A Phase II Open Label, Randomized Non-Comparative Trial of Nivolumab Alone or in Combination With Ipilimumab for the Treatment of Patients With Advanced Hypermutated Solid Tumors Detected by a Blood Based Assay
Phase: PHASE2
Conditions: Advanced Solid Tumors
Sponsor: Canadian Cancer Trials Group

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
C O N FI D E N TI A L  
 
H E A L T H C A N A D A S U B MI S SI O N  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C A N C E R R E S E A R C H I N S TI T U T E ( C RI)  & C A N A DI A N C A N C E R  T RI A L S G R O U P ( C C T G)  
 
A P H A S E II O P E N L A B E L, R A N D O MI Z E D N O N -C O M P A R A TI V E T RI A L  
O F NI V O L U M A B A L O N E O R I N C O M BI N A TI O N WI T H I PI LI M U M A B  
F O R T H E T R E A T M E N T O F P A TI E N T S WI T H A D V A N C E D H Y P E R M U T A T E D  
S O LI D T U M O R S D E T E C T E D B Y A B L O O D B A S E D A S S A Y  
 
Ni v ol u ma b I pili m u ma b i n Patie nts wit h H y per M utate d Ca ncers Detecte d i n B L o o d ( NI M B Le) 
 
C RI -C C T G Pr ot oc ol N u m b er:  0 0 0 1  
C C T G Pr ot oc ol N u m ber : I N D. 2 3 5 
 
 
 
S T U D Y C H AI R:  
Nai yer Riz vi  
 
 
C A N A DI A N  C O -C H AI R : 
Patricia T a n g  
 
 
S E NI O R I N V E S TI G A T O R S: 
Marti n S m ora gie wicz  
 
 
Ja net Da nce y 
 
 
BI O S T A TI S TI CI A N:   
D o n gs he n g T u 
 
 
S T U D Y C O O R DI N A T O R:  
Caitli n B ur ns  
 
 
R E G U L A T O R Y S P O N S O R:  
C C T G  
 
 
S U P P O R T E D B Y:  
Ca ncer Researc h I nstit ute  
 
 
Brist ol M yers S q ui b b  
 
 
& P G D X  
 
 
( F or c o nt act i nf or m ati o n of st u dy pers o n nel see Fi n al P a ge.) 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
i 
C O N FI D E N TI A L  
T A B L E O F C O N T E N T S  
 
S T U D Y A C K N O W L E D G M E N T/ DI S C L O S U R E ( S A/ D)  .................................................................................. 1 
 
T R E A T M E N T S C H E M A  ..................................................................................................................................... 2 
 
1. 0  
O BJ E C TI V E S  ......................................................................................................................................... 3 
1. 1  
Pri mar y O bjecti ve  ................................................................................................................................... 3 
1. 2  
Sec o n dar y O bjecti ves  .............................................................................................................................. 3 
1. 3  
E x pl orat or y O bjecti ves  ............................................................................................................................ 3 
 
2. 0  
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  ...................................................................... 4 
2. 1  
D N A Re pair Defects a n d T u m ori ge nesis  ................................................................................................ 4 
2. 2  
P O L E a n d P O L D 1 M utati o ns i n S oli d T u m ors ....................................................................................... 4  
2. 3  
I m m u ne C hec k p oi nt Bl oc ka de i n T u m ors wit h Hi g h M utati o nal B ur de n .............................................. 6 
2. 4  
Ni v ol u ma b  ............................................................................................................................................... 7 
2. 5  
I pili m u ma b .............................................................................................................................................. 8 
2. 6  
Ni v ol u ma b C o m bi ne d wit h I pili m u ma b.................................................................................................. 9  
2. 7  
Trial Rati o nale  ....................................................................................................................................... 1 0 
 
3. 0  
B A C K G R O U N D T H E R A P E U TI C I N F O R M A TI O N .......................................................................... 1 1  
3. 1  
Ni v ol u ma b  ............................................................................................................................................. 1 1 
3. 2  
I pili m u ma b ............................................................................................................................................ 1 3 
 
4. 0  
S T U D Y P O P U L A TI O N  ....................................................................................................................... 1 5 
4. 1  
I ncl usi o n Criteria ................................................................................................................................... 1 5 
4. 2  
A d diti o nal Criteria T o Be Met Pri or T o St u d y E nr oll me nt  ................................................................... 1 6 
4. 3  
E xcl usi o n Criteria  .................................................................................................................................. 1 8 
 
5. 0  
P A TI E N T E V A L U A TI O N F L O W S H E E T: P R E -T R E A T M E N T, O N S T U D Y, A N D A F T E R 
T R E A T M E N T ....................................................................................................................................... 2 0 
5. 1  
F oll o w - u p f or P atie nts ........................................................................................................................... 2 1 
 
6. 0  
E N T R Y/ R A N D O MI Z A TI O N P R O C E D U R E S  .................................................................................... 2 2 
6. 1  
E ntr y Pr oce d ures ................................................................................................................................... 2 2  
6. 2  
Stratificati o n  .......................................................................................................................................... 2 3 
6. 3  
Re gistrati o n a n d Ra n d o mizati o n  ........................................................................................................... 2 3 
 
7. 0  
T R E A T M E N T P L A N  ........................................................................................................................... 2 4 
7. 1  
Treat me nt Pla n  ...................................................................................................................................... 2 4 
7. 2  
D urati o n of T hera p y  .............................................................................................................................. 2 8 
7. 3  
C o nc o mita nt T hera p y ............................................................................................................................ 2 9  
 
8. 0  
C RI T E RI A F O R M E A S U R E M E N T O F S T U D Y E N D P OI N T S  ......................................................... 3 0 
8. 1  
Defi niti o ns  ............................................................................................................................................. 3 0 
8. 2  
Res p o nse a n d E val uati o n E n d p oi nts  ..................................................................................................... 3 0 
8. 3  
I m m u ne-Relate d Res p o nse Assess me nt  ................................................................................................ 3 3 
8. 4  
Res p o nse D urati o n ( R E CI S T 1. 1 a n d i R E CI S T) .................................................................................. 3 5  
8. 5  
Sta ble Disease D urati o n  ........................................................................................................................ 3 5 
8. 6  
Met h o ds of Meas ure me nt  ...................................................................................................................... 3 5 
 
 

 
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C O N FI D E N TI A L 
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C O N FI D E N TI A L  
9. 0  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ..................................................................................... 3 8 
9. 1  
Defi niti o n of a Re p orta ble Seri o us A d verse E ve nt ............................................................................... 3 8  
9. 2  
Seri o us A d verse E ve nt Re p orti n g I nstr u cti o ns ..................................................................................... 3 8 
9. 3  
Ot her Pr ot oc ol Re p orta ble E ve nts – Pre g na nc y Re p orti n g a n d E x p os ure Re p orti n g............................ 3 9  
9. 4  
C C T G Res p o nsi bilit y f or Re p orti n g Seri o us A d verse E ve nts t o Healt h Ca na da .................................. 4 1  
9. 5  
C C T G Re p orti n g Res p o nsi bilit y t o Brist ol M yers S q ui b b .................................................................... 4 1  
9. 6  
C C T G a n d Brist ol M yers S q ui b b Re p orti n g Res p o nsi bilities ............................................................... 4 1  
9. 7  
Re p orti n g Safet y Re p orts t o I n vesti gat ors ............................................................................................. 4 1  
 
1 0. 0  
P R O T O C O L T R E A T M E N T DI S C O N TI N U A TI O N A N D T H E R A P Y A F T E R S T O P PI N G  ............ 4 2 
1 0. 1  
Criteria f or Disc o nti n ui n g Pr ot oc ol Treat me nt ..................................................................................... 4 2  
1 0. 2  
D urati o n of Pr ot oc ol Treat me nt ............................................................................................................ 4 2  
1 0. 3  
T hera p y After Pr ot oc ol Treat me nt is St o p pe d ...................................................................................... 4 2  
1 0. 4  
F oll o w - u p Off Pr ot oc ol Treat me nt ........................................................................................................ 4 2 
 
1 1. 0  
C E N T R A L R E VI E W P R O C E D U R E S  ................................................................................................. 4 4 
1 1. 1  
Ce ntral Ra di ol o g y Re vie w  .................................................................................................................... 4 4 
1 1. 2  
Ce ntral P at h ol o g y Re vie w  ..................................................................................................................... 4 4 
 
1 2. 0  
C O R R E L A TI V E S T U DI E S  .................................................................................................................. 4 5 
1 2. 1  
Pr ot oc ol- Ma n date d C orrelati ve St u dies  ................................................................................................ 4 6 
1 2. 2  
O pti o nal Fres h T u m or Bi o ps y ............................................................................................................... 4 7  
1 2. 3  
Statistical A nal yses  ............................................................................................................................... 4 8 
 
1 3. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................................................. 4 9 
1 3. 1  
O bjecti ves a n d Desi g n  ........................................................................................................................... 4 9 
1 3. 2  
E n d p oi nts a n d A nal ysis  ......................................................................................................................... 4 9 
1 3. 3  
Sa m ple Size a n d D urati o n of St u d y ...................................................................................................... 5 0  
1 3. 4  
Safet y M o nit ori n g ................................................................................................................................. 5 0  
1 3. 5  
Scree ni n g M o nit ori n g ............................................................................................................................ 5 1  
 
1 4. 0  
P U B LI C A TI O N P O LI C Y  ..................................................................................................................... 5 2 
1 4. 1  
A ut h ors hi p of P a pers, Meeti n g A bstracts, Etc. ..................................................................................... 5 2  
1 4. 2  
Res p o nsi bilit y f or P u blicati o n  ............................................................................................................... 5 2 
1 4. 3  
S u b missi o n of Material f or Prese ntati o n or P u blicati o n ........................................................................ 5 2  
 
1 5. 0  
E T HI C A L, R E G U L A T O R Y A N D A D MI NI S T R A TI V E I S S U E S  ...................................................... 5 3 
1 5. 1  
Re g ulat or y C o nsi derati o ns .................................................................................................................... 5 3  
1 5. 2  
I ncl usi vit y i n Researc h .......................................................................................................................... 5 3 
1 5. 3  
O btai ni n g I nf or me d C o nse nt ................................................................................................................. 5 4  
1 5. 4  
Disc o nti n uati o n of t he Trial .................................................................................................................. 5 5  
1 5. 5  
Rete nti o n of Patie nt Rec or ds a n d St u d y Files ....................................................................................... 5 5  
1 5. 6  
Ce ntre P erf or ma nce M o nit ori n g  ............................................................................................................ 5 6 
1 5. 7  
O n -Site M o nit ori n g/ A u diti n g  ................................................................................................................ 5 6 
 
1 6. 0  
R E F E R E N C E S  ...................................................................................................................................... 5 7 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
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C O N FI D E N TI A L  
A P P E N DI X I -  
P E R F O R M A N C E S T A T U S S C A L E S/ S C O R E S  ................................................................ 6 0 
A P P E N DI X II -  M A N A G E M E N T A L G O RI T H M S F O R E N D O C RI N O P A T H Y, G A S T R OI N T E S TI N A L, 
H E P A TI C, N E U R O L O GI C A L, P U L M O N A R Y A N D S KI N A D V E R S E E V E N T S  ......... 6 1 
A P P E N DI X III -  D R U G DI S T RI B U TI O N, S U P P L Y A N D C O N T R O L  ....................................................... 6 8 
A P P E N DI X I V -  D O C U M E N T A TI O N F O R S T U D Y  .................................................................................... 7 0 
A P P E N DI X V -  N CI C O M M O N T E R MI N O L O G Y C RI T E RI A F O R A D V E R S E E V E N T S  ...................... 7 1 
A P P E N DI X VI -  T H E T N M C L A S SI FI C A TI O N O F M A LI G N A N T T U M O U R S  ....................................... 7 2 
 
 
LI S T O F C O N T A C T S  ........................................................................................................................... Fi nal P a ge  
 

 
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C O N FI D E N TI A L 
1  
C O N FI D E N TI A L  
S T U D Y A C K N O W L E D G M E N T / DI S C L O S U R E ( S A/ D) 
 
I u n dersta n d t hat t his pr ot oc ol c o ntai ns i nf or mati o n t hat is c o nfi de ntial a n d pr o prietar y t o Ca ncer Researc h 
I nstit ute, Brist ol M yers S q ui b b, a n d P G D x. 
 
I  ha ve  rea d  t he  pr ot oc ol  a n d  a gree  t hat  it  c o ntai ns  all  necessar y  details  f or  carr yi n g  o ut  t he  st u d y  as 
descri be d. I will c o n d uct t his pr ot oc ol as o utli ne d t herei n, i n acc or da nce wit h a n y m o dificati o ns t hat ma y 
occ ur  o ver  t he  d urati o n  of  t he  st u d y, a n d  acc or di n g  t o  G o o d  Cli nical  Practice  a n d  a n y  a p plica ble  l ocal 
re g ulati o ns. I will ma ke a reas o na ble eff ort t o c o m plete t he st u d y wit hi n t he ti me desi g nate d. I c o nfir m t hat 
I  a n d  st u d y  pers o n nel  partici pati n g  u n der  m y  s u per visi o n  ha ve  a de q uate  res o urce  t o  f ulfill  t heir 
res p o nsi bilities  as  o utli ne d  i n  t his  pr ot oc ol.  I  will  mai ntai n  d oc u me ntati o n  of  a n y  i n vesti gat or 
res p o nsi bilities assi g ne d t o partici pati n g st u d y pers o n nel. I c o nfir m t hat all data will be s u b mitte d i n a ti mel y 
ma n ner a n d will be acc urate, c o m plet e a n d s u p p orte d b y s o urce d oc u me nts.  I will c o m plete a n y pr ot oc ol 
s pecific trai ni n g re q uire d b y t he s p o ns or a n d t hat I u n dersta n d t he re q uire me nt t o i nf or m a d diti o nal site 
pers o n nel wit h dele gate d d uties of t his i nf or mati o n. 
 
I will pr o vi de c o pies of t he pr ot oc ol a n d access t o all i nf or mati o n f ur nis he d b y C C T G t o st u d y pers o n nel 
u n der m y s u per visi o n. I will disc uss t his  material wit h t he m t o e ns ure t hat t he y are f ull y i nf or me d a b o ut t he 
i n vesti gati o nal pr o d uct a n d t he st u d y.  
 
I u n dersta n d t hat t his trial will be re gistere d o n a p u blic trial re gistr y a n d t hat m y c o ntact i nf or mati o n a n d 
site na me will be i ncl u de d i n t he re gistr y listi n g. 
 
I will pr o vi de pr ot oc ol i nf or mati o n t o m y Researc h Et hics B oar d (R E B/I R B ), I nstit uti o nal Re vie w B oar d(s) 
[I R B(s)] or I n de pe n de nt Et hics C o m mittee(s) [I E C(s)], s u bj ect t o t he f oll o wi n g c o n diti o n: T he c o nte nts of 
t his pr ot oc ol ma y n ot be use d i n a n y ot her cli nical trial a n d ma y n ot be discl ose d t o a n y ot her pers o n or 
e ntit y wit h o ut t he pri or writte n per missi o n of t he Ca ncer Researc h I nstit ute, Brist ol M yers S q ui b b, P D G x 
a n d  CC T G.  T he  f ore g oi n g  s hall  n ot  a p pl y  t o  discl os ure  re q uire d  b y  g o ver n me ntal  re g ulati o ns  or  la ws; 
h o we ver,  I  will  gi ve  pr o m pt  n otice  t o t he  Ca ncer  Researc h  I nstit ute,  Brist ol  M yers  S q ui b b,  P D G x a n d 
C C T G of a n y s uc h discl os ure. 
 
I u n dersta n d t hat I ma y ter mi nate or s us pe n d e nr ol me nt of t he st u d y at a n y ti me if it bec o mes necessar y t o 
pr otect t he best i nterests of t he st u d y s u bj ects, h o we ver I will gi ve pr o m pt n otice t o C C T G. T he st u d y ma y 
be ter mi nate d at a n y ti m e b y C C T G or  t he Ca ncer Researc h I nstit ute, Brist ol M yers S q ui b b, a n d P D G x wit h 
or wit h o ut ca use.  
 
A n y s u p ple me ntal i nf or mati o n t hat ma y be a d de d t o t his d oc u me nt is als o c o nfi de ntial a n d pr o prietar y t o 
t he Ca ncer Researc h I nstit ute, Brist ol M yers S q ui b b, P D G x  a n d CC T G a n d m ust be ke pt i n c o nfi de nce i n 
t he sa me ma n ner as t he c o nte nts of t his pr ot oc ol. 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Q ualifie d I n vesti gat or 
Date  
( pri nte d na me a n d si g nat ure) 
 
Pr ot oc ol N u m ber: C RI -C C T G - 0 0 0 1 
 
 
C E N T E R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
2  
C O N FI D E N TI A L  
T R E A T M E N T S C H E M A  
 
T his is a n i nter nati o nal m ulti -ce nter, o pe n -la bel, ra n d o mize d p hase II n o n-c o m parati ve trial of ni v ol u ma b 
al o ne or i n c o m bi nati o n wit h i pili m u ma b f or t he treat me nt of pat ie nts wit h a d va nce d h y per m utate d s oli d 
t u m ors detecte d b y a bl o o d base d assa y. T he bi o mar ker selecti o n of eli gi ble patie nts will i nitiall y be base d 
o n detecti o n of eit her P O L E or P O L D 1 m utati o ns b y cf D N A or t u m or testi n g.  
 
T u m or testi n g ma y be c o n d ucte d i n a cli nical la b orat or y as part of sta n dar d assess me nt.  
 
F or patie nts t hat d o n ot ha ve t u m or testi n g, eli gi ble a n d c o nse nti n g patie nts will u n der g o scree ni n g f or P O L 
m utati o ns b y testi n g of cf D N A.  
 
Eli gi ble a n d c o nse nti n g patie nts wit h P O L E or P O L D 1  m utat i o ns will be ra n d o mize d 1: 1 i nt o t w o ar ms. 
 
Stratificati o n  
•  
E C O G perf or ma nce stat us ( 0,  1)  
•  
N u m ber of pri or treat me nts ( 0, 1- 2, 3 or m ore) 
 
 

 
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C O N FI D E N TI A L 
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C O N FI D E N TI A L  
1. 0 
O BJ E C TI V E S  
 
1. 1 
Pri mar y O bjecti ve  
 
T o  e val uate  efficac y  as  meas ure d  b y  o bjecti ve  res p o nse  rate  b y  R E CI S T  1. 1  of  ni v ol u ma b  
m o n ot hera p y a n d of ni v ol u ma b c o m bi ne d wit h i pili m u ma b  i n ra n d o mize d patie nts wit h a d va nce d 
s oli d t u m ors wit h detecta ble P O L E or P O L D 1 m utati o ns as deter mi ne d b y plas ma cf D N A.  
 
1. 2  
Sec o n dar y O bj ecti ves  
 
•  
T o e val uate efficac y as meas ure d b y o bj ecti ve res p o nse rate of ni v ol u ma b m o n ot hera p y a n d of 
ni v ol u ma b c o m bi ne d wit h i pili m u ma b i n all treate d patie nts wit h detecta ble P O L E or P O L D 1 
m utati o ns i n eit her plas ma cf D N A or t u m or tiss ue. 
•  
T o e val uate d urati o n of res p o nse of ni v ol u ma b m o n ot hera p y, a n d of ni v ol u ma b c o m bi ne d wit h 
i pili m u ma b, i n t h ose patie nts wit h a d va nce d s oli d t u m ors wit h detecta ble P O L E or P O L D 1 
m utati o ns i n eit her plas ma cf D N A or t u m or tiss ue. 
•  
T o assess t he safet y a n d c haracterize t o xicities of ni v ol u ma b m o n ot hera p y a n d of ni v ol u ma b  
c om bi ne d wit h i pili m u ma b i n all patie nts . 
•  
T o assess t he c orrelati o n bet wee n P O L E or P O L D 1 m utati o ns i n t u m or a n d P O L E or P O L D 1 
m utati o ns i n bl o o d.  
•  
T o e val uate res p o nse b y i R E CI S T.  
 
1. 3  
E x pl orat or y O bj ecti ves  
 
•  
T o deter mi ne Pr o gressi o n Free S ur vi val  a n d O verall S ur vi val of  ni v ol u ma b m o n ot hera p y a n d 
of  ni v ol u ma b  c o m bi ne d  wit h i pili m u ma b i n  patie nts  wit h  a d va nce d  s oli d  t u m ors  wit h 
detecta ble P O L E or  P O L D 1  m utati o ns  as  deter mi ne d  b y  plas ma  cf D N A,  a n d  i n  all  treate d 
patie nts ( detecta ble m utati o ns i n tiss ue or  plas ma cf D N A).  
•  
T o deter mi ne t he c orrelati o n bet wee n P O L E or P O L D 1 m utati o ns occ urri n g wit hi n or o utsi de 
of t he e x o n uclease d o mai n a n d t u m or m utati o n l oa d as deter mi ne d b y w h ole e x o me a n d R N A 
se q ue nci n g. 
•  
T o deter mi ne t he c orrelati o n bet wee n t u m or m utati o n b ur de n assesse d i n plas ma cf D N A a n d 
assesse d directl y i n t u m or tiss ue.  

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
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C O N FI D E N TI A L  
2. 0 
B A C K G R O U N D I N F O R M A TI O N A N D R A TI O N A L E  
 
2. 1 
D N A Re pair Defects a n d T u m ori ge nesis  
 
I n e u kar y otes, D N A i nte grit y is mai ntai ne d t hr o u g h a di verse arra y of pat h wa ys i ncl u di n g base 
e xcisi o n re pair, mis matc h re pair, n ucle oti de e xcisi o n re pair, a n d d o u ble -stra n d brea k re pair. T hese 
r o b ust defe nse s yste ms pla y a cr ucial r ole i n c o m bati n g t he esti mate d te ns of t h o usa n ds of D N A-
da ma gi n g e ve nts t hat ta ke place o n a dail y basis [ Dex h ei mer  2 0 1 3]. I ncrease d m uta ge nicit y d ue t o 
disr u pti o n  of  t hese  pat h wa ys  ca n  dri ve  carci n o ge nesis  t hr o u g h  t he  ac q uisiti o n  of  m ulti ple 
o nc o ge nic m utati o ns a n d l oss of t u m or s u p press or ge nes. T his h y per m utate d p he n ot y pe ca n be see n 
i n  s p ora dic  mali g na ncies  as  well  as  a  n u m ber  of  here ditar y  ca ncer  s y n dr o mes  s uc h  as  Ata xia-
tela n giectasia ( d o u ble-stra n d brea k re pair), Xer o der ma pi g me nt os u m ( n ucle oti de e xcisi o n re pair), 
a n d L y nc h s y n dr o me ( mis matc h re pair) [ L a n g e 2 0 1 1]. 
 
D uri n g  D N A  re plicati o n,  i n  partic ular,  t here  is  a n  i ncre ase d  ris k  f or  base  s u bstit uti o n  d ue  t o 
re plicati ve err ors ca use d b y D N A p ol y merases, w hic h ha ve err or rates of a p pr o xi matel y 1 0 - 5 per 
base pair per cell di visi o n [ Dex h ei mer 2 0 1 3]. T w o mec ha nis ms e xist t o c o u nteract t hese err ors. T he 
first i n v ol ves real-ti me pr o ofrea di n g via e x o n uclease acti vit y prese nt i n b ot h D N A p ol y merase ε, 
w hic h s y nt hesizes t he lea di n g stra n d a n d is e nc o de d b y P O L E , a n d D N A p ol y merase δ, w hic h is 
i n v ol ve d i n la g gi n g stra n d s y nt hesis a n d e nc o de d b y P O L D 1  [ Al b erts o n 2 0 0 9]. Err ors t hat esca pe s uc h 
pr o ofrea di n g  ca n  be  c orrecte d  b y  t he  sec o n d  mec ha nis m – t he  D N A  mis matc h  re pair  ( M M R) 
pat h wa y. Wit h i ntact D N A da ma ge re pair mac hi ner y t he s p o nta ne o us m utati o n rate d uri n g D N A 
re plicati o n is t heref ore ver y l o w, at less t ha n 1 0- 9 per base pair p er cell di visi o n [ Mc C ull o c h 2 0 0 8]. 
H o we ver,  w he n  t hese  hi g hl y  c o nser ve d  s yste ms  are  disr u pte d,  cells  ca n  de vel o p  hi g h  le vels  of 
m utati o ns i ncl u di n g deleteri o us, carci n o ge nic fra mes hift a n d n o nse nse m utati o ns. 
 
2. 2  
P O L E a n d P O L D 1 M utati o ns i n S oli d T u m ors 
 
W hile  ger mli ne  m utati o ns  of  b ot h 
P O L E  a n d P O L D 1  ha ve  bee n  re p orte d  i n  ass ociati o n  wit h 
micr osatellite sta ble ( M S S) c ol orectal a de n o mas a n d carci n o mas, as well as e n d o metrial ca ncers 
a n d brai n t u m ors, s o matic m utati o ns of t hese ge nes ca n be see n de m o nstrate d i n a heter o ge ne o us 
gr o u p of t u m ors [ Bri g gs 2 0 1 3; P alles 2 0 1 3 ; S hlie n 2 0 1 5] . T he Ca ncer Ge n o me Atlas ( T C G A) st u dies of 
c ol orectal a n d e n d o metrial carci n o mas i de ntifie d s p ora dic P O L E  m utati o ns i n 3 % a n d 7 % of t hese 
t u m ors,  res pecti vel y [ Atl as  2 0 1 2; C a n cer Ge n o me  Atl as  2 0 1 3] . F or  t he  m ost  part  t hese  t u m ors  were 
ass ociate d wit h hi g h  rates of t u m or m utati o nal b ur de n ( T M B) fre q ue ntl y har b ori n g m ore t ha n 1 0 0 
m utati o ns per me ga base. P O L E m utati o ns ha ve als o bee n see n i n t u m ors of t he brai n, pa ncreas, 
o var y,  breast,  l u n g,  a n d  st o mac h  as  well  as  i n  uteri ne  carci n osarc o mas [ R a y n er  2 0 1 6]. P O L D 1  
m utati o ns are less pre vale nt t h o u g h ha ve bee n s h o w n t o be prese nt i n patie nts wit h hi g hl y m utate d 
n o n- s mall cell l u n g ca ncer ( N S C L C) a n d brai n t u m ors [S hlie n 2 0 1 5 ; Rizvi 2 0 1 5] . C o m bi ni n g data fr o m 
m ulti ple c o m pre he nsi ve ge n o mic pr ofili n g st u dies s h o ws  t hat a wi de variet y of t u m ors are affecte d 
b y t hese m utati o ns  wit h pre vale nce rates ra n gi n g fr o m 5 -1 0 % i n a n ass ort me nt of t u m ors ( Fi g 1 A 
a n d 1 B). 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5  
C O N FI D E N TI A L  
 
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6  
C O N FI D E N TI A L  
2. 3  
I m m u ne C hec k p oi nt Bl oc ka de i n T u m ors wit h Hi g h M utati o nal B ur de n 
 
Ca ncer i m m u n ot hera p y rests o n t he pre mise t hat t u m ors ca n be rec o g nize d as f orei g n rat her t ha n 
as  self  a n d  ca n  be  effecti vel y  attac ke d  b y  a n  acti vate d  i m m u ne  s yste m.  A n  effecti ve  i m m u ne 
res p o nse i n t his setti n g is t h o u g ht t o rel y o n i m m u ne s ur veilla nce of a nti ge ns e x presse d o n ca ncer 
cells t hat ulti matel y res ults i n a n a da pti ve i m m u ne res p o nse a n d ca ncer cell deat h  [S c h u m a c h er 2 0 1 5; 
C he n  2 0 1 7] . T hese  ca ncer -s pecific  pe pti des  res ulti n g  fr o m  ne oa nti ge ns  ca n  be  tar gets  f or  T-cell 
rec o g niti o n  a n d  effect or  res p o nses.  T u m ors  har b ori n g  defects  i n  D N A  re pair  pr otei ns   de vel o p 
stri ki n gl y  hi g h  rates  of  base  s u bstit uti o ns  d uri n g  D N A  re plicati o n  wit h  a  s u bse q ue nt  m utati o n 
b ur de n t hat is 1 0 -2 0 f ol d hi g her t ha n i n t u m ors wit h o ut t hese i ns ults [ R a y n er 2 0 1 6]. I n N S C L C a n d 
mela n o ma, it has pre vi o usl y bee n s h o w n t hat t u m or m utati o nal b ur de n ass ociates wit h se nsiti vit y 
t o  c hec k p oi nt  bl oc ka de  wit h  P D-1  bl oc ka de [ Rizvi  2 0 1 5; S n y d er  2 0 1 4] . I n  a  c o h ort  of 3 4  N S C L C 
patie nts,  we f o u n d  t u m ors wit h  d ura ble  cli nical  be nefit  t o  a nti -P D -1  t hera p y  de m o nstrate d  hi g h 
le vels of n o ns y n o n y m o us m utati o ns a n d f o ur cases ( 1 2 %) har b ore d deleteri o us P O L E a n d P O L D 1 
e x o n uclease  d o mai n  m utati o ns. Pa n -ca ncer  ge n o mic  pr ofili n g  of  t u m ors  als o  re veals  a  clear 
ass ociati o n  bet wee n  a  h y per m utate d  p he n ot y pe  a n d  m utati o ns  affecti n g  D N A  da ma ge  re pair 
pr otei ns ( M M R deficie nt t u m ors a n d P O L E m utate d t u m ors see n i n Fi g ure 2 [ C h al mers 2 0 1 7; Ze hir 
2 0 1 7] .T hese  hi g hl y  m utate d t u m ors  pr o v o ke  a  bris k  i m m u ne  i nfiltrate  t hat  is  i m paire d  t hr o u g h 
u pre g ulati o n of i n hi bit or y T -cell si g nali n g via t he pr o gra m me d deat h -1 ( P D - 1) rece pt or pat h wa y 
i n  t he t u m or micr oe n vir o n me nt  a n d c yt ot o xic  T -l y m p h oc yte  A nti ge n  4  (C T L A - 4) pat h wa y  i n 
l y m p h n o des [ D omi n g o 2 0 1 6] . Gi ve n hi g h le vels of s o matic m utati o ns a n d i ncrease d t u m or i nfiltrati n g 
l y m p h oc ytes ( TI Ls), P O L E  a n d P O L D 1  m utate d  t u m ors prese nt a n attracti ve tar get f or i m m u ne 
c hec k p oi nt bl oc ka de a n d case re p orts of P O L E -m utate d e n d o metrial ca ncer a n d c ol orectal ca ncer 
( C R C) ha ve s h o w n a res p o nse t o pe m br oliz u ma b [ C astell u cci 2 0 1 7; Me h n ert 2 0 1 6] . 
 
