A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
Phase: PHASE3
Conditions: Advanced Cholangiocarcinoma, Metastatic Cholangiocarcinoma
Sponsor: Institut de Recherches Internationales Servier

 
Offi ci al Titl e:  A P h a s e 3, M ulti c e nt er, R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -
C o ntr oll e d St u d y  of A G -1 2 0 i n Pr e vi o u sl y Tr e at e d S u bj e ct s wit h  
N o nr e s e ct a bl e or M et a st ati c  C h ol a n gi o c ar ci n o m a wit h a n I D H 1 
M ut ati o n  
N C T N u m b er:  N C T 0 2 9 8 9 8 5 7  
D o c u m e nt  D at e : Pr ot o c ol V er si o n 6 : 0 5-M ar c h -2 0 1 9  
 

 
 
 
 
 
Cli nic al St u d y Pr ot oc ol A G 1 2 0 -C -0 0 5  
A P h ase 3, M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d St u d y 
of A G -1 2 0 i n Pre vi o usl y Tre ate d S u bjects wit h N o nresect a ble or  Met ast atic 
C h ol a n gi oc arci n o m a wit h a n I D H 1 M ut ati o n  
St u d y S p o ns or:  
A gi os P har mace uticals, I nc.  
8 8 Si d ne y Street  
Ca m bri d ge, M A 0 2 1 3 9 -4 1 6 9  
P h o ne: 6 1 7 -6 4 9 -8 6 0 0  
Fa x: 6 1 7 -6 4 9 -8 6 1 8  
Res p o nsi ble Me dical 
Officer:  
, M D 
 
A gi os P har ma ce uticals, I nc.  
Office P h o ne: 
 
E mail: 
 
St u d y Me dical 
M o nit or  
, M D 
 
P P D  
9 2 9 N ort h Fr o nt Street  
Wil mi n gt o n, N C 2 8 4 0 1  
P h o ne: + 1 8 8 8 4 8 3 7 7 2 9  
Fa x: 
 
E mail: 
 
E u dra C T N u m ber  
2 0 1 5 -0 0 5 1 1 7 -7 2  
D oc u me nt Versi o n 
( Date): 
Ori gi nal Pr ot oc ol, Versi o n 1. 0 ( 0 8 A u g ust 2 0 1 6) ( Gl o bal)  
A me n d me nt 1, Versi o n 2. 0 ( 0 5 Oct o ber 2 0 1 6) ( Gl o bal)  
A me n d me nt 2, Versi o n 3. 0 ( 0 7 N o ve m ber 2 0 1 6) ( Gl o bal)  
A me n d me nt 2, Versi o n 3. 1 ( 2 8 A pril 2 0 1 7) ( U K o nl y)  
A me n d me nt 3, Versi o n 4. 0 ( 0 1 Se pte m ber 2 0 1 7) ( Gl o bal e xce pt S o ut h K orea)  
A me n d me nt 4, Versi o n 5. 0 ( 0 4 A pril 2 0 1 8) ( Gl o bal e xce pt S o ut h K orea)  
A me n d me nt 4, Versi o n 5. 1 ( 2 0 J u ne 2 0 1 8) ( S o ut h K orea o nl y)  
A me n d me nt 4, Versi o n 5. 2 ( 1 0 A u g ust 2 0 1 8) ( Fra nce o nl y)  
A me n d me nt 5, Versi o n 6. 0 (0 1 Marc h  2 0 1 9) ( Gl o bal e xce pt S o ut h K orea)  
A me n d me nt 5, Versi o n 6. 1 ( 0 1 Marc h  2 0 1 9)  ( S o ut h K orea o nl y)  
T his st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d  Cli nical Practice, t he 
et hical pri nci ples state d i n t he Declarati o n of Helsi n ki, a n d ot her a p plica ble re g ulat or y re q uire me nts.  
C O N FI D E N TI A LI T Y N O T E:  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial a n d pr o prietar y t o A gi os P h ar mace uticals, I nc.  
A n y distri b uti o n, c o p yi n g, or discl os ure is strictl y pr o hi bite d u nless s uc h discl os ure is re q uire d b y fe deral 
re g ulati o ns or state la w. P ers o ns t o w h o m t he i nf or mati o n is discl ose d m ust k n o w t hat it is c o nfi de ntial a n d t hat it 
ma y n ot b e f urt her discl ose d b y t he m.  

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I N V E S TI G A T O R’ S A G R E EM E N T  
 
I u n d ersta n d t hat all d oc u me ntati o n pr o vi de d t o me b y A gi os P har mace uticals, I n c. ( A gi os) or its 
desi g nat e d re prese nt ati ve(s) c o ncer ni n g t his st u d y t hat has n ot bee n p u blis he d pre vi o usl y will be 
ke pt i n strict c o nfi de nce. T his d oc u me ntati o n i ncl u des t he st u d y pr ot oc ol, I n vesti gat or’s 
Br oc h ure, case re p ort f or ms, a n d ot her scie ntific d ata.  
T his st u d y will n ot c o m me nce wit h o ut t he pri or writte n a p pr o val of a pr o perl y c o n stit ute d 
I nstit uti o nal Re vie w B oar d (I R B)/I n de p e n de nt Et hics C o m mittee (I E C). N o c ha n ges will be 
ma de t o t he st u d y pr ot oc ol wit h o ut t he pri or writte n a p pr o val of A gi os a n d t he I R B/I E C, e xce pt 
w here n ecess ar y t o eli mi nate a n i m me diate hazar d t o t he s u bject.  
I h a ve rea d, u n d erst o o d, a n d a gree t o c o n d uct t his st u d y as o utli ne d i n t he pr ot oc ol a n d i n 
acc or da nce wit h t he g ui deli nes a n d all a p plica bl e g o ver n me nt re g ul ati o ns.  
 
 
I n v esti gat or Na me ( pri nt e d) 
 
I n v esti gat or Si g nat ure 
 
Date  
 
 
 
 
I n v esti gati o nal site or na me of i nstit uti o n a n d l ocati o n ( pri nte d)  

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2.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
A gi os P har mace uticals, I nc.  
N a me of I n vesti g ati o n al Pr o d uct:  
A G -1 2 0  
N a me of Acti ve I n gre die nt:  
A G -1 2 0  
Title of St u d y:  
A P hase 3, M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y of A G -1 2 0 i n 
Pre vi o usl y Treate d S u bjects wit h N o nresecta ble or Metastatic C h ola n gi ocarci n o ma wit h a n I D H 1 
M utati o n  
St u d y Ce nter(s):  
A p pr o xi matel y 5 5 st u d y ce nters gl o ball y will partici pate i n t his st u d y.  
P h ase of De vel o p me nt: 3  
P ri m ar y O bjecti ve:  
 
T o de m o nstrate t he efficac y of A G -1 2 0 base d o n pr o gressi o n -free s ur vi val ( P F S) per 
I n de pe n de nt Ra di ol o g y Ce nter (I R C) assess me nt c o m pare d t o place b o i n s u bjects wit h 
n o nresecta ble or metastatic c h ola n gi ocarci n o ma wit h a n is ocitrate de h y dr o ge nase 1 (I D H 1) 
m utati o n.  
Sec o n d ar y O bjecti ves:  
 
T o e val uate t he safet y a n d t olera bilit y of A G -1 2 0 c o m pare d t o place b o.  
 
T o e val uate P F S per I n vesti gat or assess me nt.  
 
T o c o m pare t he efficac y of A G -1 2 0 wit h place b o base d o n o verall s ur vi val ( O S), o bj ecti ve 
res p o nse rate ( O R R), d urati o n of res p o nse ( D O R), a n d ti me t o res p o nse ( T T R), wit h 
res p o nse assesse d per t he I n vesti gat or a n d b y t he I R C. 
 
T o e val uate healt h -relate d q ualit y of life ( H R Q O L) wit h A G-1 2 0 c o m pare d t o place b o as 
assesse d b y t he E ur o pea n Or ga ni sati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of 
Life Q uesti o n naires ( E O R T C -Q L Q -C 3 0 a n d E O R T C -Q L Q -BI L 2 1), t he Patie nt Gl o bal 
I m pressi o n of C ha n ge ( P GI-C), a n d t he Patie nt Gl o bal I m pressi o n of Se verit y ( P GI -S) . 
 
T o e val uate healt h ec o n o mic o utc o mes as a ssesse d b y t he 5 -le vel E ur o Q ol fi ve di me nsi o ns 
q uesti o n naire  ( E Q-5 D -5 L).  
 
T o e val uate t he p har mac o ki netics ( P K) of A G -1 2 0.  
 
T o e val uate t he P K/ p har mac o d y na mic ( P D) relati o ns hi p of A G -1 2 0 a n d 2 -h y dr o x y gl utarate 
( 2-H G) i n bl o o d sa m ples.  
E x pl or at or y O bjecti ves:  
 
T o e val uate, f or t he s u b gr o u p of place b o s u bjects w h o ha ve cr osse d o ver t o t he A G -1 2 0 ar m, 
t he ti me fr o m first d ose of A G-1 2 0 t o sec o n d d oc u me nte d pr o gressi o n o n A G -1 2 0 or deat h, 
w hic he ver occ urs first ( P F S 2).  
 
T o c orrelate baseli ne m olec ular a n d/ or pr otei n c haracteristics i n t u m or tiss ues wit h cli nical 
res p o nse. 
 
T o c orrelate baseli ne 2 -H G le vels i n plas ma sa m ples wit h cli nical res p o nse.  

