A Phase 2 Study Evaluating Futibatinib (TAS 120) Plus Pembrolizumab in the Treatment of Advanced or Metastatic Urothelial Carcinoma
Phase: PHASE2
Conditions: Advanced and Metastatic Urothelial Cancer
Sponsor: Taiho Oncology, Inc.

     Offi ci al Titl e:       A P h a s e 2 St u d y E v al u ati n g F uti b ati ni b ( T A S- 1 2 0) Pl u s  P e m br oli z u m a b i n 
t h e Tr e at m e nt of A d v a n c e d or M et a st ati c Ur ot h eli al C ar ci n o m a               
N C T I D:               N C T 0 4 6 0 1 8 5 7
D o c u m e nt D at e: Pr ot o c ol A m e n d m e nt V er si o n 1. 0: 1 0 J u n e 2 0 2 0

Cli nic al St u d y Pr ot oc o l
A P h ase 2 St u d y E v al u ati n g F uti b ati ni b ( T A S -1 2 0) Pl us 
Pe m br oliz u m a b i n t he Tre at me nt of A d v a nce d or Met ast atic 
Ur ot heli al C arci n o m a
F uti bati ni b ( T A S - 1 2 0)
Pr ot oc ol T A S - 1 2 0- 2 03
Ori gi nal Iss ue Date: 1 0 Marc h
2 0 2 0
A me n d me nt 1: 1 0 J u ne 2 0 2 0
I ND N u m ber: 1 4 6 7 8 4
E u dra C T N u m ber: 2 0 2 0- 0 0 0 9 4 5- 1 5
S p o ns or
Tai h o O nc ol o g y, I nc.
1 0 1 Car ne gie Ce nter, S uite 1 0 1
Pri ncet o n, NJ 0 8 5 4 0, U S A
T his cli nical st u d y will be c o n d ucte d i n acc or da nce wit h t he I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical 
Re q uire me nts f or P har mace uticals f or H u ma n Use (I C H), G o o d Cli nical Practice ( G C P) G ui deli nes a n d a p plica ble 
re g ulat or y re q uire me nts.
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is t he pr o pert y of Tai h o O nc ol o g y, I nc. ( T OI). T his d oc u me nt 
c o ntai ns strictl y c o nfi de ntial i nf or mati o n a n d n o part of t his d oc u me nt ma y be p u blis he d or discl ose d 
wit h o ut t he pri or writte n a p pr o val of T OI, e xce pt b y re q uest fr o m c o m pete nt a ut h orities.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
2
S U M M A R Y O F P R O T O C O L A M E N D M E N T S
T he ori gi nal pr ot oc ol f or St u d y  T A S- 1 2 0-2 0 3 was a p pr o ve d o n 1 0 Marc h 2 0 2 0; t his d o c u me nt is 
A me n d me nt 1, iss ue d 1 0 J u ne 2 0 2 0. T he ta ble bel o w s u m marizes s u bsta nti ve c ha n ges ma de i n 
t his a me n d me nt; all of t hese c ha n ges were ma de at t he re q uest of t he U S F o o d a n d Dr u g 
A d mi nistrati o n . In a d diti o n, mi n or e dit orial c ha n ges were ma de t hr o u g h o ut, i ncl u di n g u p dati n g 
of hea ders a n d f o oters, a dj ust me nt of f or matti n g, a n d c orrecti o n of t y p o gra p hical err ors.  
C h a n ge L oc ati o n a
Descri pti o n of C h a n ge
Secti o n 1. 2
Pe m br oliz u ma b
T he last para gra p h of t his secti o n was a me n de d as s h o w n:
Fi nall y, F G F R i n hi biti o n ma y als o m o d ulate t he t u m or
micr oe n vir o n me nt i n n o n -F G F R 3 -m utate d t u m ors t hr o u g h t he 
bl oc ka de of paracri ne fi br o blast gr o wt h fact ors ( F G F) si g nali n g, 
tar geti n g i m m u ne e vasi o n a n d a n gi o ge nesis a n d lea d t o e n ha nce d 
efficac y w he n c o m b i ne d wit h pe m br oliz u ma b i n b ot h wil d-t y pe 
( W T) a n d F G F R 3 -m utate d t u m ors ( Ic hi ka wa et al. 2 0 2 0; Li u et 
al. 2 0 1 4 ; Sief ker - Ra dt ke et al. 2 0 1 8).
Secti o n 4. 1
I ncl usi o n Criteri o n
T he f oll o wi n g te xt was a d de d t o i ncl usi o n criteri o n # 1:
F or patie nts w h o recei ve d pri or a dj u va nt/ ne oa dj u va nt 
c he m ot hera p y or c he m o -ra diati o n f or ur ot helial carci n o ma, a 
treat me nt-free i nter val > 1 2 m o nt hs bet wee n t he last treat me nt 
a d mi nistrati o n a n d t he date of rec urre nce is re q uire d i n or der t o 
be c o nsi dere d treat me nt -naï ve i n t he metastatic setti n g.
I ncl usi o n criteri o n # 2, ela b orati n g o n t he defi niti o n of “ u nfit f or or 
i nt olera nt t o sta n dar d plati n u m-base d c he m ot hera p y,” was a d de d.  
All re mai ni n g i ncl usi o n criteria were re n u m bere d acc or di n gl y.
Secti o n 5. 2
Defi niti o n of D ose -Li m iti n g 
T o xicit y
T w o as pects of t he D L T defi niti o n were a me n de d as f oll o ws; t he 
re mai n der of t he defi niti o n was n ot c ha n ge d:
 
Gra de 4 he mat ol o gic t o xicit y ne utr o pe nia lasti n g 7 > 5 da ys , 
e xce pt t hr o m b oc yt o pe nia
 
[ A n y Gra de 3 or Gra de 4 n o n he mat ol o gic la b orat or y val ue 
if] t he a b n or malit y persists f or > 1 wee k d oes n ot rec o ver t o 
Gra de ≤1 wit hi n 4 8 h o urs des pite best s u p p orti ve care .
Secti o n 6. 1
O p ht hal m ol o gical 
E xa mi nati o n
T he f oll o wi n g te xt was a d de d:
I n cases of reti nal pi g me nt e pit helial detac h me nt, e ve nts s h o ul d 
be m o nit ore d at 2 - t o 3- wee k i nter vals.
a.
A ll c ha n ges were als o i nc or p orate d i nt o t he st u d y s y n o psis as a p pr o priate.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
3
P R O T O C O L S Y N O P SI S
Pr ot oc ol Title: 
A P hase 2 St u d y E val uati n g F uti bati ni b ( T A S -1 2 0) Pl us Pe m br oliz u ma b i n t he Treat me nt of A d va nce d or 
Metastatic Ur ot helial Carci n o ma
R ati o n ale:
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o ns has bee n k n o w n f or deca des (Disis 2 0 1 0 ). Acc u m ulati n g e vi de nce s h o ws a c orrelati o n 
bet wee n t u m or -i nfiltrati n g l y m p h oc ytes i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n vari o us mali g na ncies. 
I n partic ular, t he prese nce of C D 8 + T-cells a n d t he rati o of C D 8 + effect or T -cells/ F o x P 3 + re g ulat or y 
T- cells ( T -re gs) c orrelates wit h i m pr o ve d pr o g n osis a n d l o n g-ter m s ur vi val i n s oli d mali g na ncies, s uc h as 
o varia n, c ol orectal, a n d pa ncreat ic ca ncer; he pat ocell ular carci n o ma; mali g na nt mela n o ma; a n d re nal cell 
carci n o ma.
T he pr o gra m me d deat h -li ga n d 1 ( P D-1) rece pt or -li ga n d i nteracti o n is a maj or pat h wa y t hat is hijac ke d b y 
t u m ors t o s u p press i m m u ne c o ntr ol. T he n or mal f u ncti o n of P D- 1, e x presse d o n t he cell s urface of 
acti vate d T -cells u n der healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or e xcessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns.
Pe m br oliz u ma b is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y ( m A b) wit h hi g h 
s pecificit y of bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D -1) rece pt or, t h us i n hi biti n g its i nteracti o n wit h 
pr o gra m me d cell deat h li ga n d 1 ( P D -L 1) a n d pr o gra m me d cell deat h li ga n d 2 ( P D -L 2) . Base d o n 
precli nical i n vitr o data, pe m br oliz u ma b has h i g h affi nit y a n d p ote nt rece pt or bl oc ki n g acti vit y f or P D 1. 
Pe m br oliz u ma b is i n dicate d f or t he treat me nt of patie nts acr oss a n u m ber of i n dicati o ns , a n d is ass ociate d 
wit h a n acce pta ble precli nical a n d cli nical safet y pr ofile as a n i ntra ve n o us (I. V.) i m m u n ot hera p y.
Pri or st u dies ha ve de m o nstrate d t hat fi br o blast gr o wt h fact or rece pt or 3 ( F G F R 3) -m uta nt ur ot helial 
carci n o mas ( U Cs) are ass ociate d wit h decrease d T-cell i nfiltrati o n. As F G F R 3 m utati o ns are e nric he d i n 
l u mi nal-li ke U C, a n d l u mi nal-li ke U C has been s h o w n t o be relati vel y less res p o nsi ve t o P D -1/ P D -L 1 
i n hi biti o n (c hec k p oi nt i n hi biti o n [ C PI]), t hese data ha ve le d t o t he s pec ulati o n t hat F G F R 3 m utati o ns ma y 
be ca usall y relate d t o p o or T -cell i nfiltrati o n a n d t hat U C patie nts har b ori n g F G F R 3 m utati o ns ma y be 
s u b o pti mal ca n di dates f or C PI s uc h as pe m br oliz u ma b.
H o we ver, Wa n g et al. ( 2 0 1 8 ) deter mi ne d t hat w hile F G F R 3 -m uta nt U C is ass ociate d wit h a si milar t u m or 
m utati o nal b ur de n a n d l o wer T -cell i nfiltrati o n, it is als o ass ociate d wit h l o wer str o mal tra nsf or mi n g 
gr o wt h fact or beta ( T G F -b) i m m u ne s u p pressi ve si g nals. T hese fi n di n gs s u g gest t hat F G F R 3 m utati o n 
stat us ma y n ot i n fact be a bi o mar ker of resista nce t o C PI, a n d pr o vi des a rati o nale f or t he c o m bi nati o n of 
F G F R -tar gete d treat me nt wit h C PI treat me nt.
M ore o ver, rece ntl y p u blis he d data ( Pala k urt hi et al. 2 0 1 9 ) s h o w t hat F G F R i n hi biti o n a n d a nti-P D - 1 
c o m bi nati o n i n d uce d si g nifica nt t u m or re gressi o n a n d i m pr o ve d s ur vi val. F or b ot h er dafiti ni b 
m o n ot hera p y a n d c o m bi nati o n treat me nts, t u m or c o ntr ol was acc o m pa nie d b y t u m or -i ntri nsic F G F R 
pat h wa y i n hi biti o n, i ncrease d T -cell i nfiltrati o n, decrease d re g ulat or y T cells, a n d d o w nre g ulati o n of 
P D -L 1 e x pressi o n o n t u m or cells. Fi nall y, F G F R i n hi biti o n ma y als o m o d ulate t he t u m or 

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
4
micr oe n v ir o n ment i n n o n -F G F R 3 -m utate d t u m ors t hr o u g h t he bl oc ka de of paracri ne fi br o blast gr o wt h 
fact ors ( F G F) si g nali n g, tar geti n g i m m u ne e vasi o n a n d a n gi o ge nesis a n d lea d t o e n ha nce d efficac y w he n 
c o m bi ne d wit h pe m br oliz u ma b i n b ot h wil d -t y pe ( W T) a n d F G F R 3 -m utate d t u m ors ( Ic hi ka wa et al. 
2 0 2 0 ; Li u et al. 2 0 1 4 ; Sief k er-Ra dt ke et al. 2 0 1 8 ).
St u d y O bjecti ves:
Pri mar y
 
T o e val uate t he o bjecti ve res p o nse rate ( O R R) of f uti bati ni b i n c o m bi nati o n wit h pe m br oliz u ma b 
i n patie nts wit h a d va nce d or metastatic U C w h o are n ot ca n di dates t o recei ve a plati n u m -base d 
treat me nt re gi me n.
Sec o n dar y
 
T o assess t he safet y of f uti bati ni b i n c o m bi nati o n wit h pe m br oliz u ma b.
 
T o e val uate t he disease c o ntr ol rate ( D C R), d urati o n of res p o nse ( D O R), pr o gressi o n -free 
s ur vi val ( P F S), a n d o verall s ur vi val ( O S).
E x pl orat or y



St u d y E n d p oi nts:
A ll varia bles base d o n t u m or res p o nse ( O R R, D C R, D O R, P F S) will be calc ulate d base d o n b ot h 
Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1 ( R E CI S T 1. 1) a n d i R E CI S T criteria.  T he 
pri mar y e val uati o n of efficac y will be base d o n R E CI S T 1. 1. All e val uati o ns of t u m or res p o nse will be 
per l ocal In vesti gat or assess me nt.
Pri mar y
 
O bjecti ve res p o nse rate ( O R R) , defi ne d as t he pr o p orti o n of patie nts e x perie nci n g a best o verall 
res p o nse of c o m plete res p o nse (C R) or partial res p o nse (P R).
Sec o n dar y
 
Disease c o ntr ol rate ( D C R), defi ne d as t he pr o p orti o n of patie nts e x perie nci n g a best o verall 
res p o nse of sta ble disease ( S D), P R, or C R.
 
D urati o n of res p o nse ( D O R), defi n e d as t he ti me fr o m t he first d oc u me ntati o n of res p o nse ( C R or 
P R) t o t he first d oc u me ntati o n of o bjecti ve t u m or pr o gressi o n or deat h d ue t o a n y ca use, 
w hic he ver occ urs first.
 
Pr o gressi o n -free s ur vi val ( P F S), defi ne d as t he ti me fr o m t he first d ose of st u d y t hera p y t o t he 
date of deat h (a n y ca use) or disease pr o gressi o n, w hic he ver occ urs first.
 
O verall s ur vi val ( O S), defi ne d as t he ti me fr o m t he date of t he first d ose t o t he deat h date.
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
5
 
Safet y a n d t olera bilit y, base d o n re p orte d a d verse e ve nts ( A Es) a n d o n -st u d y la b orat or y 
para meters, gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute – C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts (N CI -C T C A E ), Versi o n 5. 0.
E x pl orat or y

 


O ver all Desi g n:
St u d y T A S - 1 2 0-2 0 3 is a n o pe n -la bel, n o n-ra n d o mize d, m ultice nter P hase 2 st u d y e val uati n g t he
c o m bi nati o n of f uti bati ni b a n d pe m br oliz u ma b i n patie nts wit h a d va nce d or metastatic U C w h o are n ot 
ca n di dates t o recei ve a plati n u m-base d treat me nt re gi me n. 
A treat me nt c ycle is defi ne d as 2 1 da ys.  All e nr olle d patie nts will recei ve t he sa me treat me nt re gi me n:
 
F uti bati ni b at a n oral ( P O) d ose of 2 0 m g dail y ( Q D); a n d
 
Pe m br oliz u ma b at a n I. V. d ose of 2 0 0 m g e ver y 3 wee ks ( Q 3 W).
Treat me nt will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, or a n y ot her of t he criteria f or 
treat me nt disc o nti n uati o n is met; of n ote, pe m br oliz u ma b ma y be a d mi nistere d f or a ma xi m u m of 
3 5 d oses or a ma xi m u m d urati o n of 2 years, w hic he ver is earlier. 
T he st u d y will be gi n wit h a safet y lea d -i n peri o d.  D uri n g t his peri o d, a t otal of 6 patie nts wit h a d va nce d 
or metast atic U C will be e nr olle d a n d treate d f or at least o ne 2 1 -da y c ycle.  Patie nts will be e nr olle d i nt o 
t his i nitial safet y lea d-i n peri o d wit h o ut re gar d f or F G F R alterati o n stat us.
After t he first 6 patie nts ha ve c o m plete d o ne c ycle of treat me nt, a safet y a n al ysis will occ ur. After 
c o nfir mati o n of t he safet y of t he c o m bi nati o n, a t otal of 2 0 a d diti o nal patie nts will be e nr olle d i nt o eac h 
of t he f oll o wi n g 2 c o h orts:
 
C o h ort A : Patie nts wit h U C a n d F G F R 3 m utati o n or F G F R 1 - 4 f usi o n/rearra n ge me nt. Patie nts 
will be e nr olle d base d o n l ocal res ults , b ut tiss ue sa m ples will be arc hi ve d f or retr os pecti ve 
c o nfir mati o n at a ce ntral la b usi n g ne xt -ge nerati o n se q ue nci n g ( N G S).
 
C o h ort B : All ot her patie nts wit h U C (i ncl u di n g patie nts wit h ot her F G F R or n o n -F G F R ge netic 
a berrati o ns a n d patie nts wit h W T
[ n o n-m utate d] t u m ors) 
A sec o n d safet y a nal ysis will occ ur after e nr oll me nt of a t otal of 1 0 patie nts (i ncl u di n g t he 6 patie nts fr o m 
t he safet y lea d-i n), i n or der t o c o nfir m t he safet y pr ofile of t he c o m bi nati o n bef ore pr ocee di n g t o t he 
e nr oll me nt of t he re mai ni n g patie nts i n C o h orts A a n d B.
Please n ote: At eac h safet y a nal ysis, t he c o m bi nati o n of f uti bati ni b a n d pe m br oliz u ma b will be c o nsi dere d 
i nt olera ble if t he i nci de nce of u nacce pta ble t o xicit y i ncl u di n g d ose-li miti n g t o xicit y (as defi ne d i n t he 
pr ot oc ol) is ≥3 3 %. If t he c o m bi nati o n is deter mi ne d t o be i nt olera ble, t he st u d y ma y c o nti n ue wit h a 
re d uce d d ose of f uti bati ni b ( 1 6 m g Q D) if me dicall y a p pr o priate i n t he o pi ni o n of t he I nvesti gat or s a nd 
S p o ns or.
C CI
C CI
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
6
T he 6 patie nts i nitiall y e nr olle d i n t he safet y lea d -i n will als o be assi g ne d t o t he res pecti ve c o h ort base d 
o n F G F R alterati o n, s uc h t hat eac h c o h ort will c o ntai n a mi ni m u m of 2 0 a n d a ma xi m u m of 2 6 patie nts.
N u m ber of P atie nts: 
T he st u d y wi ll e nr oll a p pr o xi matel y 4 6 patie nts wit h a d va nce d or metastatic U C : 6 patie nts i n t he safet y 
lea d-i n, 2 0 patie nts wit h t u m ors p ositi ve f or a n y F G F R 3 m utati o n or F G F R f usi o n alterati o ns ( C o h ort A) 
a n d 2 0 patie nts wit h ot her F G F R a berrati o ns or wil d -t y pe (W T ) t u m ors ( C o h ort B). 
E ntr y Criteri a: 
I ncl usi o n Criteria
1.
Hist ol o gicall y c o nfir me d a d va nce d or metastatic U C f or patie nts w h o ha ve n ot recei ve d s yste mic 
treat me nt f or a d va nce d metastatic disease. F or patie nts w h o recei ve d pri or a dj u va nt/ ne oa dj u va nt 
c he m ot hera p y or c he m o -ra diati o n f or ur ot helial carci n o ma, a treat me nt-free i nter val > 1 2 m o nt hs 
bet wee n t he last treat me nt a d mi nistrati o n a n d t he date of rec urre nce is re q uire d i n or der t o be 
c o nsi dere d treat me nt -naï ve i n t he metastatic setti n g .
a.
I n safet y lea d-i n: e nr oll me nt re gar dless of F G F R stat us
b.
C o h ort A: m ust ha ve a n F G F R 3 m utati o n or F G F R 1- 4 f usi o n/rearra n ge me nt
c.
C o h ort B: all ot her patie nts wit h U C (i ncl u di n g patie nts wit h ot her F G F R or n o n-F G F R 
ge netic a ber rati o ns a n d patie nts wit h W T
[ n o n m utate d] t u m ors)
2.
U nfit f or or i nt olera nt t o sta n dar d plati n u m -base d c he m ot hera p y as defi ne d b y a n y o ne of t he 
f oll o wi n g criteria:
a.
C hr o nic ki d ne y disease c haracterize d b y t he esti mate d creati ni ne clearea nce rate (e C Cr) 
per C oc kcr oft -Ga ult f or m ula of < 6 0 m L/ mi n or esti mate d g l o mer ular filtrati o n rate 
(e G F R) of < 6 0 m L/ mi n/ 1. 7 3 m 2, c orres p o n di n g t o N CI-C T C A E v. 5. 0 Gra de ≥2
b.
I m paire d h eari n g ( meas ure d b y a u di o metr y) of > 2 5 d B at t w o c o nti g u o us test fre q ue ncies 
i n at least o ne ear, c orres p o n di n g t o N CI-C T C A E v. 5. 0 Gra de ≥2
c.
Peri p heral se ns or y ne ur o pat h y Gra de ≥ 2 b y N CI -C T C A E v. 5. 0
d.
Patie nt ref usal 
e.
In t he o pi ni o n of t he I n vesti gat or , t he patie nt is c o nsi dere d i neli gi ble t o recei ve a n y 
plati n u m -base d c he m ot hera p y 
3.
Be willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt f or t he trial. 
4.
Be ≥1 8 years of a ge .
5.
Ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us ( P S) of 0 t o 1.
6.
A de q uate or ga n f u ncti o n as defi ne d b y t he f oll o wi n g criteria:
a.
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 × 1 0 9/ L
b.
Platelet c o u nt ≥1 0 0, 0 0 0/ m m 3

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
7
c.
He m o gl o bi n ≥9. 0 g/ d L
d.
Ala ni ne a mi n otra nsferase ( A L T ) a n d as partate a mi n otra nsferase ( A S T) ≤2. 5 × u p per 
li mit of n or mal ( U L N); if li ver f u ncti o n a b n or malities are d ue t o u n derl yi n g li ver 
metastasis, A S T a n d A L T ≤5. 0 × U L N
e.
T otal bilir u bi n ≤1. 5 × U L N, or ≤3. 0 × U L N f or patie nts wit h Gil bert’s s y n dr o me
f.
Creati ni ne cleara nce ( Ccr) (calc ulate d or meas ure d val ue): ≥3 0 m L/ mi n.  F or calc ulate d 
Ccr, use t he C oc kcr oft -Ga ult f or m ula
g.
I nter nati o nal n or malize d rati o (I N R) O R pr ot hr o m bi n ti me ≤1. 5 × U L N u nless partici pa nt 
is recei vi n g a ntic oa g ula nt t hera p y as l o n g as pr ot hr o m bi n ti me or acti vate d partial 
t hr o m b o plasti n ti me (a P T T) is wit hi n t hera pe utic ra n ge of i nte n de d use of a ntic oa g ula nts
h.
P h os p h or us < 1. 5 U L N
7.
A de q uate rec o ver y fr o m t he si de effects of a n y pri or t hera p y f or n o n metastatic disease ( ge nerall y 
defi ne d as rec o ve r y of all A Es d ue t o ≤ Gra de 1 or baseli ne; h o we ver, patie nts wit h ≤ Gra de 2 
ne ur o pat h y, a ne mia, al o pecia, a n d s ki n pi g me ntati o n ma y be eli gi ble).
8.
Ha ve pr o vi de d arc hi val t u m or tiss ue sa m ple or ne wl y o btai ne d c ore or e xcisi o nal bi o ps y of a 
t u m or lesi o n n ot pre vi o usl y irra diate d. F or mali n -fi xe d, paraffi n e m be d de d tiss ue bl oc ks are 
preferre d t o sli des. Ne wl y o btai ne d bi o psies are preferre d t o arc hi ve d tiss ue.
9.
Ha ve a meas ura ble disease per R E CI S T 1. 1, as assesse d b y t he l ocal site I n vesti gat or/ra di ol o g y. 
Lesi o n s sit uate d i n a pre vi o usl y irra diate d area are c o nsi dere d meas ura ble if pr o gressi o n has bee n 
de m o nstrate d i n s uc h lesi o ns.
1 0. A male patie nt m ust a gree t o use c o ntrace pti o n d uri n g t he treat me nt peri o d a n d f or at least 
6 m o nt hs f oll o wi n g t he last d ose of st u d y treat me nt.
1 1. A fe male patie nt is eli gi ble t o partici pate if s he is n ot pre g na nt, n ot breastfee di n g, a n d at least o ne 
of t he f oll o wi n g c o n diti o ns a p plies: 
a.
N ot a w o m an of c hil d beari n g p ote ntial ( W O C B P).
b.
A W O C B P w h o a grees t o f oll o w c o ntrace pti ve g ui da nce d ur i n g t he treat me nt peri o d a n d 
f or at least 6 m o nt hs after t he last d ose of st u d y treat me nt.
c.
A W O C B P w h o has a ne gati ve ser u m pre g na nc y test wit hi n 7 da ys pri or t o treat me nt.
1 2. A bilit y t o ta ke me dicati o ns orall y (fee di n g t u be is n ot per mitte d)
1 3. Willi n g a n d a ble
t o c o m pl y wit h sc he d ule d visits a n d st u d y pr oce d ures.
E xcl usi o n Criteria
1.
Ha ve recei ve d pri or t hera p y wit h a nti -P D -1, a nti -P D -L 1/ L 2 a ge nt.
2.
Ha ve recei ve d pri or F G F R i n hi bit or treat me nt i ncl u di n g f uti bati ni b
3.
Hist or y a n d/ or c urre nt e vi de nce of a n y of t he f oll o wi n g dis or ders:
a.
N o n -t u mor relate d alterati o n of t he calci u m -p h os p h or us h o me ostasis t hat is c o nsi dere d 
cli nicall y si g nifica nt i n t he o pi ni o n of t he I n vesti gat or

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
8
b.
Ect o pic mi neralizati o n/calcificati o n, i ncl u di n g b ut n ot li mite d t o s oft tiss ue, ki d ne ys, 
i ntesti ne, or m y ocar dia a n d l u n g, c o nsi dere d cli nicall y si g nifica nt i n t he o pi ni o n of t he 
I nvesti gat or
c.
Reti nal or c or neal dis or der c o nfir me d b y reti nal/c or neal e xa mi nati o n a n d c o nsi dere d 
cli nicall y si g nifica nt i n t he o pi ni o n of t he I n vesti gat or.
4.
C orrecte d Q T i nter val usi n g Fri dericia’s f or m ula ( Q Tc F) > 4 7 0 msec. Patie nts wit h a n 
atri o ve ntric ular pace ma ker or ot her c o n diti o n (f or e xa m ple, ri g ht b u n dle bra nc h bl oc k) t hat 
re n ders t he Q T meas ure me nt i n vali d are a n e xce pti o n a n d t he criteri o n d oes n ot a p pl y.
5.
Has recei ve d maj or s ur ger y wit hi n t he pre vi o us 4 wee ks. 
6.
Has recei ve d a n y n o n -i n vesti gati o nal a ntica ncer t hera p y wit hi n t he pre vi o us 3 wee ks ( mit o m yci n 
wit hi n t he pre vi o us 5 wee ks).
7.
Is c urre ntl y partici pati n g i n a st u d y of a n i n vesti gati o nal a ge nt/ de vice, or has partici pate d i n a 
st u d y of a n i n vesti gati o nal a ge nt or use d a n i n vesti gati o nal de vice wit hi n 4 wee ks pri or t o t he first 
d ose of st u d y treat me nt.  
8.
Has recei ve d a li ve vacci ne wit hi n 3 0 da ys pri or t o t he first d ose of st u d y dr u g. E xa m ples of li ve 
vacci ne s i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  measles, m u m ps, r u bella, varicella/z oster 
(c hic ke n p o x), yell o w fe ver, ra bies, Bacill us Cal mette– G uéri n ( B C G), a n d t y p h oi d vacci ne. 
Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d vir us vacc i nes a n d are all o we d; 
h o we ver, i ntra nasal i nfl ue nza vacci nes (e. g., Fl u Mist ®) are li ve atte n uate d vacci nes a n d are n ot 
all o we d.
9.
A seri o us ill ness or me dical c o n diti o n(s) i ncl u di n g, b ut n ot li mite d t o, t he f oll o wi n g:
a.
Has a n acti ve i nfecti o n re q uiri n g s yste m ic t hera p y.
b.
M y ocar dial i nfarcti o n, se vere/ u nsta ble a n gi na, or s y m pt o matic c o n gesti ve heart fail ure 
wit hi n t he pre vi o us 6 m o nt hs
c.
Hist or y or c urre nt e vi de nce of u nc o ntr olle d ve ntric ular arr h yt h mia
d.
C hr o nic diarr hea diseases c o nsi dere d t o be cli nicall y si g nifi ca nt i n t he o pi ni o n of t he 
I nvesti gat or
e.
C o n ge nital l o n g Q T s y n dr o me, or a n y k n o w n hist or y of t orsa de de p oi ntes, or fa mil y 
hist or y of u ne x plai ne d s u d de n deat h
f.
Ha ve a n acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n t he past 2 
years (t hat is, wit h use of disease m o dif yi n g a ge nts, c ortic oster oi ds, or 
i m m u n os u p pressi ve dr u gs). Re place me nt t hera p y (f or e xa m ple, t h yr o xi ne, i ns uli n, or 
p h ysi ol o gic c ortic oster oi d re place me nt t hera p y f or a dre nal or pit uitar y i ns ufficie nc y) is 
n ot c o nsi dere d a f or m of s yste mic treat me nt a n d is all o we d.
g.
Ha ve a hist or y of ( n o ni nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
h.
Ha ve ha d a n all o ge nic tiss ue/ or ga n tra ns pla nt.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
9
1 0. Has k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) a n d/ or hist or y of He patitis B or C i nfecti o ns, 
or k n o w n t o be p ositi ve f or He patitis B a nti ge n ( H Bs A g)/ He patitis B vir us ( H B V) D N A or 
He patitis C A nti b o d y or R N A. Acti ve He patitis C is defi ne d b y a k n o w n p ositi ve He p C A b res ult 
a n d k n o w n q ua ntitati ve H C V R N A res ults greater t ha n t he l o wer li mits of detecti o n of t he assa y .
1 1. Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y t hat mi g ht 
c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he partici pa nt's partici pati o n f or t he f ull d urati o n 
of t he st u d y, or is n ot i n t he best i nterest of t he partici pa nt t o partici pate, i n t he o pi ni o n of t he 
treati n g I nvesti gat or .
1 2. Ha ve k n o w n acti ve ce ntral ner v o us s yste m metastases a n d/ or carci n o mat o us me ni n gitis. Patie nts 
wit h pre vi o usl y treate d brai n metastases ma y par tici pate pr o vi de d t he y are ra di ol o gicall y sta ble, 
t hat is, wit h o ut e vi de nce of pr o gressi o n f or at least 4 wee ks b y re peat i ma gi n g ( n ote t hat t he 
re peat i ma gi n g s h o ul d be perf or me d d uri n g st u d y scree ni n g), cli nicall y sta ble, a n d wit h o ut ster oi d 
treat me nt req uire me nt f or at least 1 m o nt h pri or t o t he first d ose of st u d y treat me nt .
1 3. T he patie nt is pre g na nt or breastfee di n g .
1 4. Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g c hr o nic s yste mic ster oi d t hera p y (i n d osi n g 
e xcee di n g 1 0 m g dail y of pre d nis o ne e q ui vale nt) or a n y ot her f or m of i m m u n os u p pressi ve 
t hera p y wit hi n 7 da ys pri or t he first d ose of st u d y dr u g.
1 5. Has a k n o w n a d diti o nal mali g na nc y t hat is pr o gressi n g or has re q uire d acti ve treat me nt wit hi n t he 
past 2 years.  Partici pa nts wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he 
s ki n, or carci n o ma i n sit u (e. g., breast carci n o ma, cer vical ca ncer i n sit u) t hat ha ve u n der g o ne 
p ote ntiall y c urati ve t hera p y are n ot e xcl u de d.
1 6. Has se vere h y perse nsiti vit y ( ≥Gra de 3) t o pe m br oliz u ma b a n d/ or a n y of its e xci pie nts.
1 7. Has a k n o w n ps yc hiatric or s u bsta nce a b use dis or der t hat w o ul d i nterfere wit h t he partici pa nt’s 
a bilit y t o c o o perate wit h t he re q uire me nts of t he st u d y.
E v al u ati o n Criteri a:
Efficac y
Efficac y para meters will be assesse d base d o n o n -site t u m or assess me nts (i ncl u di n g c o m p ute d 
t o m o gra p h y [ C T] or ma g netic res o na nce i ma gi n g [ M RI] if C T sca n is n ot feasi ble) perf or me d b y t he 
I nvesti gat or/l ocal ra di ol o gist acc or di n g t o R E CI S T 1. 1 g ui deli nes [ Eise n ha uer et al. 2 0 0 9 ]). T he pri mar y 
e n d p oi nt will be O R R, defi ne d as t he pr o p orti o n of patie nts e x perie nci n g a best o verall res p o nse of C R or 
P R.  
I n a d diti o n t o R E CI S T 1. 1, i R E CI S T will be use d. i R E CI S T is base d o n R E CI S T 1. 1, b ut a da pte d t o 
acc o u nt f or t he u ni q ue t u m or res p o nse see n wit h i m m u n ot h era pe utic dr u gs. i R E CI S T will be use d b y t he 
I nvesti gat or t o assess t u m or res p o nse a n d pr o gressi o n, a n d ma ke decisi o ns re gar di n g t he c o nti n uati o n of 
st u d y treat me nt. 
W he n cli nicall y sta ble, partici pa nts s h o ul d n ot be di sc o nti n ue d u ntil pr o gressi o n is c o nfir me d b y t he 
I nvesti gat or, w or ki n g wit h l ocal ra di ol o g y, acc or di n g t o t he r ules o utli ne d i n t he pr ot oc ol. T his all o wa nce 
t o c o nti n ue treat me nt des pite i nitial ra di ol o gic pr o gressi o n ta kes i nt o acc o u nt t he o bser vati o n t hat s o me 

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
1 0
partici pa nts ca n ha ve a tra ns ie nt t u m or flare i n t he first fe w m o nt hs after t he start of i m m u n ot hera p y, a n d 
t he n e x perie nce s u bse q ue nt disease res p o nse. T his data will be ca pt ure d i n t he cli nical data base.
Safet y
T he assess me nt of safet y will be base d o n t he i nci de nce of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) 
a n d o n-st u d y la b orat or y para meters. Gra di n g of T E A Es will be perf or me d usi n g t he N CI-C T C A E, 
Versi o n 5. 0.