Im m u ne c hec k p oi nt bl oc ka de has re v ol uti o nize d t he treat me nt of a d va nce d, micr osatellite u nsta ble 
( M SI-H)  t u m ors .  T he  p hase  II trial e val uati n g  t he  efficac y  of  a nti -P D -1  t hera p y  wit h 
pe m br oliz u ma b i n pre vi o usl y treate d patie nts wit h M SI -H a d va nce d C R C  ( n = 1 1) a n d M SI- H n o n-
C R C   t u m ors  ( n = 9)  de m o nstrate d  i m pr o ve d  i m m u n e-relate d O R R s  (ir O R R,  4 0 %  a n d  7 0 %, 
res pecti vel y)  a n d  i m m u n e-relate d P F S  (ir P F S,  7 8 %  a n d  6 7 %,  res pecti vel y)  c o m pare d  t o 
micr osatellite  sta ble t u m ors  (ir O R R  0 %,  ir P F S  1 1 %) [ Le  2 0 1 5]. A n  e x pa nsi o n  st u d y  e val u ati n g 
pe m br oliz u ma b i n 8 6 M SI -H patie nts acr oss 1 2 differe nt t u m or t y pes de m o nstrate d a 5 3 % O R R 
( 4 6/ 8 6 patie nts) a n d a re mar ka ble 2 1 % c o m plete res p o nse rate ( 1 8/ 8 6 patie nts) [ Le 2 0 1 7]. Rece ntl y, 
t he  F o o d  a n d  Dr u g  A d mi nistrati o n  gra nte d  a  la n d mar k  a p pr o val  f or  pe m br oliz u ma b  i n  M SI- H 
t u m ors re gar dless of hist ol o g y i n Ma y 2 0 1 7. D ura ble o utc o mes ha ve als o bee n de m o nstrate d f or 
M SI -H C R C patie nts treate d wit h ni v ol u ma b wit h a re p orte d 1 2 - m o nt h O S ( O S)  of 7 4 %  [ Over m a n 
2 0 1 7] . F urt her m ore, c o m bi ne d C T L A -4 a n d P D -1 i n hi biti o n ma y dri ve dee per, m ore r o b ust a nti -
t u m or res p o nses t ha n si n gle a ge nt t hera p y i n t his setti n g. Preli mi nar y data fr o m C hec k Mate 1 4 2, a 
m ulti -c o h ort p hase II st u d y of ni v ol u ma b wit h or wit h o ut i pili m u ma b i n a d va nce d M SI-H C R C, 
prese nte d at A S C O t his year de m o nstrate d a 3 1 % O R R  f or ni v ol u ma b  al o ne c o m pare d t o 5 5 % f or 
c o m bi nati o n t hera p y wit h a me dia n d urati o n of res p o nse t hat was n ot reac he d f or eit her ar m [ A n dre 
2 0 1 7] . 
 
 
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
7  
C O N FI D E N TI A L  
2. 4  
Ni v ol u ma b 
 
Ni v ol u ma b is a f ull y h u ma nize d I g G 4 m o n ocl o nal a nti b o d y t hat bi n ds t o t he i m m u ne c hec k p oi nt 
m olec ule  P D -1  wit h  hi g h  affi nit y  bl oc ki n g  its  i nteracti o n  wit h  P D -L 1  ( B 7 -H 1)  a n d  P D -L 2 
( B 7-D C).  P D -1  bl oc ka d e  ma y  lea d  t o  a  re versal  of t u m or-i n d uce d  T  cell  relate d 
i m m u n os u p pressi o n ( T-cell e x ha usti o n). Ni v ol u ma b has bee n s h o w n t o bl oc k P D -1 a n d re verse t he 
i m m u n os u p pressi o n me diate d b y t his m olec ule. 
 
P D -1 has bee n rec o g nize d as a c o m ple me ntar y c hec k p oi nt pr otei n t o C T L A - 4 a n d is e x presse d o n 
acti vate d C D 4 + a n d C D 8 + T cells, B cells, m o n oc ytes, nat ural killer T ( N K T) cells, a n d de n dritic 
cells  ( D Cs) [ A g at a  1 9 9 6].  P D- 1  si g nali n g  i n  T  cells  re g ulates  i m m u ne  res p o nses  b y  mi ni mizi n g 
da ma ge t o b ysta n der tiss ue a n d pre ve nti n g t he de vel o p me nt of a ut oi m m u nit y b y pr o m oti n g self -
t olera nce t o self-a nti ge ns [ Sz n ol 2 0 1 3]. Its maj or li ga n d P D-L 1 ( B 7 -H 1) is t y picall y e x presse d o n a 
s u bset of macr o p ha ges b ut ca n be i n d uce d b y i nfla m mat or y c yt o ki nes i n a variet y of tiss ue t y pes 
[ D o ng 1 9 9 9 ; M az a n et 2 0 0 2] . P D-L 1 is als o f o u n d o n T cells, B cell, D Cs, a n d mast cells [ A g at a 1 9 9 6]. 
W he n  acti vate d  T -cells  e x pressi n g  P D -1  e nc o u nter  P D -L 1,  T -cell  effect or  f u ncti o ns  are 
s u bse q ue ntl y  di mi nis he d.  T he  effect or  T  cell  f u ncti o ns  i ncl u di n g  c yt o ki ne  pr o d ucti o n, 
pr oliferati o n, a n d cell s ur vi val are i n hi bite d as a res ult of t he e n ga ge me nt of P D -1 t o P D - L 1. T u m or 
re gressi o n a n d pr ol o n ge d h ost s ur vi val has bee n see n i n precli nical st u dies of P D-1: P D -L 1 bl oc ka de 
i n m uri ne t u m or m o dels. T hese pr o misi n g res ults were n ote d i n se veral t u m or m o dels i ncl u di n g 
o varia n  carci n o ma,  s q ua m o us  cell  carci n o ma,  mela n o ma,  mast oc yt o ma,  he pat o ma,  a n d  ac ute 
m yel oi d  le u ke mia 
[I w ai  2 0 0 2; Str o me  2 0 0 3 ; Hir a n o  2 0 0 5] .  T u m or  re gressi o n  was  acc o m pa nie d  b y 
i ncrease d effect or T-cell f u ncti o n a n d c yt o ki ne pr o d ucti o n. 
 
T he t hera pe utic be nefit of ni v ol u ma b has bee n well esta blis he d i n N S C L C, mela n o ma , clear-cell 
re nal  cell  carci n o ma ( R C C),  classical  H o d g ki n  L y m p h o ma  (c H L),  ur ot helial  carci n o ma  ( U C), 
s q ua m o us cell carci n o ma of t he hea d a n d nec k ( S C C H N), i n a d diti o n t o ot her t u m or t y pes. I n a 
p hase  I  st u d y,  si n gle  d oses  of  ni v ol u ma b  were  f o u n d  t o  i n d uce  ra pi d  a n d  d ura ble  res p o nses  i n 
patie nts wit h s oli d t u m ors i ncl u di n g mela n o ma, c ol orectal ca ncer, a n d re nal cell carci n o ma [ Br a h mer 
2 0 1 0] .  Rece nt  cli nical  trials  ha ve  de m o nstrate d  acti vit y  of  si n gle-a ge nt  ni v ol u ma b  i n  metastatic 
mela n o ma wit h a t olera ble s afet y pr ofile. I n N S C L C, t he p hase III C hec k Mate ( C M) 0 1 7 a n d 0 5 7 
st u dies e val uate d t he r ole of ni v ol u ma b 3 m g/ k g e ver y 2 wee ks i n pre vi o usl y treate d s q ua m o us a n d 
n o ns q ua m o us  a d va nce d  N S C L C,  res pecti vel y  [ B or g h a ei  2 0 1 5; Br a h mer  2 0 1 5] .  B ot h  st u dies 
de m o nstr ate d statisticall y si g nifica nt i m pr o ve me nts i n O S: 9. 2 m o nt hs f or ni v ol u ma b  c o m pare d t o 
6. 0 m o nt hs f or d oceta xel i n C M 0 1 7 ( H R 0. 5 9, p < 0. 0 0 1) a n d 1 2. 2 m o nt hs f or ni v ol u ma b c o m pare d 
t o 9. 4 m o nt hs f or d oceta xel i n C M 0 5 7 ( H R 0. 7 3, p = 0. 0 0 2). A rece nt p u blicati o n re p orte d ver y fe w 
gra de 3 or 4 a d verse e ve nts wit h ni v ol u ma b m o n ot hera p y at t he sa me d ose a n d sc he d ule e ve n i n 
patie nts  wit h  pri or  i pili m u ma b treat me nt [ We b e  2 0 1 3].  T his  trial  als o  de m o nstrate d  o bjecti ve 
res p o nses t o si n gle-a ge nt ni v ol u ma b i n patie nts w h o were eit her i pili m u ma b refract or y ( 2 0 %-3 0 %) 
or i pili m u ma b naï ve ( ~ 3 0 %). T he y als o f o u n d a c orrelati o n of res p o nse t o t u m or cell stai ni n g f or 
P D -L 1, b ut t here were res p o nses ( 2 0 % -2 5 %) e ve n i n patie nts wit h o ut P D -L 1 stai ni n g i n t u m or b y 
i m m u n o hist oc he mistr y.  T he  pr o misi n g  cli nical  data  n ote d  a b o ve  f or  P D-1  bl oc ka d e  as  a n 
i m m u n ot hera p y tar get s u g gests its p ote ntial f or use acr oss s oli d t u m ors. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
8  
C O N FI D E N TI A L  
2. 5 
I pili m u ma b 
 
I pili m u ma b,  a  h u ma n  I g G 1  m o n ocl o nal  a nti b o d y  t o  C T L A-4,  acti vates  T  cells  b y  bl oc ki n g  t he 
i n hi bit or y acti o n of C T L A-4. T he i m m u ne res p o nse t o t u m ors is a c o mple x, m ultista ge pr ocess t hat 
be gi ns wit h t u m or-ass ociate d a nti ge n rec o g niti o n a n d T -cell acti vati o n [ Cr oft 1 9 9 4] . F ull acti vati o n 
of  naï ve  T  cells  re q uires  n ot  o nl y  sti m ulati o n  of  t he  a nti ge n  rece pt or  b y  pe pti de/ maj or 
hist oc o m pati bilit y c o m ple xes, b ut als o b y c o -sti m ulat or y si g nals. T hese si g nals are pr o vi de d b y t he 
bi n di n g of C D 2 8, a c o nstit uti vel y e x presse d T -cell s urface rece pt or, t o C D 8 0 ( B 7. 1) a n d C D 8 6 
( B 7. 2), m olec ules t hat are prese nt o n a nti ge n prese nti n g cells. C D 2 8-B 7 c o -sti m ulat or y si g nals are 
critical  f or  i n d ucti o n  of  T -cell  pr oliferati o n,  c yt o ki ne  secreti o n,  a n d  effect or  f u ncti o ns,  w hic h 
ulti matel y tra ns late i nt o cli nical effects. 
 
C T L A -4  is  a n  acti vati o n -i n d uce d  T-cell  s urface  m olec ule  t hat  bi n ds  C D 8 0  a n d  C D 8 6  b ut  wit h 
greater a vi dit y t ha n C D 2 8. C T L A -4 li gati o n d o w n -re g ulates T-cell res p o nses w hic h res ults i n a n 
a br o gati o n of t he cli nical effects pr o vi de d b y T -cell acti vati o n [ H o di 2 0 0 7]. C o n versel y, t he bl oc ka de 
of C T L A -4 i nteracti o ns wit h C D 2 8 res ults i n a n i ncrease of T cell acti vati o n. Se veral i n vitr o st u dies 
ha ve de m o nstrate d t hat m o n ocl o nal a nti b o dies a gai nst C T L A -4 e n ha nce T -cell res p o nses, w herea s 
direct cr oss -li n ki n g of C T L A- 4 wit h B 7. 1 a n d B 7. 2 res ults i n a bl oc ka de of cell c ycle pr o gressi o n, 
di mi nis he d c yt o ki ne e x pressi o n, a n d decrease d T- cell pr oliferati o n. 
 
I n vi v o, ipili m u ma b bl oc ka de of C L T A -4 pr o m otes ge nerati o n of s h ort -li ve d effect or C D 8+ T cells 
a n d a m ore persiste nt ce ntral me m or y C D 4 + T cell res p o nse [ H o key 2 0 0 8; Di Gi a c o m o]  res ulti n g i n a 
si g nifica nt i n hi biti o n of t u m or gr o wt h [v a n Els as 1 9 9 9]. 
 
Cli nicall y, t he t hera pe utic p ote ntial of i pili m u ma b has bee n clearl y esta blis he d. T he  O S  of patie nts 
wit h a d va nce d mali g na nt mela n o ma was pr ol o n ge d i n 2 ra n d o mize d, d o u ble -bli n d m ulti nati o nal 
p hase  III trials  of i pili m u ma b as  m o n ot hera p y [ H o di  2 0 1 0] a n d  i n c o m bi nati o n  wit h  dacar bazi ne 
c he m ot hera p y [ R o b ert 2 0 1 1]. T his O S  be nefit was pr o vi de d wit h a n acce pta ble safet y pr ofile. Base d 
o n a p ositi ve ris k- be nefit rati o, i pili m u ma b has bee n a p pr o ve d b y t he U. S. F D A f or use i n patie nts 
wit h  mali g na nt  mela n o ma.  C o n v i nci n g  acti vit y  has  als o  bee n  see n  i n  ot her  s oli d t u m ors.  F or 
e xa m ple, i n a ra n d o mize d p hase II trial i n b ot h N S C L C a n d S C L C [ Ly n c h  2 0 1 2], t he a d diti o n of 
i pili m u ma b t o paclita xel a n d plati n u m res ulte d i n statisticall y si g nifica nt pr ol o n ge d i m m u ne-relate d 
pr o gressi o n- free  s ur vi val,  t he  pri mar y  e n d p oi nt,  s u g gesti n g i pili m u ma b will  ha ve  acti vit y  i n 
m ulti ple s oli d t u m or t y pes. 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
9  
C O N FI D E N TI A L  
2. 6  
Ni v ol u ma b C o m bi ne d wit h I pili m u ma b 
 
T h o u g h b ot h C T L A -4 a n d P D -1 i n hi bit T -cell f u ncti o n, t he y w or k t hr o u g h differe nt mec ha nis ms.  
A ge nts bl oc ki n g o ne pat h wa y ma y lea d t o u pre g ulati o n of ot her i m m u ne me diat ors. Pre -cli nical 
st u dies  ill ustrate  str o n ger  a ntit u m or res p o nses  wit h  c o m bi ne d  C T L A-4  a n d  P D -1  i n hi biti o n.  I n 
m o use  m o dels,  si n gle  a ge nt  t hera p y  wit h  eit her  a nti -C T L A -4  or  a nti -P D -1  e n ha nce d  T -cell 
acti vati o n t o t u m or tiss ue, b ut t hese T-cells ac q uire d hi g h le vels of c o -i n hi bit or y m olec ules t hat 
ulti matel y  di mi nis he d  t he  i m m u ne  res p o nse 
[ C urr a n,  2 0 1 0].  C o m bi ne d  bl oc ka de  all o we d  re-
e x pa nsi o n  of  T -cell  s u bsets  c o nse q ue ntl y  re d uci n g  a da pti ve t u m or i m m u ne  res p o nses  a n d 
pr o m oti n g  re gressi o n  of t u m ors.  I n  cli nical  st u dies,  c o m bi nati o ns  of  i m m u n ot hera p y  a ge nts 
directe d  a gai nst  c o -i n hi bit or y  pat h wa ys  (e. g.  a nti- C T L A -4  a n d  a nti -P D -1/ L 1  t hera p y)  ha ve 
de m o nstrate d  efficac y  i n  patie nts  wit h  a d va nce d  mela n o ma  a n d  l u n g  ca ncer [ A nt o ni a  2 0 1 5; L arki n 
2 0 1 5 ; P at n aik 2 0 1 5] . I n partic ular, data fr o m a p hase I trial of c o m bi nati o n i pili m u ma b a n d ni v ol u ma b  
i n patie nts wit h a d va nce d mela n o ma de m o nstrate d t hat 3 1 % of t he patie nts w h o res p o n de d ha d 
t u m or re gressi o n of 8 0 % or m ore, a fi n di n g t hat was u nc o m m o n i n pri or i m m u n ot hera p y st u dies 
e val uati n g  eit her  a ge nt  i n di vi d uall y [ W olc h o k  2 0 1 3]. T his  s mall  p hase  1  d ose -escalati o n  trial  was 
desi g ne d t o test t he safet y of t he c o m bi nati o n of i pili m u ma b at a d ose of 3 m g/ k g i n c o m bi nati o n 
wit h ni v ol u ma b at d oses ra n gi n g fr o m 0. 3 t o 3  m g/ k g (c o h orts 1 – 3). I n lar ger, p hase III trials i n 
mela n o ma, t he  c o m bi nati o n of P D -1/ C T L A -4 bl oc ka de tra nslate d t o  n u merical i m pr o veme nts i n  
s ur vi val [ L arki n 2 0 1 5]. 
 
I n  C M- 0 1 2, a  m ulti -c oh ort  p hase I b trial  e val uati n g t he  safet y  a n d  t olera bilit y  of  ni v ol u ma b  i n 
c he m ot hera p y-nai ve N S C L C  eit her as m o n ot hera p y or i n c o m bi nati o n wit h ot her a ge nts i ncl u di n g 
i pili m u ma b, c o m bi nati o n  t hera p y  was  c haracterize d  b y  hi g h  res p o nse  rates  a n d  t olera ble  s afet y 
pr ofile [ Hell m a n n 2 0 1 7]. T he pri mar y e n d p oi nt of t he trial was safet y wit h sec o n dar y e n d p oi nts of 
O R R a n d 2 4- wee k P F S . E x pl orat or y e n d p oi nts i ncl u de d O S a n d efficac y b y P D - L 1 e x pressi o n. I n 
t he trial, patie nts were ra n d o ml y assi g ne d ( 1: 1: 1) t o recei ve ni v ol u ma b 1 m g/ k g e ver y 2 wee ks pl us 
i pili m u ma b 1 m g/ k g e ver y 6 wee ks, ni v ol u ma b 3 m g/ k g e ver y 2 wee ks pl us i pili m u ma b 1 m g/ k g 
e ver y 1 2 wee ks, or ni v ol u ma b 3 m g/ k g e ver y 2 wee ks pl us i pili m u ma b 1 m g/ k g e ver y 6 wee ks u ntil 
disease pr o gressi o n, u n acce pta ble t o xicities, or wit h dra wal of c o nse nt . T he c o nfir me d  O R R was 
4 7 % ( N 3 q 2 w + I 1 q 1 2 w) a n d 3 9 % ( N 3 q 2 w + I 1 q 6 w).  T he me dia n d urati o n of res p o nse ( D O R) 
was n ot reac he d.  T he rate of treat me nt -relate d a d verse e ve nts i n t he Q 1 2 W ( 8 2 %) a n d Q 6 W ( 7 2 %) 
ar ms were c o m para ble t o m o n ot hera p y ( 7 2 %). I n t he trial, Gra de 3/ 4 a d verse e ve nts were 3 7 %, 
3 3 %, a n d 1 9 % f or t he Q 1 2 W, Q 6 W a n d ni v ol u ma b  m o n ot hera p y ar ms, res pecti vel y. Treat me nt -
relate d Gra de 3-4 A Es lea d t o disc o nti n uati o n i n 5 % a n d 8 % of patie nts i n t he Q 1 2 W a n d Q 6 W 
c o h orts, res pecti vel y a n d were si milar t o ni v ol u ma b  m o n ot hera p y. T here were n o treat me nt -relate d 
deat hs. T he treat me nt -relate d select A Es i n patie nts a d mi nistere d t he o pti mize d d osi n g sc he d ule d 
( 3 m g/ k g of ni v ol u ma b e ver y t w o wee ks pl us 1 m g/ k g o f i pili m u ma b e ver y si x wee ks) were s ki n 
relate d ( 3 6 %), gastr oi ntesti nal ( 2 3 %), e n d ocri ne ( 2 0 %), a n d p ul m o nar y ( 5 %) a n d t here were ≤ 5 % 
treat me nt relate d gra de 3/ 4 A Es per cate g or y. 
 
T he a b o ve data s u g gests c o m bi ne d C T L A-4 a n d P D -1 i n hi biti o n ma y dri ve dee p er, m ore r o b ust 
a nti-t u m or res p o nses  t ha n  si n gle  a ge nt  t hera p y. S u p p orti n g  t his  i n  data  fr o m C M -1 4 2,  a  m ulti -
c o h ort p hase II trial of ni v ol u ma b  wit h or wit h o ut i pili m u ma b i n a d va nce d M SI-H C R C, prese nte d 
at A S C O i n 2 0 1 7 de m o nstrate d a 3 1 % O R R  f or ni v ol u ma b al o ne c o m pare d t o 5 5 % f or c o m bi nati o n 
t hera p y wit h a me dia n d urati o n of res p o nse t hat was n ot reac he d f or eit her ar m [ A n dre 2 0 1 7]. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
1 0  
C O N FI D E N TI A L  
2. 7 
Trial Rati o nale  
 
2. 7. 1 
Scree ni n g f or P O L E a n d P O L D 1 M ut ati o ns  
 
P O L E  a n d P O L D 1 e nc o de c o m p o ne nts of t he e x o n uclease, pr o ofrea di n g s u b u nits of p ol y merase ε 
a n d p ol y merase δ c o m ple xes, res pecti vel y. T hese d o mai ns e x hi bit s u bsta ntial h o m ol o g y (resi d ues 
2 6 8- 4 7 1 f or P O L E a n d 3 0 4-5 1 7 f or P O L D 1 ) a n d m utati o ns affecti n g e x o n uclease f u ncti o n are m ost 
fre q ue ntl y re p orte d t o ca use gen o mic i nsta bilit y a n d i ncrease d m uta ge nesis [ K o nst a nti n o p o ul os 2 0 1 5]. 
It  is  u nclear  w het her  m utati o ns  o utsi de  of  t hese  re gi o ns  ha ve  a  si milar  i m pact  or  act  m ore  as 
“ passe n ger”  m utati o ns [ B o ur d ais  2 0 1 7].  I m p orta ntl y,  T C G A  a n d  ot her  st u dies  ge nerall y  e m pl o y 
w h ole  e x o me  se q ue nci n g  t o  ca pt ure  rates  of  n o ns y n o n y m o us  m utati o ns.  Gi ve n  t he  c ost  a n d 
res o urces nee de d f or t his met h o d, it is c halle n gi n g t o ga u ge m utati o nal b ur de n i n r o uti ne cli nical 
practice.  I nstea d,  a n  assess me nt  of P O L E  a n d P O L D 1  m utati o ns  via  c o m merciall y  a vaila ble 
c o m pre he nsi ve  ge n o mic  se q ue nci n g  platf or ms  i ncl u di n g  cf D N A  testi n g  re prese nts  a  ra pi d  a n d 
attracti ve strate g y.  
 
2. 7. 2 
R a n d o mize d t o Niv ol u m a b a n d Niv ol u m a b i n C o m bi n ati o n wit h I pili m u m a b 
 
T he a b o ve data s u g gest t hat c o m bi nati o n i m m u n ot hera p y wit h a nti -P D -1 t hera p y i n c o nj u ncti o n 
wit h a nti -C T L A -4 bl oc ka de dri ves dee p, d ura ble res p o nses i n h y per m utate d M SI -H t u m ors - we 
h y p ot hesize t hat a si milar acti vit y will occ ur i n t u m ors wit h m utati o ns i n P O L E  a n d P O L D 1 . T o 
directl y  a d dress  t his  h y p ot hesis,  we  pr o p ose  a  p hase  II n o n- c o m parati ve  trial  of ni v ol u ma b  ± 
i pili m u ma b i n patie nts wit h a d va nce d s oli d t u m ors t hat de m o nstrate m utati o ns i n P O L E  or P O L D 1  
wit h pri mar y efficac y a nal ysis f or cli nicall y rele va nt O R R . 
 
2. 7. 3 
P ossi ble F ut ure Tri al Ex p a nsi o n  
 
T he  c urre nt  st u d y  pr ot oc ol  i ncl u des  patie nts  wit h  s oli d  t u m ors  t hat  ha ve  detecta ble  P O L E  or 
P O L D 1 m utati o ns. T he st u d y pr ot oc ol ma y be m o difie d t o i ncl u de a d diti o nal c o h orts if ne w bl o o d 
or  plas ma  base d  assa ys  f or  ot her h y per m utati o n  p he n ot y pes t hat  ma y  c orrelate  wit h  acti vit y  of 
i m m u n ot hera pies bec o me a vaila ble. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
1 5  
C O N FI D E N TI A L  
4. 0 
S T U D Y P O P U L A TI O N  
 
T he trial p o p ulati o n will c o nsist of patie nts wit h a d va nce d t u m ors ( metastatic or u nresecta ble) wit h 
detecta ble P O L E or P O L D 1 m utati o ns. 
 
T his  st u d y  is  desi g ne d  t o  i ncl u de  w o me n  a n d  mi n orities  as  a p pr o priate,  b ut  is  n ot  desi g ne d  t o 
meas ure differe nces i n i nter ve nti o n effects.  
 
T his st u d y has t w o ste ps:  
1.  Re gistrati o n f or scree ni n g f or t he prese nce of P O L E / P O L D 1 m utati o ns ( hereafter referre d t o 
as re gistrati o n). 
2.  E nr oll me nt a n d ra n d o mize d i n t he trial (if eli gi ble base d o n t he res ults of scree ni n g). 
 
T he i ncl usi o n criteria f or t his st u d y ha ve bee n caref ull y c o nsi dere d. I ncl usi o n criteria are sta n dar ds 
use d  t o  e ns ure  t hat  patie nts  w h o  e nter  t his  st u d y  are  me dicall y  a p pr o priate  ca n di dates  f or  t his 
t hera py. F or t he safet y of t he patie nts, as well as t o e ns ure t hat t he res ults of t his st u d y ca n be usef ul 
f or ma ki n g treat me nt decisi o ns re gar di n g ot her patie nts wit h si milar diseases, it is i m p orta nt t hat 
N O E X C E P TI O N S  be ma d e t o t hese criteria f or a d missi o n t o t he st u d y. Q uesti o ns a b o ut i ncl usi o n 
criteria s h o ul d be a d dresse d pri or t o re gistrati o n / ra n d o mizati o n . 
 
4. 1  
I ncl usi o n Criteria  
 
T he f oll o wi n g criteria will be re q uire d pri or t o  re gistrati o n: 
 
4. 1. 1 
Patie nts m ust ha ve hist ol o gicall y c o nfir me d a d va nce d  (metastatic or u nresecta ble) s oli d t u m ors. 
Patie nts wit h pri mar y  C N S t u m ors are i neli gi ble. 
 
4. 1. 2 
Pri or T her a py  
•  
Patie nts  m ust  ha ve  recei ve d  at  least  1  sta n dar d  ca ncer  t hera p y  f or  t heir  t u m or  t y pe  a n d 
pr o gresse d o n t heir m ost rece nt re gi me n; patie nts ma y b e  treat me nt naï ve if t he y ref use sta n dar d 
treat me nt or t here is n o sta n dar d treat me nt f or t heir ca ncer. 
•  
Pri or a dj u va nt/ ne oa dj u va nt t hera p y wit h c urati ve i nte nt is c o nsi dere d a pri or t hera p y if disease 
rec urre nce occ urs wit hi n at least 6 m o nt hs. 
•  
Patie nts ma y  n ot ha ve recei ve d pri or i m m u n ot hera p y. 
 
4. 1. 3 
Patie nts  m ust  c o nse nt  t o  bl o o d  c ollecti o n  f or  testi n g  after  re gistrati o n  b y  a  ce ntral  refere nce 
la b orat or y (see Secti o n 1 2. 0). 
 
4. 1. 4  
P atie nts  m ust  ha ve cli nicall y  a n d/ or  ra di ol o gicall y  d oc u me nte d  disease  wit h  at least  o ne lesi o n 
meas ura ble as defi ne d b y R E CI S T 1. 1 . 
 
4. 1. 5 
Patie nts m ust be ≥ 1 8 years of a ge. 
 
4. 1. 6 
E C O G perf or ma nce stat us 0 or 1 . 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
1 6  
C O N FI D E N TI A L  
4. 1. 7 
Patie nts  m ust  ha ve  a de q uate  he mat ol o g y  a n d  or ga n  f u ncti o n.  Please  refer  t o  4. 2. 3  bel o w, 
La b orat or y Re q u ire me nts, t hese la b res ults ma y be ascertai ne d base d o n patie nt c hart re vie w. It is 
n ot necessar y t o re peat t hese la bs pri or t o re gistrati o n f or t he p ur p oses of scree ni n g f or t his st u d y, 
if t he res ults are a vaila ble wit hi n t he pre vi o us 2 8 da ys. 
 
4. 1. 8 
Pati e nt c o nse nt f or scree ni n g m ust be a p pr o priatel y o btai ne d i n acc or da nce wit h a p plica ble l ocal 
a n d re g ulat or y re q uire me nts . 
 
Re vie w t he e xcl usi o n criteria t o e ns ure patie nt d oes n ot meet a n y of t hese criteria ( 4. 3).  
 
4. 2 
A d diti o nal Criteria T o Be Met Pri or T o St u d y E nr oll me nt 
 
All patie nts m ust f ulfil all of t he f oll o wi n g criteria t o be eli gi ble f or ra n d o mizati o n t o t he st u d y.  
 
4. 2. 1 
Patie nts m ust ha ve s oli d t u m ors t hat de m o nstrate P O L E or P O L D 1  m utati o ns i de ntifie d at st u d y 
e ntr y via plas ma cf D N A  testi n g or t u m or tiss ue testi n g f or P O L E a n d P O L D 1  m utati o ns. A C LI A -
certifie d testi n g of t u m or tiss ue de m o nstrati n g  P O L E or P O L D 1  m utati o n ca n q ualif y f or eli gi bilit y 
a n d ra n d o mizati o n, h o we ver plas ma will be s u b mitte d f or ce ntral cf D N A testi n g. I n t he e ve nt of 
d isc or da nce bet wee n tiss ue a n d ce ntral la b orat or y testi n g, t he patie nt will c o nti n ue i n st u d y b ut will 
n ot be i ncl u de d i n t he pri mar y a nal ysis. T hese patie nts will h o we ver be i ncl u de d i n t he sec o n dar y 
a nal ysis. 
 
4. 2. 2 
Pri or  T her a py 
•  
Patie nts m ust ha ve rec o ve re d t o ≤ gra de 1 fr o m all re versi ble t o xicit y relate d pri or s yste mic or 
ra diati o n t hera p y a n d ha ve a 2 wee ks was h o ut. 
•  
Pre vi o us maj or s ur ger y is per mitte d pr o vi de d t hat it has bee n at least 2 8 da ys pri or t o patie nt 
re gistrati o n a n d t hat w o u n d heali n g has occ urre d. 
 
4. 2. 3 
L a b or at ory Re q uire me nts  
( m ust be d o ne wit hi n 1 4 da ys pri or t o e nr oll me nt). 
 