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 
T o e val uate le vels of m uta nt I D H 1 a n d ot her ge nes i n circ ulati n g t u m or D N A o btai ne d fr o m 
plas ma at baseli ne a n d o ver t he c o urse of t he treat me nt.  
 
T o c orrelate a n y P K variati o ns wit h dr u g -meta b olizi n g e nz y me ( D M E) relate d ge nes, if t he 
data are warra nte d.  
 
T o e x pl ore a d diti o nal bi o mar kers i n bl o o d f or m or p h ol o gic, f u ncti o nal, bi ol o gic, e pi ge netic, 
a n d meta b olic c ha n ges o ver t h e c o urse of treat me nt.  
Met h o d ol o g y:  
St u d y A G 1 2 0 -C -0 0 5 is a P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of 
orall y a d mi nistere d A G -1 2 0. S u bjects, all pers o n nel i n v ol ve d i n t he e val uati o n of s u bj ects’ res p o nse 
t o treat me nt (e g, In vesti gat ors, st u d y c o or di nat ors, st u d y p har macists), a n d desi g nate d S p o ns or tea m 
me m bers will be bli n de d t o st u d y treat me nt  u ntil d oc u me nte d disease pr o gressi o n . S u bj ects are 
re q uire d t o ha ve a hist ol o gicall y-c o nfir me d dia g n osis of I D H 1 ge ne -m utate d c h ola n gi ocarci n o ma t hat 
is n ot eli gi ble f or c urati ve resecti o n, tra ns pla ntati o n, or a blati ve t hera pies. S u bj ects m ust ha ve 
pr o gressi o n of disease a n d ha ve recei ve d at least 1 b ut n ot m ore t ha n 2 pri or treat me nt re gi me ns f or 
a d va nce d disease ( n o nresecta ble or me tastatic). All s u bjects m ust ha ve recei ve d eit her a ge mcita bi ne 
or a 5 -fl u or o uracil ( 5-F U) base d c he m ot hera p y re gi me n.  
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will re vie w t he safet y data o n a re g ular basis t o 
e ns ure t he safet y of treat me nt a n d pr o p er c o n d uct of t he st u d y. T he first i nteri m safet y re vie w meeti n g 
will be c o n d ucte d w he n a p pr o xi matel y 2 0 s u bjects ha ve c o m plete d 2 c ycles of t hera p y or ha ve 
disc o nti n ue d earlier; t hereafter, meeti n gs will be c o n d ucte d a p pr o xi matel y e ver y 3 -6  m o nt hs or o n a n 
a d h oc basis. N o f or mal i nteri m a nal ysis f or efficac y will be c o n d ucte d bef ore t he pri mar y a nal ysis.  
Eac h s u bj ect’s c o urse of treat me nt will be c o m prise d of t he f oll o wi n g peri o ds:  
P re -Scree ni n g P eri o d ( O pti o n al) : A ba n ke d t u m or sa m ple (t he m ost rece nt o ne a vaila ble, prefera bl y 
c ollecte d wit hi n t he last 3 years) or fres h t u m or bi o ps y is re q uire d f or c o nfir mati o n of I D H 1 ge ne 
m utati o n stat us b y ce ntral la b orat or y testi n g as part of t he s u bject’s eli gi bilit y f or e nr oll me nt 
( R 1 3 2 C/ L/ G/ H/ S m utati o n varia nts teste d). P ote ntial s u bj ects will si g n a pre-scree ni n g c o nse nt f or t he 
p ur p ose of deter mi ni n g I D H 1 m uta nt stat us. ( P ote ntial s u bjects w h o d o n ot pr o vi de a sa m ple at pre -
scree ni n g will pr o vi de o ne at Scree ni n g.) 
P re -Tre at me nt/ Scree ni n g P eri o d : F oll o wi n g i nf o r me d c o nse nt, all s u bjects will u n der g o Scree ni n g 
pr oce d ures t o deter mi ne eli gi bilit y wit hi n 2 8 da ys pri or t o t he start of st u d y treat me nt o n C ycle 1, 
Da y  1 ( C 1 D 1), wit h t he e xce pti o n of baseli ne ra di o gra p hic sca ns, w hic h s h o ul d be perf or me d wit hi n 
2 1 da ys  pri or t o C 1 D 1. If a t u m or sa m ple is n ot c ollecte d d uri n g t he pre -scree ni n g peri o d, a ba n ke d or 
fres h bi o ps y at Scree ni n g will be c ollecte d. A d diti o nal Scree ni n g pr oce d ures i ncl u de me dical, 
s ur gical, a n d me dicati o n hist or y, ra di o gra p hic e val uati o n t o deter mi ne e xte nt of disease (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]), c o m plete p h ysical e xa mi nati o n (i ncl u di n g 
hei g ht/ wei g ht), vital si g ns, 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), 
1 2 -lea d electr ocar di o gra m ( E C G), ec h ocar di o gra p h y ( E C H O) ( or b y ot her met h o ds acc or di n g t o 
i nstit uti o nal practice) f or left ve ntric ular ejecti o n fracti o n ( L V E F) (acc or di n g t o i nstit uti o nal sta n dar d 
of care), a b uccal s wa b f or ger m -li ne m utati o n a n d D M E relate d ge ne p ol y m or p his m a nal ysis, plas ma 
sa m ple f or circ ulati n g t u m or D N A, cli nical la b orat or y assess me nts ( he mat ol o g y, ser u m c he mistr y, 
c oa g ulati o n, uri nal ysis, a n d ser u m pre g na nc y test), a n d bl o o d sa m ples f or e x pl orat or y bi o mar ker 
meas ure me nt.  
Tre at me nt P eri o d a n d E n d of Tre at me nt Visit : S u bjects w h o meet all st u d y eli gi bilit y criteria will 
be ra n d o ml y assi g ne d i n a 2: 1 rati o t o recei ve A G -1 2 0 orall y at a d ose of 5 0 0 m g o nce dail y ( Q D) or 
A G -1 2 0 -matc he d oral place b o Q D. Ra n d o mizati o n will be stratifie d b y n u m ber of pri or s yste mic 
t hera pies ( 1 vs 2). Dail y st u d y treat me nt will be gi n o n C 1 D 1. C ycles are 2 8 da ys ( +/ -2 da ys) i n 
d urati o n a n d d osi n g is c o nti n u o us. All s u bjects will c o nti n ue t o recei ve best s u p p orti ve care acc or di n g 
t o i nstit uti o nal practice t hr o u g h o ut t he st u d y, re gar dless of treat me nt ar m. St u d y visits will be 