 

 
 
 

 
 
 
 
 
 
St atistic al Met h o ds:
Deter mi nati o n of Sa m ple Size
A p pr o xi matel y 2 0 patie nts wit h U C a n d F G F R 3 m utati o ns or F G F R 1 -4 f usi o n/rearra n ge me nt will be 
e nr olle d i n C o h ort A. Sa m ple size c o nsi derati o ns are base d o n differe ntiati n g a hist orical c o ntr ol O R R per 
R E CI S T 1. 1 of 3 5 % or less, wit h a tar get O R R per R E CI S T 1. 1 of 6 5 %. Ass u mi n g t he tr ue O R R per
R E CI S T 1. 1 is 6 5 %, t he c o h ort has a n a p pr o xi mate 8 0 % p o wer t o reject t he n ull h y p ot hesis t hat t he tr ue 
O R R per R E CI S T 1. 1 is ≤3 5 %, c o nsi deri n g a 2 -si de d al p ha of 1 0 %. Wit h a sa m ple size of 2 0, o bser vi n g 
at least 1 2 res p o n ders will ha ve a 9 0 % c o nfi de nce i nter val (CI ) l o wer b o u n d e xcl u di n g 1 0 % ( O R R per 
R E CI S T 1. 1 of 6 0 % wit h 9 0 % CI ( 3 9. 4 % - 7 8. 3 %) ).
A p pr o xi matel y 2 0 patie nts wit h U C a n d wit h o ut F G F R 3 m utati o ns or F G F R 1 - 4 f usi o ns will be e nr olle d 
i n C o h ort B. Sa m ple size c o nsi derati o ns are base d o n differe nti ati n g a hist orical c o ntr ol O R R per 
R E CI S T 1. 1 of 2 5 % or less, wit h a tar get O R R per R E CI S T 1. 1 of 5 0 %. Ass u mi n g t he tr ue O R R per 
R E CI S T 1. 1 is 5 0 %, t he c o h ort has a n a p pr o xi mate 8 0 % p o wer t o reject t he n ull h y p ot hesis t hat t he tr ue 
O R R per R E CI S T 1. 1 is ≤2 5 %, c o nsi deri n g a 2 -si de d al p ha of 1 0 %. Wit h a sa m ple size of 2 0, o bser vi n g 
at least 9 res p o n ders will ha ve a 9 0 % CI l o wer b o u n d e xcl u di n g 1 0 % ( O R R per R E CI S T 1. 1 of 4 5 % wit h 
9 0 % CI ( 2 5. 9 % - 6 5. 3 %) ).
I nteri m A nal yses
C CI
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
1 1
T he f irst i nteri m a nal ysis of safet y will be perf or me d after t he 6-patie nt safet y lea d -i n peri o d; a sec o n d 
i nteri m a nal ysis of safet y will be perf or me d after a t otal of 1 0 patie nts ha ve bee n e nr olle d (i ncl u di n g t he 
i nitial 6 patie nts e nr olle d i n t he safet y lea d-i n peri o d).  At eac h i nteri m a nal ysis, t he c o m bi nati o n of 
f uti bati ni b a n d pe m br oliz u ma b will be c o nsi dere d i nt olera ble if t he i nci de nce of u nacce pta ble t o xicit y (as 
defi ne d i n t he pr ot oc ol) is > 3 3 %.
A nal ysis P o p ulati o n s
T he a nal ysis st u d y p o p ulati o ns i n t his st u d y are defi ne d as bel o w:
A n al ysis P o p ul ati o n
Defi niti o n
All E nr olle d P o p ulati o n 
All patie nts e nr olle d i n t his st u d y
All Treate d P o p ulati o n/
F ull A nal ysis Set
All patie nts i n t he All E nr olle d P o p ulati o n w h o recei ve d at least 
o ne d ose of st u d y dr u g
 
 
Efficac y A nal yses
T he efficac y a nal yses will be perf or me d f or eac h c o h ort usi n g t he All Treate d P o p ulati o n, u nless 
ot her wise s pecifie d. 
Efficac y data f or t he pri mar y a n d sec o n dar y e n d p oi nts will be s u m marize d descri pti vel y.
F or t he pri mar y efficac y a nal ysis, O R R per R E CI S T 1. 1 will be esti mate d wit h t he e xact 2 -si de d 9 0 % CI . 
O n l y t he e val uati o ns bef ore disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt will be use d f or 
t he esti mati o n.
O R R a n d D C R per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d wit h t he e xact 2 -si de d 9 5 % CI . O nl y t he 
e val uati o ns bef ore disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt will be use d f or t he 
esti mati o n.
D O R per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d o nl y i n patie nts wit h a n o bjecti ve res p o nse of C R 
or P R. Patie nts w h o are ali ve a n d pr o gressi o n -free as of t he a nal ysis c ut-off dat e will be ce ns ore d at t heir 
last e val ua ble t u m or res p o nse assess me nt pri or t o i nitiati o n of a n y ne w a ntica ncer treat me nt. Patie nts w h o 
start s u bse q ue nt a ntica ncer t hera p y wit h o ut a pri or re p orte d pr o gressi o n will be ce ns ore d at t he last t u m or 
assess me nts pri or t o i nitiati o n of t he s u bse q ue nt a ntica ncer t hera p y.
P F S per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d usi n g t he Ka pla n -Meier met h o d. Patie nts w h o die 
wit h o ut a re p orte d disease pr o gressi o n will be c o nsi dere d t o ha ve pr o gresse d o n t he date of t heir deat h. 
Patie nts w h o di d n ot pr o gress or die will be ce ns ore d o n t he date of t heir last t u m or assess me nt. Patie nts 
w h o di d n ot ha ve a n y o n -st u d y assess me nts a n d di d n ot die will be ce ns ore d o n t he first d osi n g date. 
Patie nts w h o starte d a n y s u bse q ue nt a ntica nce r t hera p y wit h o ut a pri or re p orte d pr o gressi o n will be 
ce ns ore d at t he last t u m or assess me nt pri or t o i nitiati o n of t he s u bse q ue nt a ntica ncer t hera p y.
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
C o nfi de ntial - Pr o prietar y I nf or mati o n
1 2
O verall s ur vi val will be esti mate d t he sa me as P F S. I n t he a bse nce of deat h c o nfir mati o n or f or patie nts 
ali ve as of t he O S c ut -off date, s ur vi val ti me will be ce ns ore d at t he date of t he last k n o w n ali ve date.
Safet y A nal yses
T he safet y a nal yses will be perf or me d b y eac h c o h ort a n d st u d y dr u g usi n g t he All Treate d P o p ulati o n.
All A Es will be s u m marize d ( b y i nci de nce) a n d liste d b y t he S yste m Or ga n Class, Preferre d Ter m, 
t o xicit y/se verit y gra de, a n d ca usal relati o ns hi p t o f uti bati ni b. I n a d diti o n, se parate s u m maries of seri o us 
a d verse e ve nts ( S A Es ) a n d Gra de 3 or 4 A Es will be prese nte d.
F or all A Es t hat occ ur re d bet wee n t he si g ni n g of t he i nf or me d c o nse nt f or m (I C F) a n d t he last da y of t he 
Safet y F oll o w -u p Peri o d, lists of preferre d A E ter ms, gra de, o nset date, acti o ns, o utc o me of A E, date of 
o utc o me c o nfir me d, ca usalities wit h t he st u d y dr u g, a n d c o m me nts o n A Es will be liste d b y patie nt.
He mat ol o gical a n d c he mistr y la b orat or y para meters will be gra de d acc or di n g t o t he N CI -C T C A E 
( Versi o n 5. 0) w here a p plica ble. T he w orst se verit y gra de, ti me t o ma xi m u m Gra de 3 or 4 val ue, a n d ti me 
t o res ol uti o n (ret ur n t o baseli ne gra de or bel o w) will be s u m marize d.
A list of 1 2 -lea d electr ocar di o gra m ( E C G) fi n di n gs will be prese nte d b y patie nt.
 A nal yses
T he 
 a nal yses will be perf or me d usi n g t he 
 
.
 data will be s u m marize d descri pti vel y as descri be d i n 
a se parate Statistical A nal ysis Pla n ( S A P) .
C CI
C CI
C CI
C CI

F uti b ati ni b ( T A S- 1 2 0 )
Pr ot o c ol  T A S -1 2 0 -2 0 3  – A m e n d m e nt  1
1 3
S c h e d ul e  of  E v e nts
E v al u ati o ns  o n  D a y   1 ( D 1) of  a  c y cl e s h o ul d  b e  p erf or m e d  wit hi n  2 4  h o urs  pri or t o  d osi n g,  u nl ess  ot h er wis e  n ot e d.   Pr o c e d ur es 
alr e a d y  p erf or m e d  d uri n g t h e s cr e e ni n g  p eri o d  wit hi n  7 2  h o urs  pri or t o  d osi n g  d o  n ot  n e e d t o  b e r e p e at e d  o n  C y cl e  1 ( C 1)  C 1 D 1.  T h e 
E n d  of  Tr e at m e nt ( E O T)  v isit  m ust  b e  p erf or m e d  0-7  d a y s  aft er a  d e cisi o n is  m a d e t o  dis c o nti n u e st u d y tr e at m e nt (f or  p ati e nts  w h o 
dis c o nti n u e  at  a  pl a n n e d st u d y   visit, t h at  visit  m a y  b e  c o nsi d er e d t h e  E O T  visit if  all  ass ess m e nts r e q uir e d  at  E O T  ar e  p erf or m e d).
T a bl e 1 :  
S c h e d ul e  of  E v e nts
E v al u ati o n
S c r e e ni n g
( Wit hi n  2 8  d a ys  of  1st d os e)
T r e at m e nt  P e ri o d ( 1  c y cl e  = 2 1  d a ys)
S af et y  F oll o w -
u p
S u r vi v al  F oll o w- u p  P e ri o d
( e v e r y  1 2 ± 2  w e e ks)
N ot es
C y cl e  1
C y cl e  ≥ 2
D 1
(- 1  d a y)
D 8
(-1  d a y)
D 1 5
(- 1  d a y)
D 1
(- 1  d a y)
E n d  of 
C y cl e
( ± 7 d a ys)
E n d  of  T r e at m e nt
( + 0- 7  d a ys)
3 0,  6 0,  a n d  9 0  d a ys  aft e r 
l ast  d os e ( ± 3  d a ys)
Writt e n i nf or m e d  c o ns e nt 
X
Writt e n i nf or m e d  c o ns e nt  will  b e 
o bt ai n e d  pri or t o  a n y st u d y -r el at e d 
ass ess m e nts  or  pr o c e d ur es.
R e vi e w  eli gi bilit y  crit eri a 
X
D e m o gr a p hi cs/ m e di c al  hist or y 
X
R e vi e w  of  b as eli n e si g ns  a n d 
s y m pt o ms
X
Pri or  &  c o n c o mit a nt 
m e di c ati o ns,  A E  ass ess m e nts
C oll e ct fr o m t h e ti m e  m ai n i nf or m e d 
c o ns e nt is si g n e d t hr o u g h  9 0  d a ys  aft er 
a d mi nistr ati o n  of t h e l ast  d os e  of st u d y 
t h er a p y  or  u ntil t h e st art  of  n e w 
a nti c a n c er t h er a p y,  w hi c h e v er is 
e arli er.  
P h ysi c al  e x a mi n ati o n
X   
X
X
X   
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g.
Vit al si g ns
X   
X
X
X   
X
H e art r at e,  bl o o d  pr ess ur e,  b o d y 
t e m p er at ur e,  a n d r es pir ati o n r at e.
H ei g ht  a n d  W ei g ht
X   
X
X
X   
X
H ei g ht  at s cr e e ni n g  o nl y.

F uti b ati ni b ( T A S- 1 2 0 )
Pr ot o c ol  T A S -1 2 0 -2 0 3  – A m e n d m e nt  1
1 4
E v al u ati o n
S c r e e ni n g
( Wit hi n  2 8  d a ys  of  1st d os e)
T r e at m e nt  P e ri o d ( 1  c y cl e  = 2 1  d a ys)
S af et y  F oll o w -
u p
S u r vi v al  F oll o w- u p  P e ri o d
( e v e r y  1 2 ± 2  w e e ks)
N ot es
C y cl e  1
C y cl e  ≥ 2
D 1
(- 1  d a y)
D 8
(-1  d a y)
D 1 5
(- 1  d a y)
D 1
(- 1  d a y)
E n d  of 
C y cl e
( ± 7 d a ys)
E n d  of  T r e at m e nt
( + 0- 7  d a ys)
3 0,  6 0,  a n d  9 0  d a ys  aft e r 
l ast  d os e ( ± 3  d a ys)
E C O G  p erf or m a n c e st at us 
X   
X
X
X   
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g.
1 2 -L e a d  el e ctr o c ar di o gr a m 
X
X
X   
X
H e m at ol o g y
X   
X   
X   
X   
X
X   
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g. 
M or e fr e q u e nt  ass ess m e nts
m a y  b e  p erf or m e d  if cli ni c all y i n di c at e d
C o a g ul ati o n
X   
X
X
X   
X
C h e mistr y (s er u m  or  pl as m a) 
X   
X   
X   
X   
X
X   
X
T h yr oi d  F u n cti o n  T ests
X   
X
X
E v er y  6  w e e ks u ntil  dis c o nti n u ati o n  of 
p e m br oli z u m a b.
Pr e g n a n c y t est
X
X
S er u m  pr e g n a n c y t est r e q uir e d  wit hi n 
7  d a ys  pri or t o first  d os e  f or  W O C B P. 
A d diti o n al t esti n g  ( uri n e  or s er u m)  as
r e q uir e d p er l o c al  pr a cti c e.
O p ht h al m ol o gi c al  e x a mi n ati o n 
X
S e e 
N ot e
E x a mi n ati o n t o  b e  p erf or m e d  b y  a n 
o p h t h al m ol o gist  or  q u alifi e d  d el e g at e.
At s cr e e ni n g,  4 -6  w e e ks  aft er first 
d os e,  a n d  as i n di c at e d if s y m pt o ms  or 
si g ns  of  mi n er al  d e p osits. I n  c as es  of 
reti n al  p i g m e nt e pit h eli al  d et a c h m e nt ,
e v e nts s h o ul d  b e  m o nit or e d  at 
2- 3- w e e k i nt er v als .
X
 
 
 
 
C CI
C CI

F uti b ati ni b ( T A S- 1 2 0 )
Pr ot o c ol  T A S -1 2 0 -2 0 3  – A m e n d m e nt  1
1 5
E v al u ati o n
S c r e e ni n g
( Wit hi n  2 8  d a ys  of  1st d os e)
T r e at m e nt  P e ri o d ( 1  c y cl e  = 2 1  d a ys)
S af et y  F oll o w -
u p
S u r vi v al  F oll o w- u p  P e ri o d
( e v e r y  1 2 ± 2  w e e ks)
N ot es
C y cl e  1
C y cl e  ≥ 2
D 1
(- 1  d a y)
D 8
(-1  d a y)
D 1 5
(- 1  d a y)
D 1
(- 1  d a y)
E n d  of 
C y cl e
( ± 7 d a ys)
E n d  of  T r e at m e nt
( + 0- 7  d a ys)
3 0,  6 0,  a n d  9 0  d a ys  aft e r 
l ast  d os e ( ± 3  d a ys)
Bl o o d s a m pl e f or   
 
ass ess m e nt
X
X
X
 
 
T u m
u m or tiss u e 
or tiss u e  c oll e cti o n f or 
  ass ess m e nt
X
X
M a n d at or y  tiss u e  c oll e cti o n  at  b as eli n e 
(ar c hi v al  or  n e w t u m or  bi o ps y) . 
O pti o n al t u m or  bi o ps y t o  b e 
p erf or m e d at  D a y  1  of  C y cl e  2  o nl y .
T u m or  ass ess m e nts ( C T/ M RI)  
X
( X) 
X   
X   
X   
At  b as eli n e  a n d t h e  e n d  of  e v er y  3 
c y cl es ( ± 7  d a ys),  or  as  cli ni c all y 
i n di c at e d,  u ntil r a di ol o gi c  P D  or 
i niti ati o n  of  n e w  a nti c a n c er t h er a p y 
( w hi c h e v er  c o m es first). 
F or  p ati e nts  w h o  dis c o nti n u e tr e at m e nt 
f or r e as o ns  ot h er t h a n r a di o gr a p hi c 
dis e as e  pr o gr essi o n, i m a gi n g  will  b e 
p erf or m e d  at  E O T,  (if t h e  pri or s c a n 
w as  p erf or m e d  ≥ 9 w e e ks  b ef or e  E O T) 
a n d  d uri n g  S ur vi v al  F oll o w -u p  u ntil 
r a di ol o gi c  dis e as e  pr o gr essi o n  or 
i niti ati o n  of  n e w  a nti c a n c er t h er a p y 
( w hi c h e v er  o c c urs first).
S ur vi v al st at us
X 
F or  all  p ati e nts , u nl ess p ati e nt 
wit h dr a ws  c o ns e nt  or t h e st u d y is 
t er mi n at e d  e arl y  b y t h e  S p o ns or. 
C CI
C CI
C CI

F uti b ati ni b ( T A S- 1 2 0 )
Pr ot o c ol  T A S -1 2 0 -2 0 3  – A m e n d m e nt  1
1 6
T a bl e 2: 
S c h e d ul e  of  E v e nts  – St u d y  E xt e nsi o n  P h as e
T r e at m e nt  P e ri o d ( 1  c y cl e  = 
2 1  d a ys)
S af et y  F oll o w -U p
N ot es
D ail y
At  L e ast  E v e r y 
3 C y cl es
3 0 ,  6 0,  a n d  9 0 ( ± 3 d a ys) 
Aft e r  L ast  D os e
P h ysi c al  e x a mi n ati o n
X
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g  o n  D 1 of t h e  c y cl e.
Vit al si g ns
X
X
H e art r at e,  bl o o d  pr ess ur e,  b o d y t e m p er at ur e,  a n d r es pir ati o n r at e.
W ei g ht
X
X
O p ht h al m ol o gi c al  e x a mi n ati o n
( X)
X
As  n e e d e d  d u e t o l o c al r e q uir e m e nts,  p h ysi ci a n j u d g m e nt,  a n d/ or s y m pt o ms 
or si g ns  of  mi n er al  d e p osits.
E C O G  p erf or m a n c e st at us
X
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g  o n  D 1
1 2 -L e a d  el e ctr o c ar di o gr a m 
X
X
H e m at ol o g y  a n d  c o a g ul ati o n
X
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g  o n  D 1 of t h e  c y cl e.
C h e mistr y (s er u m  or  pl as m a)
X
X
Wit hi n  2 4  h o urs  pri or t o  d osi n g  o n  D 1 of t h e  c y cl e.
T h yr oi d f u n cti o n t ests
S e e  n ot e
S e e  n ot e 
E v er y  6  w e e ks  u ntil  dis c o nti n u ati o n  of  p e m br oli z u m a b.
Pr e g n a n c y t est
X
A d diti o n al t esti n g ( uri n e  or s er u m)  as r e q uir e d  p er l o c al  pr a cti c e.
Pri or  &  c o n c o mit a nt  m e di c ati o ns, 
A E  ass ess m e nts
X
X
C oll e ct fr o m t h e ti m e  m ai n i nf or m e d  c o ns e nt is si g n e d t hr o u g h  9 0  d a ys  aft er 
a d mi nistr ati o n  of t h e l ast  d os e  of st u d y t h er a p y  or  u ntil t h e st art  of  n e w 
a nti c a n c er t h er a p y,  w hi c h e v er is  e arli er.  
T u m or  ass ess m e nts ( C T/ M RI)
X
T u m or  ass ess m e nts  m a y  b e  p erf or m e d  as  n e c ess ar y t o  d et er mi n e  c o nti n u e d 
b e n efit fr o m  tr e at m e nt,  e v er y  3  c y cl es ( ±  7  d a ys),  or  as  cli ni c all y i n di c at e d, 
u ntil r a di ol o gi c  P D  or i niti ati o n  of  n e w  a nti c a n c er t h er a p y ( w hi c h e v er 
o c c urs first).

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
1 7
T A B L E O F C O N T E N T S
S U M M A R Y O F P R O T O C O L  A M E N D M E N T S ................................ ...........................................2
P R O T O C O L  S Y N O P SI S ................................................................................................................3
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ................................................2 2
1.  
I N T R O D U C TI O N ......................................................................................................2 5
1. 1. 
Ur ot helial Ca rci n o ma..................................................................................................2 5
1. 2. 
Pe m br oliz u ma b ...........................................................................................................2 5
1. 3. 
F uti bati ni b  ( T A S - 1 2 0)...............................................................................................2 6
1. 3. 1. 
Bac k gr o u n d .................................................................................................................2 6
1. 3. 2. 
Cli nical O ver vie w .......................................................................................................2 6
1. 4. 
S u m mar y  of St u d y Rati o nale......................................................................................2 7
2. 
O BJ E C TI V E S A N D E N D P O I N T S............................................................................2 8
3. 
I NV E S TI G A TI O N A L P L A N .....................................................................................2 9
3. 1. 
O ver vie w of St u d y  Desi g n..........................................................................................2 9
3. 2. 
St u d y  Peri o ds a n d Visits f or Eac h Patie nt..................................................................3 0
3. 2. 1. 
Scree ni n g Peri o d .........................................................................................................3 0
3. 2. 2. 
Treat me nt Peri o d a n d E n d of Treat me nt Visit ............................................................3 0
3. 2. 2. 1. 
Safet y  F oll o w-U p Peri o d a n d 3 0 -Da y  Safety F oll o w -U p Visit ..................................3 1
3. 2. 3. 
P ost -Disc o nti n uati o n C o nsi derati o ns ..........................................................................3 1
3. 2. 4.  
S ur vi val F oll o w- u p................................ .....................................................................3 1
3. 2. 5. 
St u d y  C o m pleti o n a n d St u d y E xte nsi o n.....................................................................3 1
4. 
S E L E C TI O N A N D WI T H D R A W A L  O F P A TI E N T S..............................................3 2
4. 1. 
I ncl usi o n Criteria................................ ........................................................................3 2
4. 2. 
E xcl usi o n Criteria .......................................................................................................3 3
4. 3. 
Scree n Fail ure .............................................................................................................3 5
4. 4. 
Disc o nti n uati o n of Treat me nt .....................................................................................3 5
4. 5. 
Wit h dra wal fr o m t he St u d y
........................................................................................3 6
5. 
S T U D Y T R E A T M E N T ..............................................................................................3 8
5. 1. 
St u d y  Dr u g A d mi nistrati o n.........................................................................................3 8
5. 1. 1.  
F uti bati ni b................................ ...................................................................................3 8
5. 1. 2. 
Pe m br oliz u ma b ...........................................................................................................3 8
5. 2. 
Defi nit i o n of D ose-Li miti n g T o xicit y ........................................................................3 8

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
1 8
5. 3. 
D ose a n d Sc he d ule M o dificati o ns ..............................................................................3 9
5. 3. 1. 
D ose M o dificati o ns f or F uti bati ni b ............................................................................3 9
5. 3. 1. 1. 
F uti bati ni b D ose M o dificati o ns f or N o n he mat ol o gic T o xicities ................................4 0
5. 3. 1. 2. 
F uti bati ni b D ose M o dificati o ns f or He mat ol o gic T o xicities ......................................4 2
5. 3. 2. 
D ose M o dificati o ns i n Case of I n d uce d Dr u g Li ver I nj ur y  ( H y’s La w) ....................4 3
5. 3. 3. 
D ose M o dificati o ns f or Pe m br oliz u ma b .....................................................................4 4
5. 3. 3. 1. 
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt f or I m m u ne-Relate d A Es 
Ass ociate d wit h Pe m br oliz u ma b................................ ................................................4 4
5. 3. 3. 2. 
I nf usi on -Relate d Reacti o ns .........................................................................................4 7
5. 3. 3. 3. 
Ot her Per mitte d D ose I nterr u pti o n f or Pe m br oliz u ma b .............................................4 9
5. 4. 
Treat me nt C o m plia nce ................................................................................................4 9
5. 5. 
C o n c o mita nt Me dicati o ns a n d T hera pies ...................................................................4 9
5. 5. 1. 
Pr o hi bite d Me dicati o ns a n d T hera pies .......................................................................4 9
5. 5. 2.  
C o nc o mita nt Me dicati o ns a n d T hera pies Re q uiri n g Preca uti o ns............................... 5 0
5. 5. 3. 
Dr u g I nteracti o ns ........................................................................................................5 0
5. 6. 
Effecti ve C o ntrace pti o n D uri n g St u d y................................ .......................................5 1
5. 7. 
St u d y  Dr u g Materials a n d Ma na ge me nt.....................................................................5 2
5. 7. 1. 
Acc o u nta bilit y .............................................................................................................5 2
6. 
S T U D Y A S S E S S M E N T S ..........................................................................................5 3
6. 1.   
O p ht hal m ol o gical E xa mi nati o n................................ ..................................................5 4
6. 2. 
La b orat or y  Assess me nts.............................................................................................5 4
7.
...........................................................................................5 5
8. 
E F FI C A C Y E V A L U A TI O N S ....................................................................................5 6
8. 1. 
E val u ati o n of Efficac y per R E CIS T 1. 1 .....................................................................5 6
8. 1. 1. 
Met h o d of I ma gi n g .....................................................................................................5 6
8. 1. 2. 
T u m or Defi niti o ns ......................................................................................................5 7
8. 1. 3.  
R es p o nse Criteria ........................................................................................................5 8
8. 1. 3. 1. 
Tar get a n d N o n -Tar get Res p o nse Assess me nts ..........................................................5 8
8. 1. 4. 
O bjecti ve Res p o nse Assess me nt .................................................................................6 0
8. 2. 
Use of i R E CI S T t o G ui de Treat me nt Decisi o ns .........................................................6 1
9. 
S A F E T Y E V A L U A TI O N S ........................................................................................6 3
9. 1. 
A d verse E ve nts ...........................................................................................................6 3
9. 2.  
Re p orti n g of A d verse E ve nts ......................................................................................6 3
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
1 9
9. 2. 1. 
Ter ms of Re p orte d A d verse E ve nts ............................................................................6 3
9. 2. 2. 
Se verit y  of A d verse E ve nts ........................................................................................6 3
9. 2. 3. 
Ca usal Relati o ns hi p wit h St u d y  Dr u g.........................................................................6 4
9. 2. 4. 
O utc o me of A d verse E ve nts .......................................................................................6 4
9. 2. 5. 
F oll o w -u p of A d verse E ve nts .....................................................................................6 4
9. 3. 
La b orat or y  Assess me nts.............................................................................................6 5
9. 3. 1. 
Re p orti n g a n d E val uati o n of La b orat or y  Test Res ults ...............................................6 5
9. 3. 2. 
Re peat Testi n g ............................................................................................................6 5
9. 4. 
Seri o us A d verse E ve nts ..............................................................................................6 5
9. 4. 1. 
Defi niti o ns of Seri o us A d verse E ve nts .......................................................................6 5
9. 4. 2.  
Re p orti n g of Seri o us A d verse E ve nts ( wit hi n 2 4 h o urs)................................ ............6 6
9. 4. 3.  
Re p orti n g of Deat hs ( wit hi n 2 4 h o urs)................................ .......................................6 6
9. 5. 
Ot her Safet y I nf or mati o n............................................................................................6 6
9. 5. 1. 
Pre g na nc y ...................................................................................................................6 6
9. 5. 2. 
O ver d ose .....................................................................................................................6 7
9. 5. 3. 
Pe m br oliz u ma b E ve nts of Cli nical I nterest ................................................................6 7
1 0.
 E V A L U A T IO N .................................................................................6 8
1 0. 1.
 A ssessm en ts ..............................................................................................6 8
1 1.  
S T A TI S TI C A L C O N SI D E R A TI O N S .......................................................................6 9
1 1. 1. 
Esti mati o n of Sa m ple Si ze ..........................................................................................6 9
1 1. 2.  
P la n ne d I nteri m Anal ys es ...........................................................................................6 9
1 1. 3. 
A nal y sis P o p ulati o ns ..................................................................................................6 9
1 1. 4. 
Criteria f or Ha n dli n g of Patie nt Data ..........................................................................6 9
1 1. 5. 
Statistical A nal y ses .....................................................................................................7 0
1 1. 5. 1.   
De m o gra p hic a n d Baseli ne C haracteristics................................ ................................7 0
1 1. 5. 2. 
St u d y  Dr u g A d mi nistrati o n.........................................................................................7 0
1 1. 5. 3. 
Efficac y  A nalys es .......................................................................................................7 0
1 1. 5. 3. 1. 
Pri mar y  Efficac y A nalys is..........................................................................................7 0
1 1. 5. 3. 2. 
Sec o n dar y  Efficac y A nal yses .....................................................................................7 0
1 1. 5. 4. 
Safet y  A nalys es ..........................................................................................................7 1
1 1. 5. 5.
 A nal ysis ..........................................................................................7 1
1 1. 5. 6.
 A nalys is .....................................................................7 1
1 2.   
A D MI NI S T R A TI V E C O N SI D E R A TI O N S ................................ ..............................7 2
C CI
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 0
1 2. 1. 
Pr ot oc ol C o m plia nce ..................................................................................................7 2
1 2. 2. 
Pr ot oc ol De viati o ns ....................................................................................................7 2
1 2. 3. 
Pr ot oc ol A me n d me nts ................................................................................................7 2
1 2. 4. 
St u d y  Ter mi nati o n......................................................................................................7 2
1 2. 5. 
Case Re p ort F or ms .....................................................................................................7 2
1 2. 6.   
A ccess t o S o urce D ata/D oc u me nts .............................................................................7 2
1 2. 6. 1. 
S o urce Data/ D oc u me nts .............................................................................................7 3
1 2. 6. 2. 
Access t o S o urce Data ................................................................................................7 3
1 2. 7. 
Data H a n dli n g .............................................................................................................7 3
1 2. 8. 
Res p o nsi bilities of Rec or d kee pi n g .............................................................................7 3
1 2. 8. 1. 
I n vesti gat or a n d St u d y Site.........................................................................................7 3
1 2. 8. 2. 
S p o ns or .......................................................................................................................7 4
1 2. 9. 
M o nit ori n g ..................................................................................................................7 4
1 2. 1 0. 
Fi na ncial Discl os ure ...................................................................................................7 4
1 2. 1 1. 
C o m pe nsati o n f or Healt h I nj ur y .................................................................................7 4
1 2. 1 2.  
S t u d y A d mi nistrati ve Str uct ure ..................................................................................7 4
1 3. 
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E .........................................7 5
1 3. 1. 
Q ualit y  C o ntr ol...........................................................................................................7 5
1 3. 2.   
Q ualit y A ss ura nce.......................................................................................................7 5
1 4. 
E T HI C S ......................................................................................................................7 6
1 4. 1. 
Et hical C o n d uct of t he St u d y ......................................................................................7 6
1 4. 2. 
Writte n I nf or me d C o nse nt ..........................................................................................7 6
1 4. 3. 
I nstit uti o nal Re vie w B oar d/In de pe n de nt Et hics C o m mittee ......................................7 6
1 5. 
P U B LI C A TI O N P O LI C Y ..........................................................................................7 7
1 5. 1. 
P u blicati o n P olic y .......................................................................................................7 7
1 5. 2. 
Sec o n dar y  Use of Data ...............................................................................................7 7
1 6. 
R E F E R E N C E S ...........................................................................................................7 8
A P P E N DI X A. 
E C O G P E R F O R M A N C E S T A T U S ..................................................................8 0
A P P E N DI X B. 
DI E T A R Y G UI D E LI N E S F O R T R E A T M E N T O F 
H Y P E R P H O S P H A T E MI A ........................................................................................8 1
A P P E N DI X C. 
C L A S SI FI C A TI O N O F S U B S T R A T E S, I N HI BI T O R S , A N D 
I ND U C E R S O F C Y P E N Z Y M E S A N D T R A N S P O R T E R S ....................................8 2
A P P E N DI X D. 
S U M M A R Y O F T H E I R E CI S T P R O C E S S .....................................................8 4

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 1
LI S T O F T A B L E S
Ta ble 1:  
Sc he d ule of E ve nts .....................................................................................................1 3
Ta ble 2: 
Sc he d ule of E ve nts – St u d y  E xte nsi o n P hase.............................................................1 6
Ta ble 3:  
O bjecti ves a n d E n d p oi nts ...........................................................................................2 8
Ta ble 4: 
D ose M o dificati o ns f or Relate d N o n he mat ol o gic T o xicities .....................................4 0
Ta ble 5: 
D ose M o dificati o ns f or Relate d E y e T o xicities ..........................................................4 1
Ta ble 6: 
Rec o m me n dati o ns f or H y per p h os p hate mia Ma na ge me nt ..........................................4 2
Ta ble 7:     F uti bat i ni b D ose I nterr u pti o n a n d M o dificati o n Criteria f or Relate d 
He mat ol o gic T o xicities ...............................................................................................4 3
Ta ble 8:   
G ui deli nes f or Ma na ge me nt of I m m u ne- Relate d A d verse E ve nts Ass ociate d 
wit h Pe m br oliz u ma b ...................................................................................................4 5
Ta ble 9: 
G ui deli nes f or Ma na ge me nt of I nf usi o n -Relate d Reacti o ns t o 
Pe m br oliz u ma b ...........................................................................................................4 7
Ta ble 1 0:
................................................................5 5
Ta ble 1 1: 
Tar get a n d N o n -tar get Lesi o ns ...................................................................................5 9
Ta ble 1 2: 
Ti me P oi nt Res p o nse f or Patie nts wit h Tar get ( ± N o n- tar get) Disease.......................6 0
Ta ble 1 3: 
Ti me P oi nt Res p o nse f or Patie nts wit h O nl y  N o n-tar get Disease..............................6 0
Ta ble 1 4:     Defi niti o ns of A nal ys is P o p ulati o ns..........................................................................6 9
LI S T O F FI G U R E S
Fi g ure 1: 
St u d y  Sc he ma .............................................................................................................2 9
Fi g ure 2: 
I ma gi n g a n d treat me nt f or cli nicall y sta ble patie nts treate d wit h 
pe m br oliz u ma b after t he first ra di ol o gic e vi de nce of pr o gressi o n per 
R E CI S T 1. 1 .................................................................................................................6 2
C CI

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2 2
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
A b bre vi ati o n 
Defi niti o n
A E
A d verse e ve nt
A L T
Ala ni ne a mi n otra nsferase
A N C
A bs ol ute ne utr o p hil c o u nt
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
B C R P
Breast ca ncer resista nce pr otei n
Ccr
Creati ni ne cleara nce
CI
C o nfi de nce i nter val
C PI
C hec k p oi nt i n hi biti o n / i n hi bit or
C R
C o m plete res p o nse
C T
C o m p ute d to m o gra p h y
C T C A E 
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C Y P
C y t oc hr o me P 4 5 0
D C R
Disease c o ntr ol rate
D L T
D ose -li miti n g t o xicit y
D O R
D urati o n of res p o nse
E C G
Electr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
e C R F
Electr o nic case re p ort f or m
E O T
E n d of treat me nt/e n d of t hera p y
F G F R
Fi br o blast gr o wt h fact or rece pt or
G C P
G o o d Cli nical Practice
i C C A
I ntra he patic c h ola n gi ocarci n o ma
I CF
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts 
f or P har mace uticals f or H u ma n Use
I E C
I n de pe n de nt Et hics C o m mittee