He mat ol o g y  
W hite Bl o o d Cells  
 ≥ 2. 0  x 1 0 9/ L ( 2 0 0 0/ µ L) 
A bs ol ute ne utr o p hils  
≥ 1. 5 x 1 0 9/ L ( 1 5 0 0/ µ L) 
Platelets  
≥ 1 0 0 x 1 0 9/ L ( 1 0 0 x 1 03/ µ L) 
He m o gl o bi n  
≥8 0 g/ L * ( 8. 0 g/ d L) 
C he mistr y  
Bilir u bi n  
≤ 1. 5 x U L N ( u p per li mit of n or mal) * *  
A S T a n d / or A L T  
≤ 3  x U L N  
Ser u m creati ni ne  
or:  
Creati ni ne cleara nce * * *  
≤ 1. 5 x U L N  
 
≥4 0 m L/ mi n  
*  
C o ntact C C T G if he m o gl o bi n is < 8 0 g/ L a n d t he patie nt is n ot dec o m pe nsate d, is as y m pt o matic a n d 
tra nsf usi o n is n ot i n dicate d. 
* * 
If c o nfir me d Gil bert’s, eli gi bl e pr o vi di n g ≤ 3 x U L N. 
* * *   Creatini ne cleara nce t o  be  meas ured d irectly b y  2 4 h o u r  urine  s a m p lin g or  as  ca lcula ted b y 
C oc kcr oft a n d Ga ult e q uati o n bel o w : 
Fe males: G F R   = 1. 0 4 x  ( 1 4 0-a ge) x wei g ht i n k g  
 
   
ser u m creati ni ne i n μ m ol/ L  
Males: G F R   = 1. 2 3 x ( 1 4 0 -a ge) x wei g ht i n k g  
 
  
ser u m creati ni ne i n μ m ol/ L 
 
 

 
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C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
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C O N FI D E N TI A L  
4. 2. 4 
Patie nts m ust be willi n g t o c o nse nt t o pr o visi o n of arc hi val tiss ue (t u m or bl oc k or mi ni m u m of 
2 0 sli des c ut at a mi ni m u m of 4 micr o n t hic k ness - fe wer sli des ma y be acce pte d if disc usse d wit h 
C C T G)  or fres h  bi o ps y  ( o pti o nal)  f or  c orrelati ve  a nal yses  a n d t he  ce nt er/ pat h ol o gist  m ust  ha ve 
a gree d  t o  t he  s u b missi o n  of  t he  s peci me n(s).  Patie nts  will  n ot  be  e xcl u de d  if  t h e y  ha ve 
P O L E/ P O L D 1 m utati o ns  i n  t u m or  detecte d  b y  testi n g  o utsi de  of  t his  pr ot oc ol,  a n d  a d diti o nal 
arc hi val tiss ue is n ot a vaila ble a n d/ or o pti o nal fres h bi o ps y is n ot p ossi ble. 
 
4. 2. 5 
Patie nt c o nse nt m ust be a p pr o priatel y o btai ne d i n acc or da nce wit h a p pli ca ble l ocal a n d re g ulat or y 
re q uire me nts. Eac h patie nt m ust si g n a c o nse nt f or m pri or t o e nr oll me nt i n t he trial t o d oc u me nt 
t heir willi n g ness t o partici pate. 
 
Patie nts w h o ca n n ot gi ve i nf or me d c o nse nt (i.e. me ntall y i nc o m pete nt patie nts, or t h ose p h ysicall y 
i nca pacitate d s uc h as c o mat ose patie nts) are n ot t o be recr uite d i nt o t he st u d y. Patie nts c o m pete nt 
b ut  p h ysicall y  u na ble  t o  si g n  t he  c o nse nt  f or m  ma y  ha ve  t he  d oc u me nt  si g ne d  b y  t heir  nearest 
relati ve or le gal g uar dia n. Eac h patie nt will be pr o vi de d with a f ull e x pla nati o n of t he st u d y bef ore 
c o nse nt is re q ueste d. 
 
4. 2. 6 
Patie nts m ust be willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt sc he d ule, la b orat or y 
testi n g, a n d ot her re q uire me nts of t he trial. 
 
4. 2. 7  
I n acc or da nce wit h C C T G p olic y, pr ot oc ol treat me nt is t o be gi n wit hi n 2  w or ki n g da ys of patie nt  
ra n d o mizati o n. 
 
4. 2. 8  
W o me n of c hil d beari n g p ote ntial  ( W O C B P) a n d me n w h o are se x uall y acti ve wit h W O C B P m ust 
ha ve a gree d t o use a hi g hl y effecti ve c o ntrace pti ve met h o d  as i n dicate d i n Secti o n  9. 3. A w o ma n 
is c o nsi dere d t o be of "c hil d beari n g p ote ntial" if s he has ha d me nses at a n y ti me i n t he prece di n g 
1 2 c o nsec uti ve m o nt hs. I n a d diti o n t o r o uti ne c o ntrace pti ve met h o ds, "effecti ve c o ntrace pti o n" als o 
i ncl u des heter ose x ual celi bac y a n d s ur ger y i nte n de d t o pre ve nt pre g na nc y ( or wit h a si de-effect of 
pre g na nc y pre ve nti o n) defi ne d as a h ysterect o m y, bilateral o o p h orect o m y or bilateral t u bal li gati o n, 
or vasect o m y/ vasect o mize d part ner. H o we ver, if at a n y p oi nt a pre vi o usl y celi bate patie nt c h o oses 
to bec o me heter ose x uall y acti ve d uri n g t he ti me peri o d f or use of c o ntrace pti ve meas ures o utli ne d 
i n t he pr ot oc ol, he/s he is res p o nsi ble f or be gi n ni n g c o ntrace pti ve meas ures. 
 
Fe male patie nts of c hil d beari n g p ote ntial w h o are se x uall y acti ve wit h a n o n sterilize d male part ner 
m ust use at least o ne hi g hl y effecti ve met h o d of c o ntrace pti o n (fail ure rate of <  1 % per year) w hile 
o n st u d y a n d f or 2 3 wee ks after t he last d ose of ni v ol u ma b a n d or i pili m u ma b. Male part ners of a 
fe male patie nt a n d n o n-sterilize d male patie nts w h o are se x uall y acti ve wit h a fe male part ner of 
c hil d beari n g p ote ntial m ust use a n y c o ntrace pti ve met h o d wit h a fail ure rate of <  1 % per year f or 
3 1 wee ks after t he last d ose of ni v ol u ma b a n d or i pili m u ma b. Fe male part ners of a male s u bject 
m ust  use  a  hi g hl y  effecti ve  met h o d  of  c o ntrace pti o n  t hr o u g h o ut  t his  peri o d.  Cessati o n  of  birt h 
c o ntr ol  after  t his  p oi nt  s h o ul d  be  disc usse d  wit h  a  res p o nsi ble  p h ysicia n.  See Secti o n  9. 3  f or 
a d diti o nal details. 
 
W O C B P  will ha ve a pre g na nc y test t o deter mi ne eli gi bilit y as part of t he Pre -St u d y E val uati o n (see 
Secti o n 5. 0); t his ma y i ncl u de a n ultras o u n d t o r ule -o ut pre g na nc y if a false -p ositi ve is s us pecte d. 
F or e xa m ple, w he n beta -h u ma n c h ori o nic g o na d otr o pi n is hi g h a n d part ner is vasect o mize d, it ma y 
be ass oci ate d wit h t u m or pr o d ucti o n of h C G, as see n wit h s o me ca ncers. Patie nt will be c o nsi dere d 
eli gi ble if a n ultras o u n d is ne gati ve f or pre g na nc y.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
1 8  
C O N FI D E N TI A L  
W o me n m ust n ot breastfee d w hile o n st u d y a n d f or 2 3 wee ks after t he last d ose of ni v ol u ma b a n d/ or 
i pili m u ma b. 
 
4. 3  
E xcl usi o n Criteria  
 
Patie nts w h o f ulfill a n y of t he f oll o wi n g criteria are n ot eli gi ble f or a d missi o n t o t he st u d y:  
 
4. 3. 1 
Patie nts wit h a hist or y of ot her u ntreate d mali g na ncies or mali g na ncies, w hic h re q uire d t hera p y 
wit hi n t he past 2 years. Patie nts wit h a pri or or c o nc urre nt mali g na nc y w h ose nat ural hist or y or 
treat me nt d oes  n ot  ha ve  t he  p ote ntial  t o  i nterfere  wit h  t he  safet y  or  efficac y  assess me nt  of  t he 
i n vesti gati o nal re gi me n ma y be eli gi ble after c o ns ultati o n wit h t he C C T G. 
 
4. 3. 2 
Patie nts wit h pri mar y C N S t u m ors are n ot eli gi ble. 
 
4. 3. 3 
Patie nts wit h acti ve brai n metastases or le pt o me ni n geal metastases  are n ot eli gi ble . Patie nt s wit h 
brai n metastases are eli gi ble if t hese ha ve bee n treate d a n d cli nicall y sta ble . T here m ust als o be n o 
re q uire me nt  f or  i m m u n os u p pressi ve  d oses  of  s yste mic  c ortic oster oi ds  ( > 1 0 m g/ da y  pre d nis o ne 
e q ui vale nts). 
 
4. 3. 4 
Hist or y  of  pri mar y  i m m u n o deficie nc y,  hist or y  of  all o ge n eic  or ga n  tra ns pla nt  t hat  re q uires 
t hera pe utic i m m u n os u p pressi o n a n d t he use of i m m u n os u p pressi ve a ge nts wit hi n 1 4 da ys of st u d y 
dr u g a d mi nistrati o n * . 
 
*  N O T E:  I ntr a n as al/i n h ale d  c ortic oster oi ds  or  syste mic  ster oi ds  t h at  d o  n ot  t o  excee d  1 0  m g/ d ay  of 
pre d nis o ne  or  e q uiv ale nt  d ose  of  a n  alter n ative  c ortic oster oi d  are  per missi ble  i n  t he  a bse nce  of  active 
a ut oi m m u ne dise ase.  
 
4. 3. 5 
A cti ve  or  pri or  d oc u me nte d  a ut oi m m u ne  or  i nfla m mat or y  dis or ders.  I ncl u di n g,  i nfla m mat or y 
b o wel disease (e. g. c olitis or Cr o h n’s disease), di vertic ulitis wit h t he e xce pti o n of di vertic ul osis, 
celiac  disease  or  ot her seri o us  gastr oi ntesti nal  c hr o nic  c o n diti o ns  ass ociate d  wit h  diarr hea), 
s yste mic l u p us er yt he mat os us, Sarc oi d osis s y n dr o me, or We ge ner s y n dr o me ( gra n ul o mat osis wit h 
p ol ya n giitis), r he u mat oi d art hritis, h y p o p h ysitis, u veitis, etc., wit hi n t he past 3 years pr i or t o t he 
start of treat me nt. 
 
Patie nts  wit h  vitili g o,  t y pe  I  dia betes  mellit us,  resi d ual  h y p ot h yr oi dis m  d ue  t o  a ut oi m m u ne 
c o n diti o n  o nl y  re q uiri n g  h or m o ne  re place me nt,  ps oriasis  n ot  re q uiri n g  s yste mic  treat me nt,  or 
c o n diti o ns c o nsi dere d t o be of l o w ris k f or rec urre nce are per mitte d t o e nr oll. 
 
4. 3. 6 
Hist or y of h y perse nsiti vit y t o ni v ol u ma b or i pili m u ma b or a n y e xci pie nt.  
 
4. 3. 7 
A n y pre vi o us treat me nt wit h a P D -1 or a nti -P D -L 1, a nti -P D -L 2 i n hi bit or, i ncl u di n g ni v ol u ma b or 
a n a nti -C T L A 4, i ncl u di n g i pili m u ma b, or dr u g s pecificall y tar geti n g T -cell sti m ulati o n or i m m u ne 
c hec k p oi nt pat h wa ys. 
 
4. 3. 8 
Patie nts  wit h  seri o us  ill nesses  or  me dical  c o n diti o ns  w hic h  w o ul d  n ot  per mit  t he  patie nt  t o  be 
ma na ge d  acc or di n g  t o  t he  pr ot oc ol  (i ncl u di n g  c ortic oster oi d  a d mi nistrati o n),  or  w o ul d  p ut  t he 
patie nt at ris k. T his i ncl u des b ut is n ot li mite d t o:  
•  
Hist or y  of  si g nifica nt  ne ur ol o gic  or  ps yc hiatric  dis or der  w hic h  w o ul d  i m pair  t he  a bilit y  t o 
o btai n c o nse nt or li mit c o m plia nce wit h st u d y re q uire me nts. 
 
 

 
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C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
1 9  
C O N FI D E N TI A L  
•  
Acti ve  i nfecti o n  re q uir i n g  s yste mic  t hera p y;  (i ncl u di n g  a n y  patie nt  k n o w n  t o  ha ve  acti ve 
he patitis  B,  he patitis  C  or  h u ma n  i m m u n o deficie nc y  vir us  ( HI V)  or  t u berc ul osis  or  a n y 
i nfecti o n re q uiri n g s yste mic t hera p y). 
•  
Acti ve pe ptic ulcer disease or gastritis . 
•  
Acti ve p ne u m o nitis. 
 
4. 3. 9 
Patie nts recei vi n g c o nc urre nt treat me nt wit h ot her a nti -ca ncer t hera p y or ot her i n vesti gati o nal a nti -
ca ncer a ge nts. 
 
4. 3. 1 0 Patie nts w h o ha ve e x perie nce d u ntreate d a n d/ or u nc o ntr olle d car di o vasc ular c o n diti o ns a n d/ or ha ve 
s y m pt o matic car diac d ysf u ncti o n ( u nsta ble a n gi na, c o n gesti ve heart fail ure, m y o car dial i nfarcti o n 
wit hi n t he pre vi o us year or car diac ve ntric ular arr h yt h mias re q uiri n g me dicati o n, hist or y of 2 n d or 
3r d de gree atri o ve ntric ular c o n d ucti o n defects). 
 
4. 3. 1 1  Pre g na nt or lactati n g w o me n. 
 
4. 3. 1 2 Me n w h o are se x uall y acti ve wit h w o me n of c hil d beari n g p ote ntial a n d w o me n of c hil d beari n g 
p ote ntial m ust a gree t o use a de q uate c o ntrace pti o n as descri be d i n Secti o n 4. 2. 8.  

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
2 1  
C O N FI D E N TI A L  
 
1 
Bl o o d w or k Ti mi n g: Pre -treat me nt bl o o d dra ws ma y be d o ne t he da y pri or t o treat me nt if necessar y, a n d w he n treat me nt is t o be gi n o n a 
M o n d a y, ma y be d o ne o n t he pre vi o us Fri da y ( ma xi m u m 7 2 h o urs pri or t o treat me nt). I n or der t o e ns ure t hat na dir c o u nts are n o t misse d, 
e v er y eff ort s h o ul d be ma de t o d o i nteri m bl o o d dra ws wit hi n 2 4 h o urs of t he da y s pecifie d i n t he pr ot oc ol.  
2 
C o nfir mati o n t hat t he patie nt w o ul d meet t he re q uire me nts f or ra n d o mizati o n ( C B C wit h differe ntial, ser u m creati ni ne, bilir u b i n, a n d 
A S T &/ or A L T o nl y). T hese la b res ults ma y be ascertai ne d b ase d o n patie nt c hart re vie w. It is n ot  necessar y t o re peat t hese la bs pri or t o 
t h e scree ni n g ste p f or t he p ur p oses of t his st u d y, if res ults alrea d y a vaila ble wit hi n t he pre vi o us 2 8 da ys. 
3 
It is prefera ble t hat b ot h a m ylase a n d li pase are assesse d. F or sites w her e o nl y 1 of t hese para meters is r o uti nel y meas ure d t he n eit her 
li p ase or a m ylase is acce pta ble. 
4 
Fr ee T 3 a n d free T 4 will be meas ure d if T S H is a b n or mal . 
5 
T o b e d o ne a d diti o nall y e ver y 3 m o nt hs t hereafter t o f oll o w a b n or mal la b res ults felt rela te d u ntil res ol ve d t o ≤ Gra de 2. 
6 
W o m e n of c hil d -beari n g p ote ntial o nl y  ( uri ne or ser u m test). M ust be perf or me d wit hi n 7 2  h o urs pri or t o a d mi nistrati o n of st u d y dr u g . T o 
b e d o n e e ver y 4 wee ks  w he n o n -st u d y. 
7 
T u m or  mar kers i ncl u di n g C E A, C A -1 2 5, C A- 1 9 -9,  etc., as i n dicate d per sta n dar d of care testi n g f or pri mar y t u m or. If ele vate d at 
b aseli n e , will be m o nit or seriall y. If n ot ele vate d  at baseli ne,  will n ot be m o nit ore d seriall y . 
8 
St u dies at ti me of pr o gressi o n at t he discreti o n of patie nts a n d treati n g p h ysicia n if feasi ble ( o pti o nal) . 
9 
T o b e d o ne e ver y 1 2 wee ks u ntil rela pse or pr o gressi o n (i C P D) f or u p t o 2 years, f or patie nts wit h C R/i C R, P R/i P R, S D/i S D res p o nse as 
d efi n e d i n Secti o n 8. 0. F or patie nts wit h i U P D, c o nfir mat or y sca ns m ust be perf or me d a t least 4 wee ks, b ut n o l o n ger t ha n 8 wee ks, after 
i U P D was i de ntifie d. 
1 0  
First t u m or assess me nt s h o ul d be perf or me d 1 2 wee ks ( ± 1 wee k) f oll o wi n g ra n d o mizati o n.  T o e ns ure c o m para bilit y, baseli ne sca ns a n d 
s u bse q u e nt sca ns t o assess res p o nse m ust be perf or me d usi n g i de ntical tec h ni q ue (i.e. sca ns perf or me d i m me diatel y f oll o wi n g b ol us 
c o ntrast a d mi nistrati o n usi n g a sta n dar d v ol u me of c o ntrast, t he i de ntical c o ntrast a ge nt, a n d prefera bl y t he sa me sca n ner). Mai ntai n 
sc h e d ule e ver y 1 2 wee ks e ve n if c ycles are dela ye d. 
1 1  
E ver y t hree m o nt hs t hereafter t o f oll o w a d verse e ve nts felt relate d u ntil res ol ve d t o ≤ Gra de 2. A d verse E ve nts t o be e val uat e d usi n g t he 
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. 5. 0) (see A p pe n di x V).  
1 2  
See S ecti o n 1 2. 0  for details . D oc u me ntati o n of P O L E or P O L D 1 m utati o n i n t u m or O R b y cf D N A i n plas ma re q uire d pri or t o 
ra n d o mizati o n. Please ref er t o Secti o n 1 2. 1. 3 a n d t he C orrelati ve St u dies Ma n ual f or details re gar di n g c ollecti o n.  
1 3  
T o b e d o ne da y 1 of eac h c ycle ( e xcl u di n g c ycle 1) f or first 4 c ycles. 
 
5. 1  
F oll o w- u p f or Patie nts 
 
T he  f oll o w -u p  re q uire me nts  f or  i neli gi ble   ra n d o mize d patie nts  w h o  ha ve  recei ve d  n o  pr ot oc ol 
t hera p y  i ncl u de s u b missi o n  of  t he  Baseli ne  Re p ort a n d  a n  E n d  of  Treat me nt  Re p ort . Data 
s u b missi o n  f or  i neli gi ble  partici pa nts  w h o  ha ve  recei ve d  at  least  o ne  d ose  of  pr ot oc ol  t hera p y 
s h o ul d  be  acc or di n g  t o  t he  pr ot oc ol  t o  all o w  f or  treat me nt  a n d  a d verse  e ve nt  assess me nt. F or 
patie nts  wit h o ut  detecta ble  P O L E  or  P O L D 1  m utati o ns  o n  cf D N A  sc ree ni n g,  n o  f oll o w-u p  is 
re q uire d. 

 
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C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
2 2  
C O N FI D E N TI A L  
6. 0 
E N T R Y/ R A N D O MI Z A TI O N P R O C E D U R E S  
 
6. 1  
E ntr y Pr oce d ures 
 
All re gistrati o ns  a n d ra n d o mizati o ns  will  be  d o ne  t hr o u g h  t he C C T G  we b -base d,  pass w or d -
o perate d Electr o nic Data Ca pt ure ( E D C) s yste m. C o m plete details re gar di n g o btai ni n g a pass w or d, 
accessi n g t he s yste m a n d re gisteri n g/ra n d o mizi n g patie nts will be pr o vi de d at t he ti me of st u d y 
acti vati o n a n d will als o be i ncl u de d i n t he “ E D C Data Ma na ge me nt G ui de b o o k”, p oste d o n t he 
C RI -C C T G - 0 0 0 1 trial s pecific we b-site. If sites e x perie nce diffic ulties accessi n g t he s yste m a n d/ or 
re gisteri n g/ra n d o mizi n g patie nts, please c o ntact t he hel p des k (li n k i n E D C) or t he C RI -C C T G -
0 0 0 1 St u d y C o or di nat or.  
 
All patie nts w h o are re gistere d b y t he partici pati n g treat me nt ce nt er will be assi g ne d a serial n u m ber 
w hic h m ust be use d o n all d oc u me ntati o n a n d c orres p o n de nce wit h C C T G.  
 
Re gistr ati o n f or Scree ni n g 
 
All c o nse nti n g patie nts w h o are belie ve d t o be eli gi ble will be re gistere d pri or t o t he c olle cti o n a n d 
s u b missi o n of a cf D N A scree ni n g sa m ple f or P O L E/ P O L D 1. T he c o m pleti o n of a n a b bre viate d 
eli gi bilit y c hec k will be re q uire d a n d a serial n u m ber assi g ne d w hic h m ust be use d t o i de ntif y t he 
patie nt o n t he sa m ples se nt f or testi n g. Details of t he ce n tral la b orat or y i ncl u di n g sa m ple c ollecti o n 
a n d s hi p me nt are pr o vi de d i n t he C RI-C C T G - 0 0 0 1 Scree ni n g Ma n ual. 
 
T he f oll o wi n g i nf or mati o n will be re q uire d  f or scree ni n g a n d e nr oll me nt: 
•  
trial c o de ( C RI-C C T G - 0 0 0 1) 
•  
patie nt's i nitials ( ma y be c o de d)  
•  
scree ni n g inf or me d c o nse nt versi o n date, date si g ne d b y patie nt, na me of pers o n c o n d ucti n g 
c o nse nt disc ussi o n a n d date si g ne d  
•  
c o nfir mati o n of t he re q uire me nts liste d i n Secti o n 4. 0  
 
R a n d o miz ati o n 
 
F oll o wi n g recei pt of t he scree ni n g res ults, eli gi ble patie nts will be ra n d o mize d t o o ne of t w o st u d y 
ar ms. 
 
T he f oll o wi n g a d diti o nal i nf or mati o n will be re q uire d: 
•  
i nf or me d  c o nse nt  versi o n  date,  date  si g ne d  b y  patie nt,  na me  of  pers o n  c o n d ucti n g  c o nse nt 
disc ussi o n a n d date si g ne d 
•  
tiss ue ba n ki n g/ o pti o nal c o nse nt versi o n date 
•  
c onfir mati o n of t he re q uire me nts liste d i n Secti o n  4. 0, i ncl u di n g dates of esse ntial tests a n d 
act ual la b orat or y val ues 
•  
hei g ht a n d wei g ht  
•  
stratificati o n fact ors 
 
 

 
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C O N FI D E N TI A L  
6. 2 
Stratificati o n   
 
S u bj ects will be stratifie d at t he ti me of ra n d o mizati o n b y:  
•  
E C O G perf or ma nce stat us ( 0, 1)  
•  
N u m ber of pri or treat me nts ( 0, 1- 2, 3 or m ore)  
 
6. 3  
Re gistrati o n a n d Ra n d o mizati o n 
 
Re gistrati o n a n d Ra n d o mizati o n will be pr o vi de d electr o nicall y. 
 
N ote : T he vali dit y of res ults of t he trial de pe n ds o n t he a ut he nticit y of a n d t he f oll o w-u p of all 
patie nts e ntere d i nt o t he trial. U n der n o circ u msta nces, t heref ore, ma y a n all ocate d patie nt’s data 
be wit h dra w n pri or t o fi nal a nal ysis, u nless t he partici pa nt wit h dra ws fr o m t he trial a n d re q uests 
t hat data c ollecti o n/s u b missi o n cease fr o m t he p oi nt i n ti me of wit h dra wal. 
 
All  eli gi ble  patie nts  a d mitte d  t o  t he  trial  will  be  f oll o we d  b y  t he  c o or di nati n g  ce nter.  It  is  t he 
res p o nsi bilit y  of  t he  p h ysicia n  i n  c har ge t o  satisf y  hi mself  or  herself  t hat  t he  patie nt  is  i n dee d 
eli gi ble bef ore re q uesti n g re gistrati o n.  
 
All ra n d o mize d patie nts are t o be f oll o we d u ntil deat h or u ntil sites are i nf or me d b y C C T G t hat 
f urt her  f oll o w-u p  is  n o  l o n ger  re q uire d.  T he  f oll o w -u p  re q uir e me nts  f or  i neli gi ble  patie nts  are 
o utli ne d i n Secti o n 5. 1. 

 
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C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
2 4  
C O N FI D E N TI A L  
7. 0 
T R E A T M E N T P L A N  
 
Alt h o u g h  t he Ca na dia n  Ca ncer  Trials  Gr o u p  acts  as  t he  c o or di nati n g  a ge nc y  f or  t he  trial,  t he 
res p o nsi bilit y f or treat me nt of patie nts rests wit h t he i n di vi d ual i n vesti gat or. 
 
I n acc or da nce wit h C C T G p olic y, pr ot oc ol treat me nt is t o be gi n wit hi n 2 w or ki n g da ys of patie nt  
ra n d o mizati o n. 
 
7. 1 
Treat me nt Pla n  
 
7. 1. 1 
Dr u g A d mi nistr ati o n  
 
W he n  ni v ol u ma b  is  gi ve n  wit h  i pili m u ma b,  ni v ol u ma b  will  be  a d mi nistere d  first .  Pri or  t o  t he 
i pili m u ma b  i nf usi o n,  t he  patie nt’s  li ne  s h o ul d  be  fl us he d  a n d  filter  c ha n ge d.  T he  i pili m u ma b 
i nf usi o n s h o ul d n ot be starte d u ntil 3 0 mi n utes after t he e n d of t he ni v ol u ma b i nf usi o n. 
 
O ne c ycle will be defi ne d as 6 wee ks.  
 
Ar m  
A ge nt(s)  
D ose  
R o ute  
D urati o n  
S c he d ule  
1 & 2  
Ni v ol u ma b  
2 4 0 m g  
I V 
3 0 mi n  
Da y 1, t he n e ver y 2 wee ks  
2 
I pili m u ma b 
1 m g/ k g  
I V 
3 0 mi n  
Da y 1, t he n e ver y 6 wee ks  
 
7. 1. 2 
Pre me dic ati o n  
 
P re me dicati o n  (e. g.  f or  na usea)  or  h y perse nsiti vit y  pr o p h yla xis  is  n ot re q uire d. Ma na ge me nt  of 
s y m pt o ms s h o ul d ta ke place as necessar y (see Secti o n 7.1. 6 bel o w). Details of a n y pre me dicati o n 
or c o nc o mita nt me dicati o n gi ve n t o ma na ge or pre ve nt a d verse e ve nts s h o ul d be rec or de d o n t he 
electr o nic case re p ort f or m (e C R F).  
 
7. 1. 3 
P atie nt M o nit ori n g  
 
Vital  si g ns  s h o ul d  be  ta ke n  as  per  i nstit uti o nal  sta n dar d  of  care  pri or  t o,  d uri n g  a n d  after  dr u g 
a d mi nistrati o n. 
 
All patie nts s h o ul d be cl osel y m o nit ore d acc or di n g t o g ui deli nes i n Secti o n 5. 0 a n d be a d vise d t o 
c o ntact t he treati n g ce nter i n t he case of si g nifica nt t o xicities. 
 
7. 1. 4 
D ose M o dific ati o ns  
 
T he  maj or  t o xic  effects  of  ni v ol u ma b  or  i pili m u ma b  w hic h  are  a ntici pate d  t o  li mit  d osi n g  are 
h y perse nsiti vit y/ i nf usi o n relate d reacti o ns a n d p ossi ble class relate d i m m u ne relate d A Es, base d 
o n  t he  mec ha nis m  of  acti o n  of  ni v ol u ma b  a n d  i pili m u ma b  lea di n g  t o  T -cell  acti vati o n  a n d 
pr oliferati o n.  P ote ntial  i m m u ne  relate d  A Es  i ncl u de  p ne u m o nitis,  e nter oc olitis,  der matitis, 
he patitis/ he pat ot o xicit y,  ne ur o pat h y/ ne ur o m usc ular  t o xicit y,  pa ncreatitis,  ne p hritis  a n d 
en d ocri n o pat h y. Patie nts s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of i m m u ne relate d A Es. I n 
t he a bse nce of a n alter nate eti ol o g y (e. g. i nfecti o n or rela pse), si g ns or s y m pt o ms of p ne u m o nitis, 
e nter oc olitis, der matitis, he patitis/ he pat ot o xicit y, ne ur o pat h y / ne ur o m usc ular t o xicit y, pa ncreatitis, 
ne p hritis a n d e n d ocri n o pat h y s h o ul d be c o nsi dere d t o be i m m u ne- relate d. 
 
 

 
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T he g ui deli nes w hic h f oll o w o utli ne d ose a dj ust me nts f or se veral of t hese t o xic effects. If a patie nt 
e x perie nces  se veral  a d verse  e ve nts  a n d  t here  are  c o nflicti n g  rec o m me n dati o ns,  please  use  t he 
rec o m me n de d  d ose  a dj ust me nt  t hat  re q uires  t he  greatest  d ose  h ol d  or  disc o nti n uati o n.  A d verse 
e ve nts will be gra de d usi n g t he N CI C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) 
(see A p pe n di x V). 
 
D ose  a dj ust me nts  (sl o wi n g/i nterr u pti o n  of  i nf usi o n  rate,  o missi o n  of  a  d ose,  or  per ma ne nt 
disc o nti n uati o n) will be ma de f or a d verse e ve nts.  T here will be n o d ose re d ucti o ns.  
 
If t he i nf usi o n ca n n ot be a d mi nistere d, it s h o ul d be o mitte d u ntil t he ne xt pla n ned i nf usi o n. W he n 
ni v o l uma b is a d mi nistere d i n c o m bi nati o n wit h i pili m u ma b, if eit her a ge nt is wit h hel d, t he ot her 
a ge nt s h o ul d als o be wit h hel d. If d osi n g is res u me d after a dela y eit her t he c o m bi nati o n treat me nt 
or ni v ol u ma b al o ne ca n be res u me d base d o n e val uati o n of t he i n di vi d ual patie nt. 
 
Treat me nt s h o ul d n ot be gi ve n (i ncl u di n g da y 1 c ycle 1) u ntil t he la b orat or y criteria i n Secti o n 4. 2. 3 
are  met  a n d  res ol uti o n  of  all  dr u g  relate d  t o xicit y  t o  ≤ gra de  2.  Disc uss  wit h  C C T G  if 
as y m pt o matic/ n ot felt t o be cli nicall y si g nifica nt. 
 
