese ntati ves will re q uire pres u b missi o n re vie w b y t he S p o ns or.
T he S p o ns or will n ot s u p press or vet o p u blicati o ns, b ut mai ntai ns t he ri g ht t o dela y p u blicati o n i n 
or der t o pr otect i ntellect ual pr o pert y ri g h ts.
1 1
Refere nces Cite d i n t he Te xt
Br o o k me y er R, Cr o wle y J. A C o nfi de nce I nter val f or t he Me dia n S ur vi val Ti me. Bi o metrics. 
1 9 8 2; 3 8: 2 9 - 4 1.
C u n ni n g ha m 
D, 
Starli n g N, 
Ra o 
S , et al. Ca pecita bi ne 
a n d o xali plati n f or a d va nce d 
es o p ha g o gas tric ca ncer. N E n gl J Me d 2 0 0 8; 3 5 8:3 6 – 4 6.
D o n g H, Z h u G, Ta ma da K, C he n L.  B7- H 1, A t hir d me m ber of t he B 7 fa mil y, c o -sti m ulates T-
cell pr oliferati o n a n d i nterle u ki n- 1 0 secreti o n. Nat ure Me d. 1 9 9 9; 5( 1 2): 1 3 6 5 - 9.
D o n g H, Str o me S E, Sal o ma o D R, et al. T u m or -ass ociate d B 7 -H 1 pr o m otes T- cell a p o pt osis: a 
p ote ntial mec ha nis m of i m m u ne e vasi o n. Nat ure Me d. 2 0 0 2; 8( 8): 7 9 3- 8 0 0.
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 CIS 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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 3 / 1 5 0
Free ma n GJ, L o n g AJ, I wai Y, et al. E n ga ge me nt of t he P D - 1 i m m u n oi n hi bit or y rece pt or b y  a 
n o vel B 7 fa mily me m ber lea ds t o ne gati ve re g ulati o n of l ym p h oc y te acti vati o n. J E x p Me d. 
2 0 0 0; 1 9 2( 7): 1 0 2 7 - 3 4.
H o m mel G, Bretz F a n d Ma urer
W. 
P o werf ul s h ort-c uts f or m ulti ple testi n g pr oce d ures wit h 
s pecial refere nce t o gate kee pi n g strate gies. Statist Me d. 2 0 0 7; 2 6 ; 4 0 6 3- 7 3.
H o war d S C, J o nes D P, P ui C H. T he t u m or l ysis s y n dr o me. N E n gl J Me d. 2 0 1 1; 3 6 4( 1 9): 1 8 4 4 - 5 4.
H u dis C A. Trast uz u ma b -mec ha nis m of acti o n a n d use i n cli nical practice. N E n gl J Me d. 
2 0 0 7; 3 5 7( 1): 3 9 - 5 1.
I nter nati o nal A ge nc y  for Researc h o n Ca ncer W H O. 
G L O B O C A N 2 0 1 2: Esti mate d Ca ncer 
I nci de nce, M ortalit y , an d Pre vale nce W orl d wi de 
i n 2 0 1 2 [ 0 6 A pril 2 0 1 5]. A vaila ble fr o m: 
htt p:// gl o b oca n.iarc.fr/ Defa ult.as p x.
Jasse m J, Ra mla u R, Sa nt or o A, et al. P hase III trial of pe metre xe d pl us best s u p p orti ve care 
c o m pare d wit h best s u p p orti ve care i n pre vi o usl y t reate d patie nts wit h a d va nce d mali g na nt ple ural 
mes ot heli o ma. J Cli n O nc ol. 2 0 0 8; 2 6( 1 0): 1 6 9 8 -7 0 4.
Kal bfleisc h J D, Pre ntice R L . T he Statistical A nal ysis of Fail ure Ti me Data. Ne w Y or k: J o h n Wile y 
& S o ns; 1 9 8 0.
Latc h ma n Y, W o o d C R, C her n o va T, et al. P D -L 2  is a sec o n d li ga n d f or P D -1 a n d i n hi bits T cell 
acti vati o n. Nat ure I m m u n ol. 2 0 0 1; 2( 3): 2 6 1- 8.
L utz k y  J, A nt o nia SJ, Bla ke -Has ki ns A, et al. A p hase 1 st u d y of M E DI 4 7 3 6, a n a nti– P D L 1 
a nti b o d y, i n patie nts wit h a d va nce d s oli d t u m ors [ A S C O a bstract 3 0 0 1 ^]. J Cli n O nc ol. 
2 0 1 4; 3 2( 5s) :a bstr 3 0 0 1.
M ur o K, Ba n g Y, S ha n kara n V, et al. A P hase 1 B St u d y  of pe m br oliz u ma b ( pe m br o; M K -3 4 7 5) 
i n patie nts wit h a d va nce d gastric ca ncer. A n n O nc ol . 2 0 1 4; 2 5(s u p pl 5): v 1- v 4 1.
Nati o nal C o m pre he nsi ve Ca ncer Net w or k G ui deli nes f or Gastric Ca ncer. 2 0 1 5; Ver si o n 3 . 2 0 1 5.
O ki E, O ka n o S, A n d o K, et al. H E R 2 a n d pr o gra m me d deat h - 1 li ga n d-1 ( P D-L 1 ) e x pressi o n i n 
gastric carci n o ma. J Cli n O nc ol. 2 0 1 4; 3 2( N o 1 5 _s u p pl ( Ma y  2 0 S u p ple me nt)):e 1 5 0 4 1.
Ste wart B W, Wil d C P, e dit ors. W orl d Ca ncer Re p ort 2 0 1 4: I nter nati o nal A ge nc y  f or Researc h o n 
Ca ncer, W orl d Healt h Or ga nizati o n; 2 0 1 4.
Tes niere A 1, Sc hle m mer F, B oi ge V, et al. I m m u n o ge nic deat h of c ol o n ca ncer cells treate d wit h 
o xali plati n. O nc o ge ne. 2 0 1 0 Ja n 2 8; 2 9( 4): 4 8 2 - 9 1.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 4 / 1 5 0
T o palia n S L , Dra ke C G, Par d oll D M. Tar geti n g t he P D -1/ B 7 -H 1( P D -L 1) pat h wa y  to acti vate a nti-
t u m or i m m u nit y. C urr O pi n I m m u n ol . 2 0 1 2; 2 4( 2): 2 0 7- 1 2.
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.
Wa d dell T, Ver heij M, All u m W, et al. Gastric ca ncer: E S M O -E S S O -E S T R O cli nical practice 
g ui deli nes f or dia g n osis, treat me nt a n d f oll o w -u p. A n n O nc ol 2 0 1 3; 2 4 (s u p pl 6): vi 5 7 -vi 6 3.
Zafar 
S Y, C urr o w 
D, 
A ber net h y A P. 
Defi ni n g 
best s u p p orti ve care. J Cli n 
O nc ol.
2 0 0 8; 2 6( 3 1): 5 1 3 9 - 4 0.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 5 / 1 5 0
1 2
A p pe n dices
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 6 / 1 5 0
A p pe n di x I
Si g n at ure P a ges a n d Res p o nsi ble Pers o ns f or t he Tri al
D oc u me nt N o. 
O bject N o.
C CI
C CI