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Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 3
A b bre vi ati o n 
Defi niti o n
I ND
I n vesti gati o nal Ne w Dr u g
ir
I m m u ne-relate d
I RB
I nstit uti o nal Re vie w B oar d
I.V.
I ntra ve n o us
M RI
Ma g netic res o na nce i ma gi n g
N CI
Nati o nal Ca ncer I nstit ute
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val
P D
Pr o gressi ve disease
P D - 1
Pr o gra m me d deat h -li ga n d 1
P D -L 1
Pr o gra m me d cell deat h li ga n d 1
P D -L 2
Pr o gra m me d cell deat h li ga n d 2
P F S
Pr o gressi o n free s ur vi val
P- g p
P- gl yc o pr otei n
P O
Oral
P R
Partial res p o nse
P T
Preferre d ter m
Q D
O nce dail y
Q Tc F
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ula
R E CI S T 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors , Versi o n 1. 1
S A E
Seri o us a d verse e ve nt
S A P
S tatistical a nal ysis pla n
S D
Sta ble disease
S O P
Sta n dar d o perati n g pr oce d ure
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
T OI
Tai h o O nc ol o g y , I nc.
C CI
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 4
A b bre vi ati o n 
Defi niti o n
U C
Ur ot helial carci n o ma / ca ncer
U L N
U p per li mit of n or mal
W O C B P   
W o me n of c hil d beari n g p ote ntial
W T
Wil d -t ype

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Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 5
1. 
IN T R O D U C TI O N
1. 1. 
Ur ot heli al C arci n o m a
Ca ncers affecti n g t he s urface e pit heli u m of t he re nal c ollecti n g t u b ules, cal yces, pel vis, ureter, 
bla d der, a n d uret hra (c ollecti vel y “ ur ot heli u m”) are br oa dl y di vi de d i nt o t w o cate g ories: u p per 
tract ur ot helial carci n o ma ( U T U C), w hic h acc o u nts f or a p pr o xi matel y 5-1 0 % of cases; a n d 
uri nar y  bla d der ca ncer ( U B C), w hic h acc o u nts f or t he re mai n der (Mi yaza ki a n d Nis hi ya ma  
2 0 1 7 ).  U B C is m ore c o m m o n i n me n t ha n i n w o me n , wit h a ge-sta n dar dize d i nci de nce rates f or 
m ore de vel o pe d re gi o ns of ar o u n d 1 6. 3 per 1 0 0, 0 0 0 f or t he f or mer a n d 3. 6 per 1 0 0, 0 0 0 f or t he 
latter (Ferla y  et al. 2 0 1 0).  
F or patie nts wit h a d va nce d disease, s ys te mic plati n u m -base d c he m ot hera p y is t he sta n dar d 
treatme nt , a n d ma y i m pr o ve o verall s ur vi val ( O S) fr o m 6 m o nt hs or less wit h u ntreate d disease 
t o 1 2-1 5 m o nt hs   (v o n der Maase et al. 2 0 0 0 ; va n der Maase et al. 2 0 0 5).  H o we ver, l o n g-ter m 
pr o g n osis is p o or; t he 5 -year s ur vi val of patie nts wit h a d va nce d disease i s a p pr o xi matel y 1 5 %
(v o n der Maase et al. 2 0 0 5).  M ore o ver, plati n u m-base d c he m ot hera p y is ass ociate d wit h 
s u bsta ntial t o xicit y, w hic h ma y re n der it u ns uita ble f or s o me patie nts. Ne w t hera pe utic o pti o ns 
are nee de d f or patie nts wit h a d va nce d ur ot helial carci n o mas ( U C) w h o pr o gress o n or are n ot 
ca n di dates f or sta n dar d t hera p y.
1. 2. 
Pe m br oliz u m a b
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic
tra nsf or mati o ns has bee n k n o w n f or deca des ( Disis 2 0 1 0). Acc u m ulati n g e vi de nce s h o ws a 
c orrelati o n bet wee n t u m or- i nfiltrati n g ly m p h oc y tes i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n 
vari o us mali g na ncies. I n partic ular, t he prese nce of C D 8 + T -cells a n d t he rati o of C D 8 + effect or 
T- cells/ F o x P 3 + re g ulat or y T cells ( T-re gs) c orrelates wit h i m pr o ve d pr o g n osis a n d l o n g-ter m 
s ur vi val i n s oli d mali g na ncies, s uc h as o varia n, c ol orectal, a n d pa ncreatic ca ncer; he pat ocell ular 
carci n o ma; mali g na nt mela n o ma; a n d re nal cell carci n o ma.
T he pr o gra m me d deat h -li ga n d 1 ( P D-1) rece pt or -li ga n d i nteracti o n is a maj or pat h wa y t hat is 
hijac ke d b y t u m ors t o s u p press i m m u ne c o ntr ol. T he n or mal f u ncti o n of P D -1, e x presse d o n t he 
cell s urface of acti vate d T -cells u n der healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or 
e xcessi ve i m m u ne res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns.
Pe m br oliz u ma b is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y  ( m A b) 
wit h hi g h s pecificit y  of bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D-1) r ece pt or, t h us i n hi biti n g 
its i nteracti o n wit h pr o gra m me d cell deat h li ga n d 1 ( P D-L 1) a n d pr o gra m me d cell deat h li ga n d 2 
( P D-L 2). Base d o n precli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or 
bl oc ki n g acti vit y  f or P D-1. Pe m br oliz u m a b is i n dicate d f or t he treat me nt of patie nts acr oss a 
n u m ber of i n dicati o ns , a n d is ass ociate d wit h a n acce pta ble precli nical a n d cli nical safe y pr ofile 
as a n i ntra ve n o us (I. V.) i m m u n ot hera p y f or a d va nce d mali g na ncies.
Pri or st u dies ha ve de m o nstrate d t hat fi br o blast gr o wt h fact or rece pt or 3 (F G F R 3 )-m uta nt U Cs 
are ass ociate d wit h decrease d T -cell i nfiltrati o n. As F G F R 3 m utati o ns are e nric he d i n l u mi nal -
li ke U C, a n d l u mi nal-li ke U C has bee n s h o w n t o be relati vely less res p o nsi ve t o P D -1/ P D -L 1  
i n hi biti o n (c hec k p oi nt i n hi biti o n [ C PI]), t hese data ha ve le d t o t he s pec ulati o n t hat F G F R 3

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 6
m utati o ns ma y  be ca usall y relate d t o p o or T-cell i nfiltrati o n a n d t hat U C patie nts har b ori n g 
F G F R 3 m utati o ns ma y  be s u b o pti mal ca n di dates f or C PI s uc h as pe m br oliz u ma b.
H o we ver, W a n g et al. ( 2 0 1 8 ) deter mi ne d t hat w hile F G F R 3 -m uta nt U C is ass ociate d wit h a 
si milar t u m or m utati o nal b ur de n a n d l o wer T-cell i nfiltrati o n, it is als o ass ociate d wit h l o wer 
str o mal/tra nsf or mi n g gr o wt h fact or beta ( T G F-b) i m m u ne s u p pressi ve si g nals. T hese fi n di n gs 
s u g gest t hat F G F R 3 m utati o n stat us ma y  n ot i n fact be a bi o mar ker of resista nce t o C PI, a n d 
pr o vi des a rati o nale f or t he c o m bi nati o n of F G F R -tar gete d treat me nt wit h C PI treat me nt.
M ore o ver, rece ntl y p u blis he d data ( Pala k urt hi et al. 2 0 1 9 ) s h o ws t hat F G F R i n hi biti o n a n d 
a nti-P D -1 c o m bi nati o n i n d uce d si g nifica nt t u m or re gressi o n a n d i m pr o ve d s ur vi val. F or b ot h 
er dafiti ni b m o n ot hera p y a n d c o m bi nati o n treat me nts, t u m or c o ntr ol was acc o m pa nie d b y t u m or -
i ntri nsic, F G F R pat h wa y i n hi biti o n, i ncrease d T-cell i nfiltrati o n, decrease d re g ulat or y T cells, 
a n d d o w nre g ulati o n of P D- L 1 e x pressi o n o n t u m or cells. Fi nall y, F G F R i n hi biti o n ma y  als o 
m o d ulate t he t u m or micr oe n vir o n me nt i n n o n-F G F R 3 - m utate d t u m ors t hr o u g h t he bl oc ka de of 
paracri ne fi br o blast gr o wt h fact ors ( F G F) si g nali n g, tar geti n g i m m u ne e vasi o n a n d a n gi o ge nesis 
a n d lea d t o e n ha nce d efficac y w he n c o m bi ne d wit h pe m br oliz u ma b i n b ot h wil d -t ype ( W T) a n d 
F G F R 3 m utate d t u m ors ( Ic hi ka wa et al. 2 0 2 0; Li u et al. 2 0 1 4 ; Sief k er-Ra dt ke et al . 2 0 18 ).
1. 3. 
F uti b ati ni b  ( T A S-1 2 0)
1. 3. 1. 
B ac k gr o u n d
T he fi br o blast gr o wt h fact or/fi br o blast gr o wt h fact or rece pt or ( F G F/ F G F R) si g nali n g a xis has 
bee n well c haracterize d f or its r ole i n pr oliferati o n, differe ntiati o n, mi grati o n, a n d s ur vi val of 
cells, a n d it is f u n da me ntal t o e m br yo nic de vel o p me nt, re g ulati o n of a n gi o ge nesis, a n d w o u n d 
heali n g i n a d ults.  Acc or di n gl y, d ys re g ulati o n of t his si g nali n g pat h wa y has bee n ass ociate d wit h 
ma n y  de vel o p me ntal dis or ders a n d ca ncer.
F uti bati ni b is a n o vel a n d selecti ve s mal l m olec ule F G F R i n hi bit or, w hic h is t he first irre versi ble, 
c o vale nt i n hi bit or of F G F R 1 – 4 bei n g teste d i n h u ma ns.  F uti bati ni b selecti vel y  a n d irre versi bly 
bi n ds t o F G F R t o e xert a n i n hi bit or y  effect o n t he F G F/ F G F R pat h wa y. Precli nical st u dies ha ve 
s h o w n t hat f uti bati ni b selecti vely i n hi bits t he cell gr o wt h of h u ma n ca ncer cell li nes beari n g 
F G F R ge ne a b n or malities; str o n g a ntit u m or efficac y  has bee n o bser ve d wit h f uti bati ni b i n n u de 
m o use or n u de rat xe n o graft m o dels beari n g t u m ors wit h F G F R ge ne a b n or mal ities.
1. 3. 2.   
Cli nic al O ver vie w
As of 0 5 Se pte m ber 2 0 1 9, a t otal of 4 6 0 s u bjects ( 4 1 healt h y v ol u nteers a n d 4 1 9 patie nts) ha ve
bee n treate d wit h f uti bati ni b acr oss 4 cli nical trials . T o date, 2 cli nical st u dies i n healt h y 
v ol u nteers ha ve bee n c o m plete d, a n d 2 P hase 1- 2 st u dies assessi n g t he safet y , efficac y, a n d 
p har mac o ki netics ( P K) of f uti bati ni b i n a d va nce d ca ncers are c urre ntl y o n g oi n g.  
T he rec o m me n de d d ose a n d sc he d ule of f uti ba ti ni b is 2 0 m g Q D (c o nti n u o us dail y d osi n g), 
base d o n t he res ults of a P hase 1 d ose escalati o n st u d y  ( T A S- 1 2 0-1 0 1).  Acc or di n gl y, t he starti n g 
d ose of f uti bati ni b i n t his P hase 2 st u d y  is 2 0 m g Q D.
I n all, m ore t ha n 4 6 0 patie nts a n d healt hy v ol u nteers ha ve bee n treate d wit h f uti bati ni b acr oss all 
trials.  C ollecti vel y, safet y data fr o m t hese st u dies s u g gest t hat f uti bati ni b is ass ociate d wit h 
ma na gea ble t o xicit y  i n m ulti ple patie nt p o p ulati o ns. T he m ost fre q ue ntly re p orte d treat me nt -

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 7
relate d a d verse e ve nt ( AE) o verall has bee n h y p er p h os p hate mia (a mec ha nis m -base d e ve nt), 
m ostl y  of Gra des 1-2 a n d wit h o ut cli nical c o m plicati o ns.  Ot her fre q ue ntl y re p orte d treat me nt-
relate d A Es i ncl u de d t he gastr oi ntesti nal sys te m dis or ders of diarr h oea, dr y m o ut h, na usea, a n d 
st o matitis. S ki n t o xicit y a n d i ncrease d li ver e nzy m es ha ve als o bee n re p orte d, m ost of w hic h 
ha ve bee n mil d t o m o derate i n se verit y.  Oc ular t o xicities, w hic h ha ve bee n re p orte d wit h ot her 
F G F R i n hi bit ors, were o bser ve d wit h l o w fre q ue nc y  i n all trials.
E fficac y has bee n o bser ve d i n differe nt t u m or t y pes :

S oli d t u m ors har b ori n g F G F R 1 - 4 rearra n ge me nts, i ncl u di n g i ntra he patic 
c h ola n gi ocarci n o ma (i C C A), hea d a n d nec k, u n k n o w n pri mar y , a n d gastric ca ncer

Gastric ca ncer wit h F G F R 2 a m plificati o n

M yel oi d /l ym p h oi d n e o plas m wit h F G F R 1 rearra n ge me nt

Ot her s oli d t u m ors wit h differe nt F G F R a berrati o ns
Refer t o t he I n vesti gat or’s Br oc h ure f or m ore detaile d bac k gr o u n d i nf or mati o n o n f uti bati ni b .
1. 4. 
S u m m ar y of St u d y R ati o n ale
A d va nce d U C is ass ociate d wit h ver y p o or l o n g ter m pr o g n osis ; e ve n wit h sta n dar d t hera p y, t he 
maj orit y  of patie nts will pr o gress a n d t he 5-ye ar s ur vi val rate re mai ns o nl y a p pr o xi matel y  1 5 %.  
M ore o ver, ma n y patie nts are u na ble t o t olerate sta n dar d c he m ot hera p y;  f or s uc h patie nts, 
t hera pe utic o pti o ns are e ven m ore li mite d.   T here is e vi de nce t hat t he c o m bi nati o n of a P D -1/ P D -
L 1 i n hi bit or a n d a n F G F R i n hi bit or ma y  res ult i n treat me nt be nefit i n t his p o p ulati o n. T his P hase 
2 st u d y  will assess t he effect of pe m br oliz u ma b a n d f uti bati ni b o n patie nts wit h U C, i nclu di n g 
patie nts wit h F G F R 3 m utati o n / F G F R 1 - 4 f usi o n/rearra n ge me nt.

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2. 
O B J E C TI V E S A N D E N D P O I N T S
T he o bjecti ves a n d e n d p oi nts of t his st u d y  are s h o wn i n Ta ble 3 .  
A ll varia bles base d o n t u m or res p o nse will be calc ulate d base d o n t he Res p o nse E val uati o n 
Criteria i n S oli d T u m ors, Versi o n 1. 1 ( R E CI S T 1. 1), as well as i R E CIS T criteria.  T he pri mar y  
e val uati o n of efficac y will be base d o n R E CIS T 1. 1. All e val uati o ns of t u m or res p o nse will be 
per l ocal I n vesti gat or/ra di ol o gist assess me nt.
T a ble 3 :
O bjecti ves a n d E n d p oi nts
Pri m ar y
O bjecti ve res p o nse rate ( O R R) 
 
O R R, defi ne d as t he pr o p orti o n of patie nts 
e x perie nci n g a best o verall res p o nse of 
partial res p o nse ( P R) or c o m plete res p o nse 
( C R).
Sec o n d ar y 
 
Disease c o ntr ol rate ( D C R)
 
D urati o n of res p o nse ( D O R)
 
Pr o gressi o n -free s ur vi val (P F S )
 
O verall s ur vi val ( O S )
 
S afet y a n d t olera bilit y
 
D C R , defi ne d as t he pr o p orti o n of patie nts 
e x perie nci n g a best o verall res p o nse of 
sta ble disease ( S D), P R, or C R.
 
D O R defi ne d as t he ti me fr o m t he first 
d oc u me ntati o n of res p o nse ( C R or P R ) t o 
t he first d oc u me ntati o n of o bjecti ve t u m or 
p r o gressi o n or deat h d ue t o a n y ca use, 
w hic he ver occ urs first .
 
P F S, defi ne d as t he ti me fr o m first d ose of 
st u d y t hera p y t o t he date of deat h (a n y 
ca use) or disease pr o gressi o n , w hic he ver 
occ urs first .
 
O S, defi ne d as t he ti me fr o m t he date of first 
d ose t o t he deat h date.
 
Safet y base d o n re p orte d A Es a n d o n -st u d y 
la borat or y para meters, gra de d acc or di n g t o 
t he Nati o nal Ca ncer I nstit ute — C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts 
(N CI -C T C A E ), Versi o n 5. 0.
E x pl or at or y E n d p oi nts

 

 

 

 
 

 

 
 
C CI
C CI
C CI
C CI
C CI
C CI

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
2 9
3. 
I N V E S TI G A TI O N A L P L A N
3. 1. 
O ver vie w of St u d y Desi g n
St u d y  T A S- 1 2 0-2 0 3 is a n o pe n -la bel, n o nra n d o mize d, m ultice nter P hase 2 st u d y e val uati n g t he 
c o m bi nati o n of f uti bati ni b a n d pe m br oliz u ma b i n patie nts wit h a d va nce d or metastatic U C w h o 
are n ot ca n di dates t o recei ve a plati n u m -base d treate me nt re gi me n. 
T he desi g n is briefl y s u m marize d i n Fi g ure 1 .
A b brevi ati o ns: F G F R =fi br o bl ast gr o wt h f act or rece pt or; I. V. =i ntr ave n o us; m g = milli g ra ms; P D = pr o gressive 
dise ase;  P O = or al; Q D = d aily; Q 3 W =every 3 weeks; Tx =tre at me nt.
Fi g ure 1: 
St u d y Sc he m a
A treat me nt c y cle is defi ne d as 2 1 da ys. All e nr olle d patie nts will recei ve t he sa me treat me nt 
re gi me n:

F uti bati ni b at a n oral ( P O) d ose of 2 0 m g dail y ( Q D); a n d

Pe m br oliz u ma b at a n i ntra ve n o us (I. V.) d ose of 2 0 0 m g e ver y  3 wee ks ( Q 3 W).
Tre at me nt will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , or a n y ot her of t he 
criteria f or treat me nt disc o nti n uati o n is met; of n ote, pe m br oliz u ma b ma y  be a d mi nistere d f or a 
ma xi m u m of 3 5 d oses or a ma xi m u m d urati o n of 2 years, w hic he ver is ea rlier. 
T he st u d y  will be gi n wit h a safety lea d -i n peri o d. D uri n g t his peri o d, a t otal of 6 patie nts wit h 
a d va nce d or metastatic ur ot helial carci n o ma will be e nr olle d a n d treate d f or at least o ne 2 1 -d a y  
c ycle. Patie nts will be e nr olle d i nt o t his i nitial sa fet y lea d-i n peri o d wit h o ut re gar d f or F G F R
alterati o n stat us.
After t he first 6 patie nts ha ve c o m plete d o ne c y cle of treat me nt, t he first safet y a nalys is will 
occ ur. After c o nfir mati o n of t he safet y of t he c o m bi nati o n, a t otal of 2 0 a d diti o nal patie nts will 
be e nr olle d i nt o eac h of t he f oll o wi n g 2 c o h orts:
S af et y  l e a d-i n  p e r i o d  ( n = 6) 
Pts. n ot s el e ct e d f o r F G F R m ut a ti o n  st atus 
F uti b ati ni b P O 
2 0 m g Q D 
+ 
P e m br o li z u m a b I. V. 
2 0 0  m g Q 3 W 
1--- - -
I nt eri m A n a ly s is 
All p ts. 
r e c ei v e 1 
2 1 - d a y 
c y cl e 
of S af et y 
C o h ort  A  ( n = 2 0) 
F G F R 3 m ut ati o n  o r F G F R f usi o n/ r e a r r a n g e m e nt 
F uti b ati ni b P O 
2 0 m g Q D 
+ 
P e m br o li z u m a b I.V. 
2 0 0  m g Q 3 W 
T ot al of 1 0 p ts. 
(i n cl u di n g i niti al 6) 
re c ei v e 1 2 1- d a y  c y cl e 
C o h ort  B  ( n = 2 0) 
All ot h e r p ati e nt s wit h U C 
F u ti b ati nib P O 
2 0 m g Q D 
+ 
P e m br o liz u m a b I.V. 
2 0 0  m g Q 3 W 
S e c o n d  Int e ri m 
A n a l ys is 
of S af et y 
T x wil l c o nt in u e u nti l P D 
or ot h er di s c o nti n u ati o n 
crit eri a i s m et. 
P e m br o li zu m a b  m a y b e 
a d mi n ist er e d f or a 
m a xi m u m of 3 5 d o s e s 
(~ 2 y e ar s) 
T x w ill c o nt in u e u nti l P D 
or ot h er  di s c o nt in u ati o n 
crit eri a  is  m e t. 
P e m br o li z u m a b m a y  b e 
a d mi n ist er e d f or a 
m a x im u m of 3 5 d o s e s 
(~ 2 y e ar s) 

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 0

C o h ort A : Patie nts wit h U C a n d F G F R 3 m utati o n or F G F R f usi o n/rearra n ge me nt.
Patie nts will be e nr olle d base d o n l ocal res ults b ut tiss ue sa m ples will be arc hi ve d f or 
retr os pecti ve c o nfir mati o n at a ce ntral la b usi n g ne xt ge nerati o n se q ue nci n g ( N G S).

C o h ort B : All ot her patie nts wit h U C (i ncl u di n g patie nts wit h ot her F G F R or n o n -F G F R
a berrati o ns a n d patie nts wit h W T
[ n o n-m utate d] t u m ors) 
A sec o n d safet y a nal ysis will occ ur after e nr oll me nt of a t otal of 1 0 patie nts (i ncl u di n g t he 
6 patie nts fr o m t he safet y lea d -i n), i n or der t o c o nfir m t he safety pr ofile of t he c o m bi nati o n 
bef ore pr ocee di n g t o t he e nr oll me nt of t he re mai ni n g patie nts i n C o h orts A a n d B.
Please n ote: a t eac h safet y a nal ys is, t he c o m bi nati o n of f uti bati ni b a n d pe m br oliz u ma b will be 
c o nsi dere d i nt olera ble if t he i nci de nce of u nacce pta ble t o xicit y i ncl u di n g d ose-li miti n g t o xicit y
(as defi ne d i n Secti o n 5. 2 ) is ≥3 3 %. If t he c o m bi nati o n is deter mi ne d t o be i nt olera ble, t he st u dy 
ma y  c o nti n ue wit h a re d uce d d ose of f uti bati ni b ( 1 6 m g Q D) if me dically a p pr o priate i n t he 
o pi ni o n of t he I nvesti gat or a n d S p o ns or.
Of n ote, t he 6 patie nts i nitiall y  e nr olle d i n t he safet y lea d-i n peri o d will als o be assi g ne d t o t he 
res pecti ve c o h ort base d o n F G F R alterati o n, s uc h t hat eac h c o h ort will c o ntai n a mi ni m u m of 2 0 
a n d a ma xi m u m of 2 6 patie nts.
3. 2. 
St u d y Peri o d s a n d Visits f or E ac h P atie nt
T he st u d y  peri o ds / visits descri be d i n t his secti o n are defi ne d f or all patie nts.  P lease see Ta ble 1
( Sc he d ule of E ve nts) f or a n o utli ne of all assess me nts t o be perf or me d d uri n g eac h st u dy peri o d / 
visit.
F or all patie nts, t he Safet y  Assess me nt Peri o d be gi ns at t he ti me t he i nf or me d c o nse nt f or m 
(IC F) is si g ne d a n d c o nti n ues u ntil at least 9 0 da ys after t he last d ose of st u d y t hera p y. After t he 
3 0 -d a y  S afet y F oll o w -U p V isit (see bel o w), patie nts w h o ha ve n ot starte d tre at me nt wit h a ne w 
a nti-ca ncer t hera p y will be assesse d f or st u d y t hera p y-relate d seri o us a d verse e ve nts (S A Es )
o nl y .
F or eac h patie nt, t he St u d y D urati o n is defi ne d as t he ti me fr o m da y  of I C F si g nat ure t o t he last 
da y  of Disease Assess me nt F oll o w-u p / S ur vi val F oll o w -u p (see bel o w).
3. 2. 1. 
Scree ni n g Peri o d
T he Scree ni n g Peri o d is defi ne d as t he ti me fr o m w he n t he patie nt si g ns t he I CF u ntil t he date of 
first d ose of st u d y t hera p y.  Deter mi nati o n of eli gi bilit y is base d o n t he e ntr y criteria e n u merate d 
i n Secti o n 4 . N o pr ot oc ol -s pecific pr oce d ures or assess me nts ma y  be perf or me d pri or t o 
c o m pleti o n of t he IC F, e xce pt f or pr oce d ures t hat re prese nt sta n dar d- of- care.
3. 2. 2.  
Tre at me nt Peri o d a n d E n d of Tre at me nt Visit
Treat me nt disc o nti n uati o n ma y  occ ur f or a ny of t he reas o ns liste d i n Secti o n 4. 4 .  T he treat me nt 
peri o d is t he ti me fr o m first d ose of st u d y t hera p y ( Da y 1) t o t he date of last d ose of st u d y 
t hera py.  A n e n d - of-treat me nt ( E O T) visit m ust be perf or me d wit hi n 7 da ys after the decisi o n is 
ma de t o disc o nti n ue all st u d y t hera p y; at t his visit, e ver y eff ort s h o ul d be ma de t o perf or m t he 
assess me nts o utli ne d i n Ta ble 1 . F or patie nts w h o disc o nti n ue at a pla n ne d st u d y  visit, t hat visit 
ma y  be c o nsi dere d t he E O T visit if all assess me nts re q uire d at E O T are perf or me d.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 1
3. 2. 2. 1. 
S afet y F oll o w -U p Peri o d a n d 3 0 -D a y S afet y F oll o w -U p Visit 
T he safet y f oll o w-u p peri o d is t he ti me fr o m t he date of last d ose of st u d y t hera p y t hr o u g h t he 
safety f oll o w -u p visit s, w hic h m ust be perf or me d 3 0 , 6 0 a n d 9 0 da y s ( ± 3 da ys) f oll o wi n g t he last 
d ose of st u d y  t hera p y.  If t he patie nt starts ne w a ntica ncer t hera p y wit hi n 3 0 da ys of t he last d ose 
of st u d y t hera p y, t he 3 0-da y  safety f oll o w - u p visit s h o ul d be perf or me d bef ore t he start of new 
a ntica ncer t hera p y .  E ver y eff ort s h o ul d be ma de t o perf or m t he assess me nts o utline d i n Ta ble 1 .  
If t he patie nt is u na ble t o ret ur n t o t he st u d y site, a f oll o w-u p p h o ne call ca n be ma de b y t he 
st u d y site t o c ollect a ny ne w saf et y i nf or mati o n t hat occ urre d d uri n g t he safet y foll o w - u p p eri o d.
3. 2. 3. 
P ost -Disc o nti n u ati o n C o nsi der ati o ns
Patie nts w h o disc o nti n ue wit h o ut d oc u me nte d disease pr o gressi o n s h o ul d c o nti n ue t o u n der g o 
t u m or assess me nts acc or di n g t o t he Sc he d ule of E ve nts (t hat is, e ver y  9 wee ks ± 7 da y s) u ntil 
pr o gressi ve disease ( P D ) is d oc u me nte d, ne w a ntica ncer t hera py is i nitiate d, t he st u d y  is 
ter mi nate d, or t he patie nt dies, wit h dra ws c o nse nt, or is l ost t o f oll o w-u p).
3. 2. 4.  
S ur vi v al F oll o w -u p
O nce disease pr o gressi o n is c o nfir me d or ne w a ntica ncer t hera p y is i nitiate d, w hic he ver occ urs 
first, t he s ur vi val f oll o w-u p peri o d be gi ns.  D uri n g t his peri o d, t he patie nt or fa mil y  s h o ul d be 
c o ntacte d f or s ur vi val f oll o w -u p e ver y  1 2 weeks ( ± 2 wee ks ) u ntil patie nt wit h dra ws c o nse nt or 
t he st u d y is ter mi nate d earl y b y t he S p o ns or.  I n a d diti o n, all s u bse q ue nt a ntica ncer treat me nts 
will be rec or de d.
3. 2. 5. 
St u d y C o m pleti o n a n d St u d y E xte nsi o n
T he st u d y  will be c o nsi dere d c o m plete w he n :

S ur vi val e ve nts ( deat hs) ha ve bee n re p orte d f or 7 5 % of e nr olle d patie nts; or

T he trial is halte d earl y  f or a n y reas o n.
F oll o wi n g S t u d y C o m pleti o n, patie nts deri vi n g be nefit fr o m st u d y  t hera p y i n t he o pi ni o n of t he 
I n vesti gat or a n d S p o ns or ma y  be per mitte d t o c o nti n ue treat me nt wit h f uti bati ni b i n a St u d y 
E xte nsi o n p hase. D uri n g St u d y  E xte nsi o n, patie nts ma y recei ve treat me nt u ntil wit h dra wal 
criteria are met .
D uri n g t his peri o d, all safet y assess me nts are t o c o nti n ue acc or di n g t o t he sc he d ule i n Ta ble 2 . 
H o we ver, electr o nic data c ollecti o n will be re d uce d.  S pecificall y, st u d y e xte nsi o n data 
c ollecti o n is t o i ncl u de, at a mi ni m u m:

St u d y  dr u g a d mi nistrati o n;

St u d y  dr u g acc o u nta bilit y;

S A Es ;

N o n -seri o us A Es t hat are relate d t o st u d y treat me nt or res ult i n treat me nt 
disc o nti n uati o n; a n d

A n y  cases of pre g na nc y, o ver d ose, or me dicati o n err or.
--

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 2
4. 
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S
4. 1. 
I ncl usi on Criteri a
A patie nt m ust meet all of t he f oll o wi n g criteria t o be eli gi ble f or partici pati o n i n t his st u d y ; 
wai vers will n ot be gra nte d f or a n y of t he el gi bilit y criteria.
1.
Hist ol o gicall y c o nfir me d a d va nce d or metastatic U C i n patie nts w h o ha ve n ot recei ve d 
s yste mic treat me nt f or a d va nce d metastatic disease. F or patie nts w h o recei ve d pri or 
a dj u va nt/ ne oa dj u va nt c he m ot hera p y or c he m o -ra diati o n f or ur ot helial carci n o ma, a 
treat me nt-free i nter val > 1 2 m o nt hs bet wee n t he last treat me nt a d mi nistrati o n a n d the date 
of rec urre nce is re q uire d i n or der t o be c o nsi dere d treat me nt - naï ve i n t he metastatic 
setti n g.
a.
I n safety lea d -i n: e nr oll me nt re gar dless of F G F R stat us
b.
C o h ort A: m ust ha ve a n F G F R 3 m utati o n or F G F R 1 - 4 f usi o n/rearra n ge me nt
c.
C o h ort B: all ot her patie nts wit h U C (i ncl u di n g patie nts wit h ot her F G F R or n o n -
F G F R ge netic a berrati o ns a n d patie nts wit h W T
[ n o n m utate d] t u m ors)
2.
U nfit f or or i nt olera nt t o sta n dar d plati n u m -base d c he m ot hera p y as defi ne d b y a ny o ne of 
t he f oll o wi n g criteria:
a.
C hr o nic ki d ne y  disease c haracterize d b y t he esti mate d creati ni ne cleara nce rate 
(e C Cr) per C oc kcr oft-Ga ult f or m ula of < 6 0 m L / mi n or esti mate d g l o mer ular 
filtrati o n rate (e G F R) of < 6 0 m L/ mi n/ 1. 7 3 m2, c orres p o n di n g t o N CI-C T C A E 
v. 5. 0 Gra de ≥2
b.
I m paire d heari n g ( meas ure d by a u di o metr y) of > 2 5 d B at t w o c o nti g u o us test 
fre q ue ncies i n at least o ne ear, c orres p o n di n g t o N CI-C T C A E v .5. 0 Gra de ≥2
c.
Peri p heral se ns or y  ne ur o pat h y Gra de ≥2 b y  N CI-C T C A E v. 5. 0
d.
Patie nt ref usal 
e.
I n t he o pi ni o n of t he I n vesti gat or, t he patie nt is c o nsi dere d i neli gi ble t o recei ve 
a n y plati n u m- base d c he m ot hera py  
3.
Be willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt f or t he trial. 
4.
Be ≥1 8 y ears of a ge .
5.
Ha ve a n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us ( P S) of 
0 t o 1.
6.
A de q uate or ga n f u ncti o n as defi ne d b y t he f oll o wi n g criteria:
a.
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 × 1 0 9/ L
b.
Platelet c o u nt ≥1 0 0, 0 0 0/ m m 3
c.
He m o gl o bi n ≥9. 0 g/ d L
d.
Ala ni ne a mi n otra nsferase ( A L T ) a n d as partate a mi n otra nsferase ( A S T) ≤2. 5 × 
u p per li mit of n or mal ( U L N); if li ver f u ncti o n a b n or malities are d ue t o u n derl yi n g 
li ver metastasis, A S T a n d A LT ≤5. 0 × U L N.
--