7. 1. 4. 1 D ose Del ays  
 
D ose dela y criteria a p pl y f or all dr u g -relate d a d verse e ve nts (re gar dless of w het her or n ot t he e ve nt 
is attri b ute d t o ni v ol u ma b , i pili m u ma b, or b ot h). Refer t o A p pe n di x II f or f ull details of t o xicit y 
ma na ge me nt.  Ni v ol u ma b a n d i pili m u ma b a d mi nistrati o n s h o ul d be dela ye d f or t he f oll o wi n g: 
•  
A n y Gra de ≥ 2 n o n -s ki n, dr u g-relate d a d verse e ve nt, wit h t he f oll o wi n g e xce pti o ns: 
 
Gra de 2 dr u g -relate d fati g ue or la b orat or y a b n or malities d o n ot re q uire a treat me nt dela y . 
•  
A n y Gra de 3 s ki n, dr u g- relate d a d verse e ve nt 
•  
A n y  Gra de  3  dr u g -relate d  la b orat or y  a b n or malit y,  wit h  t he  f oll o wi n g  e xce pti o ns  f or  A S T, 
A L T, or t otal  bilir u bi n:  
 
If a patie nt has a baseli ne A S T, A L T, or  t otal bilir u bi n t hat is wit hi n n or mal li mits, dela y 
d osi n g f or dr u g-relate d Gra de ≥ 2 t o xicit y. 
•  
A n y a d verse e ve nt, la b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he j u d g me nt of 
t he i n vesti gat or, warra nts dela yi n g t he d ose of st u d y me dicati o n. 
 
7. 1. 4. 2 Disc o nti n u ati o n ( U n acce pt a ble T oxicity)  
 
Treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d f or t he f oll o wi n g: 
•  
A n y Gra de 2 dr u g-relate d u veitis or e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o t o pical 
t hera p y a n d d oes n ot i m pr o ve t o Gra de 1 se verit y wit hi n t he re-treat me nt peri o d O R re q uires 
s yste mic treat me nt. 
•  
A n y  Gra de  3  n o n -s ki n,  dr u g-relate d  a d verse  e ve nt  lasti n g  >  7  da ys,  wit h  t he  f oll o wi n g 
e xce pti o ns  f or  dr u g -relate d  la b orat or y  a b n or malities,  u veitis,  p ne u m o nitis,  br o nc h os pas m, 
diarr hea, c olitis, ne ur ol o gic t o xicit y, h y perse nsiti vit y reacti o ns, a n d i nf usi o n reacti o ns: 
 
Gra de  3  dr u g -relate d  u veitis,  p ne u m o nitis,  br o nc h os pas m,  diarr hea,  c olitis,  ne ur ol o gic 
t o xicit y,  h y perse nsiti vit y  reacti o n,  or  i nf usi o n  reacti o n  of  a n y  d urati o n  re q uires 
disc o nti n uati o n 
 
 

 
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 
Gra de  3  dr u g -relate d  la b orat or y  a b n or malities  d o  n ot  re q uire  treat me nt  disc o nti n uati o n 
e xce pt: 
- 
Gra de 3 dr u g -relate d t hr o m b oc yt o pe nia > 7 da ys or ass ociate d wit h blee di n g re q uires 
disc o nti n uati o n 
- 
A n y dr u g -relate d li ver f u ncti o n test ( L F T) a b n or malit y t hat meets t he f oll o wi n g criteria 
re q uire disc o nti n uati o n: 
• 
A S T or A L T > 8 x  U L N  
• 
T otal bilir u bi n > 5 x  U L N  
• 
C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N  
•  
A n y Gra de 4 dr u g -relate d a d verse e ve nt or la b orat or y a b n or malit y, e xce pt f or t he f oll o wi n g 
e ve nts w hic h d o n ot re q uire disc o nti n uati o n: 
 
Is olate d Gra de 4 a m ylase or li pase a b n or malities t hat are n ot ass ociate d wit h s y m pt o ms or 
cli nical ma nifestati o ns of pa ncreatitis a n d decrease t o < Gra de 4 wit hi n 1 wee k of o nset.  
 
Is olate d Gra de 4 electr ol yte i m bala nces/a b n or malities t hat are n ot ass ociate d wit h cli nical 
se q uelae a n d are i m pr o ve d wit h  s u p ple me ntati o n/a p pr o priate ma na ge me nt  wit hi n 7 2 h o urs 
of t heir  o nset. 
•  
A n y d osi n g i nterr u pti o n lasti n g > 6 wee ks wit h t he f oll o wi n g e xce pti o ns: 
 
D osi n g i nt err u pti o ns t o all o w f or pr ol o n ge d ster oi d ta pers t o ma na ge dr u g -relate d a d verse 
e ve nts are all o we d. Pri or t o re -i nitiati n g treat me nt i n a patie nt  wit h a d osi n g i nterr u pti o n 
lasti n g > 6 wee ks, t he C C T G  m ust be c o ns ulte d. T u m or  assess me nts s h o ul d c o nti n ue as  
per pr ot oc ol e ve n if d osi n g is i nterr u pte d. 
 
D osi n g i nterr u pti o ns > 6 wee ks t hat occ ur f or n o n - dr u g-relate d reas o ns ma y be all o we d if 
a p pr o ve d b y C C T G . Pri or t o re-i nitiati n g treat me nt i n a patie nt  wit h a d osi n g i nterr u pti o n 
lasti n g > 6 wee ks, C C T G m ust be  c o ns ulte d. T u m or assess me nts s h o ul d c o nti n ue as per 
pr ot oc ol e ve n if d osi n g is i nterr u pte d. 
•  
A n y a d verse e ve nt, la b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he j u d g me nt of 
t he in vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he patie nt  wit h c o nti n ue d ni v ol u ma b or 
i pili m u ma b d osi n g. 
 
T he assess me nt f or disc o nti n uati o n of ni v ol u ma b s h o ul d be ma de se paratel y fr o m t he assess me nt 
ma de  f or  disc o nti n uati o n  of i pili m u ma b.  Alt h o u g h  t here  is  o verla p  a m o n g  t he  disc o nti n uati o n 
criteria, if disc o nti n uati o n criteria are met f or i pili m u ma b b ut n ot f or ni v ol u ma b , treat me nt wit h 
ni v ol u ma b ma y c o nti n ue if i pili m u ma b is disc o nti n ue d. 
 
If a partici pa nt i n t he ni v ol u ma b /i pili m u ma b c o m bi nati o n ar m meets criteria f or disc o nti n uati o n 
a n d i n vesti gat or is u na ble t o deter mi ne w het her t he e ve nt is relate d t o b ot h or o ne st u d y dr u g, t he 
partici pa nt s h o ul d disc o nti n ue b ot h ni v ol u ma b a n d i pili m u ma b a n d be ta ke n off t he treat me nt p hase 
of t he trial. 
 
7. 1. 5 
M a n a ge me nt of T oxicity   
 
See A p pe n di x I I f or f ull details of t o xicit y ma na ge me nt. 
 
 

 
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F or a d verse e ve nts ( A Es) t hat are c o nsi dere d at least partl y d ue t o a d mi nistrati o n of ni v ol u ma b 
a n d/ or i pili m u ma b t he f oll o wi n g d ose a dj ust me nt g ui da nce ma y be a p plie d: 
•  
Treat  eac h  of  t he  t o xicities  wit h  ma xi m u m  s u p p orti ve  care (i ncl u di n g  h ol di n g  t he  a ge nts 
s us pecte d of ca usin g t he t o xicit y w here re q uire d). 
•  
If  t he  s y m pt o ms  pr o m ptl y  res ol ve  wit h  s u p p orti ve  care,  c o nsi derati o n  s h o ul d  be  gi ve n  t o 
c o nti n ui n g  ni v ol u ma b  or i pili m u ma b al o n g  wit h  a p pr o priate  c o nti n ui n g  s u p p orti ve  care.  If 
me dicall y  a p pr o priate,  d ose dela ys  are  per mitte d  f or ni v ol u ma b  a n d/ or i pili m u ma b (see 
A p pe n di x II). 
•  
All d ose dela ys  s h o ul d be d oc u me nte d wit h clear reas o ni n g a n d d oc u me ntati o n of t he a p pr oac h 
ta ke n. 
•  
I n  a d diti o n,  t here  are  certai n  circ u msta nces  i n  w hic h ni v ol u ma b  or i pili m u ma b s h o ul d  be 
per ma ne ntl y disc o nti n ue d. 
 
7. 1. 6 
M a n a ge me nt of I nf usi o n Re acti o n  
 
Si nce ni v ol u ma b  a n d i pili m u ma b c o ntai n o nl y h u ma n i m m u n o gl o b uli n pr otei n se q ue nces, t he y are 
u nli kel y t o be i m m u n o ge nic a n d i n d uce i nf usi o n or h y perse nsiti vi t y reacti o ns. H o we ver, if s uc h a 
reacti o n  were  t o  occ ur,  it  mi g ht  ma nifest  wit h  fe ver,  c hills,  ri g ors,  hea dac he,  ras h,  urticaria, 
a n gi oe de ma, pr urit us, art hral gias, h y p o- or h y perte nsi o n, br o nc h os pas m, or ot her s y m pt o ms. 
 
All  Gra de  3  or  4  i nf usi o n  reacti o n s  s h o ul d  be  re p orte d  as  a n  S A E  if  criteria  are  met.  I nf usi o n 
reacti o ns s h o ul d be gra de d acc or di n g t o N CI C T C A E versi o n 5. 0 g ui deli nes 
 
F or Gr a de 1 s y m pt o ms:  
( Mil d reacti o n; i nf usi o n i nterr u pti o n n ot i n dicate d; i nter ve nti o n n ot i n dicate d)  
 
Re mai n at be dsi de a n d m o nit or patie nt  u ntil rec o ver y fr o m s y m pt o ms. I nf usi o n rate ma y be sl o we d. 
If t he i nf usi o n is i nterr u pte d, t he n restart t he i nf usi o n at 5 0 % of t he ori gi nal i nf usi o n rate w he n 
s y m pt o ms res ol ve; if n o f urt her c o m plicati o ns e ns ue after 30 mi n utes, t he rate ma y be i ncrease d t o 
1 0 0 % of t he ori gi nal i nf usi o n rate. M o nit or patie nt cl osel y. 
 
T he  f oll o wi n g  pr o p h ylactic  pre me dicati o ns  are  rec o m me n de d  f or  f ut ure  i nf usi o ns: 
di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or paraceta m ol 3 2 5 t o 1 0 0 0 m g (aceta mi n o p he n) at 
least 3 0 mi n utes bef ore a d diti o nal ni v ol u ma b or i pili m u ma b a d mi nistrati o ns, sl o wi n g i nf usi o n rate 
as a b o ve. 
 
F or Gr a de 2 s y m pt o ms : 
( M o derate reacti o n re q uires t hera p y or i nf usi o n i nterr u pti o n b ut res p o n ds pr o m ptl y t o s y m pt o matic 
treat me nt [e. g.  a nti hista mi nes,  n o n-ster oi dal  a nti-i nfla m mat or y  dr u gs,  narc otics,  c ortic oster oi ds, 
br o nc h o dilat ors, I V fl ui ds]; cl ose o bser vati o n f or rec urre nce a n d treat me nt me dicati o ns ma y nee d 
t o be c o nti n ue d f or 2 4- 4 8 h o urs) 
 
 

 
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St o p t he ni v ol u ma b or i pili m u ma b i nf usi o n, be gi n a n I V i nf usi o n of n or mal sali ne, a n d treat t he 
patie nt  wit h  di p he n h y dra mi ne  5 0  m g  I V  ( or  e q ui vale nt)  a n d/ or  paraceta m ol  3 2 5  t o  1 0 0 0  m g 
(aceta mi n o p he n);  re mai n  at  be dsi de  a n d  m o nit or  patie nt  u ntil  res ol uti o n  of  s y m pt o ms. 
C ortic oster oi d or br o nc h o dilat or t hera p y ma y als o be a d mi nistere d as a p pr o priate. If t he i nf usi o n 
is i nterr u pte d, t he n restart t he i nf usi o n at 5 0 % of t he ori gi nal i nf usi o n rate w he n s y m pt o ms res ol ve; 
if n o f urt her c o m plicati o ns e ns ue after 3 0 mi n utes, t he rate ma y be i ncrease d t o 1 0 0 % of t he ori gi nal 
i nf usi o n rate. M o nit or patie nt cl osel y. If s y m pt o ms rec ur, t he n n o f urt her ni v ol u ma b or i pili m u ma b 
will be a d mi nistere d at t hat visit. A d mi nister di p he n h y dra mi ne 5 0 m g I V, a n d re mai n at be dsi de 
a n d m o nit or t he patie nt u ntil res ol uti o n of s y m pt o ms. T he a m o u nt of st u d y dr u g i nf use d m ust be 
rec or de d o n t he electr o nic case re p ort f or m (e C R F). 
 
T he  f oll o wi n g  pr o p h ylactic  pre me dicati o ns  are  rec o m me n de d  f or  f ut ure  i nf usi o ns: 
di p he n h y dra mi ne  5 0  m g  ( or  e q ui vale nt)  a n d  aceta mi n o p he n  ( or  paraceta m ol)  3 2 5  t o  1 0 0 0  m g 
s h o ul d  be  a d mi nistere d  at  least  3 0  mi n utes  bef ore  a d diti o nal  ni v ol u ma b  a d mi nistrati o ns.  If 
necessar y, c ortic oster oi ds (rec o m me n de d d ose: u p t o 2 5 m g of I V h y dr oc ortis o ne or e q ui vale nt) 
ma y be use d. 
 
Gr a de 3 s y m pt o ms :  
( Se vere  reacti o n; pr ol o n ge d  [i.e.  n ot ra pi dl y  res p o nsi ve  t o s y m pt o matic  me dicati o n a n d/ or  brief 
i nterr u pti o n of i nf usi o n]; rec urre nce of s y m pt o ms f oll o wi n g i nitial i m pr o ve me nt; h os pitalizati o n 
i n dicate d f or ot her cli nical se q uelae [e. g. re nal i m pair me nt, p ul m o nar y i nfiltrates]) 
 
Gr a de 4 s y m pt o ms:  
(life t hreate ni n g; press or or ve ntilat or y s u p p ort i n dicate d)  
 
I m me diatel y disc o nti n ue i nf usi o n of ni v ol u ma b or i pili m u ma b. Be gi n a n I V i nf usi o n of n or mal 
sali ne, a n d treat t he patie nt as f oll o ws. Rec o m me n d br o nc h o dilat ors, e pi ne p hri ne 0. 2 t o 1 m g of a 
1: 1, 0 0 0 s ol uti o ns f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 m g of a 1: 1 0, 0 0 0 s ol uti o n i njecte d 
sl o wl y f or I V a d mi nistrati o n, a n d/ or di p he n h y dra mi ne 5 0 m g I V wit h met h yl pre d nis ol o ne 1 0 0 m g 
I V ( or e q ui vale nt), as nee de d. Patie nt s h o ul d be m o nit ore d u ntil t he i n vesti gat or is c o mf orta ble t hat 
t he  s y m pt o ms  will  n ot  rec ur;  ni v ol u ma b  or  i pili m u ma b  will  be  per ma ne ntl y  disc o nti n ue d. 
I n vesti gat ors s h o ul d f oll o w t heir i nstit uti o nal g ui deli nes f or t he treat me nt of a na p h yla xis. Re mai n 
at  be dsi de  a n d  m o nit or  patie nt  u ntil  rec o ver y  fr o m  s y m pt o ms.  I n  t he  case  of  late- occ urri n g 
h y perse nsiti vit y s y m pt o ms (e. g. a p peara nce of a l ocalize d or ge neralize d pr urit us wit hi n  1 wee k 
after treat me nt), s y m pt o matic treat me nt ma y be gi ve n (e. g. oral a nti hista mi ne, or c ortic oster oi ds).  
 
Please  n ote  t hat  late  occ urri n g  e ve nts  i ncl u di n g  is olate d  fe ver  a n d  fati g ue  ma y  re prese nt  t he 
prese ntati o n of s yste mic i nfla m mati o n. Please e val uate acc or di n gl y.  
 
7. 2 
D urati o n of T hera p y  
 
Patie nts  s h o ul d  c o nti n ue  o n  trial  treat me n t  u ntil  R E CI S T  1. 1/i R E CI S T  defi ne d  pr o gressi o n  or 
u nacce pta ble t o xicit y or ot her treat me nt disc o nti n uati o n criteri o n is met (see bel o w). 
 
A n i n di vi d ual patie nt will n ot recei ve a n y f urt her i n vesti gati o nal pr o d uct if a n y of t he f oll o wi n g 
occ ur i n t he patie nt i n q uesti o n:  
•  
Patie nt re q uest . 
 
 

 
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•  
L ost t o f oll o w - u p. 
•  
Patie nt is deter mi ne d t o ha ve met o ne or m ore of t he e xcl usi o n criteri o n f or t he trial. 
•  
Partici pati o n at trial e ntr y a n d c o nti n ui n g i n vesti gati o nal t hera p y mi g ht c o nstit ute a safet y ris k . 
•  
Pre g na nc y or i nte nt t o bec o me pre g na nt. 
•  
I nitiati o n of alter nati ve a nti-ca ncer t hera p y i ncl u di n g a n ot her i n vesti gati o nal a ge nt . 
 
T here  is  n o  ma xi m u m  d urati o n  of treat me nt as  patie nts  ma y  c o nti n ue  t o  recei ve  i n vesti gati o nal 
pr o d uct be y o n d R E CI S T 1. 1/i R E CI S T defi ne d pr o gressi o n as l o n g as t he y are c o nti n ui n g t o s h o w 
cli nical  be nefit.  I n  s uc h  cases,  patie nts  ma y  c o nti n ue  t o  recei ve  treat me nt  f oll o wi n g  o bjecti ve 
pr o gressi o n at I n vesti gat or’s discreti o n a n d as a gree d wit h t he patie nt.  
 
7. 3 
C o nc o mita nt T hera p y  
 
Details  of  a n y  c o nc o mita nt  me dicati o ns  ( prescri pti o n,  n o n -prescri pti o n,  or  o ver -t he-c o u nter 
me dicati o ns) ta ke n b y t he patie nt at st u d y e ntr y a n d d uri n g pr ot oc ol t hera p y m ust be rec or de d o n 
t he a p pr o priate electr o nic case re p ort f or ms (e C R Fs). 
 
7. 3. 1 
Per mitte d  
•  
S u p p or ti ve care f or disease-relate d s y m pt o ms ma y be offere d t o all patie nts o n t he trial. 
•  
Patie nts  are  per mitte d  t o  use  t o pical,  oc ular,  i ntra -artic ular,  i ntra nasal,  a n d  i n halati o nal 
c ortic oster oi ds ( wit h mi ni mal s yste mic a bs or pti o n). P h ysi ol o gic re place me nt d oses of s yste mic 
c ortic oster oi ds are per mitte d, e ve n if >  1 0 m g/ da y pre d nis o ne e q ui vale nts. A brief c o urse of 
c ortic oster oi ds f or pr o p h yla xis (e. g. c o ntrast d ye aller g y) or f or treat me nt of n o n -a ut oi m m u ne 
c o n diti o ns (e. g. dela ye d -t y pe h y perse nsiti vit y reacti o n ca use d b y c o ntact aller ge n) is per mitte d. 
 
7. 3. 2 
N ot P er mitte d 
•  
I m m u n os u p pressi ve a ge nts (e xce pt t o treat a dr u g-relate d a d verse e ve nt) 
•  
S yste mic c ortic oster oi ds >  1 0 m g dail y pre d nis o ne e q ui vale nt (e xce pt as state d i n S ecti o n 7. 1 
a n d 7. 3. 1 t o treat a dr u g- relate d a d verse e ve nt). 
•  
A n y c o nc urre nt a nti ne o plastic t hera p y (i.e. c he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, 
ra diati o n t hera p y) e xce pt f or palliati ve ra diati o n t hera p y or sta n dar d or i n vesti gati o nal a ge nts 
f or treat me nt of ca ncer. 

 
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8. 0 
C RI T E RI A F O R M E A S U R E M E N T O F S T U D Y E N D P OI N T S  
 
8. 1 
Defi niti o ns  
 
8. 1. 1 
Ev al u a ble f or A dverse Eve nts  
 
All patie nts will be e val ua ble f or a d verse e ve nt e val uati o n fr o m t he ti me of t heir first treat me nt. 
 
8. 1. 2 
Ev al u a ble f or R es p o nse 
 
All patie nts w h o ha ve recei ve d at least o ne c ycle of t hera p y a n d ha ve t heir disease re -e val uate d will 
be  c o nsi dere d  e val ua ble  f or  res p o nse  (e xce pti o ns  will  be  t h ose  w h o  e x hi bit  o bj ecti ve  disease 
pr o gressi o n pri or t o t he e n d of c ycle 1 w h o will als o be c o nsi dere d e val ua ble). Patie nts o n t hera p y 
f or at least t his peri o d a n d w h o  meet t he ot her liste d criteria will ha ve t heir res p o nse classifie d 
acc or di n g t o t he defi niti o ns set o ut bel o w [ S ey m o ur 2 0 1 7]. 
 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he re vise d i nter nati o nal criteria 
( 1. 1) pr o p ose d b y t he R E CI S T ( Res p o nse E val uati o n Criteria i n S oli d T u m ors) c o m mittee as well 
as  t he  m o difie d  i R E CI S T  g ui deli nes [ S ey m o ur  2 0 1 7].  I n vesti gat ors  s h o ul d  n ote  t he  differe nt 
re q uire me nts f or c o nfir mat or y sca ns as well as f oll o w u p f or t he t w o criteria. 
 
8. 2  
Res p o nse a n d E val uati o n E n d p oi nts 
 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he re vise d i nter nati o nal criteria 
( 1. 1) pr o p ose d b y t he R E CI S T ( Res p o nse E val uati o n Criteria i n S oli d Tu m ors) c o m mittee as well 
as t he I m m u ne -Relate d m o difie d R E CI S T. I n vesti gat ors s h o ul d c o nti n ue treat me nt, as a p pr o priate, 
i n t he a bse nce of u nacce pta ble t o xicit y, u ntil u ne q ui v ocal disease pr o gressi o n. T his is partic ularl y 
i m p orta nt  f or  patie nts  i n  w h o m  pse u d o pr o gressi o n  ma y  ha ve  occ urre d.  F oll o w  u p  res p o nse 
assess me nts m ust be c o nti n ue d u ntil u ne q ui v ocal disease pr o gressi o n has occ urre d.  
 
8. 2. 1 
Me as ur a ble Dise ase  
 
Meas ura ble  t u m or  lesi o ns  ( n o dal,  s u bc uta ne o us,  l u n g  pare nc h y ma,  s oli d  or ga n  metastases)  are 
defi ne d as t h ose t hat ca n be acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter t o be 
rec or de d) as ≥ 2 0 m m wit h c hest x-ra y a n d as ≥ 1 0 m m wit h C T sca n or cli nical e xa mi nati o n. B o ne 
lesi o ns are c o nsi dere d meas ura ble o nl y if assesse d b y C T sca n a n d ha ve a n i de ntifia ble s oft tiss ue 
c o m p o ne nt t hat meets t hese re q uire me nts (s oft tiss ue c o m p o ne nt ≥ 1 0 m m b y C T sca n). M ali g n a nt 
ly m p h n o des m ust be ≥ 1 5 m m i n t he s h ort a xis t o be c o nsi dere d meas ura ble; o nl y t he s h ort a xis 
will  be  meas ure d  a n d  f oll o we d.  All  t u m or  meas ure me nts  m ust  be  rec or de d  i n  milli met ers  ( or 
deci mal  fracti o ns  of  ce nti mete rs).  Pre vi o usl y  irra diate d  lesi o ns  are  n ot  c o nsi dere d  meas ura ble 
u nless pr o gressi o n has bee n d oc u me nte d i n t he lesi o n. 
 
8. 2. 2 
N o n -me as ur a ble Dise ase  
 
All  ot her  lesi o ns  ( or  sites  of  disease),  i ncl u di n g  s mall  lesi o ns  are  c o nsi dere d  n o n -meas ura ble 
disease. B o ne lesi o ns wit h o ut a meas ura ble s oft tiss ue c o m p o ne nt, le pt o me ni n geal di sease, ascites, 
ple ural/ pericar dial  eff usi o ns,  l y m p ha n gitis  c utis/ p ul m o nis,  i nfla m mat or y  breast  disease, 
l y m p ha n gitic i n v ol ve me nt of l u n g or s ki n a n d a b d o mi nal masses f oll o we d b y cli nical e xa mi nati o n 
are  all  n o n -meas ura ble.  Lesi o ns  i n  pre vi o usl y  irra diate d  areas  are  n o n -me as ura ble,  u nless 
pr o gressi o n has bee n de m o nstrate d.  
 
 

 
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8. 2. 3 
T ar get Lesi o ns  
 
W he n m ore t ha n o ne meas ura ble t u m or lesi o n is prese nt at baseli ne all lesi o ns u p t o a m axi m u m of 
5 lesi o ns t ot al  (a n d a ma xi m u m of 2 lesi o ns per or g a n ) re prese ntati ve of all i n v ol ve d or ga ns s h o ul d 
be i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne. T ar get lesi o ns s h o ul d 
be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d  or ga ns,  b ut i n  a d diti o n  s h o ul d be  t h ose t hat  le n d  t he msel ves  t o re pr o d uci ble  re pe ate d 
me as ure me nts . N ote t hat pat h ol o gical n o des m ust meet t he criteri o n of a s h ort a xis of ≥ 1 5 m m b y 
C T  sca n  a n d  o nl y  t he s h ort a xis  of  t hese  n o des  will  c o ntri b ute  t o  t he  baseli ne  s u m. All  ot her 
pat h ol o gical n o des (t h ose wit h s h ort a xis ≥ 1 0 m m b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n -tar get 
lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-pat h ol o gical a n d s h o ul d n ot be 
rec or de d or f oll o we d (see 8 . 2. 4). At baseli ne, t he s u m of t he tar get lesi o ns (l o n gest dia meter of 
t u m or lesi o ns pl us s h ort a xis of l y m p h n o des: o verall ma xi m u m of 5) is t o be rec or de d. 
 
After  baseli ne,  a  val ue s h o ul d  be  pr o vi de d o n t he  C R F  f or  all  i de ntifie d  tar get lesi o ns f or  eac h 
assess me nt, e ve n if ver y s mall. If e xtre mel y s mall a n d fai nt lesi o ns ca n n ot be acc uratel y meas ure d 
b ut are dee me d t o be prese nt, a defa ult val ue of 5 m m  ma y be use d. If lesi o ns are t o o s mall t o 
meas ure a n d i n dee d are belie ve d t o be a bse nt, a defa ult val ue of 0 m m ma y be use d.  
 
8. 2. 4 
N o n -t ar get Lesi o ns 
 
All n o n -meas ura ble lesi o ns ( or sites of disease) pl us a n y meas ura ble lesi o ns o ver a n d a b o ve t h ose 
liste d as tar get lesi o ns are c o nsi dere d n o n-t ar get lesi o ns. Meas ure me nts are n ot re q uire d b ut t hese 
lesi o ns s h o ul d be n ote d at baseli ne an d s h o ul d be f oll o we d as “ prese nt” or “a bse nt”.  
 
8. 2. 5 
Res p o nse  
 
All patie nts will ha ve t heir B E S T R E S P O N S E fr o m t he start of st u d y treat me nt u ntil t he e n d of 
treat me nt classifie d as o utli ne d bel o w: 
 
C o m plete  Res p o nse  ( C R):  disa p peara nce  of t ar get a n d n o n-t ar get  lesi o ns  a n d  n or malizati o n  of 
t u m or mar kers.  Pat h ol o gical l y m p h n o des m ust ha ve s h ort a xis meas ures <  1 0 m m ( N ote : c o nti n ue 
t o rec or d t he meas ure me nt e ve n if < 1 0 m m a n d c o nsi dere d C R). Resi d ual lesi o ns ( ot her t ha n n o des 
< 1 0 m m)  t h o u g ht  t o  be  n o n- mali g na nt  s h o ul d  be  f urt her  i n vesti gate d  ( b y  c yt ol o g y  s pecialize d 
i ma gi n g or ot her tec h ni q ues as a p pr o priate f or i n di vi d ual cases [S ey m o ur 2 0 1 7 ]) bef ore C R ca n be 
acce pte d. C o nfir mati o n of res p o nse is o nl y re q uire d i n n o n-ra n d o mize d st u dies. 
 
Partial Res p o nse ( P R): at least a 3 0 % decrease i n t he s u m of meas ures (l o n gest dia meter f or t u m or 
lesi o ns a n d s h ort a xis meas ure f or n o des) of tar get lesi o ns, ta ki n g as refere nce t he baseli ne s u m of 
dia meters. N o n tar get lesi o ns m ust be n o n -P D. C o nfir mati o n of res p o nse is o nl y re q uire d i n n o n -
ra n d o mize d st u dies. 
 
Sta ble Disease ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o q ualif y 
f or P D ta ki n g as refere nce t he s mallest s u m of dia meters o n st u d y. 
 
 

 
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8. 3 
I m m u ne-Relate d Res p o nse Assess me nt  
 
O verall  res p o nse  will  als o  be  assesse d  usi n g  i R E CI S T [ S ey m o ur  2 0 1 7].  I m m u n ot hera pe utics ma y 
res ult i n i nfiltrati o n of i m m u ne cells lea di n g t o tra nsie nt i ncrease i n t he size i n mali g na nt lesi o ns, 
or u n detecta ble lesi o ns bec o mi n g detecta ble. T he criteria are i de ntical t o t h ose of R E CI S T 1. 1 i n 
ma n y res pects b ut ha ve bee n a da pte d t o acc o u nt f or  i nsta nces w here a n i ncrease i n t u m or b ur de n, 
or t he a p peara nce of ne w lesi o ns, d oes n ot reflect tr ue t u m or pr o gressi o n. 
 
Ke y differe nces are descri be d bel o w. All res p o nses defi ne d usi n g i R E CI S T criteria are desi g nate d 
wit h a prefi x. i R E CI S T ti me- p oi nt a n d best o verall res p o nses will be rec or de d se paratel y.  
 