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c o n d ucte d e ver y ot her wee k d uri n g C ycles 1 -3 ( Da ys 1 a n d 1 5), a n d Da y 1 of eac h c ycle t hereafter. 
A n E n d of Treat me nt ( E O T) Visit will be perf or me d o n t he last da y of st u d y treat me nt ( wit hi n 5 t o 
3 3  da ys of last d ose, t o acc o m m o date f or p ote ntial d osi n g dela ys of u p t o 2 8 da ys).  
Ra di o gra p hic assess me nt ( C T or M RI) f or e val uati o n of disease res p o nse will be c o n d ucte d e ver y 
6  wee ks ( ± 5 da ys) f or t he first 8 assess me nts (ie, t hr o u g h wee k 4 8) a n d e ver y 8 wee ks ( ± 5 da ys) 
t hereafter fr o m C 1 D 1, i n de pe n de nt of d ose dela ys a n d/ or d ose i nterr u pti o ns, a n d/ or at a n y ti me w he n 
pr o gressi o n of disease is s us pecte d. F or s u bj ects w h o disc o nti n ue st u d y dr u g/ place b o f or reas o ns 
ot her t ha n disease pr o gressi o n or start of a n ot her a ntica ncer a ge nt, a n assess me nt will be c o n d ucte d at 
t he E O T Visit. U p o n re q uest b y t he I n vesti gat or, t he s u bj ect a n d site staff will be u n bli n de d t o 
treat me nt assi g n me nt after d oc u me nte d disease pr o gressi o n (as assesse d b y t he I n vesti gat or a n d after 
c o ns ultati o n wit h t he S p o ns or Me dical M o nit or), a n d s u bj ects ra n d o mize d t o t he  place b o ar m w h o 
c o nti n ue t o meet eli gi bilit y criteria deter mi ne d i n t he E O T visit will be gi ve n t he o p p ort u nit y t o cr oss 
o ver t o t he acti ve treat me nt ar m a n d recei ve A G -1 2 0. F or t h ose s u bjects w h o cr oss o ver, place b o will 
n ot be c o u nte d as a pri or li ne of  t hera p y f or t he p ur p ose of eli gi bilit y. If s u bj ects cr oss o ver, t he y will 
start a gai n wit h st u d y pr oce d ures as at C 1 D 1. T hese s u bj ects will c o nti n ue t o be e val uate d f or t u m or 
res p o nse b y t he I n vesti gat or. If t he treat me nt assi g n me nt is deter mi ne d t o be A G-1 2 0 u p o n 
ra di o gra p hic disease pr o gressi o n, t he I n vesti gat or ma y c o nsi der c o nti n ui n g treat me nt wit h A G-1 2 0, 
pr o vi de d t he s u bject is cli nicall y be nefitti n g a n d t here is n o c o ntrai n dicati o n t o c o nti n ui n g treat me nt 
be y o n d pr o gressi o n (see Secti o n 9. 8  f or para meters f or treati n g be y o n d pr o gressi o n). Palliati ve 
ra di ot hera p y t o treat s y m pt o matic n o n-tar get lesi o ns t hat ca n n ot ot her wise be me dicall y ma na ge d will 
be per mitte d after disease pr o gressi o n has bee n verifie d a n d u n bli n di n g has occ urre d, wit h Me dical 
M o nit or a p pr o val (see Secti o n 9. 8. 1. 3 ). T arget a n d n o n -tar get lesi o n selecti o n a n d o bj ecti ve t u m or 
res p o nse assess me nts per Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) v 1. 1 will be 
perf or me d b y t he i nstit uti o nal ra di ol o gist(s). A n i n de pe n de nt ce ntral re vie w of res p o nse will be 
c o n d ucte d b y a n I n de pe n de nt Ra di ol o g y Ce nter (I R C) per R E CI S T v 1. 1. All sca ns will be se nt t o t he 
I R C as detaile d i n t he site -s pecific I ma gi n g C ore Ma n ual (see Secti o n  1 0. 7. 2 ). 
H R Q O L assess me nts will be c o n d ucte d pre -d ose o n C 1 D 1 a n d o n Da y 1 of e ver y c ycle t hereafter 
u ntil t he e n d of treat me nt. After E O T visit, t he H R Q O L will be c o n d ucte d e ver y 1 2  wee ks u ntil t he 
start of ne w a ntica ncer t hera p y. O ne a d diti o nal HR Q O L assess me nt will als o be c o n d ucte d at t he 
safet y f oll o w-u p visit. Healt h ec o n o mic o utc o mes assess me nts will occ ur pre -d ose o n C 1 D 1 C ycle  3, 
Da y 1 ( C 3 D 1), a n d at t he E O T Visit. C o m plia nce assess me nts will occ ur at C ycle 1, Da y 1 5 
( C 1 D 1 5), Da y 1 of e ver y c ycle t hereafter, a n d at t he E O T Visit. If s u bj ects cr oss o ver, t he y will 
f oll o w t he sa me assess me nt sc he d ule as fr o m C 1 D 1 . 
S u bj ects will be assesse d at e ver y visit f or a d verse e ve nts ( A Es) a n d c o nc o mita nt me dicati o ns,  
starti n g fr o m t he first d ose of st u dy treat me nt. T o xicit y se verit y will be 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 T er 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 
4. 0 3. A d diti o nal safet y assess me nts c o n d ucte d peri o dicall y t hr o u g h o ut t he st u d y will i ncl u de vital 
si g ns, p h ysical e xa mi nati o ns, E C O G P S, E C H O ( or ot her met h o ds acc or di n g t o i nstit uti o nal practice) 
f or deter mi nati o n of L V E F ( o nl y if cli nicall y i n dicate d), E C Gs, a n d cli nical la b orat or y assess me nts 
( he mat ol o g y, ser u m c he mistr y, a n d uri ne pre g na nc y test). 
Bl o o d sa m ples f or P K/ P D assess me nts will be dra w n o ver a 4 -h o ur peri o d o n C 1 D 1 a n d C 2 D 1. 
A d diti o nal bl o o d sa m ples f or P K/ P D assess me nts will be dra w n at 2 h o urs ( ± 1 0 mi n utes) p ost -d ose 
o n C 1 D 1 5, pre -d ose ( wit hi n 3 0  mi n utes) o n C 3 D 1 a n d Da y 1 of e ver y c ycle  t hereafter, a n d at a n y 
ti me d uri n g t he E O T Visit. 
Bl o o d a n d plas ma sa m ples will be o btai ne d f or e x pl orat or y bi o mar kers a n d c orrelati ve st u dies at 
Scree ni n g, C 1 D 1 5 ( plas ma o nl y), Da y 1 of e ver y c ycle t hereafter, a n d at t he E O T Visit.  
S u bj ects ma y c o nti n ue wit h t heir assi g ne d st u d y treat me nt u ntil disease pr o gressi o n, de vel o p me nt of 
ot her u nacce pta ble t o xicit y, c o nfir me d pre g na nc y, deat h, wit h dra wal of c o nse nt, u ntil t he s u bj ect is 
l ost t o f oll o w-u p, or t he S p o ns or u n bli n ds or e n ds t he st u d y, w hic he ver occ ur s first. S u bjects w h o are 

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deter mi ne d t o be o n A G -1 2 0 u p o n st u d y u n bli n di n g ma y c o nti n ue o n A G -1 2 0. F or s u bjects w h o are 
deter mi ne d t o be o n A G -1 2 0 u p o n ra di o gra p hic disease pr o gressi o n a n d ha ve de m o nstrate d cli nical 
be nefit, Pri nci pal I n vesti gat ors ( PIs), wit h c o ns ult fr o m t he S p o ns or, ma y kee p t he s u bj ects o n A G -
1 2 0 after t he disease pr o gressi o n.  ( See Secti o n  9. 6  f or a d diti o nal u n bli n di n g sce nari os.) 
P ost -Tre at me nt F oll o w -u p Visit : A P ost -Treat me nt F oll o w -U p Visit f or safet y will occ ur 2 8 da ys 
( n o m ore t ha n 3 3 da ys) after t he last d ose of st u d y dr u g. E ver y eff ort m ust be ma de t o perf or m 
pr ot oc ol -s pecifie d e val uati o ns u nless c o nse nt t o partici pate i n the st u d y is wit h dra w n. If a s u bj ect’s 
d ose is i nterr u pte d f or 2 8 da ys a n d t he n t he s u bj ect disc o nti n ues st u d y partici pati o n, t he E O T Visit 
will ser ve as t he P ost -Treat me nt F oll o w -u p Visit.  
P F S a n d S ur vi v al F oll o w -u p : S u bjects w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n 
disease pr o gressi o n or wit h dra wal of c o nse nt will be f oll o we d i n P F S f oll o w -u p (e ver y 6 wee ks 
t hr o u g h wee k 4 8 a n d e ver y 8 wee ks t hereafter) u ntil d oc u me nte d disease pr o gressi o n or t he i nitiati o n 
of ne w ca ncer t hera p y. If a s u bj ect be gi ns a ne w a ntica ncer t hera p y d uri n g P F S f oll o w -u p, 
i nf or mati o n o n t he ne w a ntica ncer t hera p y will be c ollecte d. 
O S f oll o w -u p assess me nts will occ ur a p pr o xi matel y e ver y 1 2 wee ks after E O T u nless t he s u bject is i n 
P F S f oll o w -u p at t hat ti me. If a s u bj ect pr o gresses or d oes n ot c o me bac k f or sca ns w hile i n P F S 
f oll o w-u p, t he n t he O S f oll o w -u p assess me nts will be gi n at t he ne xt pla n ne d O S f oll o w -u p ti me p oi nt, 
f oll o wi n g t he sc he d ule of e ver y 1 2 wee ks after E O T. O S f oll o w -u p will c o nti n ue u ntil all s u bjects 
h a ve die d, wit h dra w n c o nse nt, are l ost t o f oll o w -u p, or u ntil t he occ urre nce of 1 5 0 O S e ve nts, 
w hic he ver occ urs first.  
P ri m ar y E n d p oi nt Res ults a n d S u bse q ue nt St u d y U n bli n di n g:  O nce t he pri mar y e n d p oi nt of P F S 
( base d o n ce ntral ra di ol o g y R E CI S T 1. 1 assess ment) is statisticall y a nal yze d, t he S p o ns or will 
c o m m u nicate t he t o pli ne a g gre gate res ults of t he st u d y via p u blic discl os ure, w hic h will i ncl u de 
partici pati n g st u d y tea ms. S h ortl y after p u blic discl os ure of t he t o pli ne a g gre gate res ults, t he S p o ns or 
will c o m m u nicate t o all sites t hat treat me nt assi g n me nts of all s u bjects will be u n bli n de d a n d will als o 
i nf or m sites w hic h of t he 2  f oll o wi n g sce nari os t o p urs ue f oll o wi n g u n bli n di n g. 
If t he pri mar y e n d p oi nt is statisticall y p ositi ve, all o n g oi n g s u bj ects ( A G-1 2 0 a n d place b o -treat me nt 
assi g ne d s u bjects) will be gi ve n t he o p p ort u nit y  t o recei ve o pe n-la bel A G-1 2 0 f oll o wi n g u n bli n di n g. 
U n bli n di n g will n o l o n ger be c o nti n ge nt u p o n d oc u me nte d ra di o gra p hic disease pr o gressi o n. S u bj ects 
w h o were alrea d y recei vi n g A G -1 2 0 ma y c o nti n ue t o recei ve  A G -1 2 0 o n t he sa me assess me nt 
sc he d ule. S u bjects w h o were recei vi n g place b o a n d c o nti n ue t o meet cr oss -o ver eli gi bilit y criteria will 
be gi ve n t he o p p ort u nit y t o recei ve o pe n -la bel A G-1 2 0. F or s u bjects w h o cr oss o ver, place b o  will n ot 
be c o u nte d as a pri or li ne of t hera p y f or t he p ur p ose of eli gi bilit y. If s u bj ects cr oss o ver, t he y will 
f oll o w t he sa me assess me nt sc he d ule as fr o m C 1 D 1. Pri or t o cr ossi n g o ver, t hese s u bj ects will 
u n der g o a C T or M RI t hat will ser ve as t he ne w b aseli ne a gai nst w hic h all s u bse q ue nt R E CI S T v 1. 1 
assess me nts will be perf or me d. If t he s u bject has u n der g o ne a rece nt C T or M RI ( ≤3 wee ks pri or t o 
start of cr oss-o ver treat me nt), t he sca n d oes n ot nee d t o be re peate d. Palliati ve ra di ot hera p y t o treat 
s y m pto matic pre -e xisti n g or ne w n o n -tar get lesi o ns ( per R E CI S T v 1. 1) t hat ca n n ot ot her wise be 
me dicall y ma na ge d will be per mitte d after u n bli n di n g has occ urre d. A G -1 2 0 s h o ul d be hel d f or t he 
d urati o n of palliati ve ra di ot hera p y. A 2 -wee k was h o ut fr o m c o m pleti o n of ra di ot hera p y will be 
re q uire d pri or t o starti n g or res u mi n g A G-1 2 0. F or s u bjects recei vi n g palliati ve ra di ot hera p y pri or t o 
t he first d ose of o pe n-la bel A G-1 2 0, a re peat C T or M RI will be perf or me d u p o n c o m pleti o n of t he 
2 -wee k was h o ut peri o d t o d oc u me n t t he area t hat was irra diate d a n d t o ser ve as t he ne w baseli ne. All 
decisi o ns t o p urs ue palliati ve ra di ot hera p y will re q uire S p o ns or a n d/ or Me dical M o nit or a p pr o val.  
If t he pri mar y e n d p oi nt is statisticall y ne gati ve, all o n g oi n g A G-1 2 0 s u bj ects will be pe r mitte d t o 
c o nti n ue recei vi n g o pe n -la bel A G-1 2 0 f oll o wi n g u n bli n di n g at t he discreti o n of t he treati n g 
i n vesti gat or. Palliati ve ra di ot hera p y will be all o we d f or s u bjects w h o c o nti n ue recei vi n g A G-1 2 0 as 
descri be d i n t he prece di n g “statisticall y p ositi ve” p ara gra p h. S u bjects w h o were recei vi n g place b o 
will n ot be per mitte d t o recei ve o pe n -la bel A G-1 2 0 i n t his sce nari o a n d will c o me off st u d y. 