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 3
e.
T otal bilir u bi n ≤1. 5 × U L N, or ≤3. 0 × U L N f or patie nts wit h Gil bert’s s y n dr o me.
f.
Creati ni ne cleara nce ( Ccr) (calc ulate d or meas ure d val ue): ≥3 0 m L / mi n. F or 
calc ulate d Ccr, use t he C oc kcr oft -Ga ult f or m ula.
g.
I nter nati o nal n or malize d rati o (I N R) O R pr ot hr o m bi n ti me ≤1. 5 × U L N u nless 
partici pa nt is recei vi n g a ntic oa g ula nt t hera p y as l o n g as pr ot h r o m bi n ti me or 
a P T T is wit hi n t hera pe utic ra n ge of i nte n de d use of a ntic oa g ula nts
h.
P h os p h or us < 1. 5 U L N
7.
A de q uate rec o ver y  fr o m t he si de effects of a n y pri or t hera p y f or n o n metastatic disease
( ge nerall y defi ne d as rec o ver y of all A Es d ue t o ≤ Gra de 1 or base li ne; h o we ver, patie nts 
wit h ≤ Gra de 2 ne ur o pat h y , a ne mia, al o pecia, a n d s ki n pi g me ntati o n ma y be eli gi ble).
8.
Ha ve pr o vi de d arc hi val t u m or tiss ue sa m ple or ne wl y  o btai ne d c ore or e xcisi o nal bi o ps y 
of a t u m or lesi o n n ot pre vi o usl y  irra diate d. F or mali n-fi xe d, paraffi n e m be d de d tiss ue 
bl oc ks are preferre d t o sli des. Ne wl y o btai ne d bi o psies are preferre d t o arc hi ve d tiss ue.
9.
Ha ve a meas ura ble disease per R E CI S T 1. 1, as assesse d b y  t he l ocal site 
I n vesti gat or/ra di ol o g y. Lesi o ns sit uate d i n a pre vi o usl y irra diate d area are c o nsi dere d 
meas ura ble if pr o gressi o n has bee n de m o nstrate d i n s uc h lesi o ns. 
1 0. A male patie nt m ust a gree t o use c o ntrace pti o n d uri n g t he treat me nt peri o d a n d f or at 
least 6 m o nt hs f oll o wi n g t he last d ose of st u d y  treat me nt.
1 1. A fe male patie nt is eli gi ble t o partici pate if s he is n ot pre g na nt, n ot breastfee di n g, a n d at 
least o ne of t he f oll o wi n g c o n diti o ns a p plies: 
a.
N ot a w o m a n of c hil d beari n g p ote ntial ( W O C B P).
b.
A W O C B P w h o a grees t o f oll o w c o ntrace pti ve g ui da nce d uri n g t he treat me nt 
peri o d a n d f or at least 6 m o nt hs after t he last d ose of st u d y  treat me nt.
c.
A W O C B P w h o has a ne gati ve ser u m pre g na nc y  test wit hi n 7 da ys pri or t o 
treat me nt.
1 2. A bilit y  t o ta ke me dicati o ns orall y  (fee di n g t u be is n ot per mitte d).
1 3. Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits a n d st u d y pr oce d ures.
4. 2. 
E xcl usi o n Criteri a
A patie nt m ust n ot meet a n y of t he f oll o wi n g e xcl usi o n criteria t o be eli gi ble f or partici pati o n i n 
t his st u d y; wai vers will n ot be gra nte d f or a n y  of t he el gi bilit y criteria.
1.
Ha ve recei ve d pri or t hera p y  wit h a nti-P D -1, a nti -P D -L 1/ L 2 a ge nt. 
2.
Ha ve recei ve d pri or F G F R i n hi bit or treat me nt i ncl u di n g f uti bati ni b
3.
Hist or y  a n d/ or c urre nt e vi de nce of a n y of t he f oll o wi n g dis or ders:
a.
N o n -tu m or relate d alterati o n of t he calci u m -p h os p h or us h o me ostasis t hat is 
c o nsi dere d cli nicall y si g nifica nt i n t he o pi ni o n of t he I n vesti gat or
--

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 4
b.
Ect o pic mi neralizati o n/calcificati o n, i ncl u di n g b ut n ot li mite d t o s oft tiss ue, 
ki d ne y s, i ntesti ne, or my ocar dia a n d l u n g, c o nsi dere d cli nically si g nifica nt i n t he 
o pi ni o n of t he I n vesti gat or
c.
Reti nal or c or neal dis or der c o nfir me d b y reti nal/c or neal e xa mi nati o n a n d 
c o nsi dere d cli nicall y si g nifica nt i n t he o pi ni o n of t he I n vesti gat or.
4.
C orrecte d Q T i nter val usi n g Fri dericia ’s f or m ula ( Q Tc F) > 4 7 0 msec. Patie nts wit h a n 
atri o ve ntric ular pace ma ker or ot her c o n diti o n (f or e xa m ple, ri g ht b u n dle bra nc h bl oc k) 
t hat re n ders t he Q T meas ure me nt i n vali d are a n e xce pti o n a n d t he criteri o n d oes n ot 
a p pl y.
5.
Has recei ve d maj or s ur ger y  wit hin t he pre vi o us 4 wee ks. 
6.
Has recei ve d a n y n o n -i n vesti gati o nal a ntica ncer t hera p y wit hi n t he pre vi o us 3 wee ks 
( mit o m yci n wit hi n t he pre vi o us 5 wee ks).
7.
Is c urre ntl y partici pati n g i n a st u d y of a n i n vesti gati o nal a ge nt/ de vice, or has partici pate d 
i n a st u d y of a n i n vesti gati o nal a ge nt or use d a n i n vesti gati o nal de vice wit hi n 4 wee ks 
pri or t o t he first d ose of st u d y  treat me nt.  
8.
Has recei ve d a li ve vacci ne wit hi n 3 0 da y s pri or t o t he first d ose of st u d y dr u g. E xa m ples 
of li ve vacci nes i ncl u de, b ut are n ot li mit e d t o, t he f oll o wi n g:  measles, m u m ps, r u bella, 
varicella/z oster (c hic ke n p o x), y ell o w fe ver, ra bies, Bacill us Cal mette – G uéri n ( B C G), 
a n d t yp h oi d vacci ne. Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y  kille d vir us 
vacci nes a n d are all o we d; h o we ve r, i ntra nasal i nfl ue nza vacci nes (e. g., Fl u Mist ®) are 
li ve atte n uate d vacci nes a n d are n ot all o we d.
9.
A seri o us ill ness or me dical c o n diti o n(s) i ncl u di n g, b ut n ot li mite d t o, t he f oll o wi n g:
a.
Has a n acti ve i nfecti o n re q uiri n g sys te mic t hera p y.
b.
M y ocar dial i nfar cti o n, se vere/ u nsta ble a n gi na, or s y m pt o matic c o n gesti ve heart 
fail ure wit hi n t he pre vi o us 6 m o nt hs
c.
Hist or y  or c urre nt e vi de nce of u nc o ntr olle d ve ntric ular arr h yt h mia
d.
C hr o nic diarr hea diseases c o nsi dere d t o be cli nicall y  si g nifica nt i n t he o pi ni o n of 
t he In vesti gat or
e.
C o n ge nital l o n g Q T s y n dr o me, or a n y k n o w n hist or y of t orsa de de p oi ntes, or 
fa mil y hist or y of u ne x plai ne d s u d de n deat h
f.
Ha ve a n acti ve a ut oi m m u ne disease t hat has re q uire d s ys te mic treat me nt i n t he 
past 2 y ears (t hat is, wit h use of disease m o di f yi n g a ge nts, c ortic oster oi ds, or 
i m m u n os u p pressi ve dr u gs). Re place me nt t hera py (f or e xa m ple, t h yr o xi ne, i ns uli n, 
or p h y si ol o gic c ortic oster oi d re place me nt t hera p y f or a dre nal or pit uitar y 
i ns ufficie nc y) is n ot c o nsi dere d a f or m of sys te mic treat me nt a n d is all o we d.
g.
Ha ve a hist or y  of ( n o ni nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
h.
Ha ve ha d a n all o ge nic tiss ue/ or ga n tra ns pla nt.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 5
1 0. Has k n o w n h u ma n i m m u n o deficie nc y  vir us ( HI V) a n d/ or hist or y of He patitis B or C 
i nfecti o ns, or k n o w n t o be p ositi ve f or He patitis B a nti ge n ( H Bs A g)/ He patitis B vir us 
( H B V) D N A or He patitis C A nti b o d y or R N A. Acti ve He patitis C is defi ne d b y a k n o w n 
p ositi ve He p C A b res ult a n d k n o w n q ua ntitati ve H C V R N A res ults greater t ha n t he 
l o wer li mits of detecti o n of t he assa y .
1 1. Has a hist or y  or c urre nt e vi de nce of a n y c o n diti o n, t hera py, or la b orat or y a b n or malit y  
t hat mi g ht c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he partici pa nt's partici pati o n 
f or t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he partici pa nt t o 
partici pate, i n t he o pi ni o n of t he treati n g I n vesti gat or.
1 2. Ha ve k n o w n acti ve ce ntral ner v o us s ys te m metastases a n d/ or carci n o mat o us me ni n gitis. 
Patie nts wit h pre vi o usl y  treate d brai n metastases ma y partici pate pr o vi de d t he y are 
ra di ol o gicall y sta ble, t hat is, wit h o ut e vi de nce of pr o gressi o n f or at least 4 wee ks b y 
re peat i ma gi n g ( n ote t hat t he re peat i ma gi n g s h o ul d be perf or me d d uri n g st u d y 
scree ni n g), cli nically sta ble, a n d wit h o ut ster oi d treat me nt re q uire me nt f or at least 
1 m o n t h pri or t o t he first d ose of st u d y treat me nt. 
1 3. T he patie nt is pre g na nt or breastfee di n g.
1 4. Has a dia g n osis of i m m u n o deficie nc y  or is recei vi n g c hr o nic sys te mic ster oi d t hera py (i n 
d osi n g e xcee di n g 1 0 m g dail y  of pre d nis o ne e q ui vale nt) or a ny ot her f or m of 
i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t he first d ose of st u d y dr u g.
1 5. Has a k n o w n a d diti o nal mali g na nc y  t hat is pr o gressi n g or has re q uire d acti ve treat me nt 
wit hi n t he past 2 y ears.  Partici pa nts wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell 
carci n o ma of t he s ki n, or carci n o ma i n sit u (e. g., breast carci n o ma, cer vical ca ncer i n 
sit u) t hat ha ve u n der g o ne p ote ntiall y c urati ve t hera p y are n ot e xcl u de d.
1 6. Has se vere h y perse nsiti vit y  (≥Gra de 3) t o pe m br oliz u ma b a n d/ or a n y  of its e xci pie nts.
1 7. Has a k n o w n ps yc hi atric or s u bsta nce a b use dis or der t hat w o ul d i nterfere wit h t he 
partici pa nt’s a bilit y  t o c o o perate wit h t he re q uire me nts of t he st u d y.
4. 3. 
Scree n F ail ure 
Scree n fail ures are defi ne d as patie nts w h o c o nse nt t o partici pate i n t he cli nical st u d y  b ut are n ot 
s u bse q ue ntl y e nr olle d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o 
e ns ure tra ns pare nt re p orti n g of scree n fail ure patie nts t o res p o n d t o q ueries fr o m re g ulat or y  
a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y , scree n fail ure details, eli gi bilit y criteria, 
a n d a n y S A E after c o m pleti o n of t he IC F. 
Patie nts w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y  (scree n fail ure) ma y be 
rescree ne d a ma xi m u m of 3 ti mes. Rescree ne d patie nts s h o ul d be assi g ne d t he sa me s u bject 
i de ntificati o n c o de as f or t he i nitial scree ni n g.
4. 4. 
Disc o nti n u ati o n of Tre at me nt
P e m br oliz u ma b ma y be a d mi nistere d f or a ma xi m u m of 3 5 d oses or a ma xi m u m d urati o n of 
2 ye ars, w hic he ver is earlier.  T here is n o ma xi m u m d urati o n of f uti bati ni b t hera p y. A patie nt 
will be disc o nti n ue d fr o m a n y or all st u d y t hera p y f or a n y of t he f oll o wi n g reas o ns: 

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 6
1.
Disease pr o gressi o n
2.
U nacce pta ble A Es, or c ha n ge i n u n derl yi n g c o n diti o n s uc h t hat t he patie nt ca n n o l o n ger 
t olerate t hera py, as e vi de nce d b y a d ose dela y > 2 1 da y s fr o m t he sc he d ule d start date of 
t he ne xt c ycle or nee d f or m ore t ha n 2 d ose re d ucti o ns o utli ne d i n t his pr ot oc o l.  If s uc h 
t o xicit y is ass ociate d wit h o nl y 1 of t he treat me nt c o m p o ne nts (f uti bati ni b or 
pe m br oliz u ma b), t he patie nt ma y  disc o nti n ue t hat c o m p o ne nt a n d c o nti n ue recei vi n g t he 
ot her if me dicall y a p pr o priate i n t he o pi ni o n of t he I nvesti gat or .
3.
P h y sicia n’s decisi o n, i ncl u di n g nee d f or ot her a ntica ncer t hera p y n ot s pecifie d i n t he 
pr ot oc ol or s ur ger y  or ra di ot hera p y t o t he o nl y  site(s) of disease bei n g f oll o we d i n t he 
st u d y
4.
Pre g na nc y
5.
Ter mi nati o n of t he st u d y b y  t he S p o ns or, or
6.
At t he patie nt’s re q uest at a n y  ti me irres pecti ve of t he reas o n. 
Patie nts w h o wit h dra w c o nse nt f or f urt her treat me nt ma y c h o ose t o re mai n o n st u d y; i n s uc h a
case, all st u d y e val uati o ns s h o ul d c o nti n ue as o utli ne d i n t his pr ot oc ol.   If t he patie nt wit h dra ws
c o nse nt t o all f oll o w- u p assess me nts, t he patie nt s h o ul d be c o nsi dere d t o ha ve disc o nti n ue d t he
st u d y as descri be d i n Secti o n 4. 5 .
4. 5. 
Wit h dr a w al fr o m t he St u d y
A patie nt m a y  be wit h dra w n fr o m all st u d y i nter ve nti o ns a n d assess me nts (t hat is, disc o nti n ue d 
fr o m t he st u d y wit h o ut f oll o w-u p) f or a n y of t he f oll o wi n g reas o ns: 
1.
Deat h
2.
L os t t o f oll o w- u p

A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o 
ret ur n f or sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y site.

T he f oll o wi n g acti o ns m ust be ta ke n if a patie nt fails t o ret ur n t o t he cli nic f or a 
re q uire d st u dy visit :

T he site m ust atte m pt t o c o ntact t he patie nt a n d resc he d ule t he misse d visit as 
s o o n as p ossi ble a n d c o u nsel t he patie nt o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he patie nt wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st ud y .

Bef ore a patie nt is dee me d l ost t o f oll o w u p, t he In vesti gat or or desi g nee m ust 
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he patie nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he patie nt’s last k n o w n maili n g a d dress 
or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he 
pa tie nt’s me dical rec or d.

S h o ul d t he pa tie nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 7
3.
Patie nt wit h dra wal of c o nse nt t o f urt her f o ll o w- u p assess me nts, irres pecti ve of t he 
reas o n.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 8
5. 
S T U D Y T R E A T M E N T
5. 1. 
St u d y Dr u g A d mi nistr ati o n
Please n ote: at a n y ti me p oi nt w here f uti bati ni b a n d pe m br oliz u ma b are a d mi nistere d o n t he sa me 
da y , pe m br oliz u ma b s h o ul d be a d mi nistere d pri or t o f uti bati ni b if p ossi ble. A st u d y  c ycle is 
defi ne d as 2 1 d a y s.
5. 1. 1. 
F uti b ati ni b
F uti bati ni b is s u p plie d as 4 m g ta blets a n d will be ta ke n orall y at a d ose of 2 0 m g dail y u ntil t he 
patie nt meets a n y of t he a d mi nistrati o n disc o nti n uati o n criteria (see Secti o n 4. 4 ).  
F uti bati ni b s h o ul d be a d mi nistere d u n der fasti n g c o n diti o ns.  I t s h o ul d be ta ke n wit h a glass of 
water, o n a n e m pt y  st o mac h, at a p p r o xi matel y t he sa me ti me eac h da y. N o f o o d s h o ul d be 
c o ns u me d f or 2 h o urs pri or a n d 1 h o ur after t he d ose of f uti bati ni b, b ut patie nts ma y dri n k water 
d uri n g t his peri o d.
I n t he e ve nt of a d osi n g dela y u p t o 1 2 h o urs after t he sc he d ule d d osi n g ti me, t he patie nt s h o ul d 
still ta ke t hat da y’s d ose.  If t he d osi n g dela y c o nti n ues f or > 1 2 h o urs after t he sc he d ule d d osi n g 
ti me, or if t he patie nt v o mits after a d ose, t he patie nt s h o ul d s ki p d osi n g f or t hat da y a n d n ot 
ma ke u p f or it t he f oll o wi n g da y .
5. 1. 2. 
Pe m br oliz u m a b
Pe m br oliz u ma b is a d mi nistere d as a n I. V. i nf usi o n of 2 0 0 m g o n Da y  1 of eac h c ycle (t hat is, 
e ver y 3 wee ks).  Treat me nt c o nti n ues f or a ma xi m u m of 3 5 d oses or a ma xi m u m d urati o n of 
2 ye ars ( w hic he ver is earlier), or u ntil t he patie nt meets a n y of t he a d mi nistrati o n disc o nti n uati o n 
criteria (see Secti o n 4. 4 ).  
Pe m br oliz u ma b s h o ul d be a d m i nistere d acc or di n g t o t he i nstr ucti o ns o n t he a p pr o ve d pr o d uct 
label.
5. 2. 
Defi niti o n of D ose -Li miti n g T o xicit y
F or t his st u d y , u nacce pta ble t o xicit y will i ncl u de a n y e ve nt meeti n g t he criteria f or d ose-li miti n g 
t o xicit y ( D L T), as o utli ne d bel o w.  A n a d verse eve nt n ot meeti n g t he criteria f or a D L T ma y  als o 
be c o nsi dere d a n u nacce pta ble t o xicit y , if it is n ot t olera ble i n t he l o n g-ter m a n d necessitates 
disc o nti n uati o n of o ne or m ore ele me nts of t he c o m bi nati o n t hera p y .
D L T Defi niti o n
All t o xicities will be gra d e d usi n g t he Nati o nal Ca ncer I nstit ute – C o m m o n Ter mi n ol o g y  Criteria 
f or A d verse E ve nts ( N CI- C T C A E) Versi o n 5. 0, base d o n I n vesti gat or assess me nt. T he 
occ urre nce of a n y of t he f oll o wi n g t o xicities d uri n g C ycle 1 will be c o nsi dere d a D L T, if 
assesse d b y t he I n vesti gat or t o be relate d t o st u dy treat me nt a d mi nistrati o n.  

Gra de 4 n o n he mat ol o gic t o xicit y  ( n ot la b orat or y)

Gra de 4 ne utr o pe nia lasti n g > 5 d a y s

Gra de 4 t hr o m b oc y t o pe nia of a n y d urati o n

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
3 9

Gra de 3 t hr o m b oc yt o pe nia ass ociate d wit h cli nicall y  si g nifica nt blee di n g

A n y  n o n he mat ol o gic A E ≥Gra de 3 i n se verit y, wit h t he f oll o wi n g e xce pti o ns: 
o
Gra de 3 fati g ue lasti n g ≤3 da y s; 
o
Gra de 3 diarr hea, na usea, or v o miti n g wit h o ut use of a nti -e metics or a nti-
diarr heals per sta n dar d of care; 
o
Gra de 3 ras h wit h o ut us e of c ortic oster oi ds or a nti- i nfla m mat or y a ge nts per 
sta n dar d of care.

A n y  Gra de 3 or Gra de 4 n o n he mat ol o gic la b orat or y val ue if:
o
Cli nicall y  si g nifica nt me dical i nter ve nti o n is re q uire d t o treat t he patie nt, or
o
T he a b n or malit y lea ds t o h os pitalizati o n, or
o
T he a b n or malit y d oes n ot rec o ver t o Gra de ≤1 wit hi n 4 8 h o urs des pite best 
s u p p orti ve care, or
o
T he a b n or malit y res ults i n a dr u g i n d uce d li ver i nj ur y
o
E xce pti o ns: cli nicall y  n o nsi g nifica nt, treata ble, or re versi ble la b orat or y 
a b n or malities i ncl u di n g li ver f u ncti o n tests, uric aci d, h y per p h os p hate mia, etc.

Fe brile ne utr o pe nia Gra de 3 or Gra de 4:
o
Gra de 3 is defi ne d as A N C < 1 0 0 0/ m m 3 wit h a si n gle te m perat ure of > 3 8. 3° C 
( 1 0 1° F) or a s ustai ne d te m perat ure of ≥3 8° C ( 1 0 0. 4° F) f or m ore t ha n 1 h o ur
o
Gra de 4 is defi ne d as A N C < 1 0 0 0/ m m 3 wit h a si n gle te m perat ure of > 3 8. 3° C 
( 1 0 1° F) or a s ustai ne d te m perat ure of ≥3 8° C ( 1 0 0. 4° F) f or m ore t ha n 1 h o ur, wit h 
life-t hreate ni n g c o nse q ue nces a n d ur ge nt i nter ve nti o n i n dicate d.

Gra de 3 or hi g her vis ual i m pair me nt 

Pr ol o n ge d dela y  ( > 2 wee ks) i n i nitiati n g C ycle 2 d ue t o treat me nt-relate d t o xicit y

A n y  treat me nt-relate d t o xicit y t hat ca uses t he partici pa nt t o disc o nti n ue treat me nt 
d uri n g C ycle 1

Missi n g > 2 0 % of f uti bati ni b d oses as a res ult of dr u g-relate d A E(s) d uri n g  C y cle 1

Gra de 5 t o xicit y
5. 3. 
D ose a n d Sc he d ule M o dific ati o ns 
5. 3. 1. 
D ose M o dific ati o ns f or F uti b ati ni b
Ste p wise d ose re d ucti o ns t o 1 6 m g Q D (first re d ucti o n) a n d 1 2 m g Q D (sec o n d re d ucti o n) are 
per mitte d base d o n t o xicities.  I f d ose re d ucti o n fails t o res ult i n ac hie vi n g t he mi ni mal criteria t o 
res u me treat me nt or, if t o xicities occ ur w hic h w o ul d necessitate re d ucti o n of t he d ose of 
f uti bati ni b bel o w 1 2 m g Q D, t he patie nt s h o ul d be disc o nti n ue d fr o m f uti bati ni b. 

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 0
F oll o wi n g a d o se re d ucti o n, if a be nefit/ris k assess me nt fa v ors a n i ncrease of f uti bati ni b d ose u p 
t o t he i nitial starti n g d ose ( 2 0 m g Q D, or 1 6 m g Q D if t his is deter mi ne d as t he rec o m me n de d 
d ose ), a n a gree me nt wit h t he Sp o ns or’s m e dical m o nit or is re q uire d pri or t o t h e d ose i ncrease. 
If t o xicities relate d t o t he d ose re d ucti o n d o n ot rec o ver base d o n t he criteria defi ne d i n t he 
f oll o wi n g secti o ns wit hi n 2 1 da y s after t he last d ose of f uti bati ni b, t he patie nt will be 
disc o nti n ue d per ma ne ntl y  fr o m treat me nt (Secti o n 4. 4 ). If res u m pti o n criteria are met wit hi n 
2 1 da y s of t he last d ose of f uti bati ni b, t he patie nt ma y res u me f uti bati ni b treat me nt at t he 
a p pr o priate d ose le vel.
5. 3. 1. 1. 
F uti b ati ni b D ose M o dific ati o ns f or N o n he m at ol o gic T o xicities
D osi n g m o dificati o n g ui deli nes f or n o n he mat ol o gic a n d e ye t o xicities are pr o vi de d in Ta ble 4
a n d Ta ble 5 , res pecti vely.
T a ble 4 :
D ose M o dific ati o ns f or Rel ate d N o n he m at ol o gic T o xicities
Gr a de
D ose 
I nterr u pti o n/ Res u m pti o n
D ose A dj ust me nt
Gra de 1 or 2 
Mai ntai n treat me nt at t he sa me 
d ose le vel
N o ne
Gra de 3
Wit h h ol d treat me nt u ntil 
ret ur n t o baseli ne or Gra de ≤1
Re d uce b y 1 d ose le vel fr o m t he pre vi o us le vel, e xce pt f or 
Gra de 3 na usea a n d/ or v o miti n g c o ntr olle d b y a g gressi ve 
a ntie metic t hera p y or Gra de 3 diarr hea res p o nsi ve t o 
a nti diarr heal me dicati o n w hic h d oes n ot re q uire a d ose h ol d 
or re d ucti o n.
Gra de 4  
Disc o nti n ue treat me nt  
Per m a ne nt disc o nti n uati o n of f uti bati ni b.
Gra de 4 (la b 
a b n or malit y A E)
Wit h h ol d treat me nt u ntil 
ret ur n t o baseli ne or Gra de ≤1
F uti bati ni b will be per ma ne ntl y disc o nti n ue d if assesse d b y 
t he In vesti gat or as life t hreate ni n g.  If it is i n t he best i nterest 
of t he patie nt t o c o nti n ue treat me nt i n t he o pi ni o n of t he 
In vesti gat or a n d after disc ussi o n wit h t he S p o ns or, t he patie nt 
ca n c o nti n ue treat me nt at a re d uce d d ose le vel. H o we ver, 
f uti bati ni b s h o ul d first be hel d u ntil t o xicit y ret ur ns t o 
baseli ne or Gra de ≤1.
A b brevi ati o ns: A E = a dverse eve nt; A L T = al a ni ne a mi n otr a nsfer ase; A S T = as p art ate a mi n otr a nsfer ase. 
N ote:  I nterr u pt f uti bati ni b if a n y t o xicities are i nt olera ble, re gar dless of t he gra de (i ncl u di n g Gra de 1 a n d 2). If or w he n t he 
t o xicit y res ol ves t o a t olera ble state, c o nsi derati o n ca n be gi ve n t o res u mi n g f uti bati ni b at t he sa me d ose if dee me d a p pr o priate 
or re d uce d b y o ne d ose le vel if nee de d.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 1
T a ble 5 :
D ose M o dific ati o ns f or Rel ate d E ye T o xicities
Gr a de a n d Defi niti o n 
St u d y Dr u g M a n a ge m e nt
Gra de 1
If t here is n o e vi de nce of e ye t o xicit y o n o p ht hal m ol o gic e xa mi nati o n, c o nti n ue
f uti bati ni b t hera p y at t he sa me d ose le vel.
If dia g n osis fr o m o p ht hal m ol o gic e xa mi nati o n is keratitis or reti nal a b n or malit y 
s uc h as ce ntral ser o us reti n o pat h y ( C S R)/ reti nal pi g me nt e pit helial detac h me nts 
( R P E D), wit h h ol d f uti bati ni b u ntil si g ns a n d s y m pt o ms ha ve res ol ve d.
If t o xicit y is re versi ble (c o m plete res ol uti o n or sta bilizati o n a n d as y m pt o matic) i n 
4 w ee ks acc or di n g t o o p ht hal m ol o gic e xa mi nati o n, res u me f uti bati ni b t hera p y at 
t he ne xt l o wer d ose le vel after c o ns ultati o n wit h t he me dical m o nit or.
M o nit or f or rec urre nce e ver y 1 t o 2 w ee ks f or a m o nt h a n d as cli nicall y 
a p pr o priate t hereafter. If t here is n o rec urre nce t he n re -escalati o n ca n be 
c o nsi dere d i n c o ns ultati o n wit h t he me dical m o nit or. a
Gra de 2 
Wit h h ol d f uti bati ni b t hera p y.
If t here is n o e vi de nce of dr u g -relate d c or neal or reti nal pat h ol o g y o n 
o p ht hal m ol o gic e xa mi nati o n, wit h h ol d f uti bati ni b u ntil si g ns a n d s y m pt o ms ha ve 
res ol ve d. Res u me f uti bati ni b t hera p y at t he ne xt l o wer d ose le vel.
If dia g n osis fr o m o p ht hal m ol o gic e xa mi nati o n is keratitis or reti nal a b n or malit y, 
wit h h ol d f uti bati ni b u ntil si g ns a n d s y m pt o ms ha ve res ol ve d or sta bilize d.
If t o xicit y is Gra de 2 a n d re versi ble (c o m plete res ol uti o n or sta bilizati o n a n d 
as y m pt o matic) wit hi n 4 wee ks acc or di n g t o o p ht hal m ol o gic e xa mi nati o n, res u me 
f uti bati ni b t hera p y at t he ne xt l o wer d ose le vel after c o ns ultati o n wit h t he me dical 
m o nit or.
Gra de 3 
If t he t o xicit y is Gra de 3, re p ort as a seri o us a d verse e ve nt a n d per ma ne ntl y 
disc o nti n ue f uti bati ni b. If, h o we ver, t he t o xicit y is Gra de 3 a n d r e versi ble 
(c o m plete res ol uti o n or sta bilizati o n a n d as y m pt o matic) wit hi n 4 wee ks a n d t he 
s u bject is ha vi n g cli nical be nefit, a n d t he I n vesti gat or a n d t he S p o ns or’s me dical 
m o nit or a gree t hat re -starti n g dr u g is i n t he best i nterest of t he s u bject, t he n 
f uti bati ni b t hera p y ma y be res u me d at 2 d ose le vels l o wer if a p pr o priate.a M o nit or 
f or rec urre nce usi n g a p pr o priate i n vesti gati o ns e ver y 1 t o 2 wee ks f or a m o nt h a n d 
as cli nicall y a p pr o priate t hereafter.
F or cases of rec urre nce c o nsi der per ma ne nt disc o nti n uat i o n.
Gra de 4
Per m a ne ntl y disc o nti n ue treat me nt wit h f uti bati ni b.
Re p ort as a seri o us a d verse e ve nt a n d m o nit or res ol uti o n of t he e ve nt u ntil 
c o m plete res ol uti o n, sta bilizati o n, or t he s u bject is l ost t o f oll o w-u p or wit h dra ws 
c o nse nt ( w hic h e ver ha p pe ns f irst).
N ote:  If a patie nt has bee n deri vi n g be nefit fr o m treat me nt, a n d t he I n vesti gat or ca n de m o nstrate t hat re -i ntr o d ucti o n of st u d y 
dr u g is i n t he best i nterest of t he patie nt c o nsi deri n g t he ter mi nal nat ure of t he disease, t he dr u g ma y be re -i ntr o d uce d at a l o wer 
d ose a n d/ or i nte nsit y if t he me dical m o nit or is i n a gree me nt wit h t his asses s me nt. Wit h a p pr o priate re-c o nse nti n g, t he patie nt 
ca n be retreate d wit h a 1 - or 2 -d ose le vel re d ucti o n as a p pr o priate, al o n g wit h a p pr o priate cli nical f oll o w -u p as desi g nate d b y 
t he I n vesti gat or. T he I n vesti gat or s h o ul d als o ha ve t he patie nt re-c o nse nt, ex plai ni n g t hat re -i ntr o d ucti o n of st u d y dr u g c o ul d 
lea d t o i ncrease d ris k of rec urre nce. 
Rec o m me n dati o ns f or h y per p h os p hate mia ma na ge me nt are pr o vi de d i n Ta ble 6 . T hese 
g ui deli nes are base d o n e mer gi n g data fr o m st u dies e val uati n g F G F R i n hi bit ors, a n d fr o m t he 
e x perie nce of I n vesti gat ors partici pati n g i n o n g oi n g st u dies of f uti bati ni b.  I n a d diti o n, please see 
A p pe n di x B f or dietar y g ui deli nes f or t he treat me nt of h yper p h os p hate mia.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 2
T a ble 6 : 
Rec o m me n d ati o ns f or H y per p h os p h ate mi a M a n a ge me nt
Ser u m P h os p h or us Res ult a
( m g/ d L a n d m m ol/ L)b
Gr a de c
F uti b ati ni b D ose I nterr u pti o n a n d M o dific ati o n
Rec o m me n de d P h os p h ate Bi n der f or M a n a ge me nt of 
H y per p h os p h ate mi a
d
U L N < P < 5. 5 ( m g/ d L) 
U L N < P < 1. 7 8 ( m m ol/ L)
Gra de 1 
N o i nterr u pti o n, c o nsi der p h os p hate bi n der o nce ser u m p h os p h or us le vel 
is > U L N. 
S h o ul d ser u m p h o s p h or us le vel ra pi dl y i ncrease wit hi n 1 wee k, c o nsi der 
earl y p h os p hate -l o weri n g t hera p y; e g, Se vela mer ta blets 8 0 0 m g t hree 
ti mes per da y [ TI D].
Re -assess ser u m p h os p hate wit hi n 7 da ys.
5. 5 ≤ P ≤7. 0 ( m g/ d L) 
1. 7 8 ≤ P ≤2. 2 6 ( m m ol/ L) 
Gra de 2  
N o i nterr u pti o n, i m ple me nt p h os p hate bi n der ( m o n ot hera p y  or i n 
c o m bi nati o n), 
Start wit h Se vela mer m o n ot hera p y (ra n ge fr o m 8 0 0 m g TI D t o 2 4 0 0 m g 
TI D). 
Re -assess ser u m p h os p hate wit hi n 7 d a y s. Escalate Se vela mer or a d d 
treat me nt wit h acetaz ola mi de 2 5 0 m g Q D or TI D a n d/ or la nt ha n u m 
car b o nate ( Fosre n ol ® )  1. 0 g Q D or TI D, a n d f urt her titrati o n,e if 
p h os p hate le vel c o nti n ues t o i ncrease. 
7. 0 < P ≤1 0. 0 ( m g/ d L) 
2. 2 6 < P ≤3. 2 3 ( m m ol/ L) 
Gra de 3  
D ose re d uce f utibati ni b t o t he ne xt l o wer d ose le vel a n d i nte nsif y 
p h os p hate l o weri n g t hera p y . If t he ser u m p h os p h or us le vel has res ol ve d t o 
≤ Gra de 2 wit hi n 1 4 da y s after d ose re d ucti o n, c o nti n ue f uti bati ni b at t he 
re d uce d d ose le vel. 
Re -assess ser u m p h os p hate wit hi n 7 d a y s a n d at least o nce a wee k.
If t he ser u m p h os p h or us le vel has n ot res ol ve d t o ≤Gra de 2 after 1 4 d a y s, 
f urt her re d uce f uti bati ni b fr o m t he last re d uce d d ose le vel ( or n o l o wer 
t ha n 1 2 m g Q D).
If t he ser u m p h os p h or us le vel has n ot res ol ve d t o ≤ Gra de 2 a fter 1 4 d a y s 
of t he sec o n d d ose re d ucti o n of f uti bati ni b ( or n o l o wer t ha n 1 2 m g Q D), 
i nterr u pt d osi n g wit h f uti bati ni b u ntil it is res ol ve d t o ≤Gra de 2 bef ore 
res u mi n g f uti bati ni b at t he re d uce d d ose pri or t o d ose i nterr u pti o n.
P > 1 0. 0 ( m g/ d L) 
P > 3. 2 3 ( m m ol/ L) 
Gra de 4  
I nterr u pt f uti bati ni b u ntil it has res ol ve d t o ≤ Gra de 2, t he n res u me 
f uti bati ni b at t he ne xt l o wer d ose le vel a n d i nte nsif y p h os p hate l o weri n g 
t hera p y.
Re -assess ser u m p h os p hate wit hi n 7 da ys a n d at least o nce a wee k. If after 
2 d o se i nterr u pti o ns a n d 2 d ose re d ucti o ns t he ser u m p h os p h or us le vel has 
n ot res ol ve d t o ≤ Gra de 2 after 1 4 da y s, per ma ne ntl y disc o nti n ue 
f uti bati ni b.
A b brevi ati o ns: P = p h os p h or us; Q D = o nce a d ay; TI D =t hree ti mes a d ay; U L N = u p per li mit of n or m al
a Ser u m p h os p h or us will be teste d 4 da ys ( ± 2 4 h o urs) after Da y 1 of C ycle 1 t o i nitiate earl y i nter ve nti o n f or h y per p h os p hate m ia 
if i n dicate d.
b m m ol/ L = m g/ d L x 0. 3 2 2 9 (c o n versi o n fact or)
c T his gra di n g f or t he ra n ge of ser u m p h os p h or us le vels will be use d f or t he pr ot oc ol.
d P h os p hate bi n ders ca n be use d as m o n ot hera p y or i n c o m bi nati o n. Please c o ns ult t he dr u g pac ka ge i nsert. Se vela mer s h o ul d be 
prefera bl y ta ke n i n t he mi d dle of meals, b ot h ta blets a n d p o w der, i n or der t o i m pr o ve gastr oi ntesti nal t olera nce a n d c o m plia nce. 
If Se vela mer ca n n ot be use d, ot her p h os p hate bi n ders or h y per p h os p hate mia treat me nt dr u gs ca n be use d. La nt ha n u m car b o nate 
s h o ul d be ta ke n i nstea d j ust after meals— ta blets of F osre n ol® are q uite b i g, b ut ca n be c ut if re q uire d. N o d ose a dj ust me nts are 
nee de d i n patie nts wit h re nal or he patic i m pair me nt.
e Titrate t he d ose e ver y 2 - 3 wee ks u ntil a n acce pta ble ser u m p h os p hate le vel is reac hed.
5. 3. 1. 2. 
F uti b ati ni b D ose M o dific ati o ns f or He m at ol o gic T o xicities
Criteria f or d ose i nterr u pti o n a n d res u m pti o n f or he mat ol o gic t o xicities are prese nte d i n Ta ble 7 .