A v el u m a b 
E M R 1 0 0 0 7 0- 0 0 7 
A v el u m a b i n First-li n e G astri c C a n c er 
Si g n at ur e P a g e - Pr ot o c ol L e a d 
Tri al Titl e: 
I N D N u m b er: 
E u dr a C T N u m b er: 
A 
P h as e 
ill o p e n- la bel, m ulti c e nt er 
trial of 
m ai nt e n a n c e t h er a p y wit h a v el u m a b ( M S B 0 0 1 0 71 8 C) 
v ers us c o nti n u ati o n of first-li ne c he m ot hera p y i n 
s u bj e cts wit h 
u nr es e ct a bl e, l ocally a d v a n c e d or 
m et ast ati c, a d e n o c ar ci n o m a of t h e st o m a c h, or of t h e 
g astr o- es o p h a g e al j u n cti o n 
 
 
2 0 1 5- 0 0 3 3 0 0- 2 3 
Cli ni c al 
Tri al 
Pr ot o c ol 
D at e 
I 1 7 J ul y 2 0 1 9 N ersi o n 7. 0 
V ersi o n: 
Pr ot o c ol L e a d r es p o nsi bl e f or d esi g ni n g t h e cli ni c al tri al: 
I a p pr o ve t he desi g n of ;;;teal trial: 
Si g n at ur e 
N a m e, a c a d e mi c d e gr e e: 
 
F u n cti o n I Titl e: 
 
I nstit uti o n: 
E M D S er o n o R es e ar c h & D e v el o p m e nt I nstit ute, I nc. 
A d dr ess: 
T el e p h o n e n u m b er: 
E- m ail a d dr ess: 
4 5 A Mi d dl es e x T ur n pi ke, Bill eri c a, M A 0 1 8 2 1- 3 9 3 6, U S A 
 
 
D oc u m e nt N o.
 
O bject N o. 
 
 
 
1 3 7/1 5 0 
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D


A vel u ma b 
E M R 1 0 0 0 7 0- 0 0 7 
A v el u m a b i n First-li n e G astri c C a n c er 
Si g n at ur e P a g e - C o or di n ati n g I n v esti g at or 
Tri al Titl e 
I N D N u m b er 
E u dr a C T N u m b er 
A P h as e ill o pe n-la bel , m ultice nter trial of mai nte na nce 
t he r a p y wit h 
a vel u ma b 
( M S B O O 1 0 7 1 8 C) 
v e rs us 
c o nti n uati o n offrr st-li ne c he m ot hera p y i n su bjects wit h 
u nresecta ble , 
l ocally 
a dv a nce d 
or 
metastatic , 
a de n ocarci n o ma 
of 
t h e 
st o mac h, 
or 
of 
t he 
gastr o -es o p ha geal j u n cti o n 
... 
 
2 0 1 5- 0 0 3 3 0 0- 2 3 
Cli ni c al 
Tri al 
Pr ot o c ol 
D at e 
I 1 7 J ul y 2 0 1 9 N ersi o n 7. 0 
V ersi o n 
I a p pr o ve t he d esi g n of t h e cli nical trial a n d I u n dersta n d a n d will c o n d u ct t he trial acc or di n g t o 
t h e cli ni c al tri al pr ot o c ol , a n y a p pr o v e d pr ot o c ol a me n d me nts , I nter nati o nal C o u ncil f or 
Har m o nisati o n 
G o o d 
Cli nical 
Pr a cti ce ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d n ati o n al la ws. 
Si g nat ure 
D at e of Si g nat ure 
N a me, aca de mic d e gr e e : 
 
I nstit uti o n: 
 
A d dre ss: 
 
E- mail a d dre ss: 
 
D o c u m e nt N o. 
 
O bj e ct N o . 
 