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N u m ber of S u bjects ( Pl a n ne d):  
A t otal of a p pr o xi matel y 1 8 6 s u bjects will be ra n d o mize d i n a 2: 1 rati o, stratifie d b y  n u m ber of pri or 
s yste mic treat me nt re gi me ns f or a d va nce d disease ( 1 or 2) i nt o t he 2 treat me nt ar ms, i ncl u di n g 
a p pr o xi matel y 1 2 4 s u bjects i n t he A G -1 2 0 ar m a n d 6 2 s u bj ects i n t he place b o ar m.  
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
I ncl usi o n Criteri a: 
S u bj ects m ust meet all of t he f oll o wi n g criteria t o be e nr olle d i n t he st u d y:  
1.  Be ≥1 8 years of a ge.  
2.  Ha ve a hist o pat h ol o gical dia g n osis (fres h or ba n ke d t u m or bi o ps y sa m ple, prefera bl y 
c ollecte d wit hi n t he last 3 years) c o nsiste nt wit h n o nresecta ble or meta static 
c h ola n gi ocarci n o ma a n d are n ot eli gi ble f or c urati ve resecti o n, tra ns pla ntati o n, or a blati ve 
t hera pies. 
3.  Ha ve d oc u me nte d I D H 1 ge ne -m utate d disease (fr o m a  fres h t u m or bi o ps y or t he m ost rece nt 
ba n ke d t u m or tiss ue a vaila ble) base d o n ce ntral la b orat or y testi n g  ( R 1 3 2 C/ L/ G/ H/ S m utati o n 
varia nts teste d) . 
4.  Ha ve a n E C O G P S sc ore of 0 or 1 ( A p pe n di x  1 5. 1 ). 
5.  Ha ve a n e x pecte d s ur vi val of ≥3 m o nt hs.  
6.  Ha ve at least o ne e val ua ble a n d meas ura ble lesi o n as defi ne d b y R E CI S T v 1. 1. S u bj ects w h o 
ha ve recei ve d pri or l ocal t hera p y (i ncl u di n g b ut n ot li mite d t o e m b olizati o n, 
c he m oe m b olizati o n, ra di ofre q ue nc y a blati o n, or ra diati o n t hera p y) are eli gi ble pr o vi de d 
meas ura ble disease falls o utsi de of t he treat me nt fiel d or wit hi n t he fiel d a n d has s h o w n 
≥2 0 % gr o wt h i n size si nce p ost -treat me nt assess me nt. 
7.  Ha ve d oc u me nte d disease pr o gressi o n f oll o wi n g at least 1 a n d n o m ore t ha n 2 pri or s yste mic 
re gi me ns f or a d va nce d disease ( n o nresecta ble or metastatic) wit h pr o gressi o n o n t he 
treat me nt t hat was m ost rece ntl y gi ve n at a mi ni m u m. S u bj ects m ust ha ve recei ve d at least 1 
ge mcita bi ne - or 5 -F U -c o ntai ni n g re gi me n f or a d va nce d c h ola n gi ocarci n o ma. S yste mic 
a dj u va nt c he m ot hera p y will be c o nsi dere d a li ne of treat me nt if t here is d oc u me nte d disease 
pr o gressi o n d uri n g or wit hi n 6 m o nt hs of c o m pleti n g t he t hera p y.  
8.  Ha ve rec o ver e d fr o m t o xicities ass ociate d wit h pri or a ntica ncer t hera p y t o baseli ne u nless 
sta bilize d u n der me dical ma na ge me nt. 
9.  Ha ve a de q uate b o ne marr o w f u ncti o n as e vi de nce d b y:  
a. A bs ol ute ne utr o p hil c o u nt ≥1, 5 0 0/ m m 3 or 1. 5  × 1 0 9/ L 
b.  He m o gl o bi n ≥8  g/ d L  
c. Platelets ≥1 0 0, 0 0 0/ m m 3 or 1 0 0  ×  1 0 9/ L 
1 0.  Ha ve a de q uate he patic f u ncti o n as e vi de nce d b y:  
a. Ser u m t otal bilir u bi n ≤2  × u p per li mit of n or mal ( U L N), u nless c o nsi dere d d ue t o 
Gil bert’s disease  
b.  As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤5  ×  U L N  
1 1.  Ha ve  a de q uate re nal f u ncti o n as e vi de nce d b y:  
a. Ser u m creati ni ne < 1. 5  ×  U L N  
O R  
b.  Creati ni ne cleara nce ≥5 0 m L/ mi n base d o n t he C oc kcr oft -Ga ult gl o mer ular filtrati o n rate 
( G F R) esti mati o n: 
( 1 4 0  A ge)   ( wei g ht i n k g)  ( 0. 8 5 if fe male)/ 7 2  ser u m creati ni ne 

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1 2.  Be a ble  t o u n dersta n d a n d willi n g t o si g n t he i nf or me d c o nse nt f or m a n d t o c o m pl y wit h 
sc he d ule d visits, treat me nt pla ns, pr oce d ures, a n d la b orat or y tests, i ncl u di n g serial peri p heral 
bl o o d sa m pli n g a n d uri ne sa m pli n g, d uri n g t he st u d y.  A le gall y a ut h orize d re pre se ntati ve ma y 
c o nse nt o n be half of a s u bject w h o is ot her wise u na ble t o pr o vi de i nf or me d c o nse nt if 
acce pta ble t o a n d a p pr o ve d b y t he site’s I R B/I n de pe n de nt Et hics C o m mittee (I E C).  ( S u bjects 
w h o d o n ot s pea k o ne of t he la n g ua ges t hat t he E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, 
P GI -C, P GI -S, or E Q -5 D -5 L, are pr o vi de d i n at t his ti me will be per mitte d t o e nr oll a n d n ot 
c o m plete t hese H R Q O L/ healt h ec o n o mic o utc o me i nstr u me nts, ass u mi n g all ot her eli gi bilit y 
criteria are met.)  
1 3.  Fe male s u bjects wit h re pr o d ucti ve p ote ntia l m ust ha ve a ne gati ve ser u m pre g na nc y test pri or 
t o t he start of t hera p y, or a c o nfir mati o n fr o m a n o bstetricia n i n case of e q ui v ocal ser u m 
pre g na nc y res ults. Fe males of re pr o d ucti ve p ote ntial are defi ne d as se x uall y mat ure w o me n 
w h o ha ve n ot u n der g o ne a h ysterect o m y, bilateral o o p h orect o m y, or t u bal occl usi o n or w h o 
ha ve n ot bee n nat urall y p ost me n o pa usal (ie, w h o ha ve n ot me nstr uate d) f or at least 
2 4  c o nsec uti ve m o nt hs (ie, ha ve n ot ha d me nses at a n y ti me i n t he prece di n g 2 4  c o nsec uti ve 
m o nt hs). W o me n wit h re pr o d ucti ve p ote ntial, as well as fertile me n wit h part ners w h o are 
fe male wit h re pr o d ucti ve p ote ntial, m ust a gree t o use 2 effecti ve f or ms of c o ntrace pti o n 
(i ncl u di n g at least 1 barrier f or m) fr o m t he ti me of gi vi n g i nf or me d c o nse nt t hr o u g h o ut t he 
st u dy a n d f or 9 0 da ys ( b ot h fe males a n d males) f oll o wi n g t he last d ose of st u d y dr u g. 
Effecti ve f or ms of c o ntrace pti o n are defi ne d as h or m o nal oral c o ntrace pti ves, i njecta bles, 
patc hes, i ntra uteri ne de vices, i ntra uteri ne h or m o ne -releasi n g s yste ms, bilateral t ubal li gati o n, 
c o n d o ms wit h s per mici de, or male part ner sterilizati o n.  
E xcl usi o n criteri a:  
S u bj ects w h o meet a n y of t he f oll o wi n g criteria will n ot be e nr olle d i n t he st u d y:  
1.  Recei ve d a pri or I D H i n hi bit or.  
2.  Recei ve d s yste mic a ntica ncer t hera p y or a n i n vesti gati o nal a ge nt < 2 wee ks pri or t o Da y 1 
( was h o ut fr o m pri or i m m u n e base d a ntica ncer t hera p y is 4 wee ks). I n a d diti o n, t he first d ose 
of st u d y treat me nt s h o ul d n ot occ ur bef ore a peri o d ≥5 half -li ves of t he i n vesti gati o nal a ge nt 
has ela pse d.  
3.  Recei ve d ra di ot hera p y t o metastatic sites of disease < 2 wee ks pri or t o Da y 1.  
4.  U n der we nt he patic ra diati o n, c he m oe m b olizati o n, a n d ra di ofre q ue nc y a blati o n < 4 wee ks 
pri or t o Da y  1.  
5.  Ha ve k n o w n s y m pt o matic brai n metastases re q uiri n g ster oi ds. S u bjects wit h pre vi o usl y 
d ia g n ose d brai n metastases are eli gi ble if t he y ha ve c o m plete d t heir treat me nt a n d ha ve 
rec o vere d fr o m t he ac ute effects of ra diati o n t hera p y or s ur ger y pri or t o st u d y e ntr y, ha ve 
disc o nti n ue d c ortic oster oi d treat me nt f or t hese metastases f or at least 4 wee ks a n d ha ve 
ra di o gra p hicall y sta ble disease f or at least 3 m o nt hs pri or t o st u d y e ntr y. N ote: u p t o 1 0 m g 
per da y of pre d nis o ne e q ui vale nt will be all o we d.  
6.  Ha ve a hist or y of a n ot her pri mar y ca ncer, wit h t he e xce pti o n of: a) c urati vel y resecte d n o n -
mela n o ma  s ki n ca ncer; b) c urati vel y treate d cer vical carci n o ma i n sit u; or c) ot her pri mar y 
s oli d or li q ui d t u m or wit h n o k n o w n acti ve disease prese nt t hat, i n t he o pi ni o n of t he 
I n vesti gat or, will n ot affect s u bj ect o utc o me i n t he setti n g of c urre nt c h ola n gi ocarci n o ma 
dia g n osis.  
7.  U n der we nt maj or s ur ger y wit hi n 4 wee ks of Da y 1 or ha ve n ot rec o vere d fr o m p ost -s ur ger y 
t o xicities. 
8.  Are pre g na nt or breastfee di n g.  