C o nfir mi n g Pr o gressi o n  
 
U nli ke R E CI S T 1. 1, i R E CI S T re q uires t he c o nfir mati o n of pr o gressi o n a n d uses t he ter ms i U P D 
( u nc o nfir me d  pr o gressi o n)  a n d  i C P D  (c o nfir me d  pr o gressi o n).  C o nfir mat or y  sca ns  s h o ul d be 
perf or me d at least 4 wee ks, b ut n o l o n ger t ha n 8 wee ks after i U P D.  
 
i C P D is c o nfir me d if f urt her i ncrease i n t u m or b ur de n, c o m pare d t o t he last assess me nt, is see n as 
e vi de nce d b y o ne or m ore of t he f oll o wi n g:  
•  
C o nti n ue d i ncrease i n t u m or b ur de n (fr o m i U P D) w here R E CI S T 1. 1 defi niti o ns of pr o gressi o n 
ha d bee n met (fr o m na dir) i n tar get, n o n -tar get disease or ne w lesi o ns - Pr o gressi o n i n tar get 
disease w orse ns wit h a n i ncrease of at least 5 m m i n t he a bs ol ute val ue of t he s u m :  
- 
C o nti n ue d u ne q ui v ocal pr o g ressi o n i n n o n-tar get disease wit h a n i ncrease i n t u m or b ur de n  
- 
I ncrease i n size of pre vi o usl y i de ntifie d ne w lesi o n (s) (a n i ncrease of at least 5 m m i n t he 
a bs ol ute val ue of t he s u m of t h ose c o nsi dere d t o be tar get ne w lesi o ns) or a d diti o nal ne w 
lesi o ns. 
•  
R E CI S T  1. 1  criteria  are  met  i n  lesi o ns  t y pes  (tar get  or  n o n -tar get  or  ne w  lesi o ns)  w here 
pr o gressi o n was n ot pre vi o usl y i de ntifie d, i ncl u di n g t he a p peara nce of a d diti o nal ne w lesi o ns. 
 
If i U P D is n ot c o nfir me d at t he ne xt assess me nt, t he n t he a p pr o priate res p o nse will be assi g ne d 
(i U P D if t he criteria are still met, b ut n o w orse ni n g, or i S D, i P R or i C R if t h ose criteria are met 
c o m pare d t o baseli ne). As ca n be see n i n ta ble 2, t he pri or d oc u me ntati o n of i U P D d oes n ot precl u de 
assi g ni n g i C R, i P R, or i S D i n s u bse q ue nt ti me -p oi nt assess me nts or as best o verall res p o nse ( B O R) 
pr o vi di n g t hat i C P D is n ot d oc u me nte d at t he ne xt assess me nt after i U P D. 
 
Ne w Lesi o ns  
 
Ne w lesi o ns s h o ul d be assesse d a n d meas ure d as t he y a p pear usi n g R E CI S T 1. 1 criteria ( ma xi m u m 
of 5 le si o ns, n o m ore t ha n 2 per site, at least 1 0 m m i n l o n g a xis ( or 1 5 m m i n s h ort a xis f or n o dal 
lesi o ns),  a n d  rec or de d  as  Ne w  Lesi o ns-T ar get  ( N L T)  a n d  Ne w  Lesi o n -N o n -T ar get  ( N L N T)  t o 
all o w clear differe ntiati o n fr o m baseli ne tar get a n d n o n -tar get lesi o ns. 
 
N e w lesi o ns ma y eit her meet t he criteria of N L T or N L N T t o dri ve i U P D ( or i C P D). H o we ver, t he 
meas ure me nts of N L T s h o ul d N O T be i ncl u de d i n t he s u m of meas ures of ori gi nal tar get lesi o ns 
i de ntifie d at baseli ne. Rat her, t hese meas ure me nts will be c ollecte d o n a se parate ta ble i n t he case 
rec or d f or m. 
 
 

 
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P D is c o nfir me d i n t he Ne w Lesi o n cate g or y if t he ne xt i ma gi n g assess me nt, c o n d ucte d at least 4 
wee ks ( b ut n ot m ore t ha n 8 wee ks) after i U P D c o nfir ms f urt her pr o gressi o n fr o m i U P D wit h eit her 
a n  i ncrease  of  at least  5  m m  i n  t he  a bs ol ute  val ue  of  t he  s u m  of  N L T  O R  a n i ncrease  ( b ut  n ot 
necessaril y u ne q ui v ocal i ncrease) i n t he size of N L N T lesi o ns O R t he a p peara nce of a d diti o nal ne w 
lesi o ns. 
 
T a ble 2 : Ti me- p oi nt ( T P) i Res p o nse 
 
T ar get 
Lesi o ns *  
N o n -T ar get 
Lesi o ns *  
N e w 
Lesi o ns *  
Ti me P oi nt Res p o nse  
N o pri or 
i U P D * * 
Pri or i U P D * *; * * *  
i C R 
i C R 
N o  
i C R 
i C R 
i C R 
N o n -i C R/ N o n-
i U P D 
N o  
i P R 
i P R 
i P R 
N o n -i C R/ N o n-
i U P D 
N o  
i P R 
i P R 
i S D 
N o n -i C R/ N o n-
i U P D 
N o  
i S D 
i S D 
i U P D wit h 
n o c ha n ge 
O R decrease 
fr o m last T P 
i U P D wit h n o 
c ha n ge O R 
decrease fr o m 
last T P 
Yes  
N A  
N Ls c o nfir ms i C P D if N Ls were pre vi o usl y 
i de ntifie d a n d i ncrease i n size ( ≥5 m m i n S O M f or 
N L T or a n y i ncrease f or N L N T) or n u m ber. If n o 
c ha n ge i n N Ls (size or n u m ber) fr o m last T P, 
re mai ns i U P D 
i S D 
i U P D 
N o  
i U P D 
Re mai ns i U P D u nless i C P D c o nfir me d base d i n 
f urt her i ncrease i n size of N T disease ( nee d n ot meet 
R E CI S T 1. 1 criteria f or u ne q ui v ocal P D)  
i U P D 
N o n -i C R/ N o n-
i U P D 
N o  
i U P D 
Re mai ns i U P D u nless i C P D c o nfir me d base d o n:  
- f urt her i ncrease i n S O M of at l east 5 m m, 
ot her wise re mai ns i U P D  
i U P D 
i U P D 
N o  
i U P D 
Re mai ns i U P D u nless i C P D c o nfir me d base d o n 
f urt her i ncrease i n: 
- pre vi o usl y i de ntifie d T lesi o n i U P D S O M ≥5 m m 
a n d / or  
- N T lesi o n i U P D ( pri or assess me nt - nee d n ot be 
u ne q ui v ocal P D)  
i U P D 
i U P D 
Yes  
i U P D 
Re mai ns i U P D u nless i C P D c o nfir me d base d o n 
f urt her i ncrease i n: 
- pre vi o usl y i de ntifie d T lesi o n i U P D ≥5 m m a n d / 
or  
- pre vi o usl y i de ntifie d N T lesi o n i U P D ( nee d n ot 
be u ne q ui v ocal) a n d / or  
- size or n u m ber of ne w lesi o ns pre vi o usl y 
i de ntifie d 
N o n -
i U P D/ P D 
N o n -i U P D/ P D 
Yes  
i U P D 
Re mai ns i U P D u nless i C P D c o nfir me d base d o n  
- i ncrease i n size or n u m ber of ne w lesi o ns 
pre vi o usl y i de ntifie d  
*  
Usi n g R E CI S T 1. 1 pri n ci ples. If n o P S P D o cc urs, R E CI S T 1. 1 a n d i R E CI S T cate g ories f or C R, P R a n d S D w o ul d 
b e t h e sa me.  
* *  I n a n y lesi o n cate g or y. 
* * *  Pre vi o usl y i d e ntifie d i n assess me nt i m me diatel y pri or t o t his T P.  
 
 

 
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T a ble 3 : i R E CI S T Best O verall Res p o nse (i B O R) 
 
All  patie nts  will  ha ve  t heir  i B O R  fr o m  t he  start  of  st u d y  treat me nt  u ntil  t he  e n d  of  treat me nt 
classifie d as o utli ne d bel o w.  
 
T P R 1  
T P R 2  
T P R 3  
T P R 4  
T P R 5  
i B O R 
i C R 
i C R, i P R, 
i U P D, N E 
i C R, i P R, i U P D, 
N E  
i U P D 
i C P D 
i C R 
i U P D 
i P R, i S D, 
N E  
i C R 
i C R, i P R, i S D, 
i U P D, N E 
i C R, i P R, i S D, i U P D, i C P D, N E 
i C R 
i U P D 
i P R 
i P R, i S D, i U P D, 
N E  
i P R, i S D, i U P D, 
N E, i C P D  
i P R, i S D, i U P D, N E, i C P D 
i P R 
i U P D 
i S D, N E 
P R  
i P R, i S D, i U P D, 
N E  
i P R, i S D, i U P D, i C P D, N E 
i P R 
i U P D 
i S D 
i S D, i U P D, N E 
i S D, i U P D, i C P D, 
N E  
i S D, i U P D, I C P D, N E 
i S D 
i U P D 
i C P D 
A n yt hi n g  
A n yt hi n g  
A n yt hi n g  
i C P D 
i U P D 
i U P D 
i C P D 
A n yt hi n g  
A n yt hi n g  
i C P D 
i U P D 
N E  
N E  
N E  
N E  
i U P D 
•  
Ta ble ass u mes a ra n d o mize d st u d y w h ere c o nfir mati o n of C R or P R is n ot re q uire d.  
•  
N E = n ot e val u a ble t h at c ycle.  
•  
Desi g n ati o n “I” f or B O R ca n b e use d t o i n dicate pri or i U P D  t o ai d i n d ata i nter pretati o n. 
•  
F or p atie nts wit h n o n -tar get disease o nl y at b aseli n e, o nl y C R or n o n- C R/ n o n-P D ca n b e assi g n e d at eac h T P R 
b ut is n ot s h o w n i n t h e ta ble f or ease of prese ntati o n.  
 
8. 4  
Res p o nse D urati o n ( R E CI S T 1. 1 a n d i R E CI S T) 
 
Res p o nse d urati o n will be meas ure d fr o m t he ti me meas ure me nt criteria f or C R/ P R ( w hic he ver is 
first rec or de d) are first met u ntil t he first date t hat rec urre nt or pr o gressi ve disease is o bjecti vel y 
d oc u me nte d, ta ki n g as refere nce t he s mallest meas ure me nts rec or de d o n st u d y (i ncl u di n g baseli ne) . 
 
8. 5 
Sta ble Disease D urati o n  
 
Sta ble  disease  d urati o n  will  be  meas ure d  fr o m  t he  ti me  of ra n d o mizati o n u ntil  t he  criteria  f or 
pr o gressi o n are met, ta ki n g as refere nce t he s mallest s u m o n st u d y (i ncl u di n g baseli ne). 
 
8. 6 
Met h o ds of Meas ure me nt  
 
T he  sa me  met h o d  of  assess me nt  a n d  t he  sa me  tec h ni q ue  s h o ul d  be  use d  t o  c haracterize  eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p. Assess me nts s h o ul d be i de ntifie d 
o n a cale n dar sc he d ule a n d s h o ul d n ot be a ffecte d b y dela ys i n t hera p y. W hile o n st u d y, all lesi o ns 
rec or de d at baseli ne s h o ul d ha ve t heir act ual meas ure me nts rec or de d at eac h s u bse q ue nt e val uati o n, 
e ve n w he n ver y s mall (e. g. 2 m m). If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y 
disa p peare d, t he meas ure me nt s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt 
a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d. F or lesi o ns 
w hic h  fra g me nt/s plit  a d d  t o get her t he  l o n gest  dia meters of  t he  fra g me nte d  p orti o ns;  f or  lesi o ns 
w hic h c oalesce, meas ure t he ma xi mal l o n gest dia meter f or t he “ mer ge d lesi o n”.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
3 6  
C O N FI D E N TI A L  
8. 6. 1 
Cli nic al Lesi o ns  
 
Cli nical  lesi o ns  will  o nl y  be  c o nsi dere d  meas ura ble  w he n  t he y  are  s u perficial  a n d  ≥  1 0 m m  as 
assesse d usi n g cali pers (e. g. s ki n n o d ules). F or t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol o ur 
p h ot o gra p h y i ncl u di n g a r uler t o esti mate t he size of t he lesi o n is rec o m me n de d. If feasi ble, i ma gi n g 
is preferre d. 
 
8. 6. 2 
C hest X -r ay 
 
C hest C T is preferre d o ver c hest X -ra y, partic ularl y w he n pr o gressi o n is a n i m p orta nt e n d p oi nt, 
si nce C T is m ore se nsiti ve t ha n X-ra y, partic ularl y i n i de ntif yi n g ne w lesi o ns. H o we ver, lesi o ns ≥ 
2 0 m m o n c hest X -ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y defi ne d a n d s urr o u n de d b y 
aerate d l u n g. 
 
8. 6. 3 
C T, M RI  
 
C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns selecte d f or res p o nse 
assess me nt. T his  g ui deli ne  has  defi ne d  meas ura bilit y  of  lesi o ns  o n  C T  sca n  base d  o n  t he 
ass u m pti o n t hat C T slice t hic k ness is 5  m m or less. W he n C T sca ns ha ve slice t hic k ness greater 
t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. M RI is 
als o  acce pta ble  i n  certai n  sit uati o ns  (e. g.  f or  b o d y  sca ns).  Ot her  s pecialize d  i ma gi n g  or  ot her 
tec h ni q ues ma y als o be a p pr o priate f or i n di vi d ual case [Eise n h a u er 2 0 0 9 ]. F or e xa m ple, w hile P E T 
sca ns are n ot c o nsi dere d a de q uate t o meas ure lesi o ns, P E T-C T sca ns ma y be use d pr o vi di n g t hat 
t he meas ures are o btai ne d fr o m t he C T sca n a n d t he C T sca n is of i de ntica l dia g n ostic q ualit y t o a 
dia g n ostic C T ( wit h I V a n d oral c o ntrast).  
 
8. 6. 4 
Ultr as o u n d  
 
Ultras o u n d  is  n ot  usef ul  i n  assess me nt  of  lesi o n  size  a n d  s h o ul d  n ot  be  use d  as  a  met h o d  of 
meas ure me nt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n 
b y C T is a d vise d.  
 
8. 6. 5 
E n d osc o py, L a p ar osc o py  
 
T he utilizati o n of t hese tec h ni q ues f or o bj ecti ve t u m or e val uati o n is n ot a d vise d. H o we ver, t he y 
ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n bi o psies are o btai ne d or t o deter mi ne 
rela pse i n trials w here rec urre nce f oll o wi n g c o m plete res p o nse or s ur gical resecti o n is a n e n d p oi nt. 
 
8. 6. 6 
T u m or M arkers  
 
T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. If mar kers are i nitiall y 
a b o ve  t he  u p per  n or mal  li mit,  h o we ver,  t he y  m ust  n or malize  f or  a  patie nt  t o  be  c o nsi dere d  i n 
c o m plete res p o nse. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
3 7  
C O N FI D E N TI A L  
8. 6. 7 
Cyt ol o gy, Hist ol o gy  
 
T hese  tec h ni q ues  ca n  be  use d  t o  differe ntiate  bet wee n  P R  a n d  C R  i n  rare  cases  if  re q uire d  b y 
pr ot oc ol  (f or  e xa m ple,  resi d ual  lesi o ns  i n  t u m or  t y pes  s uc h  as  ger m  cell  t u m ors,  w here  k n o w n 
resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n t o be a p ote ntial a d verse effect of 
treat me nt  (e. g.  wit h  certai n  ta xa ne  c o m p o u n ds  or  a n gi o ge nesis  i n hi bit ors),  t he c yt ol o gical 
c o nfir mati o n of t he n e o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns d uri n g treat me nt w he n 
t he  meas ura ble  t u m or  has  met  criteria  f or  res p o nse  or  sta ble  disease  is  a d vise d  t o  differe ntiate 
bet wee n res p o nse or sta ble disease a n d pr o gressi ve disease.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
3 8  
C O N FI D E N TI A L  
9. 0 
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he N CI C o m m o n T er mi n ol o g y Criteria f or A d verse 
E ve nts  ( C T C A E)  will  be  utilize d  f or  A d verse  E ve nt  ( A E)  re p orti n g  ( versi o n  ca n  be  f o u n d  i n 
A p pe n di x I V) . All a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E. A c o p y 
of t he C T C A E ca n be d o w nl oa de d fr o m t he C T E P we b site: 
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns /ctc. ht m). 
 
All seri o us a d verse  e ve nts  ( S A E)  defi ne d  as  per  I C H  g ui deli nes  (see  bel o w)  a n d  ot her  a d verse 
e ve nts m ust be rec or de d o n case re p ort f or ms. I n a d diti o n, all “re p orta ble” seri o us a d verse e ve nts 
are s u bject t o e x pe dite d re p orti n g usi n g t he C C T G S A E f or m. T he ter m ‘re p orta ble S A E’ is use d 
i n t he defi niti o ns w hic h f oll o w t o descri be t h ose S A Es w hic h are s u bject t o e x pe dite d re p orti n g t o 
C C T G.  
 
9. 1 
Defi niti o n of a Re p orta ble Seri o us A d verse E ve nt  
 
•  
All seri o us a d verse e ve nts, w hic h are u ne x pecte d  a n d relate d t o pr ot oc ol treat me nt, occ urri n g 
d uri n g t he treat me nt peri o d a n d wit hi n 1 0 0  da ys after t he last pr ot oc ol treat me nt a d mi nistrati o n,  
m ust be re p orte d i n a n e x pe dite d ma n ner.  ( See Secti o n 9. 2 f or re p orti n g i nstr ucti o ns.) A n y late 
seri o us a d verse e ve nt occ urri n g after t his 1 0 0 da y peri o d w hic h is u ne x pecte d a n d relate d t o 
pr ot oc ol treat me nt m ust als o be re p orte d i n a n e x pe dite d ma n ner  (see Secti o n 9 . 2 f or re p orti n g 
i nstr ucti o ns). 
•  
U ne x pecte d a d verse e ve nts are t h ose w hic h are n ot c o nsiste nt i n eit her na t ure or se verit y wit h 
i nf or mati o n c o ntai ne d i n t he i n vesti gat or br oc h ure. 
•  
A d verse e ve nts c o nsi dere d relate d t o pr ot oc ol treat me nt are t h ose f or w hic h a relati o ns hi p t o 
t he pr ot oc ol a ge nt ca n n ot reas o na bl y be r ule d o ut.  
•  
A seri o us a d verse e ve nt ( S A E) is a n y  a d verse e ve nt t hat at a n y d ose:  
− 
res ults i n deat h 
− 
is life-t hreate ni n g 
− 
re q uires  i n patie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n  (e xcl u di n g 
h os pital  a d missi o ns  f or  st u d y  dr u g  a d mi nistrati o n,  tra nsf usi o nal  s u p p ort,  sc he d ule d 
electi ve s ur ger y a n d a d missi o ns f or palliati ve or ter mi nal care)  
− 
res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y 
− 
is a c o n ge nital a n o mal y/ birt h defect 
 
Me dical a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -
t hreate ni n g  or  res ult  i n  deat h  or  h os pitalizati o n  b ut  ma y  je o par dize  t he  patie nt  or  ma y  re q uire 
i nter ve nti o n t o pre ve nt o ne of t he e ve nts liste d a b o ve. 
 
9. 2  
Seri o us A d verse E ve nt Re p orti n g I nstr ucti o ns 
 
All re p orta ble seri o us a d verse e ve nts m ust be re p orte d usi n g a we b -base d Electr o nic Data Ca pt ure 
( E D C) s yste m bei n g use d f or t his trial. F or details a b o ut accessi n g t he E D C s yste m a n d c o m pleti n g 
t he o n-li ne S A E re p ort f or m, please refer t o t he C C T G Ge neric Data Ma na ge me nt G ui de b o o k f or 
E D C St u dies p oste d o n t he C RI -C C T G - 0 0 0 1 secti o n of t he C C T G we bsite (w w w.ct g. q uee ns u.ca ). 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
3 9  
C O N FI D E N TI A L  
Wit hi n 2 4 h o urs:   
C o m plete preli mi nar y  Seri o us A d verse E ve nt Re p ort a n d s u b mit t o C C T G 
via E D C s yste m.  
 
Wit hi n 7 da ys:   
U p date Seri o us  A d verse  E ve nt  Re p ort  as  m uc h  as  p ossi ble  a n d  s u b mit 
re p ort t o C C T G via E D C s yste m. 
 
E D C S A E we b a p plic ati o n i nterr u pti o n: 
I n t he rare e ve nt t hat i nter net c o n necti vit y t o t he E D C S A E s yste m is disr u pte d, please pri nt a n d 
c o m plete a pa per c o p y of t he S A E Re p ort, a vaila ble fr o m t he trial s pecific we bsite.  
 
F A X pa per S A E Re p ort t o:  
 
C RI -C C T G - 0 0 0 1 St u d y C o or di nat or 
Ca na dia n Ca ncer Trials Gr o u p  
Fa x N o.: 6 1 3- 5 3 3- 2 4 1 1 
 
Please use t he sa me ti meli nes f or s u b missi o n as f or direct E D C re p orti n g.  
 
O nce i nter net c o n necti vit y is rest ore d, t he i nf or mati o n t hat was F A X E D t o C C T G o n t he pa per 
S A E Re p ort m ust als o be e ntere d b y t he site i nt o t he E D C S A E we b a p plicati o n. 
 
L oc al i nter net i nterr u pti o n: 
If y o u are u na ble t o access t he E D C S A E s yste m, a n d c a n n ot access a pa per c o p y of t he S A E Re p ort 
fr o m t he trial we bsite, please p h o ne t he C RI -C C T G - 0 0 0 1 trial tea m ( 6 1 3- 5 3 3-6 4 3 0) t o o btai n a 
c o p y of t he S A E Re p ort b y F A X. O nce c o m plete d, t he re p ort m ust be F A X E D bac k t o C C T G as 
i n dicate d a b o ve. O nce i nter net c o n necti vit y is rest ore d, t he i nf or mati o n t hat was F A X E D t o C C T G 
o n t he pa per S A E Re p ort m ust als o be e ntere d b y t he site i nt o t he E D C S A E we b a p plicati o n. 
 
I n  cases  of  pr ol o n ge d i nter net  i nterr u pti o ns,  please  c o ntact  t he C C T G  Safet y  Des k  f or  f urt her 
i nstr ucti o ns ( 6 1 3- 5 3 3- 6 4 3 0). 
 
9. 3 
Ot her Pr ot oc ol Re p orta ble E ve nts – Pre g na nc y Re p orti n g a n d E x p os ure Re p orti n g 
 
9. 3. 1 
Pre g n a ncy Preve nti o n  
 
W o me n of C hil d beari n g P ote ntial ( W O C B P ) a n d males w h o are e nr olle d i n t he trial m ust ha ve 
a gree d t o use c o ntrace pti ve met h o d(s) as descri be d i n Eli gi bilit y Criteri o n 4. 2. 8 . I n vesti gat ors ma y 
wis h t o a d diti o nall y a d vise t he fe male part ners of male partici pa nts a b o ut pre g na nc y pre ve nti o n 
g ui deli nes w he n a p pr o priate a n d c o m plia nt wit h l ocal p olic y. 
 
9. 3. 2 
Pre g n a ncy Re p orti n g  
 
If a patie nt bec o mes pre g na nt d uri n g t he c o urse of t he st u d y, t he i n vesti gati o nal a ge nt s h o ul d be 
disc o nti n ue d i m me diatel y. 
 
Pre g na nc y itself - occ urri n g i n fe male par tici pa nts, a n d fe male part ners of male partici pa nts - is n ot 
re gar de d as a n A E u nless t here is a s us pici o n t hat t he I P u n der st u d y ma y ha ve i nterfere d wit h t he 
effecti ve ness  of  a  c o ntrace pti ve  me dicati o n.  T he  o utc o me  of  all  pre g na ncies  (s p o nta ne o us 
miscarr ia ge,  electi ve  ter mi nati o n,  ect o pic  pre g na nc y,  n or mal  birt h,  or  c o n ge nital  a b n or malit y) 
s h o ul d be f oll o we d u p a n d d oc u me nte d e ve n if t he patie nt was disc o nti n ue d fr o m t he st u d y. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 0  
C O N FI D E N TI A L  
T he i n vesti gat or is re q uire d t o re p ort t o C C T G a n y pre g na nc y occ urri n g i n fe male partici pa nts, a n d 
fe male part ners of male partici pa nts. Pre g na ncies occ urri n g u p t o 6 m o nt hs after t he last d ose of 
st u d y treat me nt a n d pre g na ncies i n fe male part ners of male partici pa nts occ urri n g u p t o 8 m o nt hs 
after t he last d ose of st u d y treat me nt  m ust als o be re p orte d. 
 
T he i n vesti gat or s h o ul d re p ort t he pre g na nc y wit hi n 2 4 h o urs of lear ni n g of t he pre g na nc y usi n g 
t he CC T G Pre g na nc y Re p orti n g F or m a vaila ble fr o m t he trial we b pa ge.  
 
O nce i nf or me d c o nse nt has bee n o btai ne d, t he f or m s h o ul d be u p date d t o pr o vi de f urt her pre g na nc y 
i nf or mati o n a n d t o reflect t he o utc o me of t he pre g na nc y. All f oll o w-u p re p orts m ust be s u b mitte d 
t o CC T G i n a ti mel y ma n ner. F or pre g na nt part ner of trial partici pa nt (a n d pre g na nt partici pa nts, if 
re q uire d b y l ocal p olic y), a c o p y of t he si g ne d si g nat ure pa ge of t he pre g na nc y f oll o w-u p c o nse nt 
m ust be s u b mitte d t o C C T G . 
 
D oc u me nts o utli ne d a b o ve (i ncl u di n g u p dates) m ust be se nt t o t he C C T G safet y des k ( 6 1 3 - 5 3 3-
2 8 1 2/ safet y- des k @ct g. q uee ns u.ca). 
 
If t he pre g na nc y res ults i n deat h (e. g. s p o nta ne o us a b orti o n, still birt h); is life-t hreate ni n g; re q uires 
i n patie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n;  res ults  i n  persiste nt  or 
si g nifica nt disa bilit y/i nca pacit y; is a c o n ge nital a n o mal y/ birt h defect, t he n a n S A E re p ort m ust be 
a d diti o nall y s u b mitte d as descri be d a b o ve. Please n ote, h os pitalizati o n f or la b o ur/ deli ver y al o ne 
d oes n ot c o nstit ute a n ‘i n patie nt h os pitalizati o n’ f or t he p ur p oses of pre g na nc y re p orti n g. 
 
9. 3. 3 
Ex p os ure Re p orti n g ( N o n-st u dy P artici p a nts)  
 
T he  i n vesti gat or  is  re q uire d  t o  re p ort  t o C C T G  a n y  i nci de nce  of  e x p os ure  t o  st u d y  a ge nt(s). 
E x p os ure is defi ne d as si g nifica nt, direct, c o ntact/i n halati o n/c o ns u m pti o n of a ge nt(s) b y n o n - st u d y 
partici pa nt (a n i n di vi d ual w h o is n ot ot her wise partici pati n g i n t his cli nical trial). A n e xa m ple of 
a n  e xp os ure  i ncl u des  a  n o n -st u d y  partici pa nt recei vi n g st u d y  me dicati o n.  T he  i n vesti gat or  is 
res p o nsi ble f or deter mi ni n g si g nifica nce, base d o n t he a ge nt t o w hic h t he i n di vi d ual is e x p ose d. 
 
T he i n vesti gat or s h o ul d re p ort t he e x p os ure i n a ti mel y ma n ner, wit hi n  2 4 h o urs of lear ni n g of t he 
e x p os ure usi n g t he C C T G E x p os ure Re p orti n g F or m a vaila ble fr o m t he trial we b pa ge. 
 
O nce i nf or me d c o nse nt has bee n o btai ne d, t he f or m s h o ul d be u p date d t o pr o vi de f urt her e x p os ure 
i nf or mati o n a n d t o reflect t he o utc o me of t he e xp os ure as t he i nf or mati o n bec o mes a vaila ble u p o n 
a p pr o priate f oll o w-u p of t he e x p ose d i n di vi d ual wit hi n 1 0 0 da ys of e x p os ure . All f oll o w-u p re p orts 
m ust be s u b mitte d t o C C T G i n a ti mel y ma n ner. A c o p y of t he si g ne d e x p os ure f oll o w- u p c o nse nt 
si g nat ure pa ge m ust als o be s u b mitte d t o C C T G . 
 
D oc u me nts o utli ne d a b o ve (i ncl u di n g u p dates) m ust be se nt t o t he C C T G safet y des k ( 6 1 3 - 5 3 3-
2 8 1 2/ safet y- des k @ct g. q uee ns u.ca). 
 
If t he e x p os ure res ults i n deat h; is life-t hreate ni n g; re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n 
of e xisti n g h os pitalizati o n; res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y; is a c o n ge nital 
a n o mal y/ birt h defect, t he n a n S A E re p ort m ust be a d diti o nall y s u b mitte d as descri be d a b o ve. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 1  
C O N FI D E N TI A L  
9. 4  
C C T G Res p o nsi bilit y f or Re p orti n g Seri o us A d verse E ve nts t o Healt h Ca na da  
 
T he C C T G will pr o vi de e x pe dite d re p orts of S A Es t o Healt h Ca na da ( Office of Cli nical Trials) f or 
t h ose  e ve nts  w hic h  meet  re g ulat or y  re q uire me nts  f or  e x pe dite d  re p orti n g,  i.e.  e ve nts  w hic h  are 
B O T H seri o us A N D u ne x pecte d  (as deter mi ne d b y refere nce t o t he I n vesti gat or Br oc h ure), A N D 
w hic h  are t h o u g ht  t o  be  relate d  t o  pr ot oc ol  treat me nt ( or  f or  w hic h  a  ca usal  relati o ns hi p  wit h 
pr ot oc ol treat me nt ca n n ot be r ule d o ut). 
 
9. 5  
C C T G Re p orti n g Res p o nsi bilit y t o Brist ol M yers S q ui b b 
 
Brist ol M yers S q ui b b  will be n otifie d of all re p orta ble seri o us a d verse e ve nts (as defi ne d i n Secti o n 
9. 1) wit hi n 4 w or ki n g  da y(s)  of  recei pt  of  re p ort  at  C C T G.  C C T G,  as  s p o ns or  will  deter mi ne 
re g ulat or y re p orta bilit y i n Ca na da. Brist ol M yers S q ui b b will be n otifie d of all pre g na ncies a n d 
o utc o mes wit hi n 4 w or ki n g da ys of recei pt of re p ort at C C T G . 
 
9. 6  
C C T G a n d Brist ol M yers S q ui b b Re p orti n g Res p o nsi bilities  
 
Brist ol M yers S q ui b b will re p ort all re g ulat or y re p orta ble seri o us a d verse e ve nts fr o m n o n -C C T G 
trials ( Safet y U p dates) wit h ni v ol u ma b a n d i pili m u ma b t o C C T G wit hi n 7 - 1 5 da ys . C C T G will 
re vie w t hese e ve nts t o deter mi ne w hic h meet t he criteria (seri o us, une x pecte d, dr u g relate d) f or 
re p orti n g t o C RI-C C T G -0 0 0 1 i n vesti gat ors. Brist ol M yers S q ui b b will re p ort t hese e ve nts t o Healt h 
Ca na da. I n a d diti o n Brist ol M yers S q ui b b will pr o vi de 6 m o nt hl y li ne listi n gs t o C C T G f or all ot her 
re p orts. 
 