 
 
13 8/ 1 5 0 
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 3 9 / 1 5 0
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A 
P hase 
III o pe n -la bel, m ultice nter 
trial of 
mai nte na nce t hera p y wit h a vel u ma b ( M S B 0 0 1 0 7 1 8 C) 
vers us c o nti n uati o n of first-li ne c he m ot hera p y in 
s u bjects wit h 
u nresecta ble, l ocally a d va nce d or 
metastatic, a de n ocarci n o ma of t he st o mac h, or of t he 
gastr o -es o p ha geal j u ncti o n
I N D N u m ber
E u dr a C T N u m ber
2 0 1 5- 0 0 3 3 0 0- 2 3
Cli nic al 
Tri al 
Pr ot oc ol 
D ate 
/ 
Versi o n
1 7 J ul y 2 0 1 9/Versi o n 7. 0
Ce nter N u m ber
Pri nci p al I n vesti g at or
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil f or Har m o nisati o n G o o d Cl i nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o btai n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I nvesti gati o nal Me dici nal 
Pr o d uct a n d a n y ot her fi na ncial ties wit h t he S p o ns or .  T he S p o ns or will use a n y s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl y i n g wit h t he re g ulat or y re q uire me nts.  I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 0 / 1 5 0
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
A d dress:
4 5 A Mi d dlese x T ur n pi ke, Billerica, M A 0 1 8 2 1, U S A
Tele p h o ne n u m ber:
E- mail a d dress:
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
Merc k Healt hcare K Ga A Dar msta dt, Ger ma n y, a n affiliate of Merc k 
K Ga A, Dar msta dt, Ger ma n y .
A d dress:
Fra n kf urter Str. 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
 