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9.  Are ta ki n g k n o w n str o n g c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 i n d ucers or se nsiti ve C Y P 3 A 4 
s u bstrate me dicati o ns wit h a narr o w t hera pe utic wi n d o w ( A p pe n di x  1 5. 2 ), u nless t he y ca n be 
tra nsferre d t o ot her me dicati o ns wit hi n ≥5 half-li ves pri or t o d osi n g. 
1 0.  E xcl usi o n criteri o n 1 0 re m o ve d i n Pr ot oc ol A me n d me nt 4, Versi o n 5. 0.  
1 1.  Ha ve a n acti ve i nfecti o n re q uiri n g s yste mic a nti -i nfecti ve t hera p y or wit h a n u ne x plai ne d 
fe ver > 3 8. 5° C wit hi n 7 da ys of Da y 1 (at t he discreti o n of t he I n vesti gat or, s u bjects wit h 
t u m or fe ver ma y be e nr olle d).  
1 2.  Ha ve a n y k n o w n h y perse nsiti vit y t o a n y of t he c o m p o ne nts of A G -1 2 0 or t he matc he d 
place b o.  
1 3.  Ha ve si g nifica nt acti ve car diac disease wit hi n 6 m o nt hs pri or t o t he start of st u d y treat me nt, 
i ncl u di n g Ne w Y or k Heart Ass ociati o n ( N Y H A) Class III or I V c o n gesti ve heart fail ure 
( A p pe n di x 1 5. 3 ); m y ocar dial i nfarcti o n; u nsta ble a n gi na; a n d/ or str o ke. 
1 4.  Ha ve L V E F < 4 0 % b y E C H O sca n ( or b y ot her met h o ds acc or di n g t o i nstit uti o nal practice) 
o btai ne d wit hi n 2 8  da ys pri or t o t he start of st u d y treat me nt.  
1 5.  Ha ve a heart -rate c orrecte d Q T i nter val ( usi n g Fri dericia’s f or m ula) ( Q T c F) ( A p pe n di x 1 5. 4 ) 
≥4 5 0 msec or ot her fact ors t hat i ncrease t he ris k of Q T pr ol o n gati o n or arr h yt h mic e ve nts (e g, 
heart fail ure, h y p o kale mia, fa mil y hist or y of l o n g Q T i nter val s y n dr o me). B u n dle bra nc h 
bl oc k a n d pr ol o n ge d Q Tc F i nter val are per mitte d wit h a p pr o val of t he Me dical M o nit or.  
1 6.  Are ta ki n g me dicati o ns t hat are k n o w n t o pr ol o n g t he Q T i nter val ( A p pe n di x  1 5. 5 ), unless 
t he y ca n be tra nsferre d t o ot her me dicati o ns wit hi n ≥5 half -li ves pri or t o d osi n g or u nless t he 
me dicati o ns ca n be pr o perl y m o nit ore d d uri n g t he st u d y. (If e q ui vale nt me dicati o n is n ot 
a vaila ble, Q T c F s h o ul d be cl osel y m o nit ore d.)  
1 7.  Ha ve k n o w n acti ve h e patitis B ( H B V) or he patitis  C ( H C V) i nfecti o ns, k n o w n p ositi ve 
h u ma n i m m u n o deficie nc y vir us ( HI V) a nti b o d y res ults, or ac q uire d i m m u n o deficie nc y 
s y n dr o me ( AI D S)-relate d ill ness. S u bjects wit h a s ustai ne d viral res p o nse t o H C V treat me nt 
or i m m u nit y t o pri or H B V i nfecti o n will be per mitte d. S u bj ects wit h c hr o nic H B V t hat is 
a de q uatel y s u p presse d per i nstit uti o nal practice will be per mitte d.  
1 8.  Ha ve a n y ot her ac ute or c hr o nic me dical or ps yc hiatric c o n diti o n, i ncl u di n g rece nt ( wit hi n 
1 2  m o nt hs of Da y  1) or acti ve s uici dal i deati o n or be ha vi or, or a la b orat or y a b n or malit y t hat 
ma y i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or i n vesti gati o nal pr o d uct 
a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of st u d y res ults a n d, i n t he j u d g me nt of 
t he I n vesti gat or, w o ul d ma ke t he s u bject i na p pr o priate f or e ntr y i nt o t his st u d y.  
1 9.  Ha ve k n o w n acti ve i nfla m mat or y gastr oi ntesti nal disease, c hr o nic diarr hea, pre vi o us gastric 
resecti o n or la p ba n d d ys p ha gia, s h ort-g ut s y n dr o me, gastr o paresis, or ot her c o n diti o ns t hat 
li mit t he i n gesti o n or gastr oi ntesti nal a bs or pti o n of dr u gs a d mi nistered orall y. 
Gastr oes o p ha geal refl u x disease u n der me dical treat me nt is all o we d (ass u mi n g n o dr u g 
i nteracti o n p ote ntial).  
2 0.  Ha ve bee n c o m mitte d t o a n i nstit uti o n b y virt ue of a n or der iss ue d eit her b y t he j u dicial or 
a d mi nistrati ve a ut h orities.  
2 1.  Are de pe n de nt o n t he S p o ns or, I n vesti gat or, or st u d y site, per l ocal i nstit uti o n re g ulati o ns.  
2 2.  Ha ve k n o w n me dical hist or y of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L).  
I n vesti g ati o n al Pr o d uct, D os a ge, a n d M o de of A d mi nistr ati o n: 
A G -1 2 0 will be pr o vi de d as 2 5 0 m g s tre n gt h ta blets t o be a d mi nistere d orall y. 
S u bj ects ra n d o mize d t o A G -1 2 0 will recei ve 5 0 0 m g Q D o n Da ys  1 t o 2 8 i n 2 8 -da y c ycles. Starti n g 
wit h C 1 D 1, d osi n g is c o nti n u o us; t here are n o pla n ne d i nter -c ycle rest peri o ds.  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
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A gi os P har mace uticals, I nc.  
D ur ati o n of Tre at me nt:  
S u bj ects ma y  c o nti n ue wit h t heir assi g ne d st u d y treat me nt u ntil disease pr o gressi o n, de vel o p me nt of 
u nacce pta ble t o xicit y, c o nfir me d pre g na nc y, deat h, u ntil t he s u bject wit h dra ws c o nse nt, is l ost t o 
f oll o w-u p, or t he S p o ns or u n bli n ds or  e n ds t he st u d y, w hic he ver occ ur s first. S u bjects w h o are 
deter mi ne d t o be o n A G -1 2 0 u p o n st u d y u n bli n di n g ma y c o nti n ue o n A G -1 2 0. F or s u bjects w h o are 
deter mi ne d t o be o n A G -1 2 0 u p o n ra di o gra p hic disease pr o gressi o n a n d ha ve de m o nstrate d cli nical 
be nefit, PIs, wit h c o ns ult fr o m t he S p o n s or, ma y kee p t he s u bjects o n A G-1 2 0 after t he disease 
pr o gressi o n.  ( See Secti o n  9. 6  f or a d diti o nal u n bli n di n g sce nari os.) 
E n d of St u d y:  
E n d of st u d y is defi ne d as t he ti me at w hic h all s u bjects ha ve die d, wit h dra w n c o nse nt, bee n l ost t o 
f oll o w-u p, or u ntil t he occ urre nce of 1 5 0 O S e ve nts. Fi nal a nal ysis f or O S will be c o n d ucte d at t he 
e n d of t he st u d y.  
Ref ere nce T her a p y, D os a ge, a n d M o de of A d mi nistr ati o n:  
S u bj ects ra n d o mize d t o place b o will recei ve A G -1 2 0 -matc he d place b o ta blets t o be a d mi nistere d 
orall y o n t he sa me sc he d ule as A G -1 2 0.  
Criteri a f or E v al u ati o n:  
Effic ac y:  
Serial ra di o gra p hic e val uati o ns  ( C T or M RI) t o deter mi ne res p o nse t o treat me nt base d o n 
R E CI S T  v 1. 1. All sca ns will be se nt t o t he I R C, as detaile d i n t he site -s pecific I ma gi n g C ore Ma n ual 
(see Secti o n  1 0. 7. 2 ). The E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, P GI -C, a n d P GI -S will assess 
H R Q O L a n d t he E Q -5 D -5 L will assess healt h ec o n o mic o utc o mes . 
S af et y:  
M o nit ori n g of A Es, i ncl u di n g seri o us A Es ( S A Es), a n d A Es lea di n g t o disc o nti n uati o n; safet y 
la b orat or y para meters; p h ysical e xa mi nati o n fi n di n gs; vital si g ns; 1 2-lea d E C Gs; L V E F; a n d 
E C O G  P S.  
T he se verit y of A Es will be assesse d b y t he N CI C T C A E versi o n 4. 0 3.  
P h ar m ac o ki netics a n d p h ar m ac o d y n a mics:  
Serial or s parse bl o o d sa m pli n g f or deter mi nati o n of p har mac o ki netic pr ofiles of A G -1 2 0 a n d 
i n hi biti o n of 2-H G.  
St atistic al met h o ds:  
T he pri mar y o bjecti ve of t he st u d y is t o de m o nstrate i m pr o ve me nt i n P F S b y I R C assess me nt f or 
s u bj ects recei vi n g treat me nt wit h A G-1 2 0 c o m pare d t o s u bjects recei vi n g place b o. Ass u mi n g a 
hazar d rati o ( H R) of 0. 5 f or P F S (e q ui vale nt t o a me dia n P F S of 3  m o nt hs i n t he place b o ar m vers us 
6  m o nt hs i n t he A G -1 2 0 ar m, ass u mi n g a n e x p o ne ntial distri b uti o n), a t otal of 1 3 1 P F S e ve nts are 
re q uire d t o pr o vi de 9 6 % p o wer at a 1-si de d al p ha of 0. 0 2 5 le vel of si g nifica nce t o reject t he n ull 
h y p ot hesis (see Secti o n  1 2. 7. 1 ) usi n g a stratifie d l o g-ra n k test. Base d o n t his, a t otal of a p pr o xi matel y 
1 8 6  s u bjects will nee d t o be ra n d o mize d i n a 2: 1 rati o t o t he A G-1 2 0 a n d place b o ar ms, res pecti vel y, 
ass u mi n g a p pr o xi matel y a 2 2 % dr o p o ut rate, a n a p pr o xi mate 2 6 -m o nt h ra n d o mizati o n peri o d, a n d a n 
a d diti o nal 6 -m o nt h f oll o w -u p f or P F S  after t he last s u bj ect is ra n d o mize d.   
Pr o gressi o n -free s ur vi val is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of first 
d oc u me ntati o n of disease pr o gressi o n or deat h d ue t o a n y ca use, w hic he ver occ urs first. S u bjects 
wit h o ut d oc u me ntati o n of disease pr o gressi o n or deat h at t he ti me of t he pri mar y a nal ysis of P F S  will 
be ce ns ore d at t he date of t he last res p o nse assess me nt  pri or t o t he start of alter nate t hera p y . Detaile d 
ce ns ori n g r ules will be s pecifie d i n t he Statistical A nal ysis Pla n ( S A P). T he pri mar y a nal ysis of P F S 
will  be base d o n I R C res p o nse assess me nts. P F S base d o n res p o nse assess me nt deter mi ne d b y t he 
I n vesti gat or will als o be a nal yze d. Ti me fr o m first d ose of st u d y dr u g t o sec o n d d oc u me nte d disease 