9. 7  
Re p orti n g Safet y Re p orts t o I n vesti gat ors 
 
C C T G will n otif y I n vesti gat ors of all Safet y Re p orts ( Seri o us A d verse E ve nts ( S A Es) fr o m t his 
trial a n d Safet y U p dates ( S Us) fr o m ot her cli nical trials) t hat are re p orta ble t o re g ulat or y a ut h orities 
i n Ca na da as re p orte d t o t he C C T G. T his i ncl u des all seri o us e ve nts t hat are u ne x pecte d a n d relate d 
(i.e. p ossi bl y, pr o ba bl y, or defi nitel y) t o pr ot oc ol treat me nt. T he re p orts will be p oste d t o t he C C T G 
trial C RI -C C T G - 0 0 0 1 we b - base d safet y m o nit ori n g utilit y. 
 
I n vesti gat ors m ust n otif y t heir Researc h Et hics B oar ds /I nstit uti o nal Re vie w B oar ds (R E Bs/I R B s) 
of e ve nts w hic h i n v ol ve c orrecti ve acti o n(s) t o be ta ke n as a res ult of t he e ve nt(s) s uc h as pr ot oc ol 
a n d/ or i nf or me d c o nse nt c ha n ges. T he date of R E B/I R B  S u b missi o n f or  t hese S A Es a n d S Us will 
nee d t o be e ntere d i nt o t he C C T G trial C RI -C C T G - 0 0 0 1 we b base d safet y  m o nit ori n g utilit y a n d 
d oc u me ntati o n of R E B/I R B  s u b missi o n m ust be retai ne d i n t he st u d y bi n der o n site. T he R E B/I R B  
s u b missi o n te m plate pr o vi de d b y C C T G ca n be use d t o assist wit h trac ki n g, s u b missi o n, fili n g a n d 
m o nit ori n g. 
 
T he  s u b missi o n  of  e ve nts t o  y o ur  et hics  b oar d s h o ul d  be  d o ne  as  s o o n  as  p ossi ble ( we  s u g gest 
wit hi n 3 0 da ys). R E B/I R B  s u b missi o ns greater t ha n 9 0 da ys fr o m t he date of n otificati o n will be 
re gar de d as deli n q ue nt a n d a maj or deficie nc y will be assi g ne d. T hese safet y re p orts are t o be file d 
i n t he trial files o n site. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 2  
C O N FI D E N TI A L  
1 0. 0 
P R O T O C O L T R E A T M E N T DI S C O N TI N U A TI O N A N D T H E R A P Y A F T E R S T O P PI N G  
 
1 0. 1 
Criteria f or Disc o nti n ui n g Pr ot oc ol Treat me nt  
 
Patie nt s w h o are cli nicall y sta ble b ut meet t he criteria f or i U P D s h o ul d be c o nti n ue d o n treat me nt 
u ntil t he ne xt disease assess me nt at least 4 wee ks later. It is rec o m me n de d t hat t he ne xt i ma gi n g 
assess me nt  be  n o  l o n ger  t ha n  8  wee ks  later  i n  or der  t o  e ns ure  patie nts  re mai n  fit  f or  sal va ge 
t hera pies. Cli nical sta bilit y is defi ne d as:  
•  
Sta bilit y or i m pr o ve me nt i n perf or ma nce stat us.  
•  
N o cli nicall y rele va nt i ncrease i n disease relate d s y m pt o ms s uc h as pai n or d ys p nea ( ge nerall y 
u n derst o o d t o mea n a re q uire me nt f or i n crease d palliati ve i nter ve nti o n as bel o w).  
•  
N o re q uire me nt f or i ncrease d ma na ge me nt of disease relate d s y m pt o ms i ncl u di n g i ncrease d 
a nal gesia, ra diati o n or ot her palliati ve care . 
 
Patie nts ma y st o p pr ot oc ol treat me nt i n t he f oll o wi n g i nsta nces:  
•  
I nterc urre nt ill ness w hic h w o ul d, i n t he j u d ge me nt of t he i n vesti gat or, affect assess me nts of 
cli nical stat us t o a si g nifica nt de gree, a n d re q uire disc o nti n uati o n of pr ot oc ol t hera p y. 
•  
U nacce pta ble t o xicit y as defi ne d i n Secti o n 7. 0. 
•  
T u m or pr o gressi o n or disease rec urre nce as defi ne d i n Secti o n 8. 0. 
•  
Re q uest b y t he patie nt.  
 
Eff orts s h o ul d be ma de t o mai ntai n t he i n vesti gati o ns sc he d ule a n d c o nti n ue f oll o w -u p, e ve n if 
patie nts  disc o nti n ue  pr ot oc ol  treat me nt  pre mat urel y  a n d/ or  n o  l o n ger  atte n d  t he  partici pati n g 
i nstit uti o n. 
 
1 0. 2  
D urati o n of Pr ot oc ol Treat me nt  
(see Secti o n 8 . 0 f or res p o nse defi niti o n) 
•  
F or c o m plete res p o n ders , t hera p y will c o nti n ue u ntil pr o gressi o n (refer t o Secti o n 8. 2) 
•  
F or partial res p o n ders, t hera p y will c o nti n ue u ntil pr o gressi o n. 
•  
F or sta ble patie nts, t hera p y will c o nti n ue u ntil pr o gressi o n (refer t o Secti o n 7. 2). 
•  
Patie nts w h o pr o gress (treat me nt fail ure) will g o off st u d y at t he ti me u ne q ui v ocal pr o gressi o n 
is d oc u me nte d cli nicall y a n d/ or ra di o gra p hicall y. 
 
1 0. 3 
T hera p y After Pr ot oc ol Treat me nt is St o p pe d  
 
At t he discreti o n of t he i n vesti gat or.  
 
1 0. 4  
F oll o w- u p Off Pr ot oc ol Treat me nt 
 
All  patie nts  will  be  see n  at  4  wee ks  after  c o m pleti o n  of  pr ot oc ol t hera p y.  C o nti n ue d  f oll o w - u p 
re q uire d f or all patie nts e ver y 3 m o nt hs t o c ollect i nf or mati o n o n o n g oi n g t o xicities, late t o xicities 
(i ncl u di n g  sec o n d  mali g na ncies)  a n d  s ur vi val  data.  T his  f oll o w-u p  will  c o nti n ue  u ntil  deat h  or 
c o ncl usi o n of t he trial. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 3  
C O N FI D E N TI A L  
F or patie nts w h o g o off pr ot oc ol treat me nt wit h C R/i C R, P R/i P R, S D/i S D or i U P D o n g oi n g, t u m or 
assess me nts will be re q uire d e ver y 3 m o nt hs u ntil rela pse (see Secti o n 5. 0 f or i n vesti gati o ns t o be 
perf or me d). Please n ote f or patie nts w h o g o off pr ot oc ol treat me nt wit h i U P D, c o nfir mat or y sca ns 
s h o ul d be perf or me d at least 4 wee ks, b ut n o l o n ger 8 wee ks, after i U P D was d oc u me nte d.  
 
A Deat h re p ort will be re q uire d o n all patie nts. D ue wit hi n 2 wee ks of k n o wle d ge of deat h (see 
A p pe n di x I V- D oc u me ntati o n f or St u d y). 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 4  
C O N FI D E N TI A L  
1 1. 0 
C E N T R A L R E VI E W P R O C E D U R E S  
 
1 1. 1 
Ce ntral Ra di ol o g y Re vie w  
 
A s part of t he trial, c o pies of x- ra ys a n d/ or sca ns ma y be c ollecte d t o e val uate ca ncer res p o nse t o 
treat me nt. T here will be n o ce ntral ra di ol o g y re vie w f or t his st u d y. 
 
1 1. 2 
Ce ntral Pat h ol o g y Re vie w  
 
T here will be n o ce ntral pat h ol o g y re vie w f or t his st u d y. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 5  
C O N FI D E N TI A L  
1 2. 0 
C O R R E L A TI V E S T U DI E S  
 
A  detaile d  C orrelati ve  St u dies  Ma n ual  will  be  pr o vi de d  o n  t he C RI -C C T G - 0 0 0 1 trial  s pecific 
we bsite, w hic h will i ncl u de details re gar di n g sa m ple pre parati o n, ha n dli n g a n d s hi p pi n g.  
 
S peci me ns c ollecte d ma y be use d b y researc hers n o w or i n t he f ut ure t o better u n dersta n d t he nat ure 
of ca ncer a n d h o w patie nts res p o n d t o treat me nt. Sa m ples will be use d f or researc h p ur p oses o nl y 
a n d will n ot be s ol d. Patie nts will n ot be i de ntifie d b y na me. T he o nl y i de ntificati o n of tiss ue will 
be b y a patie nt st u d y n u m ber assi g ne d at t he ti me of ra n d o mizati o n t o t he trial t he s ur gical/ hist ol o g y 
n u m ber  a n d/ or  patie nt  i nitials.  Material  iss ue d  t o  researc hers  will  be  a n o n y mize d  a n d  o nl y 
i de ntifie d b y a c o de d n u m ber. 
 
T esti n g  f or  here ditar y  ge n etic  defects  pre dis p osi n g  t o  mali g na nt  disease  will  n ot  be  carrie d  o ut 
wit h o ut t he e x presse d c o nse nt of t he patie nt). 
 
All patie nts o n w h o m a dia g n ostic t u m or bl oc k is c ollecte d will be a ware of t his retrie val a n d will  
ha ve gi ve n t heir c o nse nt. 
 
Ge netic T esti n g  
 
I n t he c o urse of ge netic testi n g f or t his st u d y, t here is a c ha nce t hat “cli nicall y rele va nt i nci de ntal 
fi n di n gs” ma y occ ur; t hese refer t o u na ntici pate d disc o veries ma de i n t he c o urse of researc h b ut 
t hat are o utsi de of t he sc o pe of t he researc h [T C P S 2 2 0 1 4 ] bei n g c o n d ucte d. T hese fi n di n gs c o ul d be 
i n herite d c ha n ges t hat mi g ht pre dis p ose a pers o n t o partic ular ca ncers or ot her diseases, a n d ma y 
be passe d o n i n fa milies.  
 
T he  plas ma  cf D N A  testi n g  perf or me d  at  scree ni n g  a n d  o n -st u d y  will  be  d o ne  i n  a  Cli nical 
La b orat or y  I m pr o ve me nt  A me n d me nts  ( C LI A)  la b orat or y.  T he  pa nel  is  desi g ne d  t o  i de ntif y 
s o matic m utati o ns a n d is n ot i nte n de d t o detect t he prese nce or a bse nce of ger mli ne m utati o ns. 
W hile c o m m o n ger mli ne varia nts ha ve bee n re m o ve d, t he test ma y detect rare ger mli ne m utati o ns.  
 
D uri n g  t he  i nf or me d  c o nse nt  pr ocess,  partici pa nts  will  be  t ol d  a b o ut  t he  re m ote  p ossi bilit y  of 
cli nicall y  rele va nt  i nci de ntal  fi n di n gs  bei n g  disc o vere d,  a n d  gi ve n  t he  o p p ort u nit y  t o  ma ke 
i nf or me d c h oices a b o ut w het her t he y wis h t o recei ve t his i nf or mati o n.  
 
If  a  cli nicall y rele va nt  i nci de ntal  fi n di n g  is  disc o vere d  d uri n g  t he  testi n g  f or  t his  st u d y  a n d  a 
partici pa nt  c o nse nte d  t o  lear ni n g  a b o ut  t he  res ults . T hese  res ults  will  be  i ncl u de d  i n  t he  re p ort 
pr o vi de d directl y  t o t he st u d y QI/ AI. T he QI/ AI  at t he e nr olli n g i nstit uti o n will  be res p o nsi ble f or 
f oll o wi n g  l ocal  S O Ps  wit h  re gar d  t o  c o nfir mi n g  t he  res ult,  e ns uri n g  of  ge netic  c o u nseli n g  is 
a vaila ble, o btai ni n g R E B a p pr o val (if re q uire d) a n d c o ntacti n g t he st u d y partic i pa nt. 
 
Ger mli ne testi n g ma y be perf or me d o n n or mal tiss ue as part of sec o n dar y a n d e x pl orat or y a nal yses. 
T hese a nal yses will be perf or me d at st u d y c o m pleti o n i n t he c o nte xt of researc h i n a n o n -C LI A 
certifie d la b orat or y. T heref ore, t hese res ults will n ot be discl ose d t o t he patie nt.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 6  
C O N FI D E N TI A L  
1 2. 1  
Pr ot oc ol- Ma n date d C orrelati ve St u dies  
 
1 2. 1. 1 P O L E a n d P O L D 1 Scree ni n g – T u m or Tiss ue a n d Bl o o d S peci me n ( M a n d at ory f or All P atie nts) 
 
Patie nts m ust ha ve s oli d t u m ors t hat de m o nstrate P O L E  or P O L D 1  m utati o ns i de ntifie d at st u d y 
e ntr y via plas ma cf D N A  testi n g ( P G D x) or tiss ue testi n g f or P O L E a n d P O L D 1 m utati o ns (a n y 
C LI A -certifie d tiss ue assa y). 
•  
Patie nts e nr olle d o nt o t he st u d y via C LI A -certifie d tiss ue assa y m ust als o s u b mit plas ma f or 
cf D N A testi n g ( P G D x). 
•  
Patie nts e nr olle d o nt o t he st u d y via plas ma cf D N A testi n g ( P G D x) m ust ha ve tiss ue sa m ples 
a vaila ble (arc hi val or fres h) f or a nal ysis, eit her a t u m or bl oc k or t w o c ores a n d a mi ni m u m of 
2 0 sli des of 4 micr o n t hic k ness- less ca n be acce pte d if disc usse d wit h C C T G. Patie nts m ust be 
willi n g t o c o nse nt t o pr o visi o n of arc hi val tiss ue or fres h bi o ps y ( o pti o nal). 
 
Pre -treat me nt t u m or tiss ue  s peci me ns  t hat  ha ve  bee n  pre vi o usl y  teste d  f or  P O L E  a n d  P O L D 1 
m utati o n  testi n g  usi n g  c o m pre he nsi ve  ge n o mic  pr ofili n g  will  be  all o we d  f or  trial  e ntr y  a n d 
ra n d o mizati o n. All patie nts m ust si g n t he pre -scree ni n g c o nse nt pri or bl o o d sa m ples bei n g se nt. 
 
A ma n dat or y ce ntral testi n g f or plas ma cf D N A will be re q uire d f or t he pri mar y e n d p oi nt. As s uc h, 
t w o 1 0 ml t u bes of peri p heral w h ole bl o o d will be c ollecte d fr o m patie nts pri or t o ra n d o mizati o n 
a n d  se nt  f or  c irc ulati n g t u m or D N A  ( cf D N A) testi n g f or  i de ntificati o n of P O L E   a n d P O L D 1  
m utati o ns ( P G D x). All patie nts will ha ve P O L E  a n d P O L D 1  m utati o n testi n g ce ntrall y – patie nts 
ra n d o mize d o n t he basis of arc hi val t u m or testi n g will ha ve cf D N A testi n g of peri p heral w h ole 
bl o o d perf or me d retr os pecti vel y. 
 
Patie n ts w h o d o n ot ha ve P O L E/ P O L D 1 m utati o ns will n ot be eli gi ble. 
 
Dia g n ostic pat h ol o g y re p orts are recei ve d as part of t he s u p p orti n g d oc u me ntati o n re q uire d f or t his 
trial. A c o p y m ust be s u b mitte d at t he ti me of Baseli ne F ol der c o m pleti o n. 
 
Ple ase refer t o t he C RI-C C T G - 0 0 0 1 C orrel ative St u dies a n d Scree ni n g M a n u als f or det ails. 
 
1 2. 1. 2 T u m or Tiss ue C ollecti o n  
 
T he s u b missi o n  of  a  re prese ntati ve  bl oc k  of  t he  dia g n ostic  t u m or  tiss ue  is  ma n dat or y  f or 
partici pati o n i n t his trial . Re q uests f or t his tiss ue will n o t be iss ue d as t hese sa m ples are e x pecte d 
t o  be  s u b mitte d  u p o n  ra n d o mizati o n  f or all  patie nts. O ne  t u m or  bl oc k  a n d  o ne a dj ace nt  n or mal 
tiss ue bl oc k are re q ueste d fr o m a n y of t he bi o psies or resecti o ns of t he t u m or or s olitar y lesi o ns 
f oll o wi n g a n i nitial res p o nse or bi o ps y sa m ples c ollecte d u p o n pr o gressi o n. If n o pri mar y ca ncer 
bl oc ks are a vaila ble, o ne bl oc k of metastatic tiss ue ca n be se nt i nstea d . 
 
Bl oc ks  are  t he  preferre d  material t o  c ollect,  as  it is  well  k n o w n  t hat  tiss ue  materials (i ncl u di n g 
pr otei n a n d n ucleic aci d i nte grit y) o n u nstai ne d secti o ns deteri orate ra pi dl y wit hi n 3 -6 m o nt hs after 
pre parati o n.  T his  will  o pti mize  t he  a m o u nt  of  tiss ue  a vaila ble  t o  i n vesti gat ors  a n d  per mit  t he 
preser vati o n of t he bl oc k s u b mitte d. If, at a n y ti me, t he s u b mitti n g h os pital re q uires t he bl oc k t o be 
ret ur ne d f or me dical or le gal c o ncer ns, it will be ret ur ne d b y c o urier o n re q uest. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 7  
C O N FI D E N TI A L  
W here l ocal ce nt er re g ulati o ns pr o hi bit s u b missi o n of bl oc ks of t u m or tiss ue, t he a p pr o val of t he 
C C T G m ust be s o u g ht pri or t o ra n d o mi zati o n of t he first patie nt t o all o w c ores (t w o 2 m m c ores of 
t u m or fr o m t he bl oc k) or a mi ni m u m of 20 sli des c ut at 4 micr o ns o btai ne d fr o m c ore bi o ps y, p u nc h 
bi o ps y, e xcisi o nal bi o ps y or s ur gical s peci me n  t o be s u bstit ute d i n res p o nse t o t he Ce ntral T u m o r 
Ba n k re q uest. If 2 0 sli des are n ot p ossi ble, please c o ntact C C T G t o disc uss. 
 
Dia g n ostic  pat h ol o g y  a n d  ge n o mic  testi n g  re p orts  are  recei ve d  as  part  of  t he  s u p p orti n g 
d oc u me ntati o n  re q uire d  f or  t his  trial. Recei pt  of  t hese  will  i nitiate  a  re q uest  directl y  fr o m  t he 
Q uee n’s De part me nt of Pat h ol o g y t o pat h ol o g y de part me nts f or a re prese ntati ve t u m or bl oc k. 
 
Pla n ne d pri orit y assa ys o n t u m or tiss ue i ncl u de b ut are n ot li mite d t o:  
•  
P O L E a n d P O L D 1 m utati o ns,  
•  
W h ole- e x o me se q ue nci n g, 
•  
R N A se q ue nci n g. 
 
W here arc hi val tiss ue is n ot a vaila ble, patie nts will n ot be e xcl u de d  if pri or t u m or testi n g i de ntifie d 
P O L E or P O L D 1 m utati o n a n d a d diti o nal bl oc ks/sli des are n ot a vaila ble. 
 
1 2. 1. 3 Bl o o d C ollecti o n  
 
T he C C T G is i ntereste d i n e x pl ori n g t he use of s urr o gate tiss ues s uc h as bl o o d, ser u m a n d plas ma 
i n e val uati n g p ote ntial pr o g n ostic or pre dicti ve bi o mar kers, or as e vi de nce of p har mac o d y na mics 
effects. S o me of t he researc h bl o o d c ollecte d will be teste d f or t he f oll o wi n g:  
•  
T- cell s u bsets,  
•  
Peri p hera l Blo o d M o n o n uclear Cells ( P B M C s),  
•  
H L A t y pi n g.  
 
Detaile d i nstr ucti o ns f or ti me p oi nts, sa m ple ac q uisiti o n, pre parati o n, a n d s hi p pi n g are f o u n d i n t he 
C RI -C C T G - 0 0 0 1 C orrel ative St u dies M a n u al. 
 
1 2. 2 
O pti o nal Fres h T u m or Bi o ps y  
 
B a nki n g of T u m o r Tiss ue 
Ma n dat or y s u b missi o n  of t u m or tiss ue  has  bee n  descri be d  a b o ve.  T he  s u bse q ue nt  ba n ki n g  of 
c ollecte d dia g n ostic tiss ue is n ot ma n dat or y f or partici pati o n i n t he st u d y, b ut t he partici pati o n of 
all ce nt ers is str o n gl y e nc o ura ge d. Bl oc ks will be caref ull y ba n ke d as part of t he C C T G tiss ue/t u m or 
ba n k at Q uee n’s U ni versit y i n Ki n gst o n, O ntari o.  
 
Patie nts will be re q uire d t o si g n a n o pti o nal tiss ue c o nse nt. All patie nts w h o c o nse nt t o t he fres h 
t u m or  bi o ps y  will  ha ve  t he  bi o ps y  perf or me d  at  pr o gressi o n  at  t he  discreti o n  of  t he  treati n g 
i n vesti gat or if feasi ble. Patie nts w h o c o nse nt t o t his pr oce d ure b ut a fres h bi o ps y is n ot p ossi ble 
will n ot be e xcl u de d fr o m t he st u d y.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 8  
C O N FI D E N TI A L  
Pl a n ne d pri ority ass ays o n t u m or tiss ue i ncl u de b ut are n ot li mite d t o:  
•  
P O L E a n d P O L D 1 m utati o ns  
•  
W h ole- e x o me se q ue nci n g 
•  
R N A se q ue nci n g 
 
Pr o p osals t o use t he ba n ke d s peci me ns f or t he p ur p oses of assessi n g mar kers i n v ol ve d i n pre dicti n g 
treat me nt res p o nse a n d o utc o mes ma y be s u b mitte d t o t he ba n k. A scie ntific re vie w pr ocess of a n y 
pr o p osals t o use t he tiss ue will ta ke place a n d a n y pr o p osals a p pr o ve d will ha ve u n der g o ne et hics 
a p pr o val. 
 
1 2. 3 
Statistical A nal yses  
 
A variet y of fact ors t hat c o ul d p ote ntiall y pre dict cl i nical res p o nse t o ni v ol u ma b  a n d/ or ni v ol u ma b 
i n  c o m bi nati o n  wit h i pili m u ma b will  be  i n vesti gate d  i n  peri p heral  bl o o d  (ser u m,  plas ma,  a n d 
peri p heral bl o o d m o n o n uclear cells ( P B M C s)) a n d i n t u m or s peci me ns ta ke n fr o m all patie nts pri or 
t o  treat me nt,  o n  st u d y,  a n d  at  pr o gressi o n  a n d  as  o utli ne d  i n  Secti o n 5 . 0.  Data  fr o m  t hese 
i n vesti gati o ns  will  be  e val uate d  f or  ass ociati o ns  wit h  res p o nse,  s ur vi val  (o verall  s ur vi val , 
pr o gressi o n  free  s ur vi val )  a n d/ or  safet y  (a d verse  e ve nt)  data.  I n  a d diti o n,  a nal yses  of  mar kers 
bet wee n t he treat me nt ar ms will pr o vi de t he necessar y data t o i de ntif y a n d vali date bi o mar kers wit h 
pre dicti ve  vs  pr o g n ostic  val ue.  All  sa m ples  c ollecte d  ma y  als o  be  use d  f or  f ut ure  e x pl orat or y 
a nal yses  ( u nless  restricte d  b y  l ocal  re q uire me nts)  t o  assess  bi o mar kers  ass ociate d  wit h 
i m m u n ot hera p y treat me nt. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
4 9  
C O N FI D E N TI A L  
1 3. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 3. 1 
O bjecti ves a n d Desi g n  
 
T he  pri mar y  o bj ecti ve  f or  t his  ra n d o mize d  p hase  II  o pe n  la bel  a n d  n o n -c o m parati ve  trial  is  t o 
e val uate  efficac y  as  meas ure d  b y  o bjecti ve res p o nse  rate  ( O R R)  b y  R E CI S T  1. 1  of  ni v ol u ma b 
m o n ot hera p y a n d of ni v ol u ma b c o m bi ne d wit h i pili m u ma b i n ra n d o mize d patie nts wit h a d va nce d 
s oli d  t u m ors  wit h  detecta ble  P O L E  a n d  P O L D 1  m utati o ns  as  deter mi ne d  b y  plas ma  cf D N A. 
Sec o n dar y o bj ecti ves i ncl u de e val uati n g efficac y b y O R R of ni v ol u ma b ± i pili m u ma b, d urati o n of 
res p o nse  ( D O R),  safet y  a n d  t o xicit y  i n  patie nts  recei vi n g  ni v ol u ma b  ±  i pili m u ma b,  a n d  assess 
c orrelati o n  bet wee n  P O L E/ P O L D 1  m utati o ns  i n  t u m or  a n d  P O L E/ P O L D 1  m utati o ns  i n  bl o o d. 
Patie nts will be  stratifie d b y E C O G stat us ( 0 or 1) a n d n u m ber of pri or treat me nts ( 0, 1- 2, a n d ≥ 3), 
a n d ra n d o mize d i n 1: 1 rati o t o recei ve ni v ol u ma b al o ne or i n c o m bi nati o n wit h i pili m u ma b. T he 
st u d y will accr ue u p t o 5 0 eli gi ble a n d e val ua ble patie nts per treat me nt ar m ( 1 0 0 t otal). 
 
1 3. 2 
E n d p oi nts a n d A nal ysis  
 
T he pri mar y e n d p oi nt  is O R R b y R E CI S T 1. 1 i n i m m u n ot hera p y naï ve patie nts wit h a d va nce d s oli d 
t u m ors  wit h  detecta ble  m utati o ns  as  deter mi ne d  b y  ce ntral  bl o o d-base d  assa y  (cf D N A  f or 
P O L E/ D 1 m utati o ns) . Patie nts wi t h detecta ble m utati o ns i n tiss ue b ut wit h n o detecta ble m utati o ns 
base d o n plas ma cf D N A will be e xcl u de d fr o m t his a nal ysis.  
 
Res p o nse rates will  be re p orte d usi n g perce nta ges o ver all ra n d o mize d patie nts wit h 9 0 % e xact 
c o nfi de nce  i nter vals ( CI )  of  eac h  ar m  i n  a  n o n-c o m p arati ve  a nal ysis.  I n  a d diti o n,  e xact  l o gistic 
re gressi o n m o dels will be use d t o assess t he effect of treat me nt o n o bj ecti ve res p o nse pr o ba bilit y, 
a dj usti n g f or m utati o nal l oa d val ues a n d trial site. 
 
Sec o n dar y e n d p oi nts i ncl u de: O R R of ni v ol u ma b m o n ot hera p y a n d of ni v ol u ma b c o m bi ne d wit h 
i pili m u ma b  i n  all  treate d  patie nts.  Res p o nse  rates will  be  re p orte d  usi n g  perce nta ges  o ver  all 
patie nts w h o ha ve recei ve d at least o ne d ose of treat me nt wit h 9 0 % e xact  CI  of eac h ar m i n a n o n-
c o m parati ve a nal ysis. I n a d diti o n, e xact l o gistic re gressi o n m o dels will be use d t o assess t he effect 
of treat me nt o n o bjecti ve res p o nse pr o ba bilit y, a dj usti n g f or m utati o nal l oa d val ues a n d trial site. 
 
D urati o n  of  res p o nse  ( D O R)  will  be  calc ulate d  fr o m  ti me  of  res p o nse  t o  d oc u me ntati o n  of 
pr o gressi o n or deat h or ce ns ore d at last ti me of disease assess me nt a m o n g all patie nts w h o ha ve 
res p o n de d. Ka pla n-Meier met h o d will be use d t o esti mate me dia n d urati o n of res p o nse a n d 9 0 % 
c o nfi de nce i nter val i n eac h ar m.  
 
T he res p o nses assesse d b y i R E CI S T will be a nal yze d si milarl y as t hat b y R E CI S T 1. 1.  
 
T o  assess  t he  safet y  a n d  c haracterize  t o xicities  of ni v ol u ma b  c o m bi ne d  wit h i pili m u ma b  a n d 
ni v ol u ma b  m o n ot hera p y i n all patie nts ,  esti mati o n  of t he  a d verse  e ve nt  pr ofile  associate d  wit h 
treat me nt  will  be  perf or me d. All  t o xicities  re gar dless  of  attri b uti o n will  be  re p orte d  usi n g  t he 
C T C A E  versi o n 5 . 0 criteria.  Ad verse  e ve nts rates will be re p orte d usi n g  perce nta ges  wit h  9 0 % 
e xact CI . 
 
C orrelati o n bet wee n  detecta ble  m utati o ns  i n  t u m or  a n d  detecta ble  m utati o ns  i n  bl o o d  will  be 
assesse d b y Fisc her’s e xact test i n eac h ar m.  
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5 0  
C O N FI D E N TI A L  
Detecta ble m utati o ns i n t he i nitial st u d y p o p ulati o n are P O L E/ P O L D 1 m utati o ns base d o n plas ma 
cf D N A. 
 
P F S a n d O S of  ni v ol u ma b m o n ot hera p y a n d of ni v ol u ma b c o m bi ne d wit h i pili m u ma b i n patie nts 
wit h a d va nce d s oli d t u m ors wit h detecta ble m utati o ns as deter mi ne d b y plas ma cf D N A, a n d i n all 
treate d  patie nts  ( detecta ble  m utati o ns  i n  tiss ue  or  cf D N A)  will  be  e val uate d  as  e x pl orat or y 
e n d p oi nts. 
 
Ka pla n -Meier met h o d will be use d t o esti mate pr o ba bilities of O S a n d P F S f or eac h ar m. Patie nts 
ali ve at t he ti me of trial a nal ysis w ill be ce ns ore d as of t he date of t heir last disease assess me nt. 
Me dia ns a n d 9 0 % CI will be pr o vi de d, if a vaila ble. N o f or mal c o m paris o ns will be ma de bet wee n 
t he t w o ar ms. A dj uste d a nal yses will be als o c o nsi der m utati o nal l oa d as o ne of t he c o variates. 
 
T u m ors  will  u n der g o  w h ole  e x o me  a n d  R N A  se q ue nci n g  t o  e val uate  t he  ge netic  la n dsca pe  of 
m utate d t u m or s i n res p o n ders vers us n o n -res p o n ders t o i m m u ne c hec k p oi nt bl oc ka de. 
 
Detecta ble m utati o ns i n t he i nitial st u d y p o p ulati o n are P O L E/ P O L D 1 m utati o ns base d o n plas ma 
cf D N A. 
 
1 3. 3  
Sa m ple Size a n d D urati o n of St u d y 
 
A p pr o xi matel y 1 0 0 i m m u n ot hera p y- naï ve  patie nts wit h P O L E  or P O L D 1  m utati o ns i de ntifie d at 
st u d y  e ntr y  via  eit her  circ ulati n g t u m or D N A  ( cf D N A)  ce ntral  testi n g  or  pri or  l ocal t u m or 
assess me nt (t o  be  c o nfir me d  retr os pecti vel y i n  s uc h patie nts via  ce ntral cf D N A testi n g) will  be 
e nr olle d t o t his o pe n -la bel, ra n d o mize d, n o n-c o m parati ve trial. 
 
