Clinical trial NCT03461952
Conditions: Advanced Solid Tumors
Sponsor: Canadian Cancer Trials Group
Start date: 2019-03-11; Completion date: 2022-02-09
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and effectiveness of nivolumab alone or in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA. Nivolumab and ipilimumab have been given to patients across multiple types of cancer, and safe doses and schedules have been determined.

Detailed description:
Participants in this study have been diagnosed with metastatic or unresectable solid tumors that have a mutation in POLE and/or POLD1. Nivolumab alone or in conjunction with ipilimumab is predicted to be effective against tumors with POLE and/or POLD1 mutations as these genetic changes cause increased rates of mutations in the DNA of tumor cells. These high mutation rates have been associated with response to immunotherapy agents such as nivolumab and ipilimumab.

Arms: arm 1: 240mg Q2W arm 2: Nivolumab 240mg Q2Wk + Ipilimumab 1mg/kg Q6W
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: 240mg intervention 2: 1mg/kg

Protocol documents:
Prot_SAP_001.pdf: 
 
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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.) 
 


 
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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 
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Sec o n dar y O bjecti ves  .............................................................................................................................. 3 
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E x pl orat or y O bjecti ves  ............................................................................................................................ 3 
 
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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 
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Ni v ol u ma b C o m bi ne d wit h I pili m u ma b.................................................................................................. 9  
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Trial Rati o nale  ....................................................................................................................................... 1 0 
 
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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  
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Ni v ol u ma b  ............................................................................................................................................. 1 1 
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I pili m u ma b ............................................................................................................................................ 1 3 
 
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S T U D Y P O P U L A TI O N  ....................................................................................................................... 1 5 
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I ncl usi o n Criteria ................................................................................................................................... 1 5 
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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 
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E xcl usi o n Criteria  .................................................................................................................................. 1 8 
 
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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 
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F oll o w - u p f or P atie nts ........................................................................................................................... 2 1 
 
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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 
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E ntr y Pr oce d ures ................................................................................................................................... 2 2  
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Stratificati o n  .......................................................................................................................................... 2 3 
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Re gistrati o n a n d Ra n d o mizati o n  ........................................................................................................... 2 3 
 
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T R E A T M E N T P L A N  ........................................................................................................................... 2 4 
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Treat me nt Pla n  ...................................................................................................................................... 2 4 
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D urati o n of T hera p y  .............................................................................................................................. 2 8 
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C o nc o mita nt T hera p y ............................................................................................................................ 2 9  
 
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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 
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Res p o nse a n d E val uati o n E n d p oi nts  ..................................................................................................... 3 0 
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I m m u ne-Relate d Res p o nse Assess me nt  ................................................................................................ 3 3 
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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  
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Sta ble Disease D urati o n  ........................................................................................................................ 3 5 
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Met h o ds of Meas ure me nt  ...................................................................................................................... 3 5 
 
 


 
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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 
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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  
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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  
 
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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 
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E n d p oi nts a n d A nal ysis  ......................................................................................................................... 4 9 
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Sa m ple Size a n d D urati o n of St u d y ...................................................................................................... 5 0  
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Safet y M o nit ori n g ................................................................................................................................. 5 0  
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Scree ni n g M o nit ori n g ............................................................................................................................ 5 1  
 
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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  
 
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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 
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O n -Site M o nit ori n g/ A u diti n g  ................................................................................................................ 5 6 
 
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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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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) 
 
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C E N T E R: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  


 
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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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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.  


 
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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 
4  
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]. 
 
 


 
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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 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 . 
 
 


 
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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 O N FI D E N TI A L 
1 7  
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.  
 
 


 
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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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•  
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.  




 
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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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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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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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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. 
 
 


 
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 5  
C O N FI D E N TI A L  
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 
 
 


 
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 6  
C O N FI D E N TI A L  
 
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. 
 
 


 
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 7  
C O N FI D E N TI A L  
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) 
 
 


 
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 8  
C O N FI D E N TI A L  
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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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 9  
C O N FI D E N TI A L  
•  
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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C O N FI D E N TI A L 
3 0  
C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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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C O N FI D E N TI A L  
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.  
 
 


 
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 5  
C O N FI D E N TI A L  
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 
 
 
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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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C C T G:  I N D. 2 3 5 
 
 
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C O N FI D E N TI A L  
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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C RI -C C T G:  0 0 0 1  
 
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5 5  
C O N FI D E N TI A L  
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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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  
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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C C T G:  I N D. 2 3 5 
 
 
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C O N FI D E N TI A L  
1 6. 0 
R E F E R E N C E S  
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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 
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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 
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E n gl J Me d, 2 0 1 5. 3 7 3( 2): p. 1 2 3- 3 5. 
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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. 
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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. 
 
 


 
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 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. 
 
 


 
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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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C O N FI D E N TI A L  
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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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