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 3
T a ble 7 :     F ut i b ati ni b D ose I nterr u pti o n a n d M o dific ati o n Criteri a f or Rel ate d 
He m at ol o gic T o xicitie s
C T C A E Gr a de ( v al ue) 
Rec o m me n de d d ose m o dific ati o n a n y ti m e d uri n g a c ycle of 
f uti b ati ni b
A ne mia ( H g b)
Gra de 1 ( H g b < L L N - 1 0. 0 g/ d L) 
Mai ntai n d ose le vel 
Gra de 2 ( H g b < 1 0 – 8. 0 g/ d L) 
Mai ntai n d ose le vel 
Gra de 3 ( H g b < 8. 0 - 6. 5 g/ d L) 
Wit h h ol d d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne, 
• If res ol ve d ≤7 da ys, t he n mai ntai n d ose le vel 
• If res ol ve d >7 da ys, t he n re d uce 1 d ose le vel 
Gra de 4 (life t hreate ni n g c o nse q ue nces; 
ur ge nt i nter ve nti o n i n dicate d) 
Wit h h ol d d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne, t he n re d uce 1 
d ose le vel 
Ne utr o pe nia ( A N C)
Gra de 1 ( A N C < L L N - 1 5 0 0/ m m 3)  
Mai ntai n d ose le vel 
Gra de 2 ( A N C < 1 5 0 0 - 1 0 0 0/ m m 3)  
Mai ntai n d ose le vel 
Gra de 3 ( A N C < 1 0 0 0 - 5 0 0/ m m 3)  
Mai ntai n d ose le vel 
Gra de 4 ( A N C < 5 0 0/ m m 3) 
Wit h h ol d d ose u ntil res ol ve d t o ≤ Gra de 2 or baseli ne, 
• If res ol ve d ≤7 da ys, t he n mai ntai n d ose le vel 
• If res ol ve d > 7 da ys, t he n re d uce 1 d ose le vel 
Fe brile ne utr o pe nia : A N C < 1 0 0 0/ m m 3, a n d 
wit h a si n gle te m perat ure > 3 8. 3° C ( 1 0 1° F) 
or a s ustai ne d te m perat ure ≥ 3 8° C ( 1 0 0. 4° F) 
f or m ore t ha n o ne h o ur.
Wit h h ol d d ose u ntil res ol ve d, t he n re d uce 1 d ose le vel
T hr o m b oc yt o pe nia
Gra de 1 ( P L T < L L N - 7 5, 0 0 0/ m m 3)  
Mai ntai n d ose le vel 
Gra de 2 ( P L T < 7 5, 0 0 0 - 5 0, 0 0 0/ m m 3)  
Mai ntai n d ose le vel 
Gra de 3 ( P L T < 5 0, 0 0 0 - 2 5, 0 0 0/ m m 3)  
Wit h h ol d d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne, 
• If res ol ve d ≤7 da ys, t he n mai ntai n d ose le vel 
• If res ol ve d > 7 da ys, t he n re d uce 1 d ose le vel 
Gra de 4 ( P L T < 2 5, 0 0 0/ m m 3) 
Wit h h ol d d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne, t he n re d uce 1 
d ose le vel 
A b brevi ati o ns: A N C = a bs ol ute ne utr o p hil c o u nt; C T C A E = C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts; 
H g b = he m o gl o bi n; L L N =l o wer li mit of n or m al; P L T = pl atelets.
N ote:  I nterr u pt f uti bati ni b if a n y t o xicities are i nt olera ble, re gar dless of t he gra de (i ncl u di n g Gra de 1 a n d 2). If or w he n t he 
t o xicit y res ol ves t o a t olera ble state, c o nsi derati o n ca n be gi ve n t o res u mi n g f uti bati ni b at t he sa me d ose if dee me d a p pr o priate 
or re d uce d b y o ne d ose le vel if nee de d.
5. 3. 2. 
D ose M o dific ati o ns i n C ase of I n d uce d Dr u g Li ver I nj ur y ( H y’s L a w)
F uti bati ni b will be per ma ne ntl y  disc o nti n ue d if li ver f u ncti o n test a b n or malities f ulfill H y’s La w 
criteria defi ne d as:

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 4
C o nc urre nt o bser vati o n of t he f oll o wi n g, wit h n o ot her reas o n f o u n d t o e x plai n t he fi n di n gs 
(s uc h as viral he patitis A, B, or C; pree xisti n g or ac ute li ver disease; li ver metastases; or a n ot her 
dr u g ca pa ble of ca usi n g t he o bser ve d li ver i nj ur y ):

Ele vate d a mi n otra nsferase e nz y mes of > 3 x U L N ( u p per li mit of n or mal)

Al kali ne p h os p hatase ( A L P) < 2 x U L N

Ass ociate d wit h a n i ncrease i n bilir u bi n ≥2 x U L N
5. 3. 3. 
D ose M o dific ati o ns f or Pe m br oliz u m a b
5. 3. 3. 1. 
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt f or Im m u ne - Rel ate d A Es 
A ss oci ate d wit h P e m br oliz u m a b
A Es ass ociate d wit h pe m br oliz u ma b e x p os ure ma y  re prese nt a n i m m u ne-relate d (ir) res p o nse. 
T hese ir A Es ma y  occ ur s h ortl y after t he first d ose or several m o nt hs after t he last d ose of 
pe m br oliz u ma b treat me nt a n d ma y  affect m ore t ha n o ne b o d y  sys te m si m ulta ne o usl y. T heref ore, 
earl y rec o g niti o n a n d i nitiati o n of treat me nt is critical t o re d uce c o m plicati o ns. Base d o n e xisti n g 
cli nical st u d y data, m ost i r A Es were re versi ble a n d c o ul d be ma na ge d wit h i nterr u pti o ns of 
pe m br oliz u ma b, a d mi nistrati o n of c ortic oster oi ds a n d/ or ot her s u p p orti ve care. F or s us pecte d 
ir A Es, e ns ure a de q uate e val uati o n t o c o nfir m eti ol o g y or e xcl u de ot her ca uses. A d diti o nal 
pr oce d ure s or tests s uc h as br o nc h osc o py, e n d osc o p y , s ki n bi o ps y m a y be i ncl u de d as part of t he 
e val uati o n. 
Ge neral i nstr ucti o ns f or t he ma na ge me nt of ir A Es are as f oll o ws; please see Ta ble 8 f or detaile d 
g ui deli nes.
1.
Se vere a n d life-t hreate ni n g ir A Es s h o ul d be treate d wit h I.V. c ortic oster oi d s f oll o we d b y  
oral ster oi ds. Ot her i m m u n os u p pressi ve treat me nt s h o ul d be gi n if t he ir A Es are n ot 
c o ntr olle d b y c ortic oster oi ds. 
2.
Pe m br oliz u ma b m ust be per ma ne ntl y disc o nti n ue d if t he ir A E d oes n ot res ol ve or t he 
c ortic oster oi d d ose is n ot ≤1 0 m g/ da y  wit hi n 1 2 wee ks of t he last pe m br oliz u ma b 
treat me nt. 
3.
T he c ortic oster oi d ta per s h o ul d be gi n w he n t he ir A E is ≤ Gra de 1 a n d c o nti n ue at least 4 
wee ks.
4.
If pe m br oliz u ma b has bee n wit h hel d, pe m br oliz u ma b ma y res u me after t he ir A E 
decrease d t o ≤ Gra de 1 after c ortic oster oi d ta per.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 5
T a ble 8 : 
G ui deli nes f or M a n a ge me nt of I m m u ne - Rel ate d A d verse E ve nts Ass oci ate d 
wit h Pe m br oliz u m a b
ir A Es
T o xicit y gr a de 
or c o n diti o ns 
( C T C A E V 5. 0)
Acti o n wit h
pe m br oliz u m a b
C ortic oster oi d a n d/ or 
ot her t her a pies 
M o nit ori n g
a n d f oll o w -u p 
P ne u m o nitis  
Gra de 2 
Wit h h ol d 
 
A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 1-2 
m g/ k g pre d nis o ne 
or e q ui vale nt) 
f oll o we d b y ta per
 
A d d pr o p h ylactic 
a nti bi otics f or 
o p p ort u nistic 
i nfecti o ns
 
M o nit or patie nts f or 
si g ns a n d s y m pt o ms of 
p ne u m o nitis
 
E val uate patie nts wit h 
s us pecte d p ne u m o nitis 
wit h ra di o gra p hic 
i ma gi n g a n d i nitiate 
c ortic oster oi d treat me nt
Rec urre nt 
Gra de 2, Gra de 
3 or 4
Per m a ne ntl y 
disc o nti n ue
Diarr hea / 
C olitis 
Gra de 2 or 3 
Wit h h ol d
 
A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 1-2 
m g/ k g pre d nis o ne 
or e q ui vale nt) 
f oll o we d b y ta per
 
M o nit or patie nts f or 
si g ns a n d s y m pt o ms of 
e nter oc olitis ( ie, 
diarr hea, a b d o mi nal 
pai n, bl o o d or m uc us i n 
st o ol wit h or wit h o ut 
fe ver) a n d of b o wel 
perf orati o n 
(ie, perit o neal si g ns a n d 
ile us).
 
Patie nts wit h ≥ Gra de 2 
diarr hea s us pecti n g 
c olitis s h o ul d c o nsi der 
GI c o ns ultati o n a n d 
perf or mi n g e n d osc o p y 
t o r ule o ut c olitis. 
 
Patie nts wit h 
diarr hea/c olitis s h o ul d 
be a d vise d t o dri n k 
li beral q ua ntities of 
clear fl ui ds.  If 
s ufficie nt oral fl ui d 
i nta ke is n ot feasi ble, 
fl ui d a n d electr ol ytes 
s h o ul d be s u bstit ute d 
via I . V. i nf usi o n.
Rec urre nt 
Gra de 3 or 
Gra de 4
Per m a ne ntl y 
disc o nti n ue

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 6
ir A Es
T o xicit y gr a de 
or c o n diti o ns 
( C T C A E V 5. 0)
Acti o n wit h
pe m br oliz u m a b
C ortic oster oi d a n d/ or 
ot her t her a pies 
M o nit ori n g
a n d f oll o w -u p 
A S T or A L T  
ele vati o n or 
I ncrease d 
B ilir u bi n
Gra de 2 a
Wit h h ol d

A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 0. 5 -1 
m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d 
b y ta per
 
M o nit or w it h li ver 
f u ncti o n tests (c o nsi der 
wee kl y or m ore 
fre q ue ntl y u ntil li ver 
e nz y me val ue ret ur ne d 
t o baseli ne or is sta ble
Gra de 3 b or 4 c
Per m a ne ntl y 
disc o nti n ue

A d mi nister 
c ortic oster oi ds
(i nitial d ose of 1-2 
m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d 
b y ta per
T y pe 1 dia betes 
mellit us 
( T 1 D M) or 
H y per gl yce mia
Ne w  o nset 
T 1 D M or 
Gra de 3 or 4 
h y per gl yce mia 
ass ociate d wit h 
e vi de nce of 
-cell fail ure
Wit h h ol d
d

I nitiate i ns uli n 
re place me nt t hera p y 
f or patie nts wit h 
T 1 D M 

A d mi nister a nti -
h y per gl yce mic i n 
patie nts wit h 
h y per gl yce mia 
 
M o nit or patie nts f or 
h y per gl yce mia or ot her 
si g ns a n d s y m pt o ms of 
dia betes.
H y p o p h ysitis 
Gra de 2 
Wit h h ol d

A d mi nister 
c ortic oster oi ds a n d 
i nitiate h or m o nal 
re place me nts as 
cli nicall y i n dicate d.  
 
M o nit or f or si g ns a n d 
s y m pt o ms of 
h y p o p h ysitis (i ncl u di n g 
h y p o pit uitaris m a n d 
a dre nal i ns ufficie nc y) 
Gra de 3 or 4  
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d
H y per -
t h yr oi dis m 
Gra de 2 
C o nti n ue 

Treat w it h n o n-
selecti ve beta-
bl oc kers (e g, 
pr o pra n ol ol) or 
t hi o na mi des as 
a p pr o priate 
 
M o nit or f or si g ns a n d 
s y m pt o ms of t h yr oi d 
dis or ders 
Gra de 3 or 4  
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d
H y p o -
t h yr oi dis m
Gra de 2, 3, 4 
C o nti n ue 

I nitiate t h yr oi d 
re place me nt 
h or m o nes (e g, 
le v ot h yr o xi ne or 
li ot h yr o ni ne) per 
sta n dar d of care
 
M o nit or f or si g ns a n d 
s y m pt o ms of t h yr oi d 
dis or ders. 
Ne p hritis : 
gra di n g 
acc or di n g t o 
i ncrease 
creati ni ne or 
Gra de 2 
Wit h h ol d 

A d mi nister 
c ortic oster oi ds 
( pre d nis o ne 1-2 
m g/ k g or e q ui vale nt) 
f oll o we d b y ta per.
 
M o nit or c ha n ges of 
re nal f u ncti o n
Gra de 3 or 4  
Per m a ne ntl y 
disc o nti n ue

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 7
ir A Es
T o xicit y gr a de 
or c o n diti o ns 
( C T C A E V 5. 0)
Acti o n wit h
pe m br oliz u m a b
C ortic oster oi d a n d/ or 
ot her t her a pies 
M o nit ori n g
a n d f oll o w -u p 
ac ute ki d ne y 
i nj ur y
M y ocar ditis 
Gra de 1 or 2 
Wit h h ol d

Base d o n se verit y of 
A E a d mi nister 
c ortic oster oi ds

E ns ure a de q uate 
e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de 
ot her ca uses
Gra de 3 or 4 
Per m a ne ntl y 
disc o nti n ue
All O t her 
i m m u ne-relate d 
A E s
P ersiste nt 
Gra de 2
Wit h h ol d

Base d o n se verit y of 
A E a d mi nister 
c ortic oster oi ds 

E ns ure a de q uate 
e val uati o n t o c o nfir m 
eti ol o g y or e xcl u de ot her 
ca uses
Gra de 3 
Wit h h ol d or 
disc o nti n ue 
base d o n t he 
e ve nt e  
R ec urre nt 
Gra de 3 or 
Gra de 4
Per m a ne ntl y 
disc o nti n ue
a. 
A S T/ A L T: > 3. 0 - 5. 0 x U L N if baseli ne n or mal; > 3. 0   5. 0 x baseli ne, if baseli ne a b n or mal; 
bilir u bi n: > 1. 5   3. 0 x U L N if baseli ne n or mal; > 1. 5 - 3. 0 x baseli ne if baseli ne a b n or mal
b. 
A S T/ A L T: > 5. 0 t o 2 0. 0 x U L N, if baseli ne n or mal; > 5. 0   2 0. 0 x baseli ne, if baseli ne a b n or mal; bilir u bi n: > 3. 0   1 0. 0 
x U L N if baseli ne n or mal; > 3. 0 - 1 0. 0 x baseli ne if baseli ne a b n or mal
c. 
A S T/ A L T: > 2 0. 0 x U L N, if baseli ne n or mal; > 2 0. 0 x baseli ne, if baseli ne a b n or mal; 
bilir u bi n: > 1 0. 0 x U L N if baseli ne n or mal; > 1 0. 0 x baseli ne if baseli ne a b n or mal
d. 
T he decisi o n t o wit h h ol d or per ma ne ntl y disc o nti n ue pe m br oliz u ma b is at t he discreti o n of t he I n vesti gat or or 
treati n g p h ysicia n. If c o ntr ol ac hie ve d or ≤ Gra de 2, pe m br oliz u ma b ma y be res u me d.
e. 
E ve nts t hat re q uire disc o nti n uati o n i ncl u de b ut are n ot li mite d t o: G uillai n -Barre S y n dr o me, e nce p halitis, Ste ve ns -
J o h ns o n S y n dr o me a n d t o xic e pi der mal necr ol ysis.
5. 3. 3. 2. 
I nf usi o n-Rel ate d Re acti o ns
Pe m br oliz u ma b ma y  ca use se vere or life t hreate ni n g i nf usi o n-reacti o ns, i ncl u di n g se vere 
h y perse nsiti vit y  or a na p h yla xis. Si g ns a n d s ym pt o ms us uall y  de vel o p d uri n g or s h ortl y after dr u g 
i nf usi o n a n d ge nerall y res ol ve c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. D ose 
m o dificati o n a n d t o xicit y  ma na ge me nt g ui deli nes o n pe m br oliz u ma b ass ociate d i nf usi o n reacti o n 
are pr o vi de d i n Ta ble 9 .
T a ble 9 : 
G ui deli nes f or M a n a ge me nt of I nf usi o n -Rel ate d Re acti o ns t o 
Pe m br oliz u m a b
N CI C T C A E Gr a de 
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
Gr a de 1
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot 
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he patie nt is dee me d me dicall y sta ble 
i n t he o pi ni o n of t he I n vesti gat or.
N o ne

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 8
N CI C T C A E Gr a de 
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
i n dicate d; i nter ve nti o n 
n ot i n dicate d
Gr a de 2
Re q uires t hera p y or 
i nf usi o n i nterr u pti o n 
b ut res p o n ds pr o m ptl y 
t o s y m pt o matic 
treat me nt (f or e xa m ple, 
a nti hista mi nes,
N S AI Ds, narc otics, I . V.
fl ui ds); pr o p h ylactic 
me dicati o ns i n dicate d 
f or ≤2 4 hrs.
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de 
b ut is n ot li mite d t o:
 
I V fl ui ds
 
A nti hista mi nes
 
N S AI Ds
 
Aceta mi n o p he n
 
Narc otics
I ncrease m o nitori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he patie nt is dee me d me dicall y sta ble 
i n t he o pi ni o n of t he I n vesti gat or.
If s y m pt o ms res ol ve wit hi n 1 h o ur of st o p pi n g dr u g 
i nf usi o n, t he i nf usi o n ma y be restarte d at 5 0 % of t he 
ori gi nal i nf usi o n rate (e. g. fr o m 1 0 0 m L/ hr. t o 5 0 
m L/ hr.). Ot her wise d osi n g will be hel d u ntil 
s y m pt o ms res ol ve a n d t he patie nt s h o ul d be 
pre me dicate d f or t he ne xt sc he d ule d d ose.
P atie nts w h o de vel o p Gr a de 2 t o xicit y des pite 
a de q u ate pre me dic ati o n s h o ul d be per m a ne ntl y 
disc o nt i n ue d fr o m f urt her st u d y dr u g tre at me nt
Patie nt ma y be pre me dicate d 
1. 5 h ( ± 3 0 mi n utes) pri or t o 
i nf usi o n of pe m br oliz u ma b 
wit h:

Di p he n h y dra mi ne 5 0 m g 
p o ( or e q ui vale nt d ose of 
a nti hista mi ne).

Aceta mi n o p he n 5 0 0 -
1 0 0 0 m g p o ( or 
e q ui vale nt d ose of 
a nal gesic).
Gr a des 3 or 4
Gra de 3:
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)
Gra de 4:
Life -t hreate ni n g; 
press or or ve ntilat or 
s u p p ort i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de 
b ut is n ot li mite d t o:
E pi ne p hri ne * *
I. V. fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
N o s u bse q ue nt d osi n g

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
4 9
N CI C T C A E Gr a de 
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he patie nt is dee me d me dicall y sta ble 
i n t he o pi ni o n of t he I n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla xis, e pi ne p hri ne s h o ul d be 
use d i m me diatel y.
P atie nt is per m a ne ntl y disc o nti n ue d fr o m f urt her 
st u d y dr u g tre at me nt.
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g 
t he peri o d of dr u g a d mi nistrati o n. F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts v 5. 0 ( C T C A E) at htt p://cte p.ca ncer. g o v
5. 3. 3. 3.   
Ot her Per mitte d D ose I nterr u pti o n f or Pe m br oliz u m a b
Pe m br oliz u ma b ma y  be i nterr u pte d f or sit uati o ns ot her t ha n treat me nt-relate d A Es, s uc h as 
me dical / s ur gical e ve nts or l o gistical reas o ns n ot relate d t o st u d y  t hera p y. Patie nts s h o ul d be 
place d bac k o n st u d y  t hera p y wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless ot her wise 
disc usse d wit h t he S p o ns or. T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he patie nt's 
s o urce d oc u me nts.
5. 4. 
Tre at me nt C o m pli a nce
Eac h patie nt will be i nstr ucte d t o c o m pl y  wit h t he d osi n g re gi me n of f uti bati ni b.  Pe m br oliz u ma b 
will be a d mi nistere d at t he site b y q ualifie d site pers o nnel acc or di n g t o t he pr ot oc ol.
C o m plia nce s h o ul d be d oc u me nte d i n t he patie nt’s s o urce d oc u me nts .
5. 5. 
C o nc o mit a nt Me dic ati o ns a n d T her a pies
5. 5. 1. 
Pr o hi bite d Me dic ati o ns a n d T her a pies
T he f oll o wi n g t hera pies are n ot per mitte d d uri n g t he st u d y  treat me nt peri o d:

A n y  other i n vesti gati o nal t hera p y

A n y  ot her a ntica ncer t hera p y (i ncl u di n g c he m ot hera p y, i m m u n ot hera py, bi ol o gical 
res p o nse m o difiers, or a nti ne o plastic e n d ocri ne t hera py)

Ra diati o n t hera p y ( N O T E: Ra diati o n t hera p y t o a s y m pt o matic s olitar y  lesi o n or t o t he 
brai n m a y  be all o we d at t he I n vesti gat or’s discreti o n.  E xte n de d -fiel d ra diati o n t hera py or 
palliati ve ra diati o n t o a f ocal site of meas ura ble disease is pr o hi bite d.  If it is dee me d i n 
t he best i nterest of t he patie nt a n d after disc ussi o n bet wee n t he In vesti ga t or a n d S p o ns or, 
it ca n be a d mi nistere d, b ut t he patie nt will be ce ns ore d f or t he pri mar y e n d p oi nt a nal ysis).

Li ve vacci nes wit hi n 3 0 da y s pri or t o t he first d ose of st u d y treat me nt a n d w hile 
partici pati n g i n t he st u d y.  

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
5 0

S y ste mic gl uc oc ortic oi ds f or a ny p ur p ose ot her t ha n t o m o d ulate s y m pt o ms fr o m a n A E 
t hat is s us pecte d t o ha ve a n i m m u n ol o gic eti ol o g y. T he use of p hys i ol o gic d oses of 
c ortic oster oi ds ma y be a p pr o ve d after c o ns ultati o n wit h t he S p o ns or (f or e xa m ple, f or t he 
c o ntr ol of ac ute ast h ma s ym pt o ms a n d f or patie nts wit h brai n metastases).
All treat me nts t hat t he I nvesti gat or c o nsi ders necessar y f or a patie nt’s welfare ma y be 
a d mi nistere d at t he discreti o n of t he I n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care.
5. 5. 2. 
C o nc o mit a nt Me dic a ti o ns a n d T her a pies Re q uiri n g Prec a uti o ns 
T he f oll o wi n g t hera pies are per mitte d:

Bis p h os p h o nates

De n os u ma b

Ster oi ds f or patie nts wit h brai n metastases
L ocal or re gi o nal palliati ve cr y ot hera p y  or ra diati o n, s uc h as f or b o ne pai n or palliati ve s ur ger y 
( n o n-a nti- ne o plastic i nte nt), are per mitte d ( pr o vi de d t he tar get lesi o n is n ot a site of meas ura ble 
disease a n d is n ot i n dicati ve of disease pr o gressi o n).  S t u d y t hera p y s h o ul d be cease d a mi ni m u m 
of 2 da y s pri or t o a d mi nistrati o n of palliati ve treat me nt, a n d ma y be res u me d 7 da ys after t he 
pr oce d ure or w he n t he patie nt has rec o vere d fr o m t he si de effects of t he pr oce d ure.
T he f oll o wi n g me dicati o ns/t hera pies m a y be gi ve n c o nc o mita ntl y u n der t he f oll o wi n g 
g ui deli nes: 
He mat ol o gic S u p p ort: ma y  be a d mi nistere d as me dicall y i n dicate d (t hat is, bl o o d tra nsf usi o ns, 
gra n ul oc y te c ol o ny- sti m ulati n g fact or, er yt hr o p oieti n sti m ulati n g a ge nts) acc or di n g t o t he 
i nstit uti o nal site sta n dar ds or A merica n S ociet y  of Cli nical O nc ol o g y (A S C O ) g ui deli nes 
(S mit h et al. 2 0 1 5). 
Ma na ge me nt of Diarr hea : Pr o p h ylactic treat me nt f or diarr hea is per mitte d d uri n g t he st u d y if 
cli nicall y i n dicate d acc or di n g t o the i nstit uti o nal or p u blis he d g ui deli nes ( Be ns o n et al . 2 0 0 4). 
Ma na ge me nt of Na usea/ V o miti n g : A ntie metics ma y be a d mi nistere d as cli nicall y i n dicate d 
acc or di n g t o i nstit uti o nal sta n dar ds or A S C O g ui deli nes ( Hes ket h et al . 2 0 1 7 ).
5. 5. 3.   
Dr u g I nter acti o ns
T he f oll o wi n g i nf or mati o n is base d o n res ults fr o m i n vitr o st u dies a n d preli mi nar y res ults fr o m
cli nical p har mac ol o g y st u dies of dr u g i nteracti o ns. Ca uti o n is a d vise d if t hese dr u gs are gi ve n 
c o nc o mita ntl y (see A p pe n di x C ).
C y t oc hr o me P 4 5 0 ( C Y P) 3 A i n hi bit ors a n d i n d ucers: C Y P 3 A is i n v ol ve d i n t he meta b olis m 
of f uti bati ni b. T he preli mi nar y cli nical p har mac ol o g y  res ults su g geste d t hat a str o n g C Y P 3 A 
i n hi bit or i ncrease d f uti bati ni b e x p os ure a n d t hat a str o n g C Y P 3 A i n d ucer decrease d t he 
e x p os ure. C Y P 3 A i n hi bit ors a n d i n d ucers ma y  alter t he c o nce ntrati o n a n d acti vit y of 
f uti bati ni b.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
5 1
C Y P 3 A s u bstrates : F uti bati ni b is a p ote ntial ti me-de pe n de nt i n hi bit or of C Y P 3 A H o we ver, 
preli mi nar y  cli nical p har mac ol o g y res ults s u g geste d t hat f uti bati ni b ha d n o si g nifica nt effect 
o n e x p os ure of a se nsiti ve C Y P 3 A s u bstrate.
P- gl yc o pr otei n ( P -g p) a n d breast ca ncer resista nce pr otei n ( B C R P) i n hi bi t ors: F uti bati ni b is a 
p ote ntial i n hi bit or of P -g p a n d B C R P. F uti bati ni b ma y  alter t he P K a n d acti vit y of P-g p a n d 
B C R P s u bstrates. 
P- g p a n d B C R P s u bstrates : F uti bati ni b is a s u bstrate of P-g p a n d B C R P. P -g p a n d B C R P 
i n hi bit ors ma y alter t he c o nce ntrati o n a n d acti vit y of f uti bati ni b.
5. 6. 
Effecti ve C o ntr ace pti o n D uri n g St u d y
Fe male patie nts c o nsi dere d n ot t o be of c hil d beari n g p ote ntial m ust ha ve a hist or y  of bei n g 
p ost me n o pa usal ( n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use), or 
h y sterect o my t h at is clearl y d oc u me nte d i n t he patie nt’s s o urce d oc u me nts. 
F or W O C B P, i ncl u di n g fe male st u d y  partici pa nts a n d part ners of male partici pa nts, effecti ve 
c o ntrace pti o n is re q uire d d uri n g t he st u d y a n d f or 6 m o nt hs after t he last d ose of st u d y 
me dicati o n, or l o n ger if necessar y base d o n l ocal re q uire me nts. Effecti ve c o ntrace pti o n is 
defi ne d as f oll o ws:

C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n:

O ral

I ntra va gi nal

T ra ns der mal

Pr o gest o ge n - o nly h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:

O ral

Injecta ble

Im pla nta ble

I ntra uteri ne de vice

I ntra uteri ne h or m o ne-releasi n g sys te m

Bilateral t u bal occl usi o n 

Vasect o mize d part ner wit h d oc u me ntati o n of t he s uccess of t he vasect o m y  

C o m ple te a bsti ne nce fr o m heter ose x ual i nterc o urse ( peri o dic a bsti ne nce is n ot a safe 
met h o d) 
Male patie nts wit h part ners w h o are W O C B P s h o ul d use a male c o n d o m i n c o m bi nati o n wit h at 
least o ne of t he effecti ve c o ntrace pti o n met h o ds d uri n g t he st u d y a n d f or 6 m o nt hs or l o n ger 
base d o n l ocal re q uire me nts after t he last d ose of st u d y me dicati o n. D o nati o n of s per m or o va is 
n ot all o we d d uri n g t he st u d y  a n d f or 6 m o nt hs or l o n ger base d o n l ocal re q uire me nts f oll o wi n g 
t he last d ose of st u d y dr u g.

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5. 7. 
St u d y Dr u g M ateri als a n d M a n a ge me nt
F uti bati ni b will be s u p plie d b y  t he S p o ns or . Pe m br oliz u ma b will be s u p plie d t o t he S p o ns or b y  
Merc k S har p & D o h me C or p, a n d s u p plie d t o eac h site b y  t he S p o ns or.
Detaile d i nf or mati o n , s uc h as t he re q uire me nts f or acc o u nta bilit y a n d dis p osal of st u d y  dr u g, ca n 
be f o u n d i n t he P har mac y  Ma n ual, w hic h will be pr o vi de d se parately.
Please refer t o t he I n vesti gat or’s Br oc h ures f or f uti bati ni b a n d pe m br oliz u ma b, res pecti vel y, f or 
a d diti o nal i nf or mati o n, i ncl u di n g details o n pac ka gi n g, la beli n g, a n d st ora ge rec o m me n dati o ns.  
5. 7. 1. 
Acc o u nt a bilit y
T he In vesti gat or is res p o nsi ble f or e ns uri n g t hat all st u d y dr u g recei ve d at t he site is i n ve nt orie d 
a n d acc o u nte d f or t hr o u g h o ut t he st u d y . All st u d y dr u gs will be st ore d a n d dis p ose d of acc or di n g 
t o t he S p o ns or's i nstr ucti o ns. T he dis pe nsi n g of st u d y dr u g t o t he patie nt a n d t he ret ur n of st u d y 
dr u g fr o m t he patie nt m ust be d oc u me nte d i n t he patie nt’s s o urce d oc u me nts. Patie nts m ust be 
i nstr ucte d t o ret ur n all ori gi nal c o ntai ners, w het her e m pt y or c o ntai ni n g st u d y dr u g. 
At t he c o ncl usi o n of t he st u d y , all st u d y dr u gs s u p plie d b y t he S p o ns or m ust be destr o y e d or
ret ur ne d t o t he desi g nate d de p ot, per t he i nstr ucti o ns pr o vi de d i n t he P har mac y Ma n ual.