Fa x n u m ber:
E- mail a d dress:
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, Inc.
A d dress:
4 5 A Mi d dlese x T ur n pi ke, Billerica, M A 0 1 8 2 1, U S A
Tele p h o ne n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 1 / 1 5 0
A p pe n di x II
G ui d a nce o n C o ntr ace pti o n
BI R T H C O N T R O L M E T H O D S C O N SI D E R E D A S HI G H L Y E F F E C TI V E
Acc or di n g t o t he C T F G “ Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g na nc y  testi n g i n cli nical trials” met h o ds t hat ca n ac hie ve a fail ure rate of 
less t ha n 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y are c o nsi dere d as hi g hly effecti ve birt h c o ntr ol met h o ds, s uc h as:
o
c o m bi ne d (estr o ge n a n d pr o gester o ne c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1 ( oral, i ntra va gi nal, tra ns der mal)
o
pr o gester o ne - o nly h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1 ( oral, i njecta ble, i m pla nta ble2)
o
i ntra uteri ne de vice (I U D)2
o
i ntra uteri ne h or m o ne -releasi n g sys te m (I U S)2
o
bilateral t u bal occl usi o n 2
o
vasect o mize d part ner 2, 3
o
se x ual a bsti ne nce. 4
1 H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he efficac y of t he c o ntrace pti o n met h o d.
2 C o ntrace pti o n met h o ds i n t he c o nte xt of t his g ui da nce are c o nsi dere d t o ha ve l o w  user de pe n de nc y.
3 Vasect o mise d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat t he part ner is t he s ole se x ual part ner of t he w o m a n of c hil d beari n g p ote ntial trial partici pa nt a n d t hat 
t he vasect o mize d part ner has recei ve d me dical assess me nt of t he s ur gical s uccess.
4 I n t he c o nte xt of t his g ui da nce se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e nt ire peri o d of ris k 
ass ociate d wit h t he st u d y treat me nts. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he preferre d a n d us ual lifest yle of 
t he s u bject.
D oc u me nt N o. 
O bject N o.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 2 / 1 5 0
A p pe n di x III
Pr ot oc ol A me n d me nts a n d List of C h a n ges
Pr ot oc ol Versi o n 1. 0 ( 1 4 A u g ust 2 0 1 5) was t he ori gi nal pr ot oc ol.  The pr ot oc ol was re vise d t o i ncl u de fee d bac k fr o m t he F D A, P M D A, a n d E M A, 
a n d Versi o n 2. 0 ( A me n d me nt 1) was iss ue d o n 2 3 Se pte m ber 2 0 1 5.  Versi o n 3. 0 ( A me n d me nt 2) was iss ue d o n 0 6 Ja n uar y 20 1 6 a n d i ncl u de d fee d bac k 
fr o m V ol u ntar y  Har m o nisati o n Pr oce d ure (V H P ).  Versi o n 3. 1 (Ja pa n O nl y A d de n d u m) was iss ue d o n 0 6 A pril 2 0 1 6 a n d i ncl u de d m o dificati o ns f or 
t he P har mace uticals a n d Me dical De vices A ge nc y.  Versi o n 3. 2 ( Fra nce O nl y  Ad de n d u m) was iss ue d o n 0 1 A pril 2 0 1 6 a n d i ncl u de d m o dificati o ns 
f or t he Fre nc h Nati o nal A ge nc y  for Me dici nes a n d Healt hcare Pr o d ucts Safet y  (A N S M) a n d Fre nc h Ce ntral Et hics C o m mittee re q uests.  Pr ot oc ol 