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A gi os P har mace uticals, I nc.  
pr o gressi o n ( or deat h) will be calc ulate d f or s u bjects w h o cr oss o ver fr o m t he place b o ar m t o t he 
A G -1 2 0 ar m ( P F S 2).  
Ka pla n -Meier esti mates of P F S will be prese nte d f or eac h treat me nt ar m, i ncl u di n g esti mates of t he 
me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -m o nt h, 6 -m o nt h, a n d 1 2 -m o nt h 
rates). T he H R of P F S wit h 9 5 % c o nfi de nce i nter val ( CI) c o m pari n g A G -1 2 0 wit h place b o will be 
esti mate d fr o m a C o x pr o p orti o nal hazar ds m o del. T he l o g -ra n k test will be use d t o c o m pare P F S 
bet wee n t he 2 treat me nt ar ms.  
O verall s ur vi val is a sec o n dar y e n d p oi nt of t he st u d y. S u bj ects will be f oll o we d f or s ur vi val u ntil all 
s u bj ects ha ve eit her die d, wit h dra w n c o nse nt, are l ost t o f oll o w-u p, or u ntil t he occ urre nce of 1 5 0 O S 
e ve nts, w hic he ver occ urs first. Ka pla n -Meier a nal ysis of O S will be prese nte d.  Se nsiti vit y a na l yses 
f or O S, s uc h as ta ki n g i nt o acc o u nt t he fact or of cr oss o ver, will be s pecifie d i n t he S A P. 
Ass u mi n g a n H R of 0. 6 7 f or O S ( me dia n O S of 8 m o nt hs i n t he place b o ar m vs. 1 2 m o nt hs i n t he 
A G -1 2 0 ar m, ass u mi n g a n e x p o ne ntial distri b uti o n), a t otal of 1 5 0  O S e ve nts will pr o vi de 6 4 % p o wer 
at a 1-si de d al p ha of 0. 0 2 5. Wit h a sa m ple size of 1 8 6, a d diti o nal O S f oll o w-u p of a p pr o xi matel y 
2 4  m o nt hs after last s u bject is ra n d o mize d will be nee de d t o o btai n 1 5 0 O S e ve nts.  
O R R, D O R, a n d T T R are als o sec o n dar y e n d p o i nts a n d will be a nal yze d b y t he I R C a n d b y t he 
I n vesti gat or. 
Safet y will be e val uate d b y t he i nci de nce of A Es, se verit y a n d t y pe of A Es, a n d b y e val uati o n of vital 
si g ns, E C O G P S, cli nical la b orat or y test res ults, E C Gs, a n d L V E F data (as cli nicall y i n dica te d). All 
data will be pr o vi de d i n b y -s u bj ect listi n gs. 
T he st u d y data will be a nal yze d a n d re p orte d i n t he pri mar y cli nical st u d y re p ort ( C S R) base d o n all 
s u bj ects’ data u p t o t he ti me w he n 1 3 1 P F S e ve nts ha ve bee n deter mi ne d b y I n vesti gat or assess me nt. 
A n y a d diti o nal data f or s ur vi val f oll o w -u p a n d f or s u bjects c o nti n ui n g t o recei ve st u d y treat me nt past 
t he data c ut off date f or t he C S R u ntil t he occ urre nce of 1 5 0 O S e ve nts will be re p orte d at t he e n d of 
t he st u d y i n t he fi nal C S R. 
 