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6. 
S T U D Y A S S E S S M E N T S
T h e Sc he d ule of E ve nts (Ta ble 1 a n d Ta ble 2 ) s u m marizes t he fre q ue nc y a n d ti mi n g of all 
a p plica ble st u d y assess me nts, i ncl u di n g all o wa ble wi n d o ws f or st u d y visits a n d assess me nts / 
pr oce d ures. Writte n i nf or me d c o nse nt m ust be pr o vi de d b ef ore a n y st u d y- relate d pr oce d ures are 
perf or me d. A n y A Es directl y ass ociate d wit h a scree ni n g pr oce d ure s h o ul d be re p orte d as 
descri be d i n Secti o n 9. 1 .
Assess me nt
Det ails
Re vie w of  
i ncl usi o n/e xcl usi o n criteria
See Secti o n s 4. 1 a n d 4. 2 . Eli gi bilit y m ust be c o nfir me d pri or t o first d ose of st u d y 
t hera p y.
De m o gra p hics/ me dical
hist or y
Se x, a ge, cli nical dia g n osis, date a n d met h o d of dia g n osis, pri or ca ncer t hera p y, 
rele va nt me dical hist or y ( past a n d c o nc urre nt).
Baseli ne si g ns a n d 
s y m pt o ms
Si g ns a n d s y m pt o ms occ urri n g after si g ni n g of I C F b ut bef ore a d mi nistrati o n of first 
d ose of f uti bati ni b.
P h y sical e xa mi nati o n, 
Hei g ht a n d b o d y wei g ht
Hei g ht is c ollecte d f or t he p ur p ose of B MI calc ulati o ns at baseli ne o nl y.
Vital si g ns
P ulse rate, s yst olic a n d diast olic bl o o d pres s ure, b o d y te m perat ure, a n d res pirati o n 
rate. A n y a b n or mal rea di n g s h o ul d be re peate dl y i m me diatel y.
E C O G perf or ma nce stat us 
See A p pe n di x A .
1 2 -lea d E C G
Si n gle, resti n g, se mirec u m be nt 1 2 -lea d electr ocar di o gra m ( E C G) will be perf or me d 
l ocall y.  Data c ollecti o n i ncl u des R R i nter val ( heart rate), Q T i nter val, Q Tc F i nter val 
a n d a b n or mal fi n di n gs; t he I n vesti gat or is res p o nsi ble f or i nter preti n g a n d meas uri n g 
E C G data.
He m at ol o g y
Re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, platelets, w hite bl o o d cell c o u nt w it h 
differe ntial, ne utr o p hils ( A N C), l y m p h oc ytes, m o n oc ytes, e osi n o p hils, ba s o p hils
C he mistr y (ser u m or 
plas ma)
A S T, A L T, A L P, bicar b o nate, t otal bilir u bi n, direct bilir u bi n, al b u mi n, lactate 
de h y dr o ge nase, i n or ga nic p h os p h or us, tri gl yceri de, t otal c h olester ol, creati ni ne, urea 
or bl o o d urea nitr o ge n, bicar b o nate, s o di u m, p otassi u m, c hl ori de, calci u m (c orrecte d 
val ue), ma g nesi u m, bl o o d gl uc ose, uric aci d 
F or a calc ulate d creati ni ne cleara nce ( Ccr) val ue, use t he C oc kcr oft -Ga ult f or m ula:
Male
Ccr ( m L/ mi n) = B o d y wt ( k g) ×( 1 4 0 -a ge)[ 7 2 ×ser u m creati ni ne ( m g/ d L)]
Fe m ale Ccr ( m L/ mi n) = male Ccr × 0. 8 5
T h yr oi d f u ncti o n tests 
Trii o d ot h yr o ni ne ( T 3) or free trii o d ot h yr o ni ne ( F T 3), free t h yr o xi ne ( F T 4), a n d 
t h yr oi d sti m ulati n g h or m o ne ( T S H).
C oa g ulati o n
Pr ot hr o m bi n ti me -i nter nati o nal n or malize d rati o, acti vate d partial t hr o m b o plasti n 
ti me, fi bri n o ge n
Pre g na nc y test
Ser u m β -h u ma n c h ori o nic g o na d otr o p hi n ( h u ma n c h ori o nic sti m ulati n g h or m o ne) 
test re q uire d f or W O C B P at scree ni n g a n d E O T; ser u m or uri ne at all ot her 
ti me p oi nts.
O p ht hal m ol o gical 
e xa mi nati o n
See Secti o n 6. 1
See  Secti o n 7.
Eff icac y assess me nts
See Secti o n 8 .
C CI

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Assess me nt
Det ails
A E m o nit ori n g
All A Es will be c ollecte d fr o m t he ti me t he I C F is si g ne d t hr o u g h 3 0 da ys after t he 
last d ose of a n y st u d y t hera p y (safet y f oll o w-u p) or u ntil t he start of ne w a ntit u m or 
t hera p y, w hic he ver is earlier.  See Secti o n 9 .  S A Es will be c ollecte d t hr o u g h 9 0 
da ys after t he last d ose of a n y st u d y t hera p y.
See Secti o n 1 0
C o nc o mita nt 
me dicati o n/c o nc o mita nt 
t hera p y
I ncl u di n g all me dicati o ns / t hera pies a d mi nistere d fr o m t he ti me I C F is si g ne d 
t hr o u g h 3 0 da ys after a d mi nistrati o n of t he last d ose of st u d y t herap y  or u ntil t he 
start of ne w a ntica ncer t hera p y.
S ur vi val f oll o w -u p
O nce disease pr o gressi o n per R E CI S T 1. 1 is c o nfir me d or t he first s u bse q ue nt ne w 
a ntica ncer t hera p y is i nitiate d, w hic he ver occ urs first, t he s ur vi val f oll o w-u p peri o d 
be gi ns.  D uri n g t his peri o d, t he patie nt or fa mil y s h o ul d be c o ntacte d f or s ur vi val 
f oll o w-u p e ver y 1 2 wee ks ( ± 2 w ee ks) u ntil wit h dra wal of c o nse nt, deat h, or l ost t o 
f oll o w u p, u ntil st u d y c o m pleti o n.
6. 1. 
O p ht h al m ol o gic al E x a mi n ati o n
T he c or nea a n d c o nj u ncti va are rea dil y  visi ble tiss ues, a n d t heref ore, a b n or malities of t he c or nea 
a n d c o nj u ncti va ca n us uall y  be rec o g nize d via e xter nal oc ular e xa mi nati o n a n d r o uti ne slit la m p 
bi o micr osc o p y . T he reti na is visi ble t hr o u g h f u n d osc o p y after dilati o n of t he p u pil. 
O p ht hal m ol o gic e xa mi nati o n will be perf or me d b y  a n o pt hal m olo gist or q ualifie d dele gate at 
scree ni n g a n d 4-6 wee ks after first d ose; a d diti o nal o n -st u d y e val uati o n ma y  be perf or me d as 
nee de d base d o n p h y sicia n j u d g me nt a n d/ or sy m pt o ms or si g ns of mi neral de p osits. I n cases of 
reti nal pi g me nt e pit helial detac h me nt, e ve nts s h o ul d be m o nit ore d at 2- t o 3- wee k i nter vals .
Eac h e val uati o n will e nc o m pass: 

E xter nal oc ular e xa mi nati o n

R o uti ne slit la m p bi o micr osc o p y of a nteri or oc ular str uct ures, i ncl u di n g t he a nteri or 
a n d p osteri or c ha m bers ( Fl u orescei n or r ose Be n gal or ot her d yes use d t o e val uate t he 
oc ular s urface ca n be use d acc or di n g t o i nstit uti o nal g ui deli nes a n d l ocal cli nical 
practice)

Dilati o n of t he p u pil wit h direct/i n direct f u n d osc o p y  per i nstit uti o nal g ui deli nes a n d 
l ocal cli nical practice
6. 2. 
L a b or at or y Assess me nts
All la b orat or y  assess me nts will be perf or me d l ocall y. T he la b orat or y m ust pr o vi de n or mal 
refere nce ra n ges f or he mat ol o g y, c he mistr y, a n d c oa g ulati o n tests. If j ustifie d (e g, deteri orati o n 
of t he patie nt’s healt h c o n diti o ns a n d/ or dista nce fr o m t he cli nical site) a n d all o we d b y  t he 
c o u ntr y a n d i nstit uti o n, la b orat or y tests perf or me d b y e xter nal la b orat ories ma y be use d f or t he 
st u d y. H o we ver, la b orat or y reference ra n ges a n d accre ditati o n are re q uire d. All la b orat or y  test 
res ults (i nter nal or e xter nal) m ust be re vie we d f or cli nical si g nifica nce by t he In vesti gat or. 
A n y  cli nicall y si g nifica nt e ve nts m ust be f oll o we d a n d re p orte d as re q uire d b y t he pr ot oc ol 
( please see Secti o n 9. 3. 1 ).
C CI

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7.
 
 
 
 
 
 
  
 
T a ble 1 0:
D a y of St u d y
( Ti me Wi n d o w)
C ollecti o n Ti me P oi nt ( h o urs) i n Rel ati o n t o F uti b ati ni b A d mi nistr ati o n 
( Ti me Wi n d o w)
C CI
C CI
C CI
C CI

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8. 
E F FI C A C Y E V A L U A TI O N S
Efficac y  para meters will be assesse d base d o n o n-site t u m or assess me nts (i ncl u di n g c o m p ute d 
t o m o gra p hy [ C T] or ma g netic res o na nce i ma gi n g [ M RI ] if C T sca n is n ot feasi ble) perf or me d by 
t he In vesti gat or/l ocal ra di ol o gis t acc or di n g t o R E CIS T 1. 1 g ui deli nes [ Eise n ha uer et al. 2 0 0 9]).
I n a d diti o n t o R E CIS T 1. 1, i R E CI S T will be use d. i R E CI S T is base d o n R E CI S T 1. 1, b ut 
a da pte d t o acc o u nt f or t he u ni q ue t u m or res p o nse see n wit h i m m u n ot hera pe utic dr u gs. i R E CI S T 
will be use d b y t he I n vesti gat or t o assess t u m or res p o nse a n d pr o gressi o n, a n d ma ke decisi o ns 
re gar di n g t he c o nti n uati o n of st u d y treat me nt.  
If t he I n vesti gat or deter mi nes t hat a patie nt has de vel o pe d cli nical disease pr o gressi o n 
ma nifeste d b y s y m pt o matic deteri orati o n b ut n ot s u p p orte d b y  ra di ol o gic e vi de nce of 
pr o gressi o n, t he patie nt ma y  st o p treat me nt. S ym pt o ms of cli nical disease pr o gressi o n m ust be 
d oc u me nte d i n t he patie nt’s s o urce d oc u me nts a n d m ust be re p orte d as A Es. 
Patie nts w h o disc o nti n ue wit h o ut d oc u me nte d P D per R E CI S T 1. 1 s h o ul d c o nti n ue t o u n der g o 
t u m or assess me nts/sca ns acc or di n g t o t he st u dy sc he d ule u ntil P D is d oc u me nte d per 
R E CI S T 1. 1, ne w a ntica ncer t hera p y is i nitiate d, t he st u d y is ter mi nate d, or c o nse nt is 
wit h dra w n.
8. 1. 
E v al u ati o n of Effic ac y per R E CI S T 1. 1
8. 1. 1. 
Met h o d of I m a gi n g
T he sa me met h o d of assess me nt a n d 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 eac h assess me nt ti me p oi nt. Ima gi n g -base d e val uati o n is 
preferre d t o e val uati o n b y  cli nical e xa mi nati o n w he n b ot h met h o ds ha ve bee n use d t o assess t he 
a ntit u m or effect of treat me nt. All meas ure me nts s h o ul d be rec or de d i n metric n otati o n usi n g a 
r uler or cali pers.
C o ntrast -e n ha nce d C T sca ns or M RI s are t he preferre d met h o ds f or t u m or assess me nts. If a 
c o ntrast a gent is c o ntrai n dicate d i n a patie nt, o btai n a n o n -c o ntrast c hest C T a n d e n ha nce d M RI 
of t he a b d o me n (a n d pel vis if cli nicall y  i n dicate d). A s piral C T s h o ul d be perf or me d usi n g a 
≤5 m m c o nti g u o us rec o nstr ucti o n al g orit h m. I ma ges m ust be ac q uire d of t he c hest a n d a b d o me n 
(a n d pel vis if cli nically i n dicate d or o btai ne d at Baseli ne) at eac h ti me p oi nt. O nl y C T sca ns a n d 
M RI  ma y be use d f or t u m or meas ure me nt. 
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 (e g, s ki n n o d ules, 
pal pa bl e l y m p h n o des). I n t he case of s ki n lesi o ns, d oc u me ntati o n b y  c ol or 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. 
Ultras o u n d s h o ul d n ot be use d t o meas ure t u m or lesi o ns t hat are cli nicall y  n ot easil y accessi ble 
f or o verall res p o nse e val uati o n ( f or e xa m ple, visceral lesi o ns). Ultras o u n d is a p ossi ble 
alter nati ve t o cli nical meas ure me nts of s u perficial pal pa ble n o des, s u bc uta ne o us lesi o ns, a n d 
t h yr oi d n o d ules. Ultras o u n d mi g ht als o be usef ul t o c o nfir m t he c o m plete disa p peara nce of 
s u perficial lesi o ns us uall y assesse d b y cli nical e xa mi nati o n. F or a d diti o nal g ui da nce, refer t o 
R E CI S T 1. 1 s pecificati o ns f or sta n dar d a nat o mical ra di ol o gical i ma gi n g.

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8. 1. 2. 
T u m or Defi niti o ns
Meas ura ble Lesi o ns : O nl y meas ura ble lesi o ns ca n be selecte d as tar get lesi o ns.

Meas ura ble visceral lesi o ns: Lesi o ns t hat ca n be acc uratel y  meas ure d i n at least 
1 di me nsi o n wit h t he l o n gest dia meter (t o be rec or de d) ≥1 0 m m b y  C T sca n if usi n g 
slice t hic k ness of ≤5 m m, or at least d o u ble t he slice t hic k ness of t he C T or M RI  sca n 
if t he slice t hic k ness is > 5 m m. 

Meas ura ble pat h ol o gical l y m p h n o des: A mali g na nt l y m p h n o de m ust be c o nsi dere d 
pat h ol o gicall y  e nlar ge d wit h hi g h s us pici o n of metastasis a n d meas ure ≥1 5 m m i n t he 
s h ort a xis w he n assesse d b y C T sca n. T he s h ort a xis is defi ne d as t he l o n gest li near
di me nsi o n per pe n dic ular t o t he n o de’s l o n gest dia meter as assesse d wit hi n t he sa me 
pla ne t hat t he sca n was ac q uire d.
N o n -meas ura ble Lesi o ns : All n o n-meas ura ble lesi o ns ca n o nl y be selecte d as n o n -tar get lesi ons.

S mall visceral metastatic lesi o ns t hat ha ve a l o n gest di me nsi o n < 1 0 m m, or if slice 
t hic k ness is > 5 m m, less t ha n t wice t he slice t hic k ness 

A b n or mal a n d s us pecte d metastatic l y m p h n o des t hat are ≥1 0 m m t o < 1 5 m m i n t he 
s h ort a xis

Tr ul y  n o n-meas ura ble lesi o ns (e g, ascites a n d perit o neal carci n o mat osis)
Tar get Lesi o ns : 

All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns/ or ga n a n d 5 lesi o ns i n t otal, 
re prese ntati ve of all i n v ol ve d or ga ns/tiss ues s h o ul d be i de ntifie d as tar get lesi o ns

Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size ( visceral lesi o n wit h t he 
l o n gest dia meter a n d ly m p h n o de wit h t he meas ure me nt of s h ort a xis), be 
re prese ntati ve of all i n v ol ve d or ga ns/tiss ues, 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 peate d meas ure me nts

W he n rec or di n g t u m or meas ure me nts, t he l o n gest dia meter will be meas ure d f or eac h 
n o n -n o dal tar get lesi o n. F or meas ura ble pat h ol o gical l y m p h n o des t hat ma y  be 
i de ntifie d as tar get lesi o ns, t he s h ort a xis meas ure me nt will be c o m bi ne d wit h t he 
meas ure me nts of n o n - n o dal (ie, visceral lesi o n) tar get lesi o ns. T heref ore, i n cases of 
C R w he n a b n or mal n o des ha ve bee n use d as tar get lesi o ns, t he s u m of dia meters will 
n ot re d uce t o a n ull val ue. 

Tar get lesi o ns will be f oll o we d u p a n d meas ure d at eac h s u bse q ue nt ti me p oi nt.

T he s u m of t he dia meters f or all tar get lesi o ns will be calc ulate d a n d rec or de d. T he 
baseli ne s u m will be use d as a refere nce t o f urt her c haracterize a n y o bjecti ve t u m or 
assess me nt i n t he meas ura ble di me nsi o n of t he disease. 

As si g n a meas ure me nt t o all tar get lesi o ns re gar dless of size. A n o pti o n of “t o o s mall 
t o meas ure” will be pr o vi de d if a meas ure me nt ca n n ot be assi g ne d. A val ue of zer o 
s h o ul d o nl y be assi g ne d i n t he case of a C R. 

A n o pti o n of “ n ot assessa ble” f or a lesi o n will o nl y  a p ply t o lesi o ns t hat ca n n ot be 
rea d d ue t o tec h nical reas o ns i ncl u di n g:

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
C T artifact

Patie nt p ositi o ni n g w here t he lesi o ns are o bstr ucte d or ca n n ot be see n

Lesi o ns t hat ma y  n ot be see n i n t heir e ntirety d ue t o C T slice t hic k ness

I n cases w here a lesi o n di vi des i nt o 2 lesi o ns, t he l o n gest dia meters of t he fra g me nte d 
p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 

I n cases w here 2 lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat 
w o ul d ai d i n o btai ni n g ma xi mal dia m eter meas ure me nts of eac h i n di vi d ual lesi o n. If 
t he lesi o ns ha ve tr uly c oalesce d s uc h t hat t he y are n o l o n ger se para ble, t he vect or of 
t he l o n gest dia meter i n t his i nsta nce s h o ul d be t he ma xi mal l o n gest dia meter f or t he 
“c oalesce d lesi o n.” 
N o n -tar get Lesi o ns:

N o n -tar get lesi o ns i ncl u de all n o n-meas ura ble lesi o ns a n d meas ura ble lesi o ns t hat 
ha ve n ot bee n selecte d as tar get lesi o ns. 

T he pri mar y  lesi o n s h o ul d al wa ys be classifie d as a n o n-tar get lesi o n irres pecti ve of 
its size a n d w het her or n ot it ca n be acc uratel y meas ure d. 

L y m p h n o des t hat ha ve a s h ort a xis < 1 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. 

A n y  e q ui v ocal lesi o n wit h o ut clear dia g n osis (e g, u nc haracteristic s olitar y l u n g 
n o d ule wit h o ut bi o ps y , u nc haracteristic t h yr oi d mass lesi o n wit h o ut fi ne nee dle 
as pirati o n) ma y be c o nsi dere d a n o n-tar get lesi o n if it ca n n ot be differe ntiate d fr o m a 
be ni g n lesi o n. 

All ot her lesi o ns ( or sites of disease), i ncl u di n g pat h ol o gical l y m p h n o des, s h o ul d be 
i de ntifie d as n o n-tar get lesi o ns a n d sh o ul d als o be rec or de d at Baseli ne. 
Meas ure me nts are n ot re q uire d, b ut t heir prese nce, a bse nce, or u ne q ui v ocal 
pr o gressi o n s h o ul d be f oll o we d t hr o u g h o ut t he st u d y . 

It is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g t he sa me or ga n as a 
si n gle ite m o n t he electr o nic case re p ort f or m ( e C R F) (e g, m ulti ple e nlar ge d pel vic 
l ym p h n o des or m ulti ple li ver metastases).
8. 1. 3. 
Res p o nse Criteri a
Efficac y  e val uati o n will i ncl u de t he assess me nt of tar get a n d n o n-tar get t u m or res p o nses as well 
as o bjecti ve res p o nses . Res p o nses will be assesse d as defi ne d i n t he Statistical A nalys is Pla n 
( S A P).
8. 1. 3. 1. 
T ar get a n d N o n -T ar get Res p o nse Assess me nts
Assess me nts will be base d o n t he defi niti o ns f or tar get a n d n o n- tar get lesi o ns descri be d i n
Ta ble 1 1 .

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T a ble 1 1:
T ar get a n d N o n -t ar get Lesi o ns
T A R G E T L E SI O N S
Lesi o ns Res p o nse: 
Defi niti o n:
C o m plete Res p o nse ( C R) 
Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l y m p h n o de m ust 
ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m
Partial Res p o nse ( P R) 
At least a 3 0 % decrease i n t he s u m of dia meters of t he tar get lesi o ns, 
ta ki n g as a refere nce t he baseli ne s u m dia meters
Pr o gressi ve Disease ( P D) 
At lea st a 2 0 % i ncrease i n t he s u m of dia meters of t he tar get lesi o ns, ta ki n g 
as a refere nce t he s mallest s u m o n st u d y, i ncl u di n g t he baseli ne s u m. I n 
a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n 
a bs ol ute i ncrease of at least 5 m m. Defi niti ve ne w lesi o n prese nce als o 
i n dicates pr o gressi o n. 
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, refere nci n g t he s mallest s u m dia meters w hile o n st u d y. 
N O N- T A R G E T L E SI O N S
Lesi o ns Res p o nse: 
Defi niti o n:
C o m plete Res p o nse ( C R) 
Disa p peara nce of all n o n -tar get lesi o ns a n d n or malizati o n of t u m or mar ker 
le vel. All l y m p h n o des m ust be n o n-pat h ol o gical i n size ( < 1 0 -m m s h ort 
a xis)
Partial Res p o nse ( P R) 
Persiste nce of o ne or m ore n o n -tar get lesi o n(s) a n d/ or mai nte na nce of 
t u m or mar ker le vel a b o ve t he n or mal li mits
Pr o gressi ve Disease ( P D) 
U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns (see f oll o wi n g 
defi niti o n).
A b brevi ati o ns: C R =c o m plete res p o nse; P D = pr o gressive dise ase; P R = p arti a l res p o nse; S D =st a ble dise ase
Pr o gressi o n i n N o n -tar get Disease: T here m ust be a n o verall le vel of s u bsta ntial w orse ni n g i n 
n o n -tar get disease s uc h t hat, e ve n i n t he prese nce of S D or P R i n tar get disease, t he o verall t u m or 
b ur de n has i ncrease d s ufficie nt l y t o be c o nsi dere d as P D.
Beca use w orse ni n g i n n o n -tar get disease ca n n ot be easily q ua ntifie d, a usef ul test t hat ca n be 
a p plie d w he n assessi n g patie nts f or u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n 
o verall disease b ur de n base d o n t he c ha n ge i n n o n- meas ura ble diseas e is c o m para ble i n 
ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble disease (ie, a n 
i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 7 3 % i ncrease i n “ v ol u me” [ w hic h is 
e q ui vale nt t o a 2 0 % i ncrease i n t he dia meter of a meas ur a ble lesi o 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, c y t ol o gical c o nfir mati o n 
of t he ne 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 S D is n ot ma n dat or y, b ut mi g ht be perf or me d 
t o differe ntiate bet wee n res p o nse ( or S D) a n d P D w he n s u bsta ntial c ha n ge of eff usi o n a n d or 
ascites is n ote d. 
If a patie nt is disc o nti n ue d fr o m t he st u d y bef ore P D occ urs a n d recei ves l ocal or re gi o nal 
palliati ve ra di ot hera py d uri n g t he f oll o w - u p peri o d, t he irra diati o n site m ust be o mitte d fr o m t he 

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res p o nse assess me nt of t he patie nt; h o we ver, if t he site is o bser ve d t o de m o nstrate disease 
pr o gressi o n, t his case s h o ul d be j u d ge d as P D. 
F or e q ui v ocal fi n di n gs of pr o gressi o n (e g, ver y s mall a n d u ncertai n ne w lesi o ns; c y stic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y  c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w he n pr o gressi o n was s us pecte d.
8. 1. 4. 
O bjecti ve Res p o nse Assess me nt
Assess me nts will be base d o n t he defi niti o ns pr o vi de d i n Ta ble 1 2 a n d Ta ble 1 3 .  Si nce t his is a 
n o n -ra n d o mize d st u d y, all res p o nses ( C R/ P R) m ust be c o nfir me d.
T a ble 1 2:
Ti me P oi nt Res p o nse f or P atie nts wit h T ar get ( ± N o n -t ar get) Dise ase
T ar get
Lesi o ns
N o n -T ar get 
Lesi o ns
Ne w  
Lesi o ns
O bjecti ve 
Res p o nse
C R
C R
N o
C R
C R
N o n -C R/ N o n -P D or N ot all e val uate d 
N o
P R
P R
N o n -P D or N ot all e val uate d
N o
P R
S D
N o n -P D or N ot all e val uate d
N o
S D
N ot all e val uate d 
N o n -P D
N o
N E
P D
A n y 
Yes or N o  
P D
A n y
P D
Yes or N o 
P D
A n y
A n y
Yes
P D
T a ble 1 3:
Ti me P oi nt Res p o nse f or P atie nts wit h O nl y N o n -t ar get Dise ase
N o n -T ar get Lesi o ns
Ne w  Lesi o ns
O bjecti ve Res p o nse
C R 
N o 
C R 
N o n -C R/ N o n -P D 
N o 
S D 
N ot all e val uate d 
N o 
N E
U ne q ui v ocal P D 
Yes or N o 
P D 
A n y 
Yes 
P D 
A b brevi ati o ns: C R =c o m plete res p o nse; N E = n ot ev al u a ble; P D = pr o gressive dise ase; P R = p arti al res p o nse; S D =st a ble 
dise ase
T he efficac y  e val uati o n criteria descri be d a b o ve will be use d t o deri ve t he pri mar y a n d sec o n dar y 
efficac y e n d p oi nts as defi ne d i n Secti o n 2 .

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8. 2. 
Use of i R E CI S T t o G ui de Tre at me nt Decisi o ns
U ntil ra di o gra p hic disease pr o gressi o n ba se d o n R E CIS T 1. 1, t here is n o disti nct i R E CI S T 
assess me nt.  U p o n d oc u me ntati o n of P D per R E CI S T 1. 1, patie nts w h o are cli nicall y sta ble 
s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d b y t he I n vesti gat or, w or ki n g wit h l ocal 
ra di ol o g y, acc or di n g t o t he r ules o utli ne d i n A p pe n di x D .  
Cli nical sta bilit y  is defi ne d as t he f oll o wi n g:

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y  si g nifica nt pr o gressi o n of 
disease

N o decli ne i n E C O G perf or ma nce stat us 

N o re q uire me nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesia, 
ra diati o n, or ot her palliati ve care
A n y  patie nt dee me d cli nic all y u nst a ble s h o ul d be disc o nti n ue d fr o m st u d y treat me nt at site-
assesse d first ra di ol o gic e vi de nce of P D, a n d is n ot re q uire d t o ha ve re peat t u m or i ma gi n g f or 
c o nfir mati o n of P D b y i R E CI S T.
If t he I n vesti gat or deci des t o c o nti n ue treat me nt, t he patie nt ma y c o nti n ue to recei ve st u d y  
treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m P D b y 
i R E CIS T, per I n vesti gat or assess me nt. I ma ges s h o ul d c o nti n ue t o be se nt i n t o t he S p o ns or . 
If re peat i ma gi n g d oes n ot c o nfir m P D per i R E CIS T, as asse sse d by t he I n vesti gat or, a n d t he 
patie nt c o nti n ues t o be cli nicall y  sta ble, st u d y treat me nt ma y c o nti n ue a n d f oll o w t he re g ular 
i ma gi n g sc he d ule. If P D is c o nfir me d, patie nts will be disc o nti n ue d fr o m st u d y treat me nt.
If a patie nt has c o nfir me d ra di o gra p hic pr o gressi o n (i C P D) as defi ne d i n A p pe n di x D , st u d y 
treat me nt s h o ul d be disc o nti n ue d; h o we ver, if t he patie nt is ac hie vi n g a cli nicall y mea ni n gf ul 
be nefit, a n e xce pti o n t o c o nti n ue st u d y  treat me nt ma y be c o nsi dere d f oll o wi n g c o ns ultati o n wit h 
t he S p o ns or. In t his case, if st u d y  treat me nt is c o nti n ue d, t u m or i ma gi n g s h o ul d c o nti n ue t o be 
perf or me d .
A descri pti o n of t he a da ptati o ns a n d i R E CI S T pr ocess is pr o vi de d i n A p pe n di x D, wit h 
a d diti o nal details i n t he i R E CIS T p u blicati o n (Se y m o ur et al. 2 0 1 7 ).  A s u m mar y  of i ma gi n g a n d 
treat me nt re q uire me nts after first ra di ol o gic e vi de nce of pr o gressi o n is ill ustrate d i n Fi g ure 2 .

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Fi g ure 2: 
I m a gi n g a n d tre at me nt f or cli nic all y st a ble p atie nts tre ate d wit h 
p e m br oliz u m a b after t he first ra di ol o gic evi de nce of pr o gressi o n per 
R E CI S T 1. 1
N O 
( d o e s n ot c o nfir m P D p er 
iR E CI S T) 
l . S u b j e ct m a y r e m ai n o n 
st u d y dr u g at I n v e sti g at or 
d is cr eti o n. 
2 . R e e ul ar im a e in e s c h e d ul e 
f oll o w e d; u n s c h e d ul e d 
lm a e ln e  If cli ni c all y  In d ic at e d 
3 . F ut ur e  im a e ln g  a n d  s u b je ct 
m a n a g e m e nt  p er  iR E CI S T . 
C o nt in u e t o s u b m it i ma g i n g 
t o v e n d or 
R E CI S T 1 . 1 P D I d e ntifi e d b y l n v e stle at or 
S u bj e ct  cl in ic all y st a bl e . 
R e p e at t u m or lm a e ln e at 4- 8 
w e e k s 
Y E S 
( c o nfir m s P D p er  IR E CI S T) 
1 . S u b je ct  d is c o nti n u e s  tri al 
tr e at m e nt 
2 . E x c e pt io n  p o s si bl e  u p o n 
s p o n s or  c o n s ult at io n . 
3 . T u m or  im a gi n g  d o n e o nl y if 
n e e d e d f or f oll o w- u p. 

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9. 
S A F E T Y E V A L U A TI O N S
9. 1. 
A d verse E ve nts
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce i n a cli nical st u d y patie nt a n d d oes n ot 
necessaril y  ha ve a ca usal relati o ns hi p wit h t he st u d y dr u g. A n A E ca n t heref ore be a ny 
u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a st u d y dr u g, w het her or n ot relate d t o t he st u d y dr u g. T his 
i ncl u des a ny occ urre nce t hat is ne w i n o nset or a g gra vate d i n se verit y or fre q ue nc y fr o m t he 
baseli ne c o n diti o n, or a b n or mal res ults of dia g n ostic pr oce d ures, i ncl u di n g la b orat or y test 
a b n or malities. 
All A Es will be c ollecte d fr o m t he ti me t he I C F is si g ne d t hr o u g h 3 0 d a y s after t he last d ose of 
a n y st u d y t hera p y (safety f oll o w -u p) or u ntil t he start of ne w a ntit u m or t hera p y , w hic he ver is 
earlier; S A Es will be c ollecte d t hr o u g h 9 0 da ys after t he last d ose of a n y st u d y t hera p y  F or all 
A Es t hat occ ur bet wee n si g ni n g I C F a n d first d ose of st u d y t hera p y, t here is n o nee d t o rec or d 
t h ose t hat are u nrelate d u nless it is ma n dat or y b y l ocal re g ulati o ns. All A Es will be d oc u me nte d 
i n t he e C R F.  A n y u nt o war d me dical e ve nt t hat occ urs after t he safety f oll o w -u p is n ot 
c o nsi dere d a n A E, u nless t he In vesti gat or c o nsi ders t hat t he A E is relate d t o t he st u d y  dr u g. 
Seri o us A Es relate d t o st u d y  t hera p y will be c ollecte d t hr o u g h t he s ur vival f oll o w - u p.
Si g ns a n d s y m pt o ms of a pre e xisti n g disease s h o ul d n ot be c o nsi dere d a n A E, b ut s h o ul d rat her 
be c o nsi dere d baseli ne si g ns a n d s y m pt o ms. Cli nicall y  si g nifica nt w orse ni n g of pre e xisti n g 
si g ns a n d sy m pt o ms is c o nsi dere d a n A E.
F or defi niti o n s a n d re p orti n g of pre g na ncies, o ver d oses, a n d me dicati o n err ors, refer t o 
Secti o n 9. 5 .
9. 2. 
Re p orti n g of A d verse E ve nts
9. 2. 1. 
Ter ms of Re p orte d A d verse E ve nts
All A Es will be d oc u me nte d i n t he eC R F acc or di n g t o t he e C R F C o m pleti o n G ui deli nes. 
D oc u me ntati o n s h o ul d i ncl u de o nset a n d res ol uti o n/sta bilizati o n dates, se verit y / gra de, 
relati o ns hi p t o st u d y dr u g, a n d o utc o me of t he e ve nt. H o we ver, all S A Es m ust be re p or te d o n an
S A E f or m as per t he S A E f or m c o m pleti o n g ui deli nes, as well as i n t he e C R F.
W he n a dia g n osis f or t he re p orte d si g ns or s y m pt o ms is k n o w n, t he In vesti gat or s h o ul d re p ort t he 
dia g n osis, n ot t he s y m pt o ms, as t he A E.
A d verse e ve nts ca n be s p o nta ne o us l y re p orte d or elicite d d uri n g o pe n-e n de d q uesti o ni n g, 
e xa mi nati o n, or e val uati o n of a patie nt . I n or der t o pre ve nt re p orti n g bias, patie nts s h o ul d n ot be 
q uesti o ne d re gar di n g t he s pecific occ urre nce of o ne or m ore A Es.
9. 2. 2.  
Se verit y of A d verse E ve nts
T he N CI -C T C A E Versi o n 5. 0 will be use d t o gra de t he se verit y  of A Es.

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9. 2. 3. 
C a us al Rel ati o ns hi p wit h St u d y Dr u g
T he ca usal relati o ns hi p bet wee n a n A E a n d st u d y dr u g will be assesse d usi n g t he f oll o wi n g 
2 -p oi nt scale, ta ki n g i nt o acc o u nt t he patie nt’s c o n diti o n, me dic al hist or y, c o nc o mita nt 
me dicati o ns, a n d t he te m p oral relati o ns hi p bet wee n st u d y  dr u g a d mi nistrati o n a n d o nset of t he 
e ve nt.
1.
A n A E is c o nsi dere d t o be “ Rel ate d ” if t he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce 
fr o m a d mi nistrati o n of st u d y dr u g a n d t here is a re as o n a ble p ossi bilit y t hat at least o ne 
of t he f oll o wi n g c o n diti o ns is tr ue:

A p ositi ve dec halle n ge: T his mea ns t hat t he e ve nt i m pr o ves or res ol ves after t he dr u g 
is st o p pe d (te m p orarily or per ma ne ntl y).

A p ositi ve rec halle n ge: T his mea ns t hat t he e ve nt rea p pears after t he dr u g is restarte d.

T he e ve nt ca n n ot be reas o na bl y  e x plai ne d b y t he patie nt’s cli nical state a n d/ or ot her 
t hera pies a d mi nistere d.

A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be str o n gl y  
ass ociate d wit h dr u g e x p os ure (e g, a n gi oe de ma, Ste ve ns -J o h ns o n s yn dr o me).
2.
A n A E is c o nsi dere d t o be “ N ot rel ate d ” if t here is n o re as o n a ble p ossi bilit y t hat at 
least o ne of t he f oll o wi n g c o n diti o ns is tr ue:

T he e ve nt occ urre d pri or t o st u d y  dr u g a d mi nistrati o n.