Versi o n 4. 0 ( A me n d me nt 3) was iss ue d o n 2 5 Ja n uar y 2 0 1 7 a n d i ncl u des pr o gra m -wi de c ha n ges a n d c orrecte d a n a d mi nistrati ve err or i n t he versi o n 
n u m beri n g of t he pr ot oc ol . Pr ot oc ol Versi o n 5 . 0 ( A me n d me nt 4 ) was iss ue d o n 2 8 A u g ust 2 0 1 7 a n d i ncl u des pr o gra m- wi de c ha n ges c o nsi dere d as 
n o n- s u bsta ntial as o nl y a d mi nistrati ve c h a n ges were ma de . Pr ot oc ol Versi o n 6. 0 ( A me n d me nt 5) was iss ue d o n 2 1 J u ne 2 0 1 8 a n d i ncl u de d c ha n ges 
t o t he st u d y pri mar y an d sec o n dar y en d p oi nts/ o bjecti ves c o nsi dere d as s u bsta ntial.  Versi o n 6. 1 (Ja pa n o nl y  ad de n d u m) was iss ue d o n 1 1 J ul y 2 0 1 8 
a n d Versi o n 6. 2 ( Fra nce o nl y  a d de n d u m) was iss ue d o n 0 7 A u g ust 2 0 1 8 a n d i ncl u de d A me n d me nt 5 .
Pr ot oc ol Versi o n 7 . 0 S u m m ar y of C h a n ges
T he ke y  reas o ns f or A me n d me nt 6, Pr ot oc ol versi o n 7. 0, are s u m marize d bel o w:
R ati o n ale f or C h a n ges
St u d y  EM R 1 0 0 0 7 0 - 0 0 7 was a me n de d i n J u ne 2 0 1 8 t o c ha n ge t he pri mar y  objecti ve t o i ncl u de O S i n P D -L 1 + s u bjects, i n a d diti o n t o O S i n all 
ra n d o mize d s u bjects, w here P D -L 1 stat us was defi ne d base d o n a 1 % c ut-off f or t u m or cells (refere nce pr ot oc ol E M R 1 0 0 0 7 0 - 0 0 7 A me n d me nt 5, 
V ersi o n 6).  At t hat ti me, t he pre vale nce of P D -L 1 + s u bjects was ass u me d t o be 3 5 % ( base d o n t he pre vale nce of P D -L 1 + t u m ors i n patie nts wit h 
gastric ca ncer ( G C) i n t he n o n- pr o gresse d G C c o h ort of st u d y EM R 1 0 0 0 7 0 -0 0 1).  As s uc h, 1 1 2 e ve nts i n t he P D -L 1 + s u b gr o u p were pr ojecte d t o 
occ ur t o t he 3 5 6 O S e ve nts re q uire d f or t he pri mar y a nal ys is i n all ra n d o mize d s u bjects, a n d t he pri mar y a nalys is i n b ot h a nal ysis sets was pla n ne d at 
a c o m m o n ti me p oi nt w he n b ot h c o n diti o ns are met. 
At t he ti me o f release of P r ot oc ol V ersi o n 6, t he P D -L 1 assa y utilize d was a n i n vesti gati o nal use o nl y  (I UO) assa y for
 testi n g.  Beca use 
t he a me n de d pri mar y e n d p oi nt of O S i n t he P D -L 1 + a nal ysis set w o ul d re q uire testi n g b y  vali date d assa y, vali dati o n of t he pr o p ose d P D -L 1 I H C 7 3-
1 0 p har m D x kit f or testi n g of G C sa m ples at 1 % c ut- off f or t u m or cells was i nitiate d i n Se pte m ber 2 0 1 8.
Res ults of t he P D -L 1  sc ori n g wit h vali date d assa y beca me a vaila ble i n J une 2 0 1 9.  Fr o m 4 9 9 ra n d o mize d s u bjects, 4 3 8 sa m ples we re a vaila ble f or 
P D -L 1  sc ori n g wit h t he vali date d assa y .  Less t ha n 1 5 % of t he sa m ples were sc ore d as P D-L 1 p ositi ve, w hic h is c o nsi dera bl y less t ha n t he pre vi o usl y 
ass u me d pre vale nce d uri n g Pr ot oc ol V ersi o ns 1- 6.  Base d o n t his pre vale nce, t he n u m ber of p re vi o usl y pr ojecte d e ve nts ( Pr ot oc ol V ersi o n 6) i n t he 