St u d y A G 1 2 0 -C -0 0 5  
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3.  
T A B L E O F C O N T E N T S, L IS T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
TI T L E P A G E  ................................................................................................................1  
2.  
S Y N O P SI S  ...................................................................................................................4  
3.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ...............1 3  
4.  
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 0  
5.  
I N T R O D U C TI O N ......................................................................................................2 3  
5. 1.  
Cell ular Meta b olis m a n d Ca ncer  ................................................................................2 3  
5. 1. 1.  
T he R ole of Is ocitrate De h y dr o ge nase  .......................................................................2 3  
5. 1. 2.  
T u m ori ge n esis H y p ot hesis ..........................................................................................2 4  
5. 1. 3.  
I D H M utati o ns i n C h ola n gi ocarci n o ma a n d Ot her S oli d T u m ors ..............................2 4  
5. 2.  
O ver vie w of C h ola n gi oc arci n o ma  ..............................................................................2 5  
5. 3.  
A G -1 2 0  .......................................................................................................................2 5  
5. 3. 1.  
O ver vie w  .....................................................................................................................2 5  
5. 3. 2.  
S u m mar y of N o n cli nical I nf or mati o n  .........................................................................2 5  
5. 3. 2. 1.  
P har mac o ki netic Dr u g I nteracti o ns  ............................................................................2 6  
5. 3. 2. 2.  
Safet y P h ar mac ol o g y a n d T o xic ol o g y  ........................................................................2 6  
5. 3. 3.  
S u m mar y of Cli nical Dat a  ..........................................................................................2 8  
5. 3. 3. 1.  
St u d y A G 1 2 0 -C -0 0 2  ...................................................................................................2 8  
5. 3. 3. 2.  
St u d y A G 1 2 0 -C -0 0 1  ...................................................................................................2 9  
5. 4.  
I d e ntifie d Ris ks of A G-1 2 0  ........................................................................................3 0  
5. 5.  
St u d y R ati o nale  ...........................................................................................................3 0  
6.  
T RI A L O BJ E C TI V E S A N D  E N D P OI N T S  ...............................................................3 2  
6. 1.  
Pri mar y O bj ecti ve  .......................................................................................................3 2  
6. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 2  
6. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................3 2  
6. 4.  
St u d y  E n d p oi nts  ..........................................................................................................3 3  
6. 4. 1.  
Pri mar y E n d p oi nt  ........................................................................................................3 3  
6. 4. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................3 3  
6. 4. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................3 3  
7.  
I N V E S TIG A TI O N A L P L A N  .....................................................................................3 5  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 4  
A gi os P har mace uticals, I nc.  
7. 1.  
O verall St u d y Desi g n  ..................................................................................................3 5  
7. 2.  
J ustificati o n of t he St u d y Desi g n ................................................................................3 8  
7. 3.  
Rati o nale f or t he D os e Selecte d  ..................................................................................3 9  
7. 4.  
Criteria f or St u d y Ter mi nati o n  ...................................................................................4 0  
8.  
S T U D Y P O P U L A TI O N  .............................................................................................4 1  
8. 1.  
N u m ber of S u b jects ....................................................................................................4 1  
8. 2.  
I n cl usi o n Criteria ........................................................................................................4 1  
8. 3.  
E x cl usi o n Criteria  .......................................................................................................4 2  
8. 4.  
S u bject I d e ntificati o n a n d Re gistrati o n  ......................................................................4 4  
8. 5.  
S u bject Wit h dra wal Criteria  .......................................................................................4 4  
8. 5. 1.  
Wit h dra wal fr o m St u d y Treat me nt  .............................................................................4 4  
8. 5. 2.  
St u d y Ter mi nati o n  ......................................................................................................4 5  
9.  
S T U D Y T R E A T M E N T  ..............................................................................................4 7  
9. 1.  
Descri pti o n of St u d y Treat me nt  ..................................................................................4 7  
9. 2.  
St u d y Treat me nt Pac ka gi n g a n d La beli n g  ..................................................................4 7  
9. 3.  
St u d y Treat me nt St ora ge  ............................................................................................4 7  
9. 4.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt  ..............................................................4 7  
9. 5.  
Bli n di n g  ......................................................................................................................4 7  
9. 6.  
U n bli n di n g  ..................................................................................................................4 7  
9. 7.  
St u d y Treat me nt Pre parati o n a n d A d mi nistrati o n  ......................................................4 9  
9. 8.  
Criteria f or D os e M o dificati o n, Disc o nti n uati o n of St u d y Treat me nt, 
C o nti n uati o n Be y o n d Ra di o gra p hi c Pr o gressi o n, a n d All o wa nce of Palliati ve 
Ra di ot hera p y  ...............................................................................................................5 0  
9. 8. 1.  
St u d y Treat me nt D ose M o dificati o n a n d St o p pi n g Criteria  .......................................5 0  
9. 8. 1. 1.  
D ose M o dificati o ns a n d Dela ys  ..................................................................................5 0  
9. 8. 1. 2.  
C o nti n uati o n of Treat me nt Be y o n d Ra di o gra p hi c Pr o gressi o n  ..................................5 1  
9. 8. 1. 3.  
Palliati ve Ra di ot hera p y After U n bli n di n g After Disease Pr o gressi o n  .......................5 1  
9. 8. 1. 4.  
Biliar y Tract O bstr ucti o n D uri n g Treat me nt  ..............................................................5 2  
9. 9.  
G ui deli nes f or Ma n a ge m e nt of Q T Pr ol o n gati o n  .......................................................5 2  
9. 1 0.  
D urati o n of S u bject Parti ci pati o n  ...............................................................................5 3  
9. 1 0. 1.  
Treat me nt D urati o n  .....................................................................................................5 3  
9. 1 1.  
Treat me nt C o m plia nce  ................................................................................................5 4  
9. 1 2.  
St u d y Treat me nt Acc o u nta bilit y  .................................................................................5 4  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
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9. 1 3.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Treat me nts  .................................................5 5  
9. 1 3. 1.  
Pri or Me dicati o ns a n d Pr oce d ures  ..............................................................................5 5  
9. 1 3. 2.  
C o nc o mita nt T hera p y Re q uiri n g Caref ul M o nit ori n g  ................................................5 5  
9. 1 3. 3.  
Pr o hi bite d C o nc o mita nt T hera p y  ................................................................................5 5  
9. 1 3. 4.  
Dr u g -Dr u g I nteracti o ns  ...............................................................................................5 5  
9. 1 3. 5.  
All o we d C o nc o mita nt Me dicati o ns, Pr oce d ures, a n d Treat me nts  ..............................5 6  
1 0.  
S T U D Y A S S E S S M E N T S  ..........................................................................................5 7  
1 0. 1.  
Sc he d ule of E ve nts  .....................................................................................................5 7  
1 0. 2.  
I nf or me d C o nse nt .......................................................................................................6 4  
1 0. 3.  
De m o gra p hi c Data a n d Me dical, S ur gical, a n d M e dicati o n Hist or y  ..........................6 4  
1 0. 4.  
Ge ne M utati o n A nal ysis a n d M olec ular C haracteri zati o n  ..........................................6 4  
1 0. 5.  
Safet y Assess me nts  .....................................................................................................6 4  
1 0. 5. 1.  
I n d e pe n de nt Data M o nit ori n g C o m mittee ..................................................................6 4  
1 0. 5. 2.  
P h ysical E x a mi nati o n a n d E C O G Perf or ma nce St at us  ..............................................6 5  
1 0. 5. 3.  
Vital Si g ns  ..................................................................................................................6 5  
1 0. 5. 4.  
Electr ocar di o gra m a n d Assess me nt of Left Ve ntric ular Ejecti o n Fracti o n  ................6 5  
1 0. 5. 5.  
Safet y La b orat or y Assess me nts  ..................................................................................6 5  
1 0. 5. 6.  
A d verse E v e nts  ...........................................................................................................6 6  
1 0. 6.  
E x pl orat or y Bl o o d Sa m ples  ........................................................................................6 7  
1 0. 7.  
Efficac y Assess me nts  .................................................................................................6 7  
1 0. 7. 1.  
Res p o nse t o Treat me nt  ...............................................................................................6 7  
1 0. 7. 2.  
I n d e pe n de nt Ra di ol o g y Ce nter ...................................................................................6 8  
1 0. 7. 3.  
Healt h -Relate d Q ualit y of Lif e I nstr u me nts  ...............................................................6 8  
1 0. 7. 4.  
Healt h Ec o n o mic O utc o mes Assess me nt  ...................................................................6 9  
1 0. 8.  
P har mac o ki netic Assess me nts  ....................................................................................6 9  
1 0. 9.  
P har mac o d y na mic Ass ess me nts  .................................................................................6 9  
1 0. 1 0.  
Sa m ple Pr ocessi n g, St ora ge, a n d S hi p me nt  ................................................................6 9  
1 1.  
A D V E R S E E V E N T S ..................................................................................................7 0  
1 1. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................7 0  
1 1. 1. 1.  
A d verse E v e nt  .............................................................................................................7 0  
1 1. 1. 2.  
Relate d A d vers e E ve nt  ...............................................................................................7 1  
1 1. 1. 3.  
Seri o us A d verse E v e nt  ................................................................................................7 2  
1 1. 2.  
Pr oce d ures f or Re p orti n g A d verse E v e nts a n d Seri o us A d verse E v e nts  ....................7 2  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
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1 1. 2. 1.  
Dia g n osis vers us Si g ns a n d S y m pt o ms  ......................................................................7 4  
1 1. 2. 2.  
A d verse E v e nts Occ urri n g Sec o n d ar y t o Ot her E v e nts  ..............................................7 4  
1 1. 2. 3.  
A d verse E v e nts of S peci al I nt erest  .............................................................................7 5  
1 1. 2. 3. 1.  
Q Tc F Pr ol o n gati o n  .....................................................................................................7 5  
1 1. 2. 4.  
Persiste nt or Rec urre nt A d verse E ve nts  .....................................................................7 5  
1 1. 2. 5.  
A b n or mal La b orat or y Val ues  .....................................................................................7 5  
1 1. 2. 6.  
Deat hs  .........................................................................................................................7 6  
1 1. 2. 7.  
Pr o gressi o n of C h ola n gi o carci n o ma  ...........................................................................7 6  
1 1. 2. 8.  
Pre -e xisti n g Me dical C o n diti o ns  ................................................................................7 6  
1 1. 2. 9.  
H os pitalizati o n  or Pr ol o n ge d H os pitalizati o n  .............................................................7 7  
1 1. 2. 1 0.  
O ver d ose or I nc orrect A d mi nistrati o n  ........................................................................7 7  
1 1. 3.  
Ot her P ote ntial Ris ks  ..................................................................................................7 8  
1 1. 3. 1.  
Le u k o e nce p hal o pat h y  .................................................................................................7 8  
1 1. 3. 2.  
Se ns ori m ot or Ne ur o pat h y/ P ol y n e ur o pat h y  ................................................................7 8  
1 1. 4.  
Pre g n a nc y Re p orti n g  ..................................................................................................7 9  
1 1. 5.  
F oll o w -u p of S u bjects After A d verse E ve nts  .............................................................8 0  
1 1. 5. 1.  
I n v esti gat or F oll o w-U p  ...............................................................................................8 0  
1 1. 5. 2.  
S p o ns or F oll o w -u p ......................................................................................................8 0  
1 1. 5. 3.  
P ost -st u d y A d vers e E ve nts .........................................................................................8 0  
1 2.  
S T A TI S TI C A L M E T H O D S  .......................................................................................8 1  
1 2. 1.  
Ge neral Met h o ds  .........................................................................................................8 1  
1 2. 2.  
Sa m ple Siz e Esti mati o n  ..............................................................................................8 1  
1 2. 3.  
A nal ysis Sets  ...............................................................................................................8 1  
1 2. 4.  
Ra n d o mizati o n a n d Stratificati o n  ...............................................................................8 2  
1 2. 5.  
Dis p ositi o n  ..................................................................................................................8 2  
1 2. 6.  
Baseli ne E v al uati o ns  ...................................................................................................8 2  
1 2. 7.  
Effica c y A nal yses  .......................................................................................................8 2  
1 2. 7. 1.  
A nal ysis f or t he Pri mar y E n d p oi nt  .............................................................................8 3  
1 2. 7. 2.  
A nal ys es f or t he Se c o n dar y Efficac y E n d p oi nts  ........................................................8 4  
1 2. 7. 2. 1.  
O verall S ur vi val  ..........................................................................................................8 4  
1 2. 7. 2. 2.  
Pr o gressi o n Free S ur vi val per I n vesti gat or  .................................................................8 5  
1 2. 7. 2. 3.  
O bjecti ve Res p o nse Rate  ............................................................................................8 5  
1 2. 7. 2. 4.  
D urati o n of Res p o nse  .................................................................................................8 5  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 7  
A gi os P har mace uticals, I nc.  
1 2. 7. 2. 5 . 
Ti me t o Res p o nse  .......................................................................................................8 6  
1 2. 8.  
A nal ys es of Healt h -Relat e d Q ualit y of Life a n d Healt h Ec o n o mic O utc o mes  ..........8 6  
1 2. 8. 1.  
Healt h -Relate d Q ualit y of Lif e A nal ys es  ...................................................................8 6  
1 2. 8. 2.  
Healt h Ec o n o mic O utc o mes A nal ys es  ........................................................................8 6  
1 2. 9.  
E x p os ure a n d Safet y A nal yses  ....................................................................................8 6  
1 2. 9. 1.  
A d verse E v e nts  ...........................................................................................................8 6  
1 2. 9. 2.  
La b orat or y A b n or malities  ...........................................................................................8 7  
1 2. 9. 3.  
Ot her Safet y D ata  .......................................................................................................8 7  
1 2. 1 0.  
P har m ac o ki netic A n al ys es  ..........................................................................................8 8  
1 2. 1 1.  
P har mac o d y na mic A n al yses  .......................................................................................8 8  
1 2. 1 2.  
E x pl orat or y A nal yses  ..................................................................................................8 8  
1 2. 1 2. 1.  
A nal ysis of P F S 2  ........................................................................................................8 8  
1 2. 1 2. 2.  
Ot h er E x pl orat or y A nal yses  .......................................................................................8 8  
1 2. 1 3.  
Pr oce d ures f or H a n dli n g Missi n g, U n use d, a n d S p uri o us Data  .................................8 9  
1 2. 1 4.  
I nteri m A nal yses .........................................................................................................8 9  
1 3.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ..................................................................9 0  
1 3. 1.  
G o o d Cli nical Practice  ................................................................................................9 0  
1 3. 2.  
Et hical C o nsi derati o ns  ................................................................................................9 0  
1 3. 3.  
S u bject I nf or mati o n a n d I nf or me d C o nse nt  ...............................................................9 0  
1 3. 4.  
S u bject C o nfi de ntialit y  ...............................................................................................9 0  
1 3. 5.  
Pr ot oc ol C o m plia nce  ..................................................................................................9 1  
1 3. 6.  
Data Ma na ge me nt  .......................................................................................................9 1  
1 3. 7.  
S o urce D oc u m e nt/ Case Re p ort F or m C o m pleti o n  .....................................................9 1  
1 3. 8.  
Direct Access t o S o urce Data  .....................................................................................9 2  
1 3. 9.  
Rec or d Rete nti o n  ........................................................................................................9 2  
1 3. 1 0.  
Lia bilit y a n d I ns ur a nce  ...............................................................................................9 2  
1 3. 1 1.  
P u blicati o n of St u d y Fi n di n gs a n d Us e of I nf or mati o n  ..............................................9 2  
1 4.  
LI S T O F R E F E R E N C E S  ............................................................................................9 4  
1 5.  
A P P E N DI C E S  ............................................................................................................9 7  
1 5. 1.  
Easter n C o o perati v e O nc ol o g y Gr o u p Perf or ma n ce Stat us Sc ori n g  ..........................9 7  
1 5. 2.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  .........................................................................9 7  
1 5. 3.  
Ne w Y or k Heart Ass ociati o n Classificati o n  ...............................................................9 8  
1 5. 4.  
Fri deri cia’s F or m ula  ...................................................................................................9 8  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 8  
A gi os P har mace uticals, I nc.  
1 5. 5.  
Me dicati o ns K n o w n t o Pr ol o n g t he Q T I nter v al  ........................................................9 8  
1 5. 6.  
E x a m ples of Str o n g a n d M o derate C Y P 3 A 4 I n hi bit ors  .............................................9 9  
1 5. 7.  
Re prese ntati ve E x a m ples of L o w -Fat a n d Hi g h -Fat, Hi g h -Cal orie M eals  .................9 9  
1 5. 8.  
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 v e nts  .........9 9  
1 5. 9.  
R E CI S T v 1. 1 ...............................................................................................................9 9  
 