T here is n o reas o na ble p ossi bilit y  t hat t he st u d y dr u g ca use d t he e ve nt. (“ n o 
reas o na ble p ossi bilit y” mea ns t here is n o e vi de nce t o s u g gest a ca usal relati o ns hi p 
bet wee n t he st u d y dr u g a n d t he A E)

T he e ve nt d oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of 
st u d y dr u g a n d c o ul d ha ve bee n pr o d uce d b y a d oc u me nte d pre-e xisti n g c o n diti o n, 
c o nc o mita nt me dicati o n or patie nt’s cli nical state. 
9. 2. 4.   
O utc o me of A d verse E ve nts
Rec or d t he o utc o me of A Es as f oll o ws:

Res ol ve d

N ot res ol ve d

Fatal
9. 2. 5. 
F oll o w -u p of A d verse E ve nts
A n y  o n g oi n g A Es s h o ul d be f oll o we d u ntil t he earliest occ urre nce of o ne of t he f oll o wi n g:

T he A E has res ol ve d or sta bilize d

C o m pleti o n of safet y f oll o w-u p visit

S tart of ne w a ntit u m or t hera py

Wit h dra wal of c o nse nt

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
Deat h

Ot her (e g, tra nsfer t o a n ot her h os pital)
9. 3. 
L a b or at or y Assess me nts
9. 3. 1. 
Re p orti n g a n d E v al u ati o n of L a b or at or y Test Res ults
All la b orat or y res ults m ust be re vie we d b y  t he I n vesti gat or. A ne w la b orat or y or i nstr u me ntal 
a b n or malit y t hat has a cli nical i m pact o n a patie nt (i ncl u di n g e g, res ulti n g i n st u d y dr u g d ose 
re d ucti o n, treat me nt dela y, treat me nt disc o nti n uati o n or re q uire me nt of i nter ve nti o n) is 
c o nsi dere d a n A E, u nless it is c o nsi dere d part of cli nical ma nifestati o ns t o a cli nical dia g n osis 
t hat is alrea dy re p orte d as a n A E.
All la b orat or y  val ues t hat are o ut of t he n or mal ra n ge are t o be e val uate d f or t heir cli nical i m pact 
bef ore e x p osi n g t he patie nt t o t he ne xt d ose of f uti bati ni b. 
T he N CI -C T C A E Versi o n 5. 0 will be use d t o gra de t he se verit y  of la b orat or y data.
9. 3. 2. 
Re pe at Testi n g
E val uati o n o f a ny cli nicall y si g nifica nt la b orat or y test will be re peate d, as cli nicall y i n dicate d, 
u ntil t he val ue ret ur ns t o t he baseli ne le vel or cli nicall y  sta bilizes, or u ntil a n ot her treat me nt is 
gi ve n.
9. 4. 
Seri o us A d verse E ve nts
9. 4. 1. 
Defi niti o ns of Seri o us A d verse E ve nt s
A n S A E is a n y u nt o war d me dical occ urre nce t hat at a n y d ose: 

Res ults i n deat h

Deat h d ue t o disease pr o gressi o n or rela pse is n ot c o nsi dere d a n S A E u nless t he 
in vesti gat or dee ms it p ossi bl y  relate d t o t he st u d y dr u g.

Is life-t hreate ni n g

T he ter m "life -t hreate ni n g" refers t o a n e ve nt i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y 
mi g ht ha ve ca use d deat h if it were m ore se vere.

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 t o treat 
t he A E. 

T he f oll o wi n g are n ot c o nsi dere d h os pitalizati o ns f or t he p ur p oses of assessi n g 
seri o us ness ( h o we ver, o ne of t he ot her seri o us criteria ma y a p ply):

E mer ge nc y  r o o m visits < 2 4 h o urs;

H os pitalizati o ns f or pre pla n ne d pr oce d ures;

H os pitalizati o n f or st u d y -relate d treat me nt a n d pr oce d ures.

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
Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y, w here disa bilit y is defi ne d as 
a s u bsta ntial disr u pti o n of a pers o n’s a bilit y  t o c o n d uct n or mal life f u ncti o ns, eit her 
re p orte d or defi ne d as per cli nical j u d g me nt.

Is a c o n ge nital a n o maly/ birt h defect (if e x p os ure t o pr o d uct j ust bef ore c o nce pti o n or 
d uri n g pre g na nc y  res ulte d i n a n a d verse o utc o me i n t he c hil d).

Is a ny ot her i m p orta nt me dical e ve nt t hat base d u p o n a p pr o priate me dical j u d ge me nt 
ma y  je o par dize t he patie nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he ot her o utc o mes liste d i n t he defi niti o ns a b o ve. (e g, ma y  n ot res ult i n deat h, 
be life -t hreate ni n g, or re q uire h os pitalizati o n). 
9. 4. 2. 
Re p orti n g o f Seri o us A d verse E ve nts ( wit hi n 2 4 h o urs)
All S A Es occ urri n g fr o m t he ti me t he I C F is si g ne d t hr o u g h t he Safet y F oll o w -u p Peri o d 
( 90 d a y s after t he last d ose of st u d y dr u g or disc o nti n uati o n of t he Safety F oll o w -u p Peri o d, 
w hic he ver is earlier) m ust be re p orte d t o S p o ns or’s P har mac o vi gila nce gr o u p or its desi g nee 
wit hi n 2 4 h o urs fr o m t he ti me t he In vesti gat or first bec o mes a ware of t he S A E . 
C o m pre he nsi ve i nf or mati o n a vaila ble at t he ti me of i nitial re p orti n g (i ncl u di n g narrati ve 
descri pti o n, me dical hist o r y, a n d c o nc o mita nt me dicati o ns) nee ds t o be pr o vi de d wit h caref ul 
c o nsi derati o n re gar di n g ca usalit y  a n d seri o us criteri o n. T he S A E re p orti n g pr ocess a n d c o ntact 
i nf or mati o n are pr o vi de d i n s u p ple me nt g ui deli nes.
After t he i nitial S A E n otificati o n t o t he S p o ns or’s P har mac o vi gila nce gr o u p or its desi g nee, all 
f oll o w-u p S A E i nf or mati o n will be s u b mitte d eac h ti me t he y  bec o me a vaila ble (f or e xa m ple, 
cli nical dia g n osis, o utc o me, ca usalit y assess me nt, res ults of s pecific i n vesti gati o ns) o n a f oll o w 
u p S A E f or m. T he In vesti gat or als o m ust s u b mit f urt her i nf or mati o n if it is re q uire d b y t he 
S p o ns or or t he direct or of t he st u d y site or a n i nstit uti o nal re vie w b oar d ( I RB)/i n de pe n de nt et hics 
c o m mittee (I E C). E ver y  S A E s h o ul d be f oll o we d u ntil it has res ol ve d, sta bilize d, or ret ur ne d t o 
baseli ne.
9. 4. 3. 
Re p orti n g of De at hs ( wit hi n 2 4 h o urs)
All deat hs (e xce pt disease pr o gressi o n) occ urri n g fr o m t he ti me t he I C F is si g ne d t hr o u g h t he 
Safet y  F oll o w-u p Peri o d ( 9 0 d a y s after t he last d ose of st u d y dr u g or disc o nti n uati o n, w hic he ver 
is earlier) m ust be re p orte d wit hi n 2 4 h o urs fr o m t he ti me t he I n vesti gat or first bec o mes a ware of 
t he deat h. T he pri mar y ca use of t he deat h s h o ul d be re p orte d as t he S A E ter m, if a vaila ble, a n d 
e ntere d o n t he deat h pa ge of t he e C R F.
9. 5. 
Ot her S afet y I nf or m ati o n
9. 5. 1. 
Pre g n a nc y
If a patie nt i na d verte ntl y bec o mes pre g na nt w hile i n t he st u d y , t he st u d y treat me nt m ust be 
i m me diatel y disc o nti n ue d. Pre g na nc y i nf or mati o n i n a fe male patie nt ( or f or t he fe male part ner 
of a male patie nt) s h o ul d be re p orte d as s o o n as p ossi ble fr o m t he ti me t he In vesti gat or first 
bec o mes a ware of a pre g na nc y  or its o utc o me. T his s h o ul d be perf or me d b y c o m pleti n g a 
Pre g na nc y  F or m a n d fa xi n g or e-maili n g it t o S p o ns or’s P har mac o vi gila nce or desi g nee.

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Ne w a n d/ or c orrecte d i nf or mati o n re gar di n g t he pre g na nc y o btai ne d after s u b mitti n g t he i nitial 
Pre g na nc y  F or m m ust be s u b mitte d usi n g a n u p date d Pre g na nc y F or m t o t he S p o ns or’s 
P har mac o vi gila nce or desi g nee. Pre g na ncies m ust be f oll o we d t o o utc o me b y  t he In vesti gat or, 
e ve n after st u d y c o m pl eti o n. 
If t he o utc o me of t he pre g na nc y is a still birt h, c o n ge nital a n o maly/ birt h defect, or a seri o us e ve nt 
i n t he m ot her, it s h o ul d be re p orte d as a n S A E t o t he S p o ns or’s P har mac o vi gila nce or desi g nee. 
Li ve birt hs will be f oll o we d u p b y  t he In vesti gat or. A n y  i nf or mati o n t hat ma y be ass ociate d wit h 
t he st u d y dr u g s h o ul d be re p orte d e ve n after st u dy c o m pleti o n.
9. 5. 2. 
O ver d ose
F or t his st u d y , a n o ver d ose of f uti bati ni b is defi ne d as t he acci de ntal or i nte nti o nal use of t he 
dr u g i n a n a m o u nt hi g her t ha n t he d ose b ei n g st u die d. An o ver d ose of pe m br oliz u ma b will be 
defi ne d as a n y d ose of 1 0 0 0 m g or ≥5 ti mes t he i n dicate d d ose. A n o ver d ose or i nc orrect 
a d mi nistrati o n of st u d y treat me nt is n ot itself a n A E, b ut it ma y res ult i n a n A E. A n o ver d ose t hat 
res ults i n a n A E s h o ul d be re p orte d via fa xi n g or e maili n g t o S p o ns or’s P har mac o vi gila nce or 
desi g nee wit hi n 2 4 h o urs fr o m t he ti me t he I n vesti gat or first bec o mes a ware of its occ urre nce.
N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o ver d ose of pe m br oliz u ma b o r 
f uti bati ni b; t here is n o k n o w n a nti d ote i n t he case of f uti bati ni b o ver d ose. I n t he e ve nt of 
o ver d ose, t he partici pa nt s h o ul d be o bser ve d cl osel y  f or si g ns of t o xicit y. A p pr o priate s u p p orti ve 
treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d.
9. 5. 3. 
Pe m br oli z u m a b E ve nts of Cli nic al I nterest
Selecte d n o n -seri o us a n d S A Es are als o k n o w n as E ve nts of Cli nical I nterest ( E CI ) f or 
pe m br oliz u ma b, a n d m ust be re p orte d t o t he S p o ns or.
E ve nts of cli nical i nterest f or t his trial i ncl u de: 
1.
a n o ver d ose of pe m br oliz u ma b, as defi ne d i n Secti o n 9. 5. 2 , t hat is n ot ass ociate d wit h 
cli nical s ym pt o ms or a b n or mal la b orat or y  res ults.
2.
a n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he U L N a n d a n 
ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o 2 X t he U L N a n d, at t he 
sa me ti me, a n A L P la b val ue t hat is less t ha n 2 X t he U L N , as deter mi ne d b y w a y of
pr ot oc ol -s pecifie d la b orat or y testi n g or u nsc he d ule d la b orat or y testi n g. *
* N ote:  T hese criteria are base d u p o n a vaila ble re g ulat or y  g ui da nce d oc u me nts. T he p ur p ose of 
t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire a n a dditi o nal 
e val uati o n f or a n u n derl yi n g eti ol o g y . T he trial site g ui da nce f or assess me nt a n d f oll o w u p of 
t hese criteria ca n be ma de a vaila ble. It m a y als o be a p pr o priate t o c o n d uct a d diti o nal e val uati o n 
f or a n u n derl yi n g eti ol o g y i n t he setti n g of a b n or malities of li ver bl o o d tests i ncl u di n g A S T, 
A L T, bilir u bi n, a n d A L P t hat d o n ot meet t he criteria n ote d a b o ve. I n t hese cases, t he decisi o n t o 
pr ocee d wit h a d diti o nal e val uati o n will be ma de t hr o u g h c o ns ultati o n bet wee n t he st u d y  
I n vesti gat ors a n d t he S p o ns or Me dical M o nit or . H o we ver, a b n or malities of li ver bl o o d tests t hat 
d o n ot meet t he criteria n ote d a b o ve are n ot E CIs f or t his trial.
F or d ose m o dificati o n a n d ot her g ui deli nes relate d t o e ve nts of i nterest f or b ot h pe m br oliz u ma b 
a n d f uti bati ni b, please see Secti o n 5. 3 of t his pr ot oc ol.

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1 0.
E V A L U A TI O N
1 0. 1.
 Assess me nts
Patie nts will be e nr olle d base d o n l ocal assess me nt of F G F R m utati o n stat us; h o we ver, tiss ue 
sa m ples (if a vaila ble fr o m fres h bi o ps y [ preferre d] or arc hi ve d tiss ue c ollecte d after ter mi nati o n 
of t he last t hera pe utic re gi me n ) will be arc hi ve d f or ce ntral retr os pecti ve c o nfir mati o n.
O n -st u d y c ollecti o n of t u m or tiss ue an d bl o o d/ plas m a 
c ollecti o n of t u m or tiss ue a n d bl o o d/ plas ma w ill b e p erfo rm ed  
will be perf or me d fro m  p atien ts w h o  
fr o m patie nts w h o 
co n sen t
c o nse nt, , acco rd in g  to  th e sch ed u le in  
acc or di n g t o t he sc he d ule i n Ta ble 1 .  
.  
 
 
 
C CI
C CI
C CI

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1 1. 
S T A TI S TI C A L C O N SI D E R A TI O N S
T he statistical a nal ys is met h o ds will be d oc u me nte d i n detail i n t he S A P.
1 1. 1. 
Esti m ati o n of S a m ple Si ze
A p pr o xi matel y  2 0 patie nts will be e nr olle d i n C o h ort A. Sa m ple size c o nsi derati o ns are base d o n 
differe ntiati n g a hist orical c o ntr ol O R R per R E CI S T 1. 1 of 3 5 % or less, wit h a tar get O R R per 
R E CI S T 1. 1 of 6 5 %. Ass u mi n g t he tr ue O R R per R E CI S T 1. 1 is 6 5 %, t he c o h ort has a n 
a p pr o xi mate 8 0 % p o wer t o reject t he n ull h y p ot hesis t hat t he tr ue O R R per R E CI S T 1. 1 is ≤3 5 %, 
c o nsi deri n g a 2 -si de d al p ha of 1 0 %. Wit h a sa m ple size of 2 0, o bser vi n g at least 1 2 res p o n ders 
will ha ve a 9 0 % CI l o wer b o u n d e xcl u di n g 1 0 % ( O R R per R E CI S T 1. 1 of 6 0 % wit h 9 0 % CI  
( 3 9. 4 % - 7 8. 3 %) ).
A p pr o xi matel y  2 0 patie nts will be e nr olle d i n C o h ort B. Sa m ple size c o nsi derati o ns are base d o n 
differe ntiati n g a hist orical c o ntr ol O R R per R E CI S T 1. 1 of 2 5 % or less, wit h a tar get O R R per 
R E CI S T 1. 1 of 5 0 %. Ass u mi n g t he tr ue O R R per R E CI S T 1. 1 is 5 0 %, t he c o h ort has a n 
a p pr o xi mate 8 0 % p o wer t o reject t he n ull h y p ot hesis t hat t he tr ue O R R per R E CI S T 1. 1 is ≤2 5 %, 
c o nsi deri n g a 2 -si de d al p ha of 1 0 %. Wit h a sa m ple size of 2 0, o bser vi n g at least 9 res p o n ders 
will ha ve a 9 0 % C I l o wer b o u n d e xcl u di n g 1 0 % ( O R R per R E CI S T 1. 1 of 4 5 % wit h 9 0 % CI  
( 2 5. 9 % - 6 5. 3 %) ).
1 1. 2. 
P l a n ne d Interi m A n al ys es
T he f irst i nteri m a nalys is of safety will be perf or me d after t he 6-patie nt safet y  lea d-i n peri o d; a 
sec o n d i nteri m a nal ys is of safety will be perf or me d after a t otal of 1 0 patie nts ha ve bee n e nr olle d 
(i ncl u di n g t he i nitial 6 patie nts e nr olle d i n t he safet y lea d-i n peri o d).
1 1. 3. 
A n al ysis P o p ul ati o ns
T he a nal ys is p o p ulati o ns i n t he st u d y are defi ne d i n Ta ble 1 4 .
T a ble 1 4 :     Defi niti o ns of A n al ysis P o p ul ati o ns
A n al ysis P o p ul ati o n
Defi niti o n
All E nr olle d P o p ulati o n
All patie nts e nr olle d i n t his st u d y
All Treate d P o p ulati o n/ F ull A nal ysis Set 
All e nr olle d patie nts i n t he All E nr olle d P o p ulati o n w h o recei ve d at 
least o ne d ose of st u d y dr u g
 
 
1 1. 4. 
Criteri a f or H a n dli n g of P atie nt D at a
T he criteria f or ha n dli n g of patie nt data are pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P).
C CI
C CI

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1 1. 5. 
St atistic al A n al yses
1 1. 5. 1. 
De m o gr a p hic a n d B aseli ne C h ar acteristics
T he n u m ber of pa tie nts i n eac h st u d y p o p ulati o n a n d t he reas o ns f or e xcl usi o n will be 
s u m marize d. In eac h a nal y sis p o p ulati o n, t he distri b uti o n of mai n patie nt bac k gr o u n d, disease 
c haracteristics, a n d baseli ne la b orat or y  val ues a n d cli nical fi n di n gs will be s u m marize d. T hese 
patie nt attri b utes will be s u m marize d usi n g fre q ue nc y  distri b uti o n or descri pti ve statistics as 
a p pr o priate.
1 1. 5. 2. 
St u d y Dr u g A d mi nistr ati o n
I n t he All-Treate d P o p ulati o n , t he f oll o wi n g data will be prese nte d se paratel y  f or f uti bati ni b a n d 
pe m br oliz u ma b b y  eac h c o h ort a n d st u d y dr u g :

A d mi nistrati o n Stat us

T he t otal d ose, t otal d urati o n of a d mi nistrati o n a n d t he n u m ber of a d mi nistrati o n 
c ycles will be s u m marize d

Stat us of ad mi nistrati o n co m pleti o n

T he rate of a d mi nistrati o n c o m pleti o n will be prese nte d b y c ycle.

T he prese nce or a bse nce of st u d y  disc o nti n uati o n a n d reas o ns f or st u d y 
disc o nti n uati o n will be ta b ulate d b y  c ycle.

D ose inte nsit y

Act ual d ose inte nsit y  a n d relati ve d ose inte nsit y i n eac h patie nt will be calc ulate d, a n d 
descri pti ve statistics will b e prese nte d.
1 1. 5. 3. 
Effic ac y A n al yses
T he efficac y a nal ys es will be perf or me d f or eac h c o h ort usi n g t he All Treate d P o p ulati o n, u nless 
ot her wise s pecifie d. 
1 1. 5. 3. 1. 
Pri m ar y Effic ac y A n al ys is
O R R per R E CI S T 1. 1 will be esti mate d wit h t he e xact 2 -si de d 9 0 % c o nfi de nce i nter val ( CI). 
O nl y  t he e val uati o ns bef ore disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt will be 
use d f or t he esti mati o n.
1 1. 5. 3. 2. 
Sec o n d ar y Effic ac y A n al ys es
O R R a n d D C R per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d wit h t he e xact 2- si de d 9 5 % CI . 
O nl y  t he e val uati o ns bef ore disease pr o gressi o n or i nitiati o n of ne w a ntica ncer treat me nt will be 
use d f or t he esti mati o n.
D O R per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d o nl y  i n patie nts wit h a n o bjecti ve res p o nse 
of C R or P R. Patie nts w h o are ali ve a n d p r o gressi o n-free as of t he a nalys is c ut- off date will be 
ce ns ore d at t heir last e val ua ble t u m or res p o nse assess me nt pri or t o i nitiati o n of a n y ne w 
a ntica ncer treat me nt. Patie nts w h o start s u bse q ue nt a ntica ncer t hera p y wit h o ut a pri or re p orte d 

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pr o gressi o n wi ll be ce ns ore d at t he last t u m or assess me nts pri or t o i nitiati o n of t he s u bse q ue nt 
a ntica ncer t hera p y.
P F S per R E CI S T 1. 1 a n d i R E CI S T will be esti mate d usi n g t he Ka pla n -Meier met h o d. Patie nts 
w h o die wit h o ut a re p orte d disease pr o gressi o n will be c o nsi dere d t o ha ve pr o gresse d o n t he date 
of t heir deat h. Patie nts w h o di d n ot pr o gress or die will be ce ns ore d o n t he date of t heir last 
t u m or assess me nt. Patie nts w h o di d n ot ha ve a ny o n -st u d y assess me nts a n d di d n ot die will be 
ce ns ore d o n t he first d osi n g date. Patie nts w h o starte d a n y  s u bse q ue nt a ntica ncer t hera p y wit h o ut 
a pri or re p orte d pr o gressi o n will be ce ns ore d at t he last t u m or assess me nt pri or t o i nitiati o n of t he 
s u bse q ue nt a ntica ncer t hera py.
O verall s ur vi val will be esti mate d t he sa me as P F S. I n t he a bse nce of deat h c o nfir mati o n or f or 
patie nts ali ve as of t he O S c ut - off date, s ur vi val ti me will be ce ns ore d at t he date of t he last 
k n o w n ali ve date.
1 1. 5. 4. 
S afet y A n al ys es
T he safet y a nal ys es will be perf or me d b y  eac h c o h ort a n d st u d y dr u g usi n g t he All Treat e d 
P o p ulati o n.
All A Es will be s u m marize d ( b y  i nci de nce) a n d liste d b y t he Sys te m Or ga n Class, Preferre d 
Ter m, t o xicit y /se verit y gra de, a n d ca usal relati o ns hi p t o f uti bati ni b. In a d diti o n, se parate 
s u m maries of S A Es a n d Gra de 3 or 4 A Es will be prese nte d.
F or all A Es t hat occ urre d bet wee n t he si g ni n g of t he I C F a n d t he last da y  of t he Safety F oll o w - u p 
Peri o d, lists of preferre d A E ter ms, gra de, o nset date, acti o ns, o utc o me of A E, date of o utc o me 
c o nfir me d, ca usalities wit h t he st u d y  dr u g, a n d c o m me nts o n A Es will be liste d b y patie nt.
He mat ol o gical a n d c he mistr y  la b orat or y para meters will be gra de d acc or di n g t o t he 
N CI -C T C A E ( Versi o n 5. 0) w here a p plica ble. T he w orst se verit y gra de, ti me t o ma xi m u m 
Gra de 3 or 4 val ue, a n d ti me t o res ol uti o n (ret ur n t o baseli n e gra de or bel o w) will be 
s u m marize d.
A list of 1 2 -lea d E C G fi n di n gs will be prese nte d b y patie nt.
1 1. 5. 5.
 A n a ly sis
 d ata will be liste d b y  c o h ort usi n g t he All Treate d P o p ulati o n.
1 1. 5. 6.
 A n a ly sis
T h e 
 an al
a nalysys es w ill b e p erfo rm ed  u sin g  th e 
.
 d ata w ill b e su m m arized  
d escrip tiv el
descri pti vely  as d escrib ed  in  a sep arate S A P .
y as descri be d i n a se parate S A P.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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1 2. 
A D MI NI S T R A TI V E C O N SI D E R A TI O N S
1 2. 1. 
Pr ot oc ol C o m pli a nce
T he In vesti gat or m ust a gree t o c o m pl y wit h all as pects of t he pr ot oc ol.  I n t he e ve nt t hat t he 
In vesti gat or is u na ble t o c o nti n ue t he st u d y a n d a n ot her s uita ble pers o n is desi g nate d as t he
In vesti gat or , t he S p o ns or m ust be n otifie d i n a d va nce. T he ne w In vesti gat or m ust acce pt t he 
res p o nsi bilit y i n writi n g a n d be a p pr o ve d b y t he S p o ns or a n d t he I R B/I E C.
1 2. 2. 
Pr ot oc ol De vi ati o ns
T he In vesti gat or m a y  i m ple me nt a de viati o n fr o m, or a c ha n ge i n, t he pr ot oc ol t o eli mi nate a n 
i m me diate hazar d(s) t o st u d y patie nts wit h o ut pri or IR B /IE C a p pro val/fa v ora ble o pi ni o n. As 
s o o n as p ossi ble, t he i m ple me nte d de viati o n or c ha n ge a n d t he reas o ns f or it s h o ul d be 
d oc u me nte d a n d s u b mitte d t o t he I R B /IE C a n d S p o ns or.
T he In vesti gat or is t o rec or d a n y de viati o n fr o m t he pr ot oc ol i n t he s o urce d oc u me nts, descri bi n g 
t his de part ure a n d t he circ u msta nces u n der w hic h it was re q uire d.
1 2. 3. 
Pr ot oc ol A me n d me nts
All pr ot oc ol a me n d me nts m ust be iss ue d b y  t he S p o ns or, a n d si g ne d a n d date d b y  t he 
I n vesti gat or. D oc u me ntati o n of a me n d me nt a p pr o val b y t he In vesti gat or a n d I R B /IE C m ust be 
pr o vi de d t o t he S p o ns or.
If t he c ha n ges i n v ol ve o nl y l o gistic or a d mi nistrati ve as pects of t he st u d y, t hese c ha n ges will be 
n otifie d i n writi n g b y t he S p o ns or.
1 2. 4. 
St u d y Ter mi n ati o n
If t he S p o ns or a n d/ or t he In vesti gat or s h o ul d disc o ver c o n diti o ns arisi n g d uri n g t he st u d y t hat 
i n dicate it s h o ul d be ter mi nate d, a n a p pr o priate sc he d ule f or ter mi nati o n will be i nstit ute d. T he 
S p o ns or als o reser ves t he ri g ht t o disc o nti n ue t his st u d y  f or a d mi nistrati ve or discreti o nar y 
reas o ns at a ny ti me.
1 2. 5. 
C ase Re p ort F or ms
T he In vesti gat or s h o ul d c o m plete all e C R Fs i n acc or da nce wit h t he e C R F C o m pleti o n 
G ui deli nes. Data i n t he e C R Fs s hall be c o nsiste nt wit h s o urce d oc u me nts.
I n t his st u dy, all rele va nt pers o n nel will recei ve electr o nic data ca pt ure access acc or di n g t o t heir 
r oles i n t he st u d y.
A n e C R F s h o ul d be c o m plete d f or eac h scree ne d a n d e nr olle d patie nt.
T he I n vesti gat or, or assi g ne d pers o n nel, s h o ul d verif y t he data a n d c orrect as necessar y pri or t o 
a p pr o val of t he e C R Fs.
1 2. 6. 
A ccess t o S o urce D at a/ D oc u me nts
T he In vesti gat or a n d t he site m ust ma ke all st u d y -relate d rec or ds a vaila ble f or st u d y-relate d 
m o nit ori n g, a u dit, I R B /I E C re vie w, a n d re g ulat or y i ns pecti o n.

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1 2. 6. 1. 
S o urce D at a/ D oc u me nts
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds s uc h as h os pital rec or ds, cli nical a n d 
office c harts, la b orat or y  n otes, me m ora n da, patie nt’s e val uati o n c hec klists, p har mac y dis pe nsi n g 
rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, micr ofil m or ma g netic me dia, X-r a y, patie nt 
files, a n d rec or ds ke pt at t he phar mac y , la b orat ories, a n d me dical-tec h nical de part me nts i n v ol ve d 
i n t he st u d y.
S pecific details re gar di n g s o urce d oc u me nts a n d s o urce data t o be rec or de d directl y  o n t he 
e C R Fs f or t he st u d y s h o ul d be i de ntifie d wit h t he In vesti gat or pri or t o a n d d uri n g t he st u d y.
1 2. 6. 2. 
Access t o S o urce D at a
T he S p o ns or’s st u d y m o nit or, or ot her re prese ntati ves, s h o ul d verif y t he e ntries i n t he e C R F a n d 
s o urce d oc u me nts t o c o nfir m t he c o m plete ness a n d acc urac y of t he data. If t here are a n y 
discre pa ncies bet wee n t he e ntries i n e C R Fs a n d s o urce d oc u me nts, t he m o nit or will q uer y  t he 
In vesti gat or .
1 2. 7. 
D at a H a n dli n g
All st u d y  i nf or mati o n is c o nfi de ntial. T he patie nt’s a n d In vesti gat or’s pers o nal data w hic h ma y  
be i ncl u de d i n t he S p o ns or’s data base s hall be treate d i n c o m plia nce wit h all a p plica ble la ws a n d 
re g ulati o ns.
W he n pr ocessi n g a n d arc hi vi n g pers o nal data pertai ni n g t o t he In vesti gat or a n d t o t he patie nts, 
t he S p o ns or or its re prese ntati ves s hall ta ke all a p pr o priate meas ures t o safe g uar d a n d pre ve nt 
access t o t his data b y a n y u na ut h orize d t hir d part y .
1 2. 8. 
Res p o nsi bilities of Rec or d kee pi n g
1 2. 8. 1. 
I n vesti g at or a n d St u d y Site
T he I n vesti gat or a n d t he st u d y site are res p o nsi ble f or t he rete nti o n of all st u d y d oc u me nts 
acc or di n g t o i nstit uti o nal p olicies, l ocal la ws, a n d I nter nati o nal C o u ncil f or Har m o nisati o n of 
Tec h nical Re q uire me nts f or P har mace uticals f or H u ma n Use ( I CH) E 6 G ui deli nes. I n
m ulti nati o nal trial s, n o n- U nite d States sites will be c o nsi dere d n o n-I n vesti gati o nal Ne w Dr u g 
(I N D) sites. N o n-I N D sites will be re q uire d t o f oll o w l ocal re g ulati o ns a n d I C H G ui deli nes.
T he I n vesti gat or a n d t he st u d y site a gree t o i nf or m t he S p o ns or i n writi n g of t he i nte nti o n t o 
re m o ve or destr oy a n y st u d y -relate d rec or ds. Pri or t o c o ntacti n g t he S p o ns or , t he I n vesti gat or 
a n d st u d y site m ust e ns ure t hat t he a p plica ble re g ulat or y re q uire me nts ha ve bee n satisfie d. T he 
S p o ns or will e val uate t he re q uests fr o m t he In vesti gat or a n d t he st u d y site a n d will pr o vi de 
a ut h orizati o n f or destr ucti o n of s uc h rec or ds i n writi n g.
I n t he e ve nt t hat all rete nti o n of rec or ds re q uire me nts ha ve bee n f ulfille d, b ut t he Sp o ns or 
re q uests t hat t he I n vesti gat or a n d st u d y site mai ntai n t he rec or ds f or a l o n ger peri o d of ti me, 
a d diti o nal arra n ge me nts will be ma de.

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1 2. 8. 2. 
S p o ns or
T he S p o ns or m ust retai n all S p o ns or -s pecific esse ntial d oc u me nts i n c o nf or ma nce wit h t he 
a p plica ble re g ulat or y re q uire me nts of t he c o u ntries w here t he pr o d uct is a p pr o ve d, a n d w here t he 
S p o ns or i nte n ds t o a p pl y f or a p pr o vals.
If t he S p o ns or disc o nti n ues t he cli nical de vel o p me nt of t he st u d y  dr u g, t he S p o ns or m ust 
mai nt ai n all S p o ns or -s pecific esse ntial d oc u me nts i n c o nf or ma nce wit h t he a p plica ble re g ulat or y 
re q uire me nts.
1 2. 9. 
M o nit ori n g
T he S p o ns or a n d desi g nee will be all o we d t o c o n d uct site visits t o t he i n vesti gati o n facilities f or 
t he p ur p ose of m o nit ori n g a ny as pect of t he st u d y. T he I n vesti gat or a n d t he site a grees t o all o w 
t he m o nit or t o i ns pect t he dr u g st ora ge area, st u d y dr u g st oc ks, dr u g acc o u nta bilit y rec or ds, 
patie nt c harts a n d st u d y s o urce d oc u me nts, a n d ot her rec or ds relati ve t o st u d y  c o n d uct.
1 2. 1 0. 
Fi n a nci al Discl os ure
Fi na ncial discl os ure f or I n vesti gat ors will be o btai ne d a n d rec or d kee pi n g of fi na ncial rec or ds 
will be i n acc or da nce wit h l ocal re g ulat or y re q uire me nts. In vesti gat ors will pr o vi de t he S p o ns or 
wit h s ufficie nt, acc urate fi na ncial i nf or mati o n u p o n t he S p o ns or’s re q uest.
1 2. 1 1. 
C o m pe ns ati o n f or He alt h I nj ur y 
T he cli nical st u d y is i ns ure d acc or di n g t o a p plica ble re g ulat or y re q uire me nts. A c o p y of t he 
C o m pe nsati o n P olic y  D oc u me nt will be pr o vi de d t o t he st u d y site b y t he S p o ns or.
I n t he case of a c o m pe nsati o n clai m, e xcl u di n g clai ms t hat ha ve arise n d ue t o me dical 
mal practice or ne gli ge nce, t he le gall y res p o nsi ble pers o n is clearl y i de nti fie d.
S p o ns or s h o ul d a d dress t he p olicies a n d pa y me nt pr oce d ures of c o m pe nsati o n f or t he e ve nt of 
st u d y-relate d i nj uries as state d i n t he C o m pe nsati o n P olic y D oc u me nt.
W he n patie nts recei ve c o m pe nsati o n, t he p olicies a n d pa y me nt pr oce d ure of c o m pe nsati o n 
sh o ul d c o m pl y  wit h t he C o m pe nsati o n P olic y D oc u me nt.
1 2. 1 2. 
S t u d y A d mi nistr ati ve Str uct ure 
T he st u d y  or ga nizati o n details will be mai ntai ne d i n a s u p ple me nt.