We h y p ot hesize t hat f or t his a nal ysis treat me nt wit h i m m u n ot hera p y will s h o w a cli nicall y rele va nt 
O R R of >  3 0 % wit h si n gle a ge nt ni v ol u ma b or >  5 0 % wit h c o m bi nati o n ni v ol u ma b + i pil i m u ma b 
i n patie nts wit h a d va nce d s oli d t u m ors wit h detecta ble P O L E or P O L D 1 m utati o ns. 
 
A sa m ple size of 5 0 e val ua ble patie nt s i n eac h ar m will ac hie ve 9 0 % p o wer t o s h o w a cli nicall y 
mea ni n gf ul O R R. T hese calc ulati o ns ass u me a si n gle a ge nt p 0 <  1 3 %, p 1 > 3 0 % a n d c o m bi nati o n 
t hera p y p 0 < 3 0 %, p 1 > 5 0 %. B ot h ass u me a t w o-si de d α  a n d β  of 0. 1 0. 
 
A d diti o nal e nr oll me nt of u p t o 2 0 % will be per mitte d as nee de d t o re place patie nts f o u n d t o n ot 
de m o nstrate P O L E or P O L D 1 m utati o ns o n ce ntral cf D N A. 
  
As  a d diti o nal  bl o o d- base d  assa ys  bec o me  a vaila ble,  t he  st u d y  ma y  be  a me n de d  t o  i ncl u de 
a d diti o nal c o h orts. 
 
Patie nts will be accr ue d fr o m a p pr o xi matel y f o ur ca ncer treat me nt ce nters i n t he U nite d States a n d 
f o ur ca ncer treat me nt ce nters acr oss Ca na da o ver a peri o d of a p pro xi matel y 2 4 m o nt hs. 
 
1 3. 4  
Safet y M o nit ori n g 
 
A d verse e ve nts will be m o nit ore d o n a n o n g oi n g basis b y t he ce ntral office a n d t heir fre q ue ncies 
re p orte d bi-a n n uall y at i n vesti gat ors’ meeti n gs.  
 
T he trial ma y be disc o nti n ue d if t he trial is ter mi nate d b y t he  data a n d safet y m o nit ori n g c o m mittee 
(if a p plica ble), t he F o o d a n d Dr u g A d mi nistrati o n ( F D A), or ot her re g ulat or y a ut h orities. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5 1  
C O N FI D E N TI A L  
A n y  u nf oresee n  deat hs  or  seri o us  a d verse  e ve nts  ma y,  after  a  disc ussi o n  bet wee n  t he  S p o ns or, 
pri nci pal i n vesti gat or a n d i n vest i gat ors at ot her sites, pr o m pt a n i nterr u pti o n t o trial accr ual pe n di n g 
a f ull i n vesti gati o n i nt o t he circ u msta nces s urr o u n di n g t he e ve nt.  
 
1 3. 5  
Scree ni n g M o nit ori n g 
 
T he esti mate d m utati o n rate i n t he scree ne d p o p ulati o n is 7 -1 5 % base d o n pri or p u blicati o ns. T he 
fre q ue nc y of P O L m utati o ns detecte d i n bl o o d will be assesse d after e ver y 5 0 patie nts scree ne d. If 
t he fre q ue nc y is < 5 %, t he scree ni n g a p pr oac h will be re vie w e d b y t he trial c o m mittee t o deter mi ne 
w het her m o dificati o ns t o t he pr ot oc ol are re q uire d t o i m pr o ve t he efficie nc y of scree ni n g b y, f or 
e xa m ple, tar geti n g s pecific t u m or hist ol o gies or ot her a p pr oac hes. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5 2  
C O N FI D E N TI A L  
1 4. 0 
P U B LI C A TI O N P O LI C Y 
 
1 4. 1  
A ut h ors hi p of Pa pers, Meeti n g A bstracts, Etc . 
 
1 4. 1. 1 T he res ults of t his st u d y will be p u blis he d. Pri or t o trial acti vati o n, t he c hair will deci de w het her t o 
p u blis h t he trial u n der a gr o u p title, or wit h na mi n g of i n di vi d ual a ut h ors. If t he latter a p pr oac h is 
ta ke n, t he f ollo wi n g r ules will a p pl y:  
•  
T he first a ut h or will  be base d o n o verall e nr oll me nt a n d scie ntific c o ntri b uti o n. 
•  
A  li mite d  n u m ber  of  t he  me m bers  of  t he Ca na dia n  Ca ncer  Trials  Gr o u p ,  Ca ncer  Researc h 
I nstit ute, B M S, P D G x a n d a d diti o nal i n vesti gat ors fr o m partici pati n g ce nters, ma y be cre dite d 
as a ut h ors de pe n di n g u p o n t heir le vel of i n v ol ve me nt i n t he st u d y. 
•  
A d diti o nal a ut h ors, u p t o a ma xi m u m of 1 5, will be t h ose w h o ha ve ma de t he m ost si g nifica nt 
c o ntri b uti o n t o t he o verall s uccess of t he st u d y. T his c o ntri b uti o n will be assesse d, i n part b ut 
n ot e ntirel y, i n ter ms of patie nts e nr olle d a n d will be re vie we d at t he e n d of t he trial b y t he 
st u d y c hair. 
 
1 4. 1. 2  I n a n a p pr o priate f o ot n ote, or at t he e n d of t he article, t he f oll o wi n g state me nt will be ma de: 
 
" A st u d y c o or di nate d b y t he Ca na dia n Ca ncer Trials Gr o u p. Partici pati n g 
i n vesti gat ors  i ncl u de d:  (a list  of  t he  i n di vi d uals  w h o  ha ve  c o ntri b ute d 
patie nts a n d t heir i nstit uti o ns)."  
 
1 4. 2  
Res p o nsi bilit y f or P u blicati o n 
 
It will be t he res p o nsi bilit y of t he S t u d y C hair t o  write u p t he res ults of t he st u d y wit hi n a reas o na ble 
ti me of its c o m pleti o n. If after a peri o d of si x m o nt hs f oll o wi n g st u d y cl os ure t he ma n uscri pt has 
n ot bee n s u b mitte d, t he ce ntral office reser ves t he ri g ht t o ma ke ot her arra n ge me nts t o e ns ure ti mel y 
p u blicati o n. 
 
Disse mi n ati o n of Tri al Res ults  
C C T G will i nf or m partici pati n g i n vesti gat ors of t he pri mar y p u blicati o n of t his trial. T he c o m plete 
j o ur nal refere nce a n d, if w here p u blicl y a vaila ble, t he direct li n k t o t he article will be p oste d o n t he 
Cli nical Trial Res ults p u blic site of t he C C T G we b s ite (htt p:// w w w.ct g. q u ee ns u.ca ). 
 
1 4. 3  
S u b missi o n of Material f or Prese ntati o n or P u blicati o n 
 
Material ma y n ot be s u b mitte d f or prese ntati o n or p u blicati o n wit h o ut pri or re vie w b y t he Ca ncer 
Researc h I nstit ute, C o l u m bia U ni versit y a n d, t he C C T G  Se ni or I n vesti gat or , Se ni or Bi ostatisticia n, 
St u d y  C o or di nat or,  a n d  a p pr o val  of  t he  St u d y  C hair.  I n di vi d ual  partici pati n g  ce nt ers  ma y  n ot 
prese nt o utc o me res ults fr o m t heir o w n ce nt ers se paratel y. S u p p orti n g gr o u ps a n d a ge ncies will be 
ac k n o wle d ge d. 

 
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C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5 3  
C O N FI D E N TI A L  
1 5. 0 
E T HI C A L, R E G U L A T O R Y A N D A D MI NI S T R A TI V E I S S U E S  
 
1 5. 1 
Re g ulat or y C o nsi derati o ns 
 
All  i nstit uti o ns  m ust  c o n d uct  t his  trial  i n  acc or da nce  wit h  I nter nati o nal  C o nfere nce  o n 
Har m o nizati o n- G o o d Cli nical Practice (I C H -G C P) G ui deli nes.  
 
T his trial is bei n g c o n d ucte d u n der a Cli nical Trial A p plicati o n ( C T A) wit h Healt h Ca na da. As a 
res ult,  t he  c o n d uct  of  t his  trial  m ust  c o m pl y  wit h  Di visi o n  5  of  t he  Ca na dia n  Re g ulati o ns 
Res pecti n g F o o d a n d Dr u gs ( F o o d a n d Dr u gs Act). 
 
T his  trial  is  bei n g  c o n d ucte d  u n der  a n  I N D  or  relate d  arra n ge me nt  i n  ot her  c o u ntries  a n d  all 
a p plica ble La ws, Re g ulati o ns a n d P olicies m ust be f oll o we d.  
 
1 5. 2 
I ncl usi vit y i n Researc h 
 
C C T G d oes n ot e xcl u de i n di vi d uals fr o m partici pati o n i n cli nical trials o n t he basis of attri b utes 
s uc h as c ult ure, reli gi o n, race, nati o nal or et h nic ori gi n, c ol o r, me ntal or p h ysical disa bilit y (e xce pt 
i nca pacit y),  se x ual  orie ntati o n,  se x/ ge n der,  occ u pati o n,  et h nicit y,  i nc o me,  or  cri mi nal  rec or d, 
u nless t here is a vali d reas o n (i.e. safet y) f or t he e xcl usi o n . 
 
I n acc or da nce wit h t he Declarati o n of Helsi n ki a n d t he Tri-C o u ncil P olic y State me nt ( T C P S), it is 
t he p olic y of C C T G t hat v ul nera ble pers o ns or gr o u ps will n ot be a ut o maticall y e xcl u de d fr o m a 
cli nical trial (e xce pt f or  i nc o m pete nt pers o ns) if partici pati o n i n t he trial ma y be nefit t he patie nt or 
a gr o u p t o w hic h t he pers o n bel o n gs. 
 
H o we ver,  e xtra  pr otecti o ns  ma y  be  necessar y  f or  v ul nera ble  pers o ns  or  gr o u ps.  It  is  t he 
res p o nsi bilit y  of  t he  l ocal  i n vesti gat or  a n d  researc h  et hics  b oar d  (R E B/I R B )  t o  e ns ure  t hat 
a p pr o priate  mec ha nis ms  are  i n  place  t o  pr otect  v ul nera ble  pers o ns/ gr o u ps.  I n  acc or da nce  wit h 
T C P S, researc hers a n d R E B/I R B s s h o ul d pr o vi de s pecial pr otecti o ns f or t h ose w h o are v ul nera ble 
t o a b use, e x pl oitati o n or discri mi nati o n. As v ul nera ble p o p ulati o ns ma y be s usce pti ble t o c oerci o n 
or u n d ue i nfl ue nce, it is es peciall y i m p orta nt t hat i nf or me d c o nse nt be o btai ne d a p pr o priatel y.  
 
Ce nt ers are e x pecte d t o e ns ure c o m plia nce wit h l ocal R E B/I R B  or i nstit uti o nal p olic y r e gar di n g 
partici pati o n of v ul nera ble pers o ns/ gr o u ps. F or e xa m ple, if a v ul nera ble pers o n/ gr o u p w o ul d be 
eli gi ble f or partici pati o n i n a C C T G cli nical trial u n der t his p olic y b ut e xcl u de d b y l ocal p olic y, it 
is e x pecte d t hat t he y w o ul d n ot be e nr olle d i n t he trial. U S sites s h o ul d f oll o w all a p plica ble p olicies 
a n d re g ulati o ns. It is t he ce nt er’s res p o nsi bilit y t o e ns ure c o m plia nce wit h all l ocal S O Ps. 
 
It  is C C T G’s  p olic y  t hat  pers o ns  w h o  ca n n ot  gi ve  i nf or me d  c o nse nt  (i.e.  me ntall y  i nc o m pete nt 
pers o ns, or t h ose p h ysicall y i nca pacitate d s uc h as c o mat ose pers o ns) are n ot t o be recr uite d i nt o 
C C T G  st u dies.  It  is  t he  res p o nsi bilit y  of  t he  l ocal  i n vesti gat or  t o  deter mi ne  t he  s u bject’s 
c o m pete nc y,  i n  acc or da nce  wit h  a p plica ble  l ocal  p olicies  a n d  i n  c o nj u ncti o n  wit h  t he  l ocal 
R E B/I R B  (if a p plica ble). 
 
 

 
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S u bj ects w h o were c o m pete nt at t he ti me of e nr ol lme nt i n t he cli nical trial b ut bec o me i nc o m pete nt 
d uri n g t heir partici pati o n d o n ot a ut o maticall y ha ve t o be re m o ve d fr o m t he st u d y. W he n re -c o nse nt 
of t he patie nt is r e q uire d, i n vesti gat ors m ust f oll o w a p plica ble l ocal p olicies w he n deter mi ni n g if it 
is  acce pta ble  f or  a  s u bstit ute  decisi o n  ma ker  t o  be  use d. C C T G  will  acce pt  re -c o nse nt  fr o m  a 
s u bstit ute decisi o n ma ker. If t his patie nt s u bse q ue ntl y re gai ns ca pacit y, t he patie nt s h o ul d be re -
c o nse nte d as a c o n diti o n of c o nti n ui n g partici pati o n . 
 
1 5. 3  
O btai ni n g I nf or me d C o nse nt 
 
It is e x pecte d t hat c o nse nt will be a p pr o priatel y o btai ne d f or eac h partici pa nt/ p ote ntial partici pa nt 
i n a C C T G trial, i n acc or da nce wit h I C H -G C P se cti o n 4. 8. T he ce nt er is res p o nsi ble f or e ns uri n g 
t hat all l ocal p olicies are f oll o we d. 
 
A d diti o nall y,  i n  acc or da nce  wit h  G C P  4. 8. 2, C C T G  ma y  re q uire  t hat  partici pa nts/ p ote ntial 
partici pa nts be i nf or me d of a n y ne w i nf or mati o n ma y i m pact a partici pa nt’s/ p ot e ntial partici pa nt’s 
willi n g ness t o partici pate i n t he st u d y . 
 
Base d  u p o n  a p plica ble  g ui deli nes  a n d  re g ulati o ns  ( Declarati o n  of  Helsi n ki,  I C H -G C P),  a 
partici pati n g i n vesti gat or (as defi ne d o n t he partici pa nts list) is ulti matel y res p o nsi ble, i n ter ms of 
lia bilit y a n d c o m plia nce, f or e ns uri n g i nf or me d c o nse nt has bee n a p pr o priatel y o btai ne d. C C T G 
rec o g nizes t hat i n ma n y ce nters ot her pers o n nel (as desi g nate d o n t he partici pa nts list) als o pla y a n 
i m p orta nt  r ole  i n  t his  pr ocess.  I n  acc or da nce  wit h  G C P  4. 8. 5, it  is  acce pta ble  f or  t he Q ualifie d  
I n vesti gat or t o dele gate t he res p o nsi bilit y f or c o n d ucti n g t he c o nse nt disc ussi o n. 
 
C C T G re q uires t hat eac h partici pa nt si g n a c o nse nt f or m pri or t o t heir e nr oll me nt i n t he st u d y t o 
d oc u me nt  his/ her  willi n g ness  t o  ta ke  part. C C T G  ma y  als o  re q uire,  as  i n dicate d  a b o ve,  t hat 
partici pa nts/ p ote ntial partici pa nts be i nf or me d of ne w i nf or mati o n i f it bec o mes a vaila ble d uri n g 
t he c o urse  of t he st u d y.  I n  c o nj u ncti o n  wit h  G C P  4. 8. 2,  t he  c o m m u nicati o n  of  t his i nf or mati o n 
s h o ul d be d oc u me nte d. 
 
C C T G all o ws t he use of tra nslat ors i n o btai ni n g i nf or me d c o nse nt. Pr o visi o n of tra nslat ors is t he 
res p o nsi bilit y of t he l ocal ce nter. Center s s h o ul d f oll o w a p plica ble l ocal p olicies w he n pr oc uri n g 
or usi n g a tra nslat or f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt t o partici pate i n a cli nical trial. 
 
I n acc or da nce wit h I C H-G C P 4. 8. 9, if a s u bject is u na ble t o rea d t he n i nf or me d c o nse nt ma y be 
o btai ne d b y ha vi n g t he c o nse nt f or m rea d a n d e x plai ne d t o t he s u bject. 
 
1 5. 3. 1 O bt ai ni n g C o nse nt f or Pre g n a ncy/ Ex p os ure Re p orti n g 
 
I nf or mati o n  fr o m  a n d/ or  a b o ut  t he  s u bject  (i.e.  t he  pre g na nt  fe male,  t he  ne w b or n  i nfa nt,  male 
part ner , e x p ose d i n di vi d ual) s h o ul d n ot be c ollecte d a b o ut or fr o m t he m u nless or u ntil t he y are a 
willi n g partici pa nt i n t he researc h. T he ri g hts a n d pr otecti o ns offere d t o partici pa nts i n researc h 
a p pl y a n d c o nse nt m ust be o btai ne d pri or t o c ollecti n g a n y i nf or mati o n a b o ut or fr o m t he m. If t he 
mai n c o nse nt f or m a de q uatel y a d dresses t he c ollecti o n of i nf or mati o n re gar di n g t he o utc o me of a 
pre g na nc y  of  a  trial  partici pa nt,  a  “ Pre g na nc y  F oll o w -u p  c o nse nt  f or m  will  n ot  be  re q uire d  b y 
C C T G.  
 
Trial -s pecific c o nse nt f or ms f or “ Pre g na nc y F oll o w-u p” a n d “ E x p os ure F oll o w -u p” ca n be f o u n d 
o n t he trial we b pa ge.  T he a p pr o priate c o nse nt f or m m ust be use d t o o btai n c o nse nt fr o m a n y n o n -
trial partici pa nt (s uc h as t he pre g na nt part ner or e x p ose d i n di vi d ual). 
 
 

 
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Partici pa nts  will  n ot  be  wit h dra w n  fr o m  t he  mai n  trial  as  a  res ult  of  ref usi n g  or  wit h dra wi n g 
per missi o n t o pr o vi de i nf or mati o n relate d t o t he pre g na nc y /e x p os ure. Si milarl y, male partici pa nts 
will n ot be wit h dra w n fr o m t he mai n st u d y s h o ul d t heir part ner ref use/ wit h dra w per missi o n. 
 
O bt ai ni n g C o nse nt f or Rese arc h o n C hil dre n  
 
I n  t he  case  of  c ollecti n g  i nf or mati o n  a b o ut  a  c hil d  (i.e.  t he  c hil d  res ulti n g  fr o m  a  pre g na nt 
partici pa nt/ part ner or a n e x p ose d c hil d), c o nse nt m ust be o btai ne d fr o m t he pare nt/ g uar dia n. 
 
F or re p orti n g a n e x p os ure, t he pare nt/ g uar dia n is re q uire d t o si g n a n “E x p os ure F oll o w- u p” c o nse nt 
f or m (e ve n if t he y are a partici pa nt i n t he mai n st u d y) pri or t o c ollecti n g i nf or mati o n a b o ut t he 
c hil d. 
 
1 5. 4 
Disc o nti n uati o n of t he Trial  
 
If t his trial is disc o nti n ue d f or a n y reas o n b y t he C C T G all ce nte rs will be n otifie d i n writi n g of t he 
disc o nti n ua nce  a n d  t he  reas o n(s)  w h y.  If  t he  reas o n(s)  f or  disc o nti n ua nce  i n v ol ve  a n y  p ote ntial 
ris ks t o t he healt h of patie nts partici pati n g o n t he trial or ot her pers o ns, t he C C T G will pr o vi de t his 
i nf or mati o n t o ce nters as well. 
 
If t his trial is disc o nti n ue d at a n y ti me b y t he ce nter ( pri or t o cl os ure of t he trial b y t he C C T G), it 
is t he res p o nsi bilit y of t he q ualifie d i n vesti gat or t o n otif y t he C C T G of t he disc o nti n uati o n a n d t he 
reas o n(s) w h y. 
 
W het her t he trial is disc o nti n ue d b y t he C C T G or l ocall y b y t he ce nte r, it is t he res p o nsi bilit y of 
t he q ualifie d  i n vesti gat or t o n otif y t he l ocal Researc h Et hics B oar d a n d all cli nical trials s u bjects of 
t he disc o nti n ua nce a n d a n y p ote ntial ris ks t o t he s u bjects or ot her pers o ns.  
 
1 5. 5 
Rete nti o n of Patie nt Rec or ds a n d St u d y Files  
 
All esse ntial d oc u me nts m ust be mai ntai ne d as per C. 0 5. 0 1 2 a n d i n acc or da nce wit h I C H- G C P . 
 
T he Q ualifie d  I n vesti gat or m ust e ns ure c o m plia nce wit h t he Re g ulati o ns a n d t he G C P G ui deli ne 
fr o m e ver y pers o n i n v ol ve d i n t he c o n d uct of t he cli nical trial at t he site. 
 
F or Ca na dia n ce nters e sse ntial d oc u me nts m ust be retai ne d f or 2 5 years f oll o wi n g t he c o m pleti o n 
of t he trial at t he ce nte r (2 5 years p ost fi nal a nal ysis, last data c ollecte d, or cl os ure n otificati o n t o 
R E B/I R B ,  w hic he ver  is  later),  or  u ntil  n otifie d  b y C C T G  t hat  d oc u me nts  n o  l o n ger  nee d  t o  be 
retai ne d. 
 
F or i nter nati o nal partici pati n g re gi o ns, l ocal re g ulat or y g ui da nce s h o ul d be f oll o we d wit h res pect 
t o d urati o n of rec or ds rete nti o n, u nless ot her wise c o ntract uall y dictate d. 
 
I n  acc or da nce  wit h  G C P  4. 9. 7,  u p o n  re q uest  b y  t he  m o nit or,  a u dit or, R E B/I R B  or  re g ulat or y 
a ut h orit y,  t he  i n vesti gat or/i nstit uti o n  m ust  ma ke  all  re q uire d  tr ial-relate d  rec or ds  a vaila ble  f or 
direct access . 
 
C C T G will i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n t he esse ntial d oc u me nts n o l o n ger nee d 
t o be retai ne d. 
 
 

 
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1 5. 6 
Ce ntre Perf or ma nce M o nit ori n g  
 
F or ms are t o be s u b mitte d acc or di n g t o t he sc he d ule i n t he pr ot oc ol. T here are mi ni m u m sta n dar ds 
f or perf or ma nce. 
 
T his st u d y is eli gi ble f or i ncl usi o n i n t he Ce ntr e Perf or ma nce I n de x ( C PI) . 
 
1 5. 7 
O n - Site M o nit ori n g/ A u diti n g 
 
C C T G site m o nit ori n g/a u diti n g will be c o n d ucte d at partici pati n g ce nt ers i n t he c o urse of t he st u d y 
as part of t he o verall q ualit y ass ura nce pr o gra m. T he m o nit ors/a u dit ors will re q uire access t o patie nt 
me dical rec or ds t o verif y t he data, as well as esse ntial d oc u me nts, sta n dar d o perati n g pr oce d ures 
(i ncl u di n g electr o nic i nf ormati o n), et hics a n d p har mac y d oc u me ntati o n (if a p plica ble). 
 
A s  t his  trial  is  c o n d ucte d  u n der  a  C T A  wit h  Healt h  Ca na da,  y o ur  site  ma y  be  s u bj ect  t o  a n 
i ns pecti o n b y t he Healt h Ca na da I ns pect orate. 
 
C RI a n d Bi o p har ma Part ners ha ve reser ve d t he ri g ht t o a u di t partici pati n g ce nters. A u dits ma y o nl y 
be c o n d ucte d after c o ns ultati o n wit h C C T G.  

 
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1 6. 0 
R E F E R E N C E S  
A gata, Y., et al., E x pressi o n of t he P D -1 a nti ge n o n t he s urface of sti m ulate d m o use T a n d B l y m p h oc ytes. I nt 
I m m u n ol, 1 9 9 6. 8( 5): p. 7 6 5- 7 2. 
Al berts o n, T. M., et al., D N A p ol y merase e psil o n a n d delta pr o ofrea di n g s u p press discrete m utat or a n d ca ncer 
p he n ot y pes i n mice. Pr oc Natl Aca d Sci U S A, 2 0 0 9. 1 0 6( 4 0): p. 1 7 1 0 1- 4. 
A n dre, T., et al., C o m bi nati o n of ni v ol u ma b ( ni v o) + i pili m u ma b (i pi) i n t he treat me nt o f patie nts ( pts) wit h 
deficie nt  D N A  mis matc h  re pair  ( d M M R)/ hi g h  micr osatellite  i nsta bilit y  ( M SI -H)  metastatic  c ol orectal  ca ncer 
( m C R C): C hec k Mate 1 4 2 st u d y. J o ur nal of Cli nical O nc ol o g y, 2 0 1 7. 3 5( 4-s u p pl): p. a bstr 3 5 3 1. 
A nt o nia S, G. S., C h o w L, Ni v ol u ma b a n d i pili m u ma b i n first -li ne N S C L C: i nteri m p hase I res ults. A merica n 
S ociet y of Cli nical O nc ol o g y A n n ual Meeti n g; 2 0 1 5; C hica g o, U S A. 
Atlas,  C. G.,  C o m pre he nsi ve  m olec ular  c haracterizati o n  of  h u ma n  c ol o n  a n d  rectal  ca ncer.  Nat ure,  2 0 1 2. 
4 8 7( 7 4 0 7): p. 3 3 0- 3 3 7. 
B or g haei, H., et al., Ni v ol u ma b vers us D oceta xel i n A d va nce d N o ns q ua m o us N o n – S mall -Cell  L u n g Ca ncer. 
Ne w E n gla n d J o ur nal of Me dici ne, 2 0 1 5. 3 7 3( 1 7): p. 1 6 2 7- 1 6 3 9. 
B o ur dais,  R.,  et  al.,  P ol y merase  pr o ofrea di n g  d o mai n  m utati o ns:  Ne w  o p p ort u nities  f or  i m m u n ot hera p y  i n 
h y per m utate d c ol orectal ca ncer be y o n d M M R deficie nc y. Crit Re v O nc ol He mat ol, 2 0 1 7. 1 1 3: p. 2 4 2- 2 4 8. 
Bra h mer, J. R., et al., P hase I st u d y of si n gle -a ge nt a nti-pr o gra m me d deat h -1 ( M D X -1 1 0 6) i n refract or y s oli d 
t u m ors: safet y, cli nical acti vit y, p har mac o d y na mics, a n d i m m u n ol o gic c orrelates. J Cli n O nc ol, 2 0 1 0. 2 8( 1 9): p. 
3 1 6 7- 7 5. 
Bra h mer, J., et al., Ni v ol u ma b vers us D oceta xel i n A d va nce d S q ua m o us -Cell N o n -S mall -Cell L u n g Ca ncer. N 
E n gl J Me d, 2 0 1 5. 3 7 3( 2): p. 1 2 3- 3 5. 
Bri g gs,  S.  a n d  I.  T o mli ns o n ,  Ger mli ne  a n d  s o matic  p ol y merase  ε  a n d  δ  m utati o ns  defi ne  a  ne w  class  of 
h y per m utate d c ol orectal a n d e n d o mest u d y ca ncers. J P at h ol., 2 0 1 3. 2 3 0. 
Ca na dia n  I nstit ute  of  Healt h  Researc h,  Nat ural  Scie nces  a n d  E n gi neeri n g  Researc h  C o u ncil  of  Ca na da,  a n d 
S ocial Scie nces a n d H u ma nities Researc h C o u ncil of Ca na da, Tri -C o u ncil P olic y State me nt: Et hical C o n d uct 
f or Researc h I n v ol vi n g H u ma ns, Dece m ber 2 0 1 4.  
Ca ncer  Ge n o me  Atlas,  N.,  I nte grate d  ge n o mic  c haracterizati o n  of  e n d o mest u d y  carci n o ma.  Nat ure,  2 0 1 3. 
4 9 7( 7 4 4 7): p. 6 7- 7 3. 
Castell ucci, E., et al., D N A P ol y merase vare psil o n Deficie nc y Lea di n g t o a n Ultra m utat or P he n ot y pe: A N o vel 
Cli nicall y Rele va nt E ntit y. O nc ol o gist, 2 0 1 7. 2 2( 5): p. 4 9 7- 5 0 2. 
C hal mers, Z. R., et al., A nal ysis of 1 0 0, 0 0 0 h u ma n ca ncer ge n o mes re veals t he la n dsca pe of t u m or m utati o nal 
b ur de n. Ge n o me Me dici ne, 2 0 1 7. 9( 1): p. 3 4. 
C he n,  D. S.  a n d  I.  Mell ma n,  Ele me nts  of  ca ncer  i m m u nit y  a n d  t he  ca ncer -i m m u ne  set  p oi nt.  Nat ure,  2 0 1 7. 
5 4 1( 7 6 3 7): p. 3 2 1- 3 3 0. 
Cr oft, M., L. M. Bra dle y, a n d S. L. S wai n, Nai ve vers us me m or y C D 4 T cell res p o nse t o a nti ge n. Me m or y cells 
are  less  de pe n de nt  o n  access or y  cell  c osti m ulati o n  a n d  ca n  res p o n d  t o  ma n y  a nti ge n -prese nti n g  cell  t y pes 
i ncl u di n g resti n g B cells. J I m m u n ol, 1 9 9 4. 1 5 2( 6): p. 2 6 7 5- 8 5. 
C urra n, M. A., et al., P D -1 a n d C T L A -4 c o m bi nati o n bl oc ka de e x pa n ds i nfiltrati n g T cells a n d re d uces re g ulat or y 
T a n d m yel oi d cells wit hi n B 1 6 mela n o ma t u m ors. Pr oc Natl Aca d Sci U S A, 2 0 1 0. 1 0 7( 9): p. 4 2 7 5- 8 0. 
De x hei mer, T. S., D N A Re pair Pat h wa ys a n d M ec ha nis ms, i n D N A Re pair of Ca ncer Ste m Cells, L. A. Mat he ws, 
S. M. Ca barcas, a n d E. M. H urt, E dit ors. 2 0 1 3, S pri n ger Net herla n ds: D or drec ht. p. 1 9 - 3 2. 
 