 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 9  
A gi os P har mace uticals, I nc.  
LI S T O F T A B L E S  
Ta ble 1:  
Ma na ge me nt of A d vers e E ve nts  .................................................................................5 1  
Ta ble  2:  
Ma na ge me nt of Q T Pr ol o n gati o n b y C T C A E Gra de  .................................................5 3  
Ta ble  3:  
Sc he d ule of Assess me nts  ............................................................................................5 9  
Ta ble 4:  
P har mac o ki netic/ P har mac o d y n a mic Sa m pli n g ( 2 -H G) a n d 
Electr ocar di o gra m Sc h e d ule *  .....................................................................................6 3  
Ta ble  5:  
Ca usal Attri b uti o n G ui da nce  ......................................................................................7 1  
Ta ble 6:  
Disease  Res p o nse Criteria f or Tar get a n d N o n -tar get Lesi o ns .................................1 0 1  
Ta ble 7:  
O verall Disease Res p o ns e Criteria  ...........................................................................1 0 1  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
T he Citric Aci d C ycle  .................................................................................................2 3  
 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 0  
A gi os P har mace uticals, I nc.  
4.  
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  
2 -H G  
2 -h y dr o x y gl utarate  
5 -F U  
5 -fl ur o uracil 
α -K G  
Al p ha -ket o gl utarate  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
AI D S  
Ac q uire d i m m u n o deficie nc y s y n dr o me  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A M L  
Ac ute m yel o ge n o us le u ke mia  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase  
A U C 0 -1 2 hr 
Area u n der t he c o nce ntrati o n × ti me c ur ve fr o m 0 t o 1 2 h o urs  
B C R P  
Breast ca ncer resista nce pr otei n  
BI D  
T wice dail y  
B U N  
Bl o o d urea nitr o ge n  
C x D x  
C ycle x, Da y x  
CI  
C o nfi de nce i nter val  
CI M P  
C yt osi ne -g ua ni ne di n ucle oti de isla n d met h ylat or p he n ot y pe  
C ma x  
Ma xi m u m c o nce ntrati o n  
C p G  
C yt osi ne -g ua ni ne di n ucle oti de  
C O 2  
Car b o n di o xi de  
C R  
C o m plete res p o nse  
C S R  
Cli nical st u d y re p ort  
C T  
C o m p ute d t o m o gra p h y  
C Y P  
C yt oc hr o me  P 4 5 0  
D DI  
Dr u g -dr u g i nteracti o n  
D L T  
D ose -li miti n g t o xicit y 
D M E  
Dr u g -meta b olizi n g e nz y me  
D N A  
De o x yri b o n ucleic aci d  
D O R  
D urati o n of res p o nse  
E C G  
Electr ocar di o gra m  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 1  
A gi os P har mace uticals, I nc.  
A b bre vi ati o n  
Defi niti o n  
E C H O  
Ec h ocar di o gra p h y  
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 D C  
Electr o nic data ca pt ure  
E O R T C -Q L Q -BI L 2 1  
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer  - Q ualit y Of 
Life Q uesti o n naire - C h ola n gi ocarci n o ma a n d Gall bla d der Ca ncer M o d ule  
E O R T C -Q L Q -C 3 0  
E ur o pea n Or ga nisati o n f or Researc h a n d Tr eat me nt of Ca ncer  - Q ualit y Of 
Life Q uesti o n naire –  C ore Q uesti o n naire  
E O T  
E n d of treat me nt  
E Q -5 D -5 L  
5 -le vel E ur o Q ol fi ve di me nsi o ns q uesti o n naire  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