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1 3. 
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
T he S p o ns or will perf or m q ualit y c o ntr ol a n d q ualit y  ass ura nce pr oce d ures i n acc or da nce wit h 
t he S p o ns or's sta n dar d o perati n g pr oce d ures ( S O Ps) t o e ns ure t he q ualit y of t he cli nical st u d y.
1 3. 1. 
Q u alit y C o ntr ol
T he S p o ns or is res p o nsi ble f or c o ntr olli n g t he q ualit y of t he cli nical st u d y acc or di n g t o t he S O Ps 
re gar di n g st u dy o perati o n, m o nit ori n g, data c ollecti o n a n d ma na ge me nt, statistical a nal ys is, a n d 
ha n dli n g of safet y i nf or mati o n t o verif y  t hat t he st u d y-relate d acti vities ha ve bee n f ulfille d.
1 3. 2. 
Q u alit y A ss ur a nce
T o e ns ure c o m plia nce wit h G o o d Cli nical Practice ( G C P ) a n d all a p plica ble re g ulat or y 
re q uire me nts, t he S p o ns or ma y  c o n d uct a q ualit y ass ura nce a u dit. A ut h orize d re prese ntati ves of 
t he S p o ns or, a re g ulat or y a ut h orit y , or a n I R B/I E C ma y visit t he site t o perf or m a u dits or 
i ns pecti o ns, i ncl u di n g s o urce data verificati on. T he I n vesti gat or a n d t he site will ma ke e ver y  
eff ort t o hel p wit h t he perf or ma nce of t he a u dits a n d i ns pecti o ns, gi vi n g access t o all necessar y  
facilities, data a n d d oc u me nts pertai ni n g t o t he cli nical st u d y. 
T he p ur p ose of a n a u dit or i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y-
relate d acti vities a n d d oc u me nts t o e ns ure t hat t hese acti vities were c o n d ucte d, a n d data were 
rec or de d, a nal yze d, a n d acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, I C H G C P E 6 G ui deli nes, 
a n d a n y a p plica ble l ocal re g ulat or y  re q uire me nts. T he In vesti gat or a n d t he site s h o ul d c o ntact t he 
S p o ns or i m me diatel y  if c o ntacte d by a re g ulat or y a ge nc y re gar di n g a n i ns pecti o n.
A n y  res ults arisi n g fr o m s uc h i ns pecti o ns will be i m me diatel y c o m m u nicate d b y t he I n vesti gat or
a n d t he site t o t he S p o ns or. T he In vesti gat or a n d t he S p o ns or will ta ke c orrecti ve acti o ns f or all 
fi n di n gs a n d o bser vati o ns f o u n d d uri n g a u dits a n d/ or i ns pecti o ns. T he a u dit ors a n d i ns pect ors 
will n ot discl ose pri vate i nf or mati o n u nless re q uire d b y  law.

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1 4. 
E T HI C S
1 4. 1. 
Et hic al C o n d uct of t he St u d y
It is ma n dat or y t hat all c o nsi derati o ns re gar di n g t he pr otecti o n of patie nts be carrie d o ut i n 
acc or da nce wit h t he latest versi o ns of t he pr ot oc ol, I C H G C P G ui deli nes, t he et hical pri nci ples 
t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, a n d all a p plica ble re g ulat or y re q uire me nts.
1 4. 2. 
Writte n I nf or me d C o nse nt
T he I C F(s) m ust be a p pr o ve d b y  t he I R B/I E C bef ore patie nt’s si g n c o nse nt f or a n y st u d y-relate d 
acti vit y. It m ust be i n a la n g ua ge t hat t he patie nt ca n rea d a nd u n dersta n d. T he I C F pr ocess 
s h o ul d be i n acc or da nce wit h pri nci ples t hat ori gi nate d i n t he Declarati o n of Helsi n ki, c urre nt 
I C H a n d G C P G ui deli nes, a n d a p plica ble re g ulat or y re q uire me nts. Eac h patie nt ( or a le gall y  
acce pta ble re prese ntati ve) m ust gi ve writte n c o nse nt acc or di n g t o l ocal re q uire me nts. 
T he I n vesti gat or(s) m ust mai ntai n t he ori gi nal, si g ne d IC F. A c o p y  of t he si g ne d I CF m ust be 
gi ve n t o t he patie nt.
T here m ust be d oc u me ntati o n i n eac h patie nt’s case hist or y/ me dical rec or d t hat i nf or me d c o nse nt 
was o btai ne d pri or t o a n y st u d y  pr oce d ure bei n g perf or me d. Patie nts m ust be re-c o nse nte d t o t he 
m ost c urre nt versi o n of t he I C F(s) d uri n g t heir partici pati o n i n t he st u d y (i ncl u di n g d uri n g
s ur vi val f oll o w-u p).
1 4. 3. 
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee
T he st u d y m ust be a p pr o ve d b y  a n a p pr o priately c o nstit ute d I R B/I E C, as re q uire d i n t he 
a p plica ble l ocal re g ulati o n s uc h as I C H E 6 G ui deli nes ( Part 3), C o de of Fe deral Re g ulati o ns 
Title 2 1, Part 5 6, a n d Or di na nce of t he Mi nistr y  of Healt h a n d Welfare N o. 2 8, C ha pter I V, 
Secti o n 1 bef ore t he st u d y is i nitiate d. At t he e n d of t he st u d y , t he In vesti gat or will n otif y  t he 
I RB/I E C of t he c o ncl usi o n of t he st u d y  a n d its o utc o me.

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1 5. 
P U B LI C A TI O N P O LI C Y
1 5. 1. 
P u blic ati o n P olic y
T he S p o ns or mai ntai ns t he ri g ht t o use t he res ults of t his st u d y  i n t heir ori gi nal f or m a n d/ or i n a 
gl o bal re p ort f or s u b missi o n t o g o ver n me ntal a n d re g ulat or y  a ut h orities of a n y c o u ntr y or re gi o n.
T he res ults of t he st u d y ma y  be prese nte d d uri n g scie ntific s ym p osia a n d/ or p u blis he d i n a 
scie ntific j o ur nal o nly after re vie w b y t he S p o ns or i n acc or da nce wit h t he g ui deli nes set f ort h i n 
t he a p plica ble p u blicati o n.
T he I n vesti gat or(s) a n d t he S p o ns or will disc uss a n d deter mi ne t he prese nter(s) or a ut h or(s) a n d 
ti mi n g of a ny prese ntati o n or p u blicati o n relate d t o t his st u d y  a n d/ or its res ults. A ut h ors hi p will 
be deter mi ne d b y m ut ual a gree me nt a n d i n li ne wit h I nter nat i o nal C o m mittee of Me dical J o ur nal 
E dit ors a ut h ors hi p re q uire me nts.
1 5. 2. 
Sec o n d ar y Use of D at a
T he S p o ns or mai ntai ns t he ri g ht t o sec o n dar y  use of data i n t his st u d y.
Sec o n dar y  use of data descri bes t he use of data fr o m t his st u d y f or ot her st u d y/st u dies f or 
p u r p oses i ncl u di n g, b ut n ot li mite d t o, dr u g de vel o p me nt a n d/ or aca de mic researc h. Sec o n dar y 
use of data als o i ncl u des e xter nal offeri n gs of st u d y  data t o d o mestic a n d/ or f orei g n 
or ga nizati o n(s ), ot her c o m pa nies a n d researc her(s), o n a case by case basis.

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7 8
1 6. 
R E F E R E N C E S
Be ns o n A B, Aja ni J A, Catala n o R B, E n gel ki n g C, K or n bla u S M, Marte ns o n J A, et al.  
Rec o m me n de d g ui deli nes f or t he treat me nt of ca ncer treat me nt -i n d uce d diarr hea.  
J Cli n O nc ol . 2 0 0 4; 2 2: 2 9 1 8- 2 9 2 6.
Disis M L . I m m u ne re g ulati o n of ca ncer. J Cli n O ncol. 2 0 1 0; 2 8( 2 9): 4 5 3 1 - 4 5 3 8.
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, et al.  Ne w res p o nse 
e val uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 1. 1).  
E ur J C a ncer. 2 0 0 9; 4 5: 2 2 8 - 2 4 7.
Ferla y  J, S hi n H R, Bra y F, F or ma n D, Mat hers C, Par ki n D M. Esti mates of w orl d wi de b ur de n of 
ca ncer i n 2 0 0 8: G L O B O C A N 2 0 0 8. I nt J C a ncer. 2 0 1 0; 1 2 7: 2 8 9 3 - 2 9 1 7. 
Hes ket h PJ, Kris M G, Basc h E, B o hl ke K, Bar b o ur S Y, Clar k- S n o w R A, et al.  A ntie metics: 
A merica n S ociet y of Cli nical O nc ol o g y Cli nical Practice G ui deli ne U p date.  J Cli n O nc ol.  
2 0 1 7; 3 5: 3 2 4 0 - 3 2 6 1.
Ic hi ka wa K, Wata na be Mi ya n o S, Mi n os hi ma Y, Mats ui J, F u na has hi Y. Acti vate d F G F 2 
si g nali n g pat h wa y i n t u m or vasc ulat ure is esse ntial f or ac q uire d resista nce t o a nti-V E G F 
t hera py. Sci Re p . 2 0 2 0; 1 0( 1): 2 9 3 9. 
Li u L, Ye T H, Ha n Y P, S o n g H, Z ha n g Y K, Xia Y, et al. Re d ucti o ns i n m yel oi d-deri ve d 
s u p press or cells a n d l u n g metastases usi n g A Z D 4 5 4 7 treat me nt of a metastatic m uri ne 
breast t u m or m o del. Cell P hysi ol Bi oc he m. 2 0 1 4; 3 3( 3): 6 3 3  6 4 5. 
Mi yaza ki J, Nis hi y a ma H.  E pi de mi ol o g y of ur ot helial carci n o ma. I nt J Ur ol o gy. 
2 0 1 7; 2 4( 1 0): 7 3 0 - 7 3 4.
Pala k urt hi S, K ura g uc hi M, Zac hare k SJ, Z u daire E, H ua n g W, B o nal D M, et al. T he c o m bi ne d 
effect of F G F R i n hi biti o n a n d P D- 1 bl oc ka de pr o m otes t u m or -i ntri nsic i n d ucti o n of 
a ntit u m or acti vit y. C a ncer I m m u n ol Res. 2 0 1 9; 7( 9): 1 4 5 7 - 1 4 7 1.
Se y m o ur L, B o gaerts J, Perr o ne A, F or d R, Sc h wartz L H, Ma n dre kar S, 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. L a ncet O nc ol.
2 0 1 7 ; 1 8:e 1 4 3-e 5 2.
Sief ker -Ra dt ke A O, A p ol o A B, Bi valac q ua TJ, S piess P E, Blac k P C. I mm u n ot hera p y  wit h 
chec k p oi nt b l oc ka de i n t he treat me nt of u r ot helial carci n o ma. J Ur ol. 2 0 1 8; 1 9 9: 1 1 2 9 - 1 1 4 2.
S mit h TJ, B o hl ke K, L y ma n G H, Cars o n K R, Cra wf or d J, Cr oss SJ, et al.  Rec o m me n dati o ns f or 
t he use of W B C gr o wt h fact ors: A merica n S ociety of Cli nical O nc ol o g y cli nical p ractice 
g ui deli ne u p date.  J Cli n O nc ol. 2 0 1 5; 3 3: 3 1 9 9 - 3 1 2 1.
V o n der Maase H, Ha nse n S W , R o berts J T, D o gli otti L, Oli ver T, M o ore MJ, et al. Ge mcita bi ne 
a n d cis plati n vers us met h otre xate, vi n blasti ne, d o x or u bici n, a n d cis plati n i n a d va nce d or 
metastatic bla d der ca ncer: res ults of a lar ge, ra n d o mize d, m ulti nati o nal, m ultice nter, 
p hase III st ud y . J Cli n O nc ol. 2 0 0 0; 1 8( 1 7): 3 0 6 8 - 3 0 7 7.
V o n der Maase H, Se n gel o v L, R o berts J T, Ricci S, D o gli otti L , Oli ver T, et al. L o n g -ter m 
s ur vi val res ults of a ra n d o mize d trial c o m pari n g ge mcita bi ne pl us cis plati n, wit h 
met h otre xate, vi n blasti ne, d o x or u bici n, pl u s cis plati n i n patie nts wit h bla d der ca ncer.
J Cli n O nc ol. 2 0 0 5; 2 3( 2 1): 4 6 0 2 - 4 6 0 8.

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Wa n g L, Saci A, Sza b o P M, C hasal o w S D, Castill o -Marti n M, D o mi n g o -D o me nec h J, et al. 
E M T- a n d str o ma-relate d ge ne e x pressi o n a n d resista nce t o P D-1 bl oc ka de i n ur ot helial 
ca ncer. N at ure C o m m u nic ati o ns. 2 0 1 8; 9( 1): 3 5 0 3.

F uti bati ni b ( T A S -1 2 0)
Pr ot oc ol T A S -1 2 0 -2 0 3 – A me n d me nt 1
8 0
A P P E N DI X A.
E C O G P E R F O R M A N C E S T A T U S
G R A D E  
E C O G 
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n. 
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 de ntar y nat ure, e g, li g ht h o use w or k, office w or k. 
2  
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities. U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs. 
3  
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of w a ki n g h o urs. 
4  
C o m pletel y disa ble d. Ca n n o t carr y o n a n y self-care. T otall y c o nfi ne d t o be d or c hair. 
5  
Dea d
Fr o m : O ke n M M, Creec h, R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he Easter n C o o perati ve 
O nc ol o g y Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5: 6 4 9 -5 5.

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A P P E N DI X B.
DI E T A R Y G UI D E LI N E S F O R T R E A T M E N T O F 
H Y P E R P H O S P H A T E MI A
T he best wa y  t o li mit p h os p h or us i n t he diet is t o li mit f o o ds hi g hest i n p h os p h or us, i ncl u di n g: 

Fast f o o d, c o n ve nie nce f o o ds, a n d pr ocesse d f o o ds, w hic h ma y  be f ull of p h os p h or us 
a d diti ves 

Be vera ges t hat c o ntai n p h os p h or us (l o o k f o r t he letters " p h os" i n t he i n gre die nt list) 
Als o, l o o k f or a n y i n gre die nt t hat c o ntai ns " p h os" i n t he ter m s uc h as: 

Calci u m p h os p hate 

Dis o di u m p h os p hate 

P h os p h oric aci d 

M o n o p otassi u m p h os p hate 

S o di u m aci d p y r o p h os p hate 

S o di u m tri p ol y p h os p hate 
Listi n g of S o me L o wer a n d Hi g her P h os p h or us F o o ds 
Hi g her P h os p h or us F o o ds 
L o w er P h os p h or us F o o ds 
Mil k, p u d di n g, y o g urt, s o y mil k, n o n dair y crea mers a n d 
e nric he d rice mil k 
U ne nric he d rice mil k 
Pr ocesse d c heeses a n d c heese s prea ds 
A s mall a m o u nt of Brie or S wiss c heese 
Har d c heeses, ric otta or c otta ge c heese, fat -free crea m c heese  
Re g ular or l o w -fat crea m c heese 
Ice crea m or fr oze n y o g urt 
S her bet, s or bet or fr oze n fr uit p o ps 
S o u ps ma de wit h hi g her p h os p h or us i n gre die nts ( mil k, drie d 
peas, bea ns, le ntils) 
S o u ps ma de wit h l o wer p h os p h or us i n gre die nts ( br ot h - or 
water -base d wit h ot her l o wer p h os p h or us i n gre die nts) 
W h ole grai ns, i ncl u di n g w h ole -grai n brea ds, crac kers, cereal, 
rice a n d pasta 
W hite brea d, crac kers, cereals, rice a n d pasta 
Q uic k brea ds, bisc uits, c or n brea d, m uffi ns, pa nca kes or 
waffles 
W hite di n ner r olls, brea d, ba gels or E n glis h m uffi ns 
Drie d peas (s plit, blac k -e ye d), bea ns ( blac k, gar ba nz o, li ma, 
ki d ne y, na v y, pi nt o) or le ntils 
Gree n peas, gree n bea ns or wa x bea ns 
Pr ocesse d meats (ie, b ol o g na, ha m a n d h ot d o gs), a n d meat, 
p o ultr y or seaf o o d wit h " p h os" i n t he i n gre die nts 
All -nat ural lea n beef, p or k, la m b, p o ultr y, seaf o o d or ot her fis h 
wit h o ut " p h os" i n t he i n gre die nts 
Or ga n meats, walle ye, p oll oc k or sar di nes 
All -nat ural lea n beef, p or k, la m b, p o ultr y, seaf o o d or ot her fis h 
wit h o ut " p h os" i n t he i n gre die nts 
N uts a n d see ds 
P o pc or n or pretzels 
Pea n ut b utter a n d ot her n ut b utters 
Ja m, jell y or h o ne y 
C h oc olate, i ncl u di n g c h oc olate dri n ks 
Jell y bea ns, har d ca n d y, fr uit s nac ks or g u m dr o ps 
C olas a n d pe p per -t y pe s o das, s o me fla v ore d waters, b ottle d 
teas, s o me dri n k mi xes (an y  wit h " p h os" i n t he i n gre die nts) 
Le m o n -li me s o da, gi n ger ale, r o ot beer, plai n water or s o me 
dri n k mi xes (a n y wit h o ut " p h os" i n t he i n gre die nts) 
Alt h o u g h a f o o d or dri n k ma y be l o w i n p h os p h or us, li mitati o n of p orti o n size a n d t he n u m ber of ser vi n gs y o u eat or dri n k eac h 
da y ma y still be rec o m me n de d. 
Fr o m: Rac hael Maj or o wicz, R. D. N., L. D. ( Fe b, 2 0 1 6). W h y is a l o w -p h os p h or us diet usef ul i n ma na gi n g ki d ne y disease? W hat 
f o o ds c o ntai n p h os p h or us? htt ps:// w w w. ma y ocli nic. or g/f o o d -a n d -n utriti o n/e x pert -a ns wers/fa q -2 0 0 5 8 4 0 8 .

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A P P E N DI X C.
C L A S SI FI C A TI O N O F S U B S T R A T E S, I N HI BI T O R S , A N D 
I N D U C E R S O F C Y P E N Z YM E S A N D T R A N S P O R T E R S
T he classificati o n bel o w is base d o n t he F D A Draft G ui da nce f or I n d ustr y , Cli nical Dr u g 
I nteracti o n St u dies —
St u d y  Desi g n, Data A nalys is, a n d Cli nical Im plicati o ns, Oct o ber 2 0 1 7. 
( htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/
U C M 2 9 2 3 6 2. p df)
E x a m ple of C Y P 3 A I n hi bit ors
C yt oc hr o me 
P 4 5 0 ( C Y P) 
E nz y mes
Str o n g I n hi bit ors a
≥ 5 -f ol d i ncrease i n A U C
M o derate i n hi bit ors
b
≥ 2 b ut < 5- f ol d i ncrease i n A U C
C Y P 3 A 
b oce pre vir, clarit hr o m yci n, c o bicistat, 
c o ni va pta n, da n o pre vir a n d rit o na vir, diltiaze m, 
el vite gra vir a n d rit o na vir, gra pefr uit j uice,c  
i n di na vir a n d rit o na vir, i delalisi b, itrac o naz ole, 
ket oc o naz ole, l o pi na vir a n d rit o na vir, parita pre vir 
a n d rit o na vir a n d ( o m bitas vir a n d/ or dasa b u vir), 
p osac o naz ole, rit o na vir, sa q ui na vir a n d rit o na vir, 
tela pre vir, ti pra na vir a n d rit o na vir, 
tr olea n d o m yci n, v oric o naz ole
a pre pita nt, ci meti di ne, 
ci pr ofl o xaci n, cl otri maz ole, 
criz oti ni b, c ycl os p ori ne, 
dr o ne dar o ne, er yt hr o m yci n, 
fl uc o naz ole, fl u v o xa mi ne, 
i mati ni b, t ofis o pa m, vera pa mil
a. 
Str o n g i n hi bit ors are dr u gs t hat i ncrease  t he area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) of se nsiti ve i n de x 
s u bstrates of a gi ve n meta b olic pat h wa y ≥5 -f ol d.
b. 
M o derate i n hi bit ors are dr u gs t hat i ncrease t he A U C of se nsiti ve i n de x s u bstrates of a gi ve n meta b olic pat h wa y ≥2 t o 
< 5 -f ol d.
c. 
T he effect of gra pefr uit j uice varies wi del y a m o n g bra n ds a n d is c o nce ntrati o n -, d ose-, a n d pre parati o n de pe n de nt. 
St u dies ha ve s h o w n t hat it ca n be classifie d as a “str o n g C Y P 3 A i n hi bit or” w he n a certai n pre parati o n was use d (e g, 
hi g h d ose, d o u ble stre n gt h) or as a “ m o derate C Y P 3 A i n hi bit or” w he n a n ot her pre parati o n was use d (e g, l o w d ose, 
si n gle stre n gt h).
E x a m ple of C Y P 3 A I n d uce rs
C yt oc hr o me 
P 4 5 0 ( C Y P) 
E nz y mes
Str o n g I n d ucers
≥ 8 0 % decrease i n A U C
M o derate I n d ucers
5 0- 8 0 % decrease i n A U C
C Y P 3 A
car ba maze pi ne, e nzal uta mi de, 
mit ota ne, p he n yt oi n, rifa m pi n, St. 
J oh n’s w ort a
b ose nta n, efa vire nz, etra viri ne, m o dafi nil
a. 
T he effect of St. J o h n’s w ort varies wi del y a n d is pre parati o n -de pe n de nt.
E x a m ple of I n hi bit ors f or P -g p a n d B C R P
Tra ns p orters 
Ge ne
I n hi bit or

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P- g p a
A B C B 1
A m i o dar o ne, car ve dil ol, clarit hr o m yci n, dr o ne dar o ne, 
itrac o naz ole, la pati ni b, l o pi na vir a n d rit o na vir, 
pr o pafe n o ne, q ui ni di ne, ra n olazi ne, rit o na vir, 
sa q ui na vir a n d rit o na vir, tela pre vir, ti pra na vir a n d 
rit o na vir, vera pa mil
B C R P b
A B C G 2
C urc u mi n, c ycl os p ori ne A, eltr o m b o pa g
a. 
P- g p: ( 1) A U C f ol d -i ncrease of di g o xi n ≥2 wit h c o -a d mi nistrati o n a n d ( 2) i n vitr o i n hi bit or.
b. 
B C R P: ( 1) A U C f ol d- i ncrease of s ulfasalazi ne ≥1. 5 wit h c o -a d mi nistrati o n a n d ( 2) i n vitr o i n hi bit or. C ycl os p ori ne A 
a n d eltr o m b o pa g were als o i ncl u de d, alt h o u g h t he a vaila ble D DI i nf or mati o n was wit h r os u vastati n, w here i n hi biti o n 
of b ot h B C R P a n d O A T Ps ma y ha ve c o ntri b ute d t o t he o bser ve d i nteracti o n.
E x a m ple of S u bstr ates f or P -g p a n d B C R P
Tra ns p orters
Ge ne
S u bstrate
P- g p a
A B C B 1
Da bi gatra n, di g o xi n, 
fe x ofe na di ne
B C R P b
A B C G 2
R os u vastati n, s ulfasalazi ne
a. 
P- g p: ( 1) A U C f ol d -i ncrease ≥2 wit h vera pa mil or q ui ni di ne c o -a d mi nistrati o n a n d ( 2) i n vitr o tra ns p ort b y P - g p 
e x pressi o n s yste ms, b ut n ot e xte nsi vel y meta b olize d.
b. 
B C R P: ( 1) A U C f ol d- i ncrease ≥2 wit h p har mac o ge netic alterati o n of A B C G 2 ( 4 2 1 C > A) a n d ( 2) i n vitr o tra ns p ort b y 
B C R P e x pressi o n s yste ms.

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A P P E N DI X D.
S U M M A R Y O F T H E I R E CI S T P R O C E S S
Assess me nt at Scree ni n g a n d Pri or t o R E CI S T 1. 1 Pr o gressi o n
U ntil ra di o gra p hic disease pr o gressi o n base d o n R E CI S T 1. 1, t here is n o disti nct i R E CI S T 
assess me nt.
Assess me nt a n d Decisi o n at R E CI S T 1. 1 Pr o gressi o n
F or patie nts w h o s h o w e vi de nce of ra di ol o gical P D b y  R E CI S T 1. 1 as deter mi ne d b y t he 
I n vesti gat or, t he I n vesti gat or will deci de w het her t o c o nti n ue a patie nt o n st u d y treat me nt u ntil 
re peat i ma gi n g is o btai ne d ( usi n g i R E CI S T f or patie nt ma na ge me nt). T his deci si o n b y t he 
I n vesti gat or s h o ul d be base d o n t he patie nt’s o verall cli nical c o n diti o n.
Cli nical sta bilit y  is defi ne d as t he f oll o wi n g: 

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y si g nifica nt pr o gressi o n of
disease

N o decli ne i n E C O G perf or ma nce sta t us 

N o re q uire me nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesia, 
ra diati o n, or ot her palliati ve care
A n y  patie nt dee me d cli nic all y u nst a ble s h o ul d be disc o nti n ue d fr o m st u d y treat me nt at site-
assesse d first ra di ol o gic e vi de nce of P D, a n d is n ot re q uire d t o ha ve re peat t u m or i ma gi n g f or 
c o nfir mati o n of P D b y i R E CI S T.
If t he I n vesti gat or deci des t o c o nti n ue treat me nt, t he patie nt ma y c o nti n ue t o recei ve st u d y 
treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m P D b y  
i R E CIS T, per I n vesti gat or assess me nt.
T u m or flare ma y  ma nifest as a n y fact or ca usi n g ra di o gra p hic pr o gressi o n per R E CI S T 1. 1, 
i ncl u di n g:

I ncrease i n t he s u m of dia meters of tar get lesi o n(s) i de ntifie d at baseli ne t o ≥ 2 0 % a n d 
≥ 5 m m fr o m na dir
N ote: t h e i R E CIS T p u blicati o n uses t he ter mi n ol o g y  “s u m of meas ure me nts”, b ut 
“s u m of dia meters” will be use d i n t his pr ot oc ol, c o nsiste nt wit h t he ori gi nal 
R E CI S T 1. 1 ter mi n ol o g y.

U ne q ui v ocal pr o gressi o n of n o n- tar get lesi o n(s) i de ntifie d at baseli ne

De vel o p me nt of ne w lesi o n(s)
i R E CIS T defi nes ne w res p o nse cate g ories, i ncl u di n g i U P D ( u nc o nfir me d pr o gressi ve disease) 
a n d i C P D (c o nfir me d pr o gressi ve disease). F or p ur p oses of i R E CI S T assess me nt, t he first visit 
s h o wi n g pr o gressi o n acc or di n g t o R E CIS T 1. 1 will be ass i g ne d a visit ( o verall) res p o nse of 
i U P D, re gar dless of w hic h fact ors ca use d t he pr o gressi o n.
At t his visit, tar get a n d n o n- tar get lesi o ns i de ntifie d at baseli ne by R E CI S T 1. 1 will be assesse d 
as us ual.
Ne w lesi o ns will be classifie d as meas ura ble or n o n- meas ura ble, usi n g t he sa me size t hres h ol ds 
a n d r ules as f or baseli ne lesi o n assess me nt i n R E CI S T 1. 1. Fr o m meas ura ble ne w lesi o ns, u p t o 5 

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lesi o ns t otal ( u p t o 2 per or ga n), ma y be selecte d as Ne w Lesi o ns – Tar get.  T he s u m of 
dia meters of t hese lesi o ns will be calc ulate d, a n d ke pt disti nct fr o m t he s u m of dia meters f or 
tar get lesi o ns at baseli ne.  All ot her ne w lesi o ns will be f oll o we d q ualitati vel y as Ne w Lesi o ns –
N o n -tar get.
Assess me nt at t he C o nfir m at ory I m a gi n g
O n t he c o nfir mat or y  i ma gi n g, t he patie nt will be classifie d as pr o gressi o n c o nfir me d ( wit h a n 
o verall res p o nse of i C P D), or as s h o wi n g persiste nt u nc o nfir me d pr o gressi o n ( wit h a n o verall 
res p o nse of u nc o nfir me d pr o gressi ve disease [i U P D]), or as s h o wi n g disease sta bilit y or res p o nse 
(i S D/i P R/i C R).
C o nfir m ati o n of Pr o gressi o n
Pr o gressi o n is c o nsi dere d c o nfir me d, a n d t he o verall res p o nse will be i C P D, if A N Y of t he 
f oll o wi n g occ urs:

A n y  of t he fact ors t hat were t he basis f or t he i nitial i U P D s h o w w orse ni n g

F or tar get lesi o ns, w orse ni n g is a f urt her i ncrea se i n t he s u m of dia meters of 
≥5 m m, c o m pare d t o a n y pri or i U P D ti me p oi nt

F or n o n -tar get lesi o ns, w orse ni n g is a n y si g nifica nt gr o wt h i n lesi o ns o verall, 
c o m pare d t o a pri or i U P D ti me p oi nt; t his d oes n ot ha ve t o meet t he 
“ u ne q ui v ocal” sta n dar d of R E CI S T 1. 1

F or ne w lesi o ns, w orse ni n g is a n y of t hese:

A n i ncrease i n t he ne w lesi o n s u m of dia meters b y ≥ 5 m m fr o m a pri or i U P D ti me 
p oi nt 

Visi ble gr o wt h of ne w n o n- tar get lesi o ns 

T he a p peara nce of a d diti o nal ne w lesi o ns

A n y  ne w fact or a p pears t hat w o ul d ha ve tri g gere d P D b y R E CIS T 1. 1
Persiste nt i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o verall res p o nse re mai ns i U P D, if:

N o ne of t he pr o gressi o n -c o nfir mi n g fact ors i de ntifie d a b o ve occ urs A N D

T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) re mai ns a b o ve t he i nitial P D 
t hres h ol d ( by R E CI S T 1. 1)
A d diti o nal i ma gi n g f or c o nfir mati o n s h o ul d be sc he d ule d 4 t o 8 wee ks fr o m t he i ma gi n g o n 
w hic h i U P D is see n. T his ma y  c orres p o n d t o t he ne xt visit i n t he ori gi nal visit sc he d ule.  T he 
assess me nt of t he s u bse q ue nt c o nfir mati o n i ma gi n g pr ocee ds i n a n i de ntical ma n ner, wit h 
p ossi ble o utc o mes of i C P D, i U P D, a n d i S D/i P R/i C R.
Res ol uti o n of i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o vera ll res p o nse bec o mes i S D/i P R/i C R, if:

N o ne of t he pr o gressi o n -c o nfir mi n g fact ors i de ntifie d a b o ve occ urs, A N D
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
T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) is n ot a b o ve t he i nitial P D 
t hres h ol d. 
T he res p o nse is classifie d as i S D or i P R ( de pe n di n g o n t he s u m of dia meters of t he tar get 
lesi o ns), or i C R if all lesi o ns res ol ve.
I n t his case, t he i nitial i U P D is c o nsi dere d t o be pse u d o-pr o gressi o n, a n d t he le vel of s us pici o n 
f or pr o gressi o n is “reset”. T his mea ns t hat t he ne xt visit t hat s h o ws ra dio gra p hic pr o gressi o n, 
w he ne ver it occ urs, is a gai n classifie d as i U P D b y i R E CI S T, a n d t he c o nfir mati o n pr ocess is 
re peate d bef ore a res p o nse of i C P D ca n be assi g ne d.
M a n a ge me nt F oll o wi n g t he C o nfir m at ory I m a gi n g
If re peat i ma gi n g d oes n ot c o nfir m P D per i RE CI S T, as assesse d b y  t he I n vesti gat or, a n d t he 
patie nt c o nti n ues t o be cli nicall y  sta ble, st u d y treat me nt ma y c o nti n ue a n d f oll o w t he re g ular 
i ma gi n g sc he d ule. If P D is c o nfir me d, patie nts will be disc o nti n ue d fr o m st u d y treat me nt.
N O T E: If a patie nt has c o nfir me d ra di o gra p hic pr o gressi o n (i C P D) as defi ne d a b o ve, b ut t he 
patie nt is ac hie vi n g a cli nicall y  mea ni n gf ul be nefit, a n e xce pti o n t o c o nti n ue st u d y  treat me nt ma y 
be c o nsi dere d f oll o wi n g c o ns ultati o n wit h t he S p o ns or. I n t his case, if st u d y treat me nt i s 
c o nti n ue d, t u m or i ma gi n g s h o ul d c o nti n ue t o be perf or me d f oll o wi n g t he i nter vals as o utli ne d i n 
t he pr ot oc ol a n d s u b mitte d t o t he ce ntral i ma gi n g ve n d or.
Detecti o n of Pr o gressi o n at Visits After Pse u d o -pr o gressi o n Res olves
After res ol uti o n of pse u d o - pr o gressi o n (i.e., ac hie ve me nt of i S D/i P R/i C R), i U P D is i n dicate d b y 
a n y of t he f oll o wi n g e ve nts:

Tar get lesi o ns

S u m of dia meters reac hes t he P D t hres h ol d ( ≥ 2 0 % a n d ≥ 5 m m i ncrease fr o m 
na dir) eit her f or t he first ti me, or after res ol uti o n of pre vi o us pse u d o -pr o gressi o n. 
T he na dir is al wa y s t he s mallest s u m of dia meters see n d uri n g t he e ntire trial, 
eit her bef ore or after a n i nsta nce of pse u d o- pr o gressi o n.

N o n -tar get lesi o ns

If n o n-tar get lesi o ns ha ve ne ver s h o w n u ne q ui v ocal pr o gressi o n, t heir d oi n g s o f or 
t he first ti me res ults i n i U P D.

If n o n-tar get lesi o ns ha ve s h o w n pre vi o us u ne q ui v ocal pr o gressi o n, a n d t his 
pr o gressi o n has n ot res ol ve d, i U P D res ults fr o m a n y  si g nifica nt f urt her gr o wt h of 
n o n -tar get lesi o ns, ta ke n as a w h ole.

Ne w lesi o ns

Ne w lesi o ns a p pear f or t he first ti me

A d diti o nal ne w lesi o ns a p pear

Pre vi o usl y  i de ntifie d ne w tar get lesi o ns s h o w a n i ncrease of ≥5 m m i n t he ne w 
lesi o n s u m of dia meters, fr o m t he na dir val ue of t hat s u m

Pre vi o usl y  i de ntifie d n o n-tar get lesi o ns s h o w a ny si g nificant gr o wt h

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If a ny of t he e ve nts a b o ve occ ur, t he o verall res p o nse f or t hat visit is i U P D, a n d t he i U P D 
e val uati o n pr ocess (see Assess me nt at t he C o nfir mat or y  Ima gi n g a b o ve) is re peate d. Pr o gressi o n 
m ust be c o nfir me d bef ore i C P D ca n occ ur.
T he decisi o n pr oce ss is i de ntical t o t he i U P D c o nfir mati o n pr ocess f or t he i nitial P D, wit h o ne 
e xce pti o n:  if ne w lesi o ns occ urre d at a pri or i nsta nce of i U P D, a n d at t he c o nfir mat or y  i ma gi n g 
t he b ur de n of ne w lesi o ns has i ncrease d fr o m its s mallest val ue (f or ne w tar get lesi o ns, t he s u m 
of dia meters is ≥ 5 m m i ncrease d fr o m its na dir), t he n i U P D ca n n ot res ol ve t o i S D or i P R. I t will 
re mai n i U P D u ntil eit her a decrease i n t he ne w lesi o n b ur de n all o ws res ol uti o n t o i S D or i P R, or 
u ntil a c o nfir mat or y  fact or ca uses i C P D.
A d di ti o nal details a b o ut i R E CIS T are pr o vi de d i n t he i R E CI S T p u blicati o n (Se y m o ur et al.  
2 0 1 7 ).