P D -L 1 + s u bjects will n ot be reac he d.  Th us, t he c o n diti o n of meeti n g t he pre -s pecifie d n u m ber of P D-L 1 + e ve nts f or t he Fi nal A nal y sis data c ut-off 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 3 / 1 5 0
has bee n re m o ve d as a tri g ger f or t he Fi nal A nal ys is i n t he P r ot oc ol V ersi o n 7. T he Fi nal A nal ys is will be tri g gere d b y  the e ve nts i n t he I TT p o p ulati o n 
as well as a mi ni m u m f oll o w- u p ti me of 1 8 m o nt hs
f or pri mar y  anal ys is w hic h is e x pecte d t o e ns ure s ufficie ntly mat ure data f or O S i n P D -L 1 + 
s u bjects.  T he p ri mar y anal y sis of O S i n P D -L 1 + s u bjects will be c o n d ucte d at t he sa me ti me as O S i n all ra n d o mize d s u bjects wit h s u bsta ntiall y 
re d uce d p o wer, acc or di n g t o t he e n d p oi nt defi niti o n as i n P r ot oc ol V ersi o n 6.
T he sa m pli n g f or P K a n d 
a nal ys is was li mite d t o 2 ye ars fr o m ra n d o mizati o n, as f urt her sa m pli n g will n ot a d d val ue t o p har mac o ki netic a n d 
 e val uati o n. T heref ore, t he last sa m pli n g p oi nt will be at Wee k 1 0 9. T his will a v oi d u n necessar y b ur de n t o t he s u bjects.
T he a b o ve -me nti o ne d c ha n ges are c o nsi dere d s u bsta ntial base d o n t he ‘ Detaile d g ui da nce o n t he re q uest t o t he c o m pete nt a ut h orities f or a ut h orizati o n 
of a cli nical trial o n a me dici nal pr o d uct f or h u ma n use, t he n otificati o n of s u bsta ntial a me n d me nts a n d t he declarati o n of t he e n d of t he trial ( C T -1)’.
Pr ot oc ol Versi o n 7 . 0 Det aile d List of C h a n ges
C ha n ges t o t he cli nical trial pr ot oc ol te xt wit h t he e xce pti o n of mi n or e dit orial c ha n ges t o t he cli nical trial pr ot oc ol te xt are prese nte d i n t he ta ble 
bel o w. A d diti o ns a n d a me n de d te xt are s h o w n i n b ol d.
Deleti o ns are mar ke d usi n g stri ke t hr o u g h.
C o m p aris o n wit h Cli nic al Tri al Pr ot oc ol Versi o n 6. 0, 2 1 J u ne 2 0 1 8 ( A me n d me nt 5)
C h a n ge
Secti o n
P a ge
Pre vi o us W or di n g
Ne w W or di n g
R ati o n ale
S p o ns or 
Me dical 
res p o nsi ble pers o n 
c ha n ge d fr o m Ilaria 
C o nti
t o 
H o n g 
Z ha n g
Title Pa ge a n d 
Si g nat ure 
Pa ge - Pr ot oc ol 
Lea d
1, 
1 3 5
St u d y Pers o n nel 
u p date d
Last s u bject o ut date 
c ha n ge d fr o m Q 4 t o 
Q 3
S y n o psis 
Pla n ne d Trial 
Peri o d
1 1
La st s u bject o ut: Q 4, 2 0 1 9
La st s u bject o ut: Q3 , 2 0 1 9
U p date d as t he date 
o n w hic h data 
c ollecti o n is 
c o m plete d f or all 
t he pri mar y a nal ysis
is 1 3 Se p 2 0 1 9
A s t he pre vale nce 
of P D -L 1 + s u bjects 
S y n o psis
1 8
T he data c ut -off f or t he pri mar y a nal ysis will 
ta ke place o n a pr os pecti vel y-deter mi ne d date, 
T he data c ut -off f or t he pri mar y a nal ysis will ta ke 
place o n a pr os pecti vel y -deter mi ne d date, u p o n 
As per t he res ults of 
t he P D-L 1 sc ori n g 
D oc u me nt N o. 
O bject N o.
C CI
C CI