 

 
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5 8  
C O N FI D E N TI A L  
Di Giac o m o, A. M., et al., T hera pe utic efficac y of i pili m u ma b, a n a nti -C T L A -4 m o n ocl o nal a nti b o d y, i n pati e nts 
wit h metastatic mela n o ma u nres p o nsi ve t o pri or s yste mic treat me nts: cli nical a n d i m m u n ol o gical e vi de nce fr o m 
t hree patie nt cases. Ca ncer I m m u n ol o g y, I m m u n ot hera p y, 2 0 0 9. 5 8( 8): p. 1 2 9 7- 1 3 0 6. 
D o mi n g o, E., et al., S o matic P O L E pr o ofrea di n g d o mai n m utati o n, i m m u ne res p o nse, a n d pr o g n osis i n c ol orectal 
ca ncer: a retr os pecti ve, p o ole d bi o mar ker st u d y. T he La ncet Gastr oe nter ol o g y & He pat ol o g y, 2 0 1 6. 1( 3): p. 2 0 7 -
2 1 6. 
D o n g, H., et al., B 7 -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 Me d, 1 9 9 9. 5( 1 2): p. 1 3 6 5- 9. 
Eise n ha uer E, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, Da nce y J, Ar b uc k S, G w yt her S, M o o ne y 
M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pla n R, Lac o m be D, Ver weij J. Ne w res p o nse e va l uati o n criteria i n 
s oli d t u m ors: Re vise d R E CI S T g ui deli ne versi o n 1. 1. E ur J Ca n 4 5: 2 2 8- 4 7, 2 0 0 9. 
Hell ma n n,  M. D.,  et  al.,  Ni v ol u ma b  pl us  i pili m u ma b  as  first -li ne  treat me nt  f or  a d va nce d  n o n-s mall-cell  l u n g 
ca ncer  ( C hec k Mate  0 1 2):  res ults  of  a n  o pe n -la bel, p hase  1,  m ultic o h ort  st u d y.  T he  La ncet  O nc ol o g y,  2 0 1 7. 
1 8( 1): p. 3 1- 4 1. 
Hira n o,  F.,  et  al.,  Bl oc ka de  of  B 7 -H 1  a n d  P D -1  b y  m o n ocl o nal  a nti b o dies  p ote ntiates  ca ncer  t hera pe utic 
i m m u nit y. Ca ncer Res, 2 0 0 5. 6 5( 3): p. 1 0 8 9- 9 6. 
H o di, F. S., C yt ot o xic T-l y m p h oc yte- ass ociate d a nti ge n - 4. Cli n Ca ncer Res, 2 0 0 7. 1 3( 1 8 Pt 1): p. 5 2 3 8- 4 2. 
H o di,  F. S.,  et  al.,  I m pr o ve d  S ur vi val  wit h  I pili m u ma b  i n  P atie nts  wit h  Metastatic  Mela n o ma.  Ne w  E n gla n d 
J o ur nal of Me dici ne, 2 0 1 0. 3 6 3( 8): p. 7 1 1-7 2 3. R o bert, C., et al., I pili m u ma b pl u s d acar bazi ne f or pre vi o usl y 
u ntreate d metastatic mela n o ma. N E n gl J Me d, 2 0 1 1. 3 6 4( 2 6): p. 2 5 1 7- 2 6. 
H o ke y, D. A., et al., C L T A -4 bl oc ka de i n vi v o pr o m otes t he ge nerati o n of s h ort -li ve d effect or C D 8 T cells a n d 
a m ore persiste nt ce ntral me m or y C D 4 T cell re s p o nse. J Me d Pri mat ol, 2 0 0 8. 3 7 S u p pl 2: p. 6 2- 8. 
I wai,  Y.,  et  al.,  I n v ol ve me nt  of  P D-L 1  o n  t u m or  cells  i n  t he  esca pe  fr o m  h ost  i m m u ne  s yste m  a n d  t u m or 
i m m u n ot hera p y b y P D- L 1 bl oc ka de. Pr oc Natl Aca d Sci U S A, 2 0 0 2. 9 9( 1 9): p. 1 2 2 9 3- 7. 
K o nsta nti n o p o ul os, P. A.  a n d  U. A.  Mat ul o nis,  P O L E  m utati o ns  as  a n  alter nati ve  pat h wa y  f or  micr osatellite 
i nsta bilit y i n e n d o mest u d y c a ncer: I m plicati o ns f or L y nc h s y n dr o me testi n g. Ca ncer, 2 0 1 5. 1 2 1( 3): p. 3 3 1- 3 3 4. 
La n ge, S. S., K. Ta kata, a n d R. D. W o o d, D N A p ol y meras es a n d ca ncer. Nat Re v Ca ncer., 2 0 1 1. 1 1. 
Lar ki n, J., et al., C o m bi ne d Ni v ol u ma b a n d I pili m u ma b or M o n ot hera p y i n U ntreate d Mela n o ma. N E n gl J Me d, 
2 0 1 5. 3 7 3( 1): p. 2 3- 3 4. 
Le, D. T., et al., P D -1 Bl oc ka de i n T u m ors wit h Mis matc h -Re pair Deficie nc y. Ne w E n gla n d J o ur n al of Me dici ne, 
2 0 1 5. 3 7 2( 2 6): p. 2 5 0 9- 2 5 2 0. 
Le, D. T., et al., Mis matc h-re pair deficie nc y pre dicts res p o nse of s oli d t u m ors t o P D- 1 bl oc ka de. Scie nce, 2 0 1 7. 
L y nc h, T.J., et al., I pili m u ma b i n c o m bi nati o n wit h paclita xel a n d car b o plati n as first -li ne treat me nt i n sta ge 
III B/I V n o n-s mall-cell l u n g ca ncer: res ults fr o m a ra n d o mize d, d o u ble -bli n d, m ultice nter p hase II st u d y. J Cli n 
O nc ol, 2 0 1 2. 3 0( 1 7): p. 2 0 4 6- 5 4. 
Maza net, M. M. a n d C. C. W. H u g hes, B 7 -H 1 Is E x presse d b y H u ma n E n d ot helial Cells a n d S u p presses T Ce ll 
C yt o ki ne S y nt hesis. T he J o ur nal of I m m u n ol o g y, 2 0 0 2. 1 6 9( 7): p. 3 5 8 1- 3 5 8 8. 
Mc C ull oc h,  S. D.  a n d  T. A.  K u n kel,  T he  fi delit y  of  D N A  s y nt hesis  b y  e u kar y otic  r e plicati ve  a n d  tra nslesi o n 
s y nt hesis p ol y merases. Cell Res, 2 0 0 8. 1 8( 1): p. 1 4 8- 6 1. 
Me h nert, J. M., e t al., I m m u ne acti vati o n a n d res p o nse t o pe m br oliz u ma b i n P O L E-m uta nt e n d o mest u d y ca ncer. 
J Cli n I n vest, 2 0 1 6. 1 2 6( 6): p. 2 3 3 4- 4 0. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
5 9  
C O N FI D E N TI A L  
O ver ma n, M.J ., et al., Ni v ol u ma b i n patie nts wit h D N A mis matc h re pair deficie nt/ micr osatellite i nsta bilit y hi g h 
metastatic c ol orectal ca ncer: U p date fr o m C hec k Mate 1 4 2. J o ur nal of Cli nical O nc ol o g y, 2 0 1 7. 3 5( 4 _s u p pl): p. 
5 1 9- 5 1 9. 
P alles, C., et al., Ger mli ne m utati o ns  affecti n g t he pr o ofrea di n g d o mai ns of P O L E a n d P O L D 1 pre dis p ose t o 
c ol orectal a de n o mas a n d carci n o mas. Nat Ge net, 2 0 1 3. 4 5( 2): p. 1 3 6- 4 4. 
P at nai k  A,  S. M.,  G u be ns  M.,  P hase  I  st u d y  of  pe m br oliz u ma b  pl us  i pili m u ma b  as  sec o n d -li ne  t hera p y  f or 
a d va nce d N S C L C:  K E Y N O T E -0 2 1 c o h ort D. A merica n S ociet y of Cli nical O nc ol o g y A n n ual Meeti n g; 2 0 1 5; 
C hica g o, U S A. 
Ra y ner, E., et al., A pa n o pl y of err ors: p ol y merase pr o ofrea di n g d o mai n m utati o ns i n ca ncer. Nat Re v Ca ncer, 
2 0 1 6. 1 6( 2): p. 7 1- 8 1. 
Riz vi, N. A., et al., Ca ncer  i m m u n ol o g y. M utati o nal la n dsca pe deter mi nes se nsiti vit y t o P D-1 bl oc ka de i n n o n -
s mall cell l u n g ca ncer. Scie nce, 2 0 1 5. 3 4 8. 
Sc h u mac her, T. N. a n d R. D. Sc hrei ber, Ne oa nti ge ns i n ca ncer i m m u n ot hera p y. Scie nce, 2 0 1 5. 3 4 8( 6 2 3 0): p. 6 9 -
7 4. 
Se y m o ur  L,  B o gaerts  J,  P err o ne  A  et  al.  i R E CI S T:  G ui deli nes  f or  res p o nse  criteria  f or  use  i n  trials  testi n g 
i m m u n ot hera pe utics. La ncet O nc ol. 2 0 1 7; 1 8: 1 4 3- 5 2. 
S hlie n, A., et al., C o m bi ne d here ditar y a n d s o matic m utati o ns of re plicati o n err or re pair ge nes res ult i n ra pi d 
o nset o f ultra-h y per m utate d ca ncers. Nat Ge net, 2 0 1 5. 4 7( 3): p. 2 5 7 - 2 6 2. 
S n y der, A., et al., Ge netic basis f or cli nical res p o nse t o C T L A -4 bl oc ka de i n mela n o ma. N E n gl J Me d., 2 0 1 4. 
3 7 1. 
Str o me, S. E., et al., B 7 -H 1 bl oc ka de a u g me nts a d o pti ve T -cell i m m u n ot hera p y f or s q ua m o us cell carci n o ma. 
Ca ncer Res, 2 0 0 3. 6 3( 1 9): p. 6 5 0 1- 5. 
Sz n ol, M. a n d L. C he n, A nta g o nist a nti b o dies t o P D- 1 a n d B 7- H 1 ( P D - L 1) i n t he treat me nt of a d va nce d h u ma n 
ca ncer. Cli n Ca ncer Res, 2 0 1 3. 1 9( 5): p. 1 0 2 1- 3 4. 
va n  Elsas,  A.,  A. A.  H ur witz,  a n d  J . P.  Allis o n,  C o m bi nati o n  i m m u n ot hera p y  of  B 1 6  mela n o ma  usi n g  a nti-
c yt ot o xic T l y m p h oc yte -ass o ciate d a nti ge n 4 ( C T L A -4) a n d gra n ul oc yte/ macr o p ha ge c ol o n y -sti m ulati n g fact or 
( G M-C S F) -pr o d uci n g  vacci nes  i n d uces  rejecti o n  of  s u bc uta ne o us  a n d  metastatic  t u m ors acc o m pa nie d  b y 
a ut oi m m u ne de pi g me ntati o n. J E x p Me d, 1 9 9 9. 1 9 0( 3): p. 3 5 5- 6 6. 
We ber, J. S., et al., Safet y, efficac y, a n d bi o mar kers of ni v ol u ma b wit h vacci ne i n i pili m u ma b -refract or y or -
nai ve mela n o ma. J Cli n O nc ol, 2 0 1 3. 3 1( 3 4): p. 4 3 1 1- 8. 
W olc h o k, J. D., et al., Ni v ol u ma b pl us i pili m u ma b i n a d va nce d mela n o ma. N E n gl J Me d, 2 0 1 3. 3 6 9( 2): p. 1 2 2-
3 3. 
Ze hir,  A.,  et  al.,  M utati o nal  la n dsca pe  of  metastatic  ca ncer  re veale d  fr o m  pr os pecti ve  cli nical  se q ue nci n g  of 
1 0, 0 0 0 patie nts. Nat Me d, 2 0 1 7. a d va nce o nli ne p u b licati o n. 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 0  
C O N FI D E N TI A L  
A P P E N DI X I - P E R F O R M A N C E S T A T U S S C A L E S/ S C O R E S  
 
P E R F O R M A N C E S T A T U S C RI T E RI A  
K ar n ofsky a n d L a nsky p erf or m a nce sc ores are i nte n d e d t o b e m ulti ples of 1 0.  
E C O G ( Z u br o d)  
Kar n ofs k y  
La ns k y *  
Sc ore  
Descri pti o n  
Sc ore  
Descri pti o n  
Sc ore  
Descri pti o n  
0 
F ull y acti ve, a ble t o carr y o n all 
pre- disease p erf or ma n ce 
wit h o ut restricti o n.  
1 0 0  
N or mal, n o c o m plai nts, n o 
e vi d e n ce of disease.  
1 0 0  
F ull y acti ve, n or mal.  
9 0  
A ble t o carr y o n n or mal acti vit y; 
mi n or si g ns or s y m pt o ms of 
disease.  
9 0  
Mi n or restricti o ns i n p h ysic all y 
stre n u o us acti vit y. 
1 
Restricte d i n p h ysicall y 
stre n u o us acti vit y b ut 
a m b ulat or y a n d a ble t o carr y 
o ut w or k of a li g ht or se d e ntar y 
nat ure, e. g. li g ht h o use w or k, 
offi ce w or k.  
8 0  
N or mal acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease. 
8 0  
Acti ve, b ut tires m ore q uic kl y.  
7 0  
Cares f or self, u n a ble t o carr y o n 
n or mal acti vit y or d o acti ve w or k.  
7 0  
B ot h greater restricti o n of a n d 
less ti me s p e nt i n pla y acti vit y. 
2 
A m b ulat or y a n d ca p a ble of all 
selfcare b ut u n a ble t o carr y o ut 
a n y w or k a cti vities. U p a n d 
a b o ut m ore t h a n 5 0 % of wa ki n g 
h o urs.  
6 0  
Re q uires o ccasi o n al assista n ce, b ut 
is a ble t o care f or m ost of his/ h er 
n ee ds.  
6 0  
U p a n d ar o u n d, b ut mi ni mal 
acti ve pla y; ke e ps b us y wit h 
q uieter acti vities.  
5 0  
Re q uires c o nsi d era ble assista n ce 
a n d fre q u e nt me dical care.  
5 0  
Gets dress e d, b ut lies ar o u n d 
m u c h of t h e d a y; n o acti ve pla y; 
a ble t o p artici p ate i n all q uiet 
pla y a n d acti vities.  
3 
Ca pa ble of o nl y li mite d 
selfcare; c o nfi n e d t o b e d or 
c hair m ore t h a n 5 0 %  of wa ki n g 
h o urs.  
4 0  
Disa ble d, re q uires s p ecial care a n d 
assista n ce.  
4 0  
M ostl y i n b e d; p artici p ates i n 
q uiet acti vities.  
3 0  
Se verel y disa ble d, h os pitalizati o n 
i n dicate d. Deat h n ot i m mi n e nt. 
3 0  
I n b e d; n ee ds assista n ce e ve n f or 
q uiet pla y.  
4 
C o m pletel y disa ble d. Ca n n ot 
carr y o n a n y selfcar e. T otall y 
c o nfi ne d t o b e d or c h air.  
2 0  
V er y sic k, h os pitalizati o n 
i n dicate d. Deat h n ot i m mi n e nt. 
2 0  
Ofte n slee pi n g; pla y e ntirel y 
li mite d t o ver y p assi ve a cti vities. 
1 0  
M ori b u n d, fatal pr o cesses 
pr o gressi n g ra pi dl y.  
1 0  
N o pla y; d o es n ot get o ut of be d.  
* T h e c o n versi o n of t he La ns k y t o E C O G scales is i nte n de d f or N CI r e p orti n g p ur p oses o nl y.  
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 1  
C O N FI D E N TI A L  
A P P E N DI X II -  M A N A G E M E N T A L G O RI T H M S F O R E N D O C RI N O P A T H Y, 
G A S T R OI N T E S TI N A L, H E P A TI C, N E U R O L O GI C A L,  P U L M O N A R Y A N D S KI N 
A D V E R S E E V E N T S  
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 2  
C O N FI D E N TI A L  
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 3  
C O N FI D E N TI A L  
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 4  
C O N FI D E N TI A L  
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 5  
C O N FI D E N TI A L  
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 6  
C O N FI D E N TI A L  
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 7  
C O N FI D E N TI A L  
 
 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 8  
C O N FI D E N TI A L  
A P P E N DI X I II - D R U G DI S T RI B U TI O N, S U P P L Y A N D C O N T R O L 
 
Distri b uti o n  
 
Ni v ol u ma b a n d i pili m u ma b f or t he U S will be s u p plie d b y Brist ol M yers S q ui b b a n d distri b ute d directl y 
b y t he c o m pa n y t o partici pati n g A merica n ce nters. F or Ca na da, ni v ol u ma b a n d i pili m u ma b will be s u p plie d 
b y Brist ol M yers S q ui b b a n d distri b ute d b y a Ca na dia n de p ot directl y t o Ca na dia n ce nters. 
 
I n vesti gati o nal pr o d uct s h o ul d be store d i n a sec ure area acc or di n g t o l ocal re g ulati o ns a n d u n der t he st ora ge 
c o n diti o ns sti p ulate d o n t he i n vesti gati o nal pr o d uct la bel  
 
I niti al Dr u g S u p ply 
O nce a ce nter is l ocall y acti vate d (f oll o wi n g recei pt a n d re vie w of all re q uire d d oc u me ntati o n), C C T G  will 
a ut h orize a start -u p s u p pl y of ni v ol u ma b a n d i pili m u ma b t o be s hi p pe d directl y t o t he ce nter. Dr u g will be 
s hi p pe d t o t he ce nter wit hi n 1 0 w or ki n g da ys of l ocal acti vati o n.  
 
N ote: s hi p me nt will n ot  be ma de o n M o n da ys a n d wee ke n ds  f or A merica n sites an d t he y will n ot be ma de 
o n T h urs da ys, Fri da ys a n d wee ke n ds f or Ca na dia n sites. 
 
Dr u g acc o u nta bilit y a n d dr u g re - or der f or ms will be a vaila ble o n t he C RI-C C T G - 0 0 1 trial we bsite.  
 
Dr u g Or deri n g Res u p ply 
F or  re -s u p pl y  of ni v ol u ma b  a n d i pili m u ma b ,  sites s h o ul d  pri nt off  a n d  s u b mit a  Dr u g  Re-S u p pl y  F or m 
a vaila ble o n t he C RI -C C T G - 0 0 0 1 we bsite . T his f or m s h o ul d be s u b mitte d directl y t o t he distri b ut or. O nce 
recei ve d, Brist ol M yers S q ui b b a n d t he Ca na dia n dr u g ve n d or  will pr ocess t he re q uest a n d i nitiate s hi p me nt 
of re -s u p pl y. 
 
Please all o w s ufficie nt ti me f or s hi p me nt of dr u g ( u p t o 1 0 w or ki n g da ys). N ote: s hi p me nt will n ot  be ma de 
o n  M o n da ys a n d  wee ke n ds  f or  A merica n  sites  a n d  t he y  will n ot be  ma de  o n  T h urs da ys,  Fri da ys  a n d 
wee ke n ds f or Ca na dia n sites. 
 
Dr u g Acc o u nt a bility 
T he i n vesti gati o nal pr o d ucts are t o be prescri be d o nl y b y t he Q ualifie d I n vesti gat or or S u b -i n vesti gat ors 
ha vi n g t his dele gate d d ut y  o n t he partici pa nts list. U n der n o circ u msta nces will t he i n vesti gat or all o w t he 
dr u g t o be use d ot her t ha n as directe d b y t he pr ot oc ol. Acc urate rec or ds m ust be mai ntai ne d , acc o u nti n g f or 
t he  recei pt,  dis pe nsati o n,  ret ur n  a n d/ or  destr ucti o n of  t he  i n vesti gati o nal  pr o d uct utilizi n g  t he Dr u g 
Acc o u nta bilit y L o g, a vaila ble o n t he  C RI -C C T G - 0 0 0 1 trial we bsite. At t he e n d of t he st u d y, it m ust be 
p ossi ble t o rec o ncile s hi p me nt rec or ds wit h rec or ds of usa ge/ret ur ne d st oc k b y c o m pleti o n of t he st u d y dr u g 
acc o u nta bilit y f or m. A n y discre pa ncies m ust be acc o u nte d f or a n d d oc u me nte d.  
 
Dr u g Destr ucti o n  
 
Dr u g Destr ucti o n of Ex pire d Me dic ati o n  
T he C C T G St u d y C o or di nat or m ust be c o ntacte d pri or t o destr ucti o n of e x pire d me dicati o n t o e ns ure a n 
e xte nsi o n of e x pir y date is n ot e x pecte d. E x pire d trial me dicati o n ma y be destr o ye d per l ocal p olic y, A F T E R 
acc o u nta bilit y  a n d  rec o nciliati o n  has  bee n  c o m plete d  a n d  d oc u me nte d  b y  t he  site.  D oc u me ntati o n  of 
destr ucti o n m ust be ke pt o n file i n t he site p har mac y a n d is s u bject t o o n site m o nit ori n g/a u dit. 
 
 

 
P R O T O C O L D A T E:  2 0 1 8 -M A Y -3 0  
 
C RI -C C T G:  0 0 0 1  
 
C C T G:  I N D. 2 3 5 
 
 
C O N FI D E N TI A L 
6 9  
C O N FI D E N TI A L  
Dr u g Destr ucti o n of U n use d Me dic ati o n ( E n d of Tri al) 
I nstr ucti o ns f or ret ur n or destr ucti o n of u n use d dr u g will be s u p plie d at t he ti me of e x pir y a n d at trial cl os ure. 
 
* * P L E A S E N O T E * *  
D R U G F R O M T HI S S U P P L Y I S T O B E U S E D  
O N L Y F O R P A TI E N T S R E GI S T E R E D O N T HI S S T U D Y  
 
St u d y dr u g s hi p pe d t o partici pati n g ce nt ers ma y be tra nsferre d fr o m t he mai n h os pital p har mac y t o a satellite 
p har mac y, pr o vi de d se parate dr u g acc o u nta bilit y rec or ds are mai ntai ne d i n eac h p har mac y a n d a p pr o priate 
st ora ge is a vaila ble. I n vesti gati o nal a ge nt ma y N O T h o we ver, be tra nsferre d t o p har macies or p h ysicia ns 
o utsi de t he partici pati n g ce nt er. 

 
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7 0  
C O N FI D E N TI A L  
A P P E N DI X I V - D O C U M E N T A TI O N F O R  S T U D Y  
 
F oll o w- u p is re q uire d f or patie nts fr o m t he ti me of re gistrati o n a n d will a p pl y t o all eli gi ble a n d i neli gi ble 
patie nts. T his  trial  will  use  a  we b -base d  Electr o nic  Data  Ca pt ure  ( E D C)  s yste m  f or  all  data  c ollecti o n 
i ncl u di n g S A E re p orti n g (see Secti o n 9. 0 f or details re gar di n g S A E re p orti n g). F or details a b o ut accessi n g 
t he  E D C  s yste m  a n d  c o m pleti n g  t he  o n-li ne  Case  Re p ort  F or ms,  please  refer  t o  t he  Data  Ma na ge me nt 
G ui de b o o k p oste d o n t he C RI- C C T G -0 0 0 1 area of t he C C T G we b -site (w w w.ct g. q uee ns u.ca ). 
 
T he E L E C T R O NI C C R Fs t o be use d i n t his trial are: 
 
Electr o nic Case Re p ort F or m  
T o b e C o m plete d/ S u b mitte d Electr o nicall y:  
S u p p orti n g D o c u me ntat i o n t o be 
se nt usi n g S u p p orti n g D oc u me nt 
U pl o a d T o ol *  
P A TI E N T 
R E GI S T R A TI O N A N D 
E N R O L L M E N T  
At t he ti me of patie nt re gistrati o n a n d e nr oll me nt  
(see E N T R Y/ R E GI S T R A TI O N P R O C E D U R E S).  
C o p y of t he scree ni n g c o nse nt 
f or m si g nat ure pa ge, if e nr olle d 
base d o n P O L E/ P O L D 1 
m utati o n b y t u m or tiss ue 
testi ng, c o p y of re p ort wit h 
res ults, c o p y of re p ort fr o m 
plas ma cf D N A testi n g 
perf or me d at scree ni n g.  
B A S E LI N E R E P O R T  
D u e wit hi n 2  wee ks  of p atie nt re gistrati o n.  
C o pies of si g nat ure pa ges of 
mai n, a n d o pti o nal c o nse nt  
f or ms; rele va nt pat h ol o g y & 
ra di ol o g y re p orts. 
T R E A T M E N T R E P O R T  
T o b e c o m plete d e ver y 6  wee ks  (i.e. after ea c h c ycle). D u e 
wit hi n 2  wee ks  of e n d of c o urse. T his re p ort d o c u me nts 
treat me nt, a d verse e v e nts, i n vesti gati o ns a n d res p o nse 
assess me nt f or eac h c o urse.  
Rele va nt ra di ol o g y re p orts.  
C O R R E L A TI V E S T U DI E S  See Secti o n 1 2. 0 . 
 
E N D O F T R E A T M E N T 
R E P O R T  
T o b e c o m plete d w h e n p atie nt g oes off pr ot o c ol treat me nt. 
D u e wit hi n 2  wee ks  of e n d of pr ot o c ol treat me nt.  
 
4 W E E K P O S T 
T R E A T M E N T R E P O R T  
T o b e c o m plete d o n ce  o n all p atie nts, 4 wee ks after g oi n g 
off pr ot o c ol treat me nt. D u e wit hi n 2  wee ks  after c o ntact 
wit h p atie nt.  
Rele va nt ra di ol o g y re p orts.  
F O L L O W -U P R E P O R T  
F oll o w -u p Re p ort t o b e c o m plete d e ver y 3 m o nt hs  u ntil 
d eat h or c o n cl usi o n of trial . D u e wit hi n 2  wee ks  after 
c o ntact wit h p atie nt. 
Rele va nt ra di ol o g y re p orts.  
R E L A P S E/ 
P R O G R E S SI O N R E P O R T  
T o b e c o m plete d at t h e ti me of disease rela pse or 
pr o gressi o n. D u e wit hi n 2 wee ks  after c o ntact wit h p atie nt. 
Rele va nt ra di ol o g y re p orts.  
D E A T H R E P O R T * *  
Re q uire d f or all p atie nts w hile st u d y is o p e n. D u e wit hi n 
2  wee ks  of k n o wle d g e of d eat h.  
A ut o ps y r e p or t, if d o ne. 
S E RI O U S A D V E R S E 
E V E N T ( S A E) R E P O R T  
All re p orta ble seri o us a d verse e ve nts m ust b e re p orte d as 
d escri b e d i n Secti o n 9 . 0. Preli mi n ar y  C CT G Seri o us 
A d verse E ve nt Re p ort d u e wit hi n 2 4 h o urs. U p d ate d C C T G 
Seri o us A d verse E ve nt Re p ort d ue wit hi n 7 d a ys . 
All rele va nt test re p orts, 
a d missi o n, disc har ge 
s u m maries/ n otes a n d ot her 
d oc u me ntati o n, as re q ueste d.  
*  S o urce d oc u me nts ot h er t h a n t h ose liste d a b o ve ma y b e re q u este d  t o c o nfir m eli gi bilit y, c o m plia n ce, e n d p oi nts, a n d/ or 
seri o us a d verse e ve nts. S u p p orti n g d o c u me nts s h o ul d b e u pl o a d e d i m me diatel y after t h e re p ort t h e y refer t o h as b ee n 
s u b mitte d electr o nicall y. 
* *  N B  It is t he i n vesti gat or's res p o nsi bilit y t o i n vesti gate & re p ort t he date/ca use of deat h of a n y patie nt w h o dies d uri n g t his peri o d. 
A n y deat h t hat occ urs d uri n g t his pr ot oc ol t hera p y or wit hi n 3 0 da ys after last d ose m ust als o be re p orte d as a Seri o us A d ver se 
E ve nt as descri be d i n Secti o n 9. 0.  

 
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A P P E N DI X V - N CI C O M M O N T E R MI N O L O G Y C RI T E RI A F O R A D V E R S E E V E N T S  
 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he N CI C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E) versi o n 5. 0 will be utilize d f or A d verse E ve nt ( A E) re p orti n g . All a p pr o priate treat me nt areas 
s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 5 . 0. A c o p y of t he C T C A E versi o n 5. 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site: 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m . 
 
 
 

 
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7 2  
C O N FI D E N TI A L  
A P P E N DI X VI - T H E T N M C L A S SI FI C A TI O N O F M A LI G N A N T T U M O U R S  
 
T he 7t h E diti o n of t he T N M Classificati o n of Mali g na nt T u m o u rs has rece ntl y bee n release d. T o facilitate 
t his  pr ocess,  e d ucati o nal  res o urces  ha ve  bee n  ma de  a vaila ble  t o  pr o m ote  t he  use  of  sta gi n g  (visit  
htt p:// w w w.ca ncersta gi n g. or g ). T hese sta gi n g criteria s h o ul d be use d f or ne w trials. 
 

 
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C O N FI D E N TI A L  
Fi n al P a ge  
C O N FI D E N TI A L  
LI S T O F C O N T A C T S  
 
P A TI E N T R E GI S T R A TI O N  
All patie nts m ust  be re gistere d wit h C C T G bef ore  a n y treat me nt is gi ve n.  
 
 
 
C o ntact  
T el. #  
Fa x #  
P RI M A R Y C O N T A C T S F O R 
G E N E R A L P R O T O C O L -
R E L A T E D Q U E RI E S  
(i ncl u di n g eli gi bilit y q uesti o ns a n d 
pr ot oc ol ma na ge me nt)  
Caitli n B ur ns  
St u d y C o or di nat or, C C T G  
E mail:  
c b ur ns @ct g. q uee ns u.ca  
or  
Dr. J a net Da nce y  
Se ni or I n vesti gat or, C C T G  
E mail:  
j da nce y @ct g. q uee ns u.ca 
or  
Dr. Marti n S m ora gie wicz  
Se ni or I n vesti gat or, C C T G 
E mail:  
ms m ora gie wi cz @ct g. q uee ns u. ca  
6 1 3 -5 3 3 -6 4 3 0  
6 1 3 -5 3 3 -2 4 1 1  
S T U D Y C O -C H AI R S  
Dr. Nai yer Riz vi  
St u d y C hair  
E mail:  
nar 2 1 4 4 @c u mc.c ol u m bia.e d u  
6 4 6 -3 7 1 -3 1 4 1  
2 1 2 -3 0 5 -3 0 3 5  
or  
Dr. P atricia T a n g  
Ca na dia n C o -C hair  
E mail:  
patricia.ta n g @al berta healt hser vices.ca  
4 0 3 -5 2 1 -3 6 8 8  
4 0 3 -2 8 3 -1 6 5 1  
S E RI O U S A D V E R S E E V E N T 
R E P O R TI N G  
See pr ot oc ol Secti o n  9. 0 f or details 
of re p orta ble e ve nts.  
Dr. J a net Da nce y,  
Se ni or I n vesti gat or, C C T G  
or  
Dr. Marti n S m ora gie wicz,  
Se ni or I n vesti gat or, C C T G  
or  
Caitli n B ur ns  
St u d y C o or di nat or, C C T G  
6 1 3 -5 3 3 -6 4 3 0  
6 1 3 -5 3 3 -2 4 1 1  
D R U G O R D E RI N G  
See A p pe n di x III f or f ull details.  
See A p pe n di x III a n d trial we bsite  : 
htt ps:// w w w.ct g. q uee ns u.ca/tri als/i n d/i 2 3 5 -cri-cct g -0 0 0 1  
F or details a n d c o ntact i nf or mati o n  
E L E C T R O NI C D A T A C A P T U R E 
( E D C) A N D RI P P L E  
(tec h nical s u p p ort)  
C C T G H o me P a ge ( T o ol b o x):  
htt ps://sc o o b y.ct g. q uee ns u.ca  
E mail S u p p ort Staff at: s u p p ort @ct g. q uee ns u.ca