P P D P P D
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 4 / 1 5 0
is l o wer t ha n i nitial 
f orecaste d 3 5 %. 
Fr o m  c urre nt 
e nr olle d n u m ber of 
s u bjects, it is 
i mp ossi ble t o e ver 
reac h 1 1 2 e ve nts 
a ntici pate d f or 
pri mar y a nal ysis i n 
P D -L 1 p ositi ve 
s u bjects.
u p o n w hic h t he tar get n u m ber of 3 5 6 O S e ve nts 
i n all ra n d o mize d s u bjects a n d 1 1 2 O S e ve nts i n 
P D -L 1 + s u bjects are pr ojecte d t o ha ve bee n 
reac he d, a n d t he last s u bject ra n d o mize d i n t he 
st u d y has bee n f oll o we d f or at least 1 8 m o nt hs 
fr o m ra n d o mizati o n.
[ ….]
F or O S i n P D -L 1 + s u bjects, a pre vale nce rate of 
3 5 % i n all ra n d o mize d s u bjects is ass u me d, a n d 
a me dia n O S of 1 9. 3 m o nt hs i n t he a vel u ma b 
ar m c orres p o n di n g t o a hazar d rati o of 0. 5 4.
w hic h t he tar get n u m ber of 3 5 6 O S e ve nts i n all 
ra n d o mize d s u bjects a n d 1 1 2 O S e ve nts i n P D - L 1 + 
s u bjects are pr ojecte d t o ha ve bee n reac he d, a n d t he 
last s u bject ra n d o mize d i n t he st u d y has bee n 
f oll o we d f or at least 1 8 m o nt hs fro m  ra n d o mizati o n.
[ ….]
F or O S i n P D -L 1 + s u bjects, at pl a n ni n g st a ge a
pre vale nce rate of 3 5 % i n all ra n d o mize d s u bjects 
w a s is ass u me d, a n d a me dia n O S of 1 9. 3 m o nt hs i n 
t he a vel u ma b ar m c orres p o n di n g t o a hazar d rati o of 
0. 5 4.
wit h vali date d assa y 
a vaila ble i n J u ne 
2 0 1 9 , t he n u m ber of 
pre vi o usl y 
pr ojecte d e ve nts 
( Pr ot oc ol V ersi o n 
6) i n t he P D - L 1 + 
s u bjects will not be 
reac he d.  T h us, t he 
c o n diti o n of 
meeti n g t he pre -
s pecifie d n u m ber of 
P D -L 1 + e ve nts f or 
t he Fi nal A nal ysis 
data c ut -of f has 
bee n re m o ve d as a 
tri g ger f or t he Fi nal 
A nal ysis .  T he Fi nal 
A nal ysis will be 
tri g gere d b y t he 
e ve nts i n t he I T T 
p o p ulati o n as we ll 
as a mi ni m u m 
f oll o w-u p ti me of 
1 8 m o nt hs f or 
pri mar y a nal ysis 
w hic h is e x pecte d 
t o e ns ure 
s ufficie ntl y mat ure 
data f or O S i n P D -
L 1 + s u bjects .  T he 
pri mar y a nal ysis of 
O S i n P D - L 1 + 
s u bjects will be 
c o n d ucte d at t he 
sa me ti me as O S i n 
all ra n d o mize d 
s u bjects wit h 
s u bsta ntiall y 
re d uce d p o wer.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 5 / 1 5 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 6 / 1 5 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 7 / 1 5 0
be at Wee k 1 0 9 t o 
a v oi d u n necessar y 
b ur de n t o t he 
s u bjects, e xce pt f or 
s u bjects still o n 
treat me nt be y o n d 
Wee k 1 0 9.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 8 / 1 5 0
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CIC CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 4 9 / 1 5 0
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne G astric C a ncer
E M R 1 0 0 0 7 0 - 0 0 7
1 5 0 / 1 5 0
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI

SAP_001.pdf: 
A vel u m a b  
A vel u m a b i n First -li ne G astric C a ncer 
E M R 1 0 0 0 7 0 -0 0 7  
 
 
 
 
 
 
 
 
A p pe n di x 1 6. 1. 9  
D oc u me nt ati o n of St atistic al Met h o ds  
 
•  
E M R 1 0 0 0 7 0 -0 0 7 Statistical A nal ysis Pla n; Versi o n 4. 0, 2 3 J ul y 2 0 1 9  
 
 
1/ 1 2 7
C CI
C CI






































































































































































































E L E C T R O NI C SI G N A T U R E S
D oc u me nt: ct p-e mr 1 0 0 0 7 0- 0 0 7-s a p- v 4
Si g ne d B y
E ve nt N a me
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y
H H: m m ‘ G M T’ Z)
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
D oc u me nt N o
O bject N o. 
1 0 0/ 1 2 7
C CI
C CI
P P D
P P D
P P D
P P D


1 0 1/ 1 2 7
C CI


1 0 2/ 1 2 7
C CI


1 0 3/ 1 2 7
C CI


1 0 4/ 1 2 7
C CI


 
1 0 5/ 1 2 7
C CI
C CI


1 0 6/ 1 2 7
C CI


1 0 7/ 1 2 7
C CI


1 0 8/ 1 2 7
C CI


1 0 9/ 1 2 7
C CI


1 1 0/ 1 2 7
C CI


1 1 1/ 1 2 7
C CI


1 1 2/ 1 2 7
C CI


1 1 3/ 1 2 7
C CI


1 1 4/ 1 2 7
C CI


1 1 5/ 1 2 7
C CI


1 1 6/ 1 2 7
C CI


1 1 7/ 1 2 7
C CI


1 1 8/ 1 2 7
C CI


1 1 9/ 1 2 7
C CI


1 2 0/ 1 2 7
C CI


1 2 1/ 1 2 7
C CI


1 2 2/ 1 2 7
C CI


1 2 3/ 1 2 7
C CI


1 2 4/ 1 2 7
C CI


1 2 5/ 1 2 7
C CI


1 2 6/ 1 2 7
C CI


1 2 7/ 1 2 7
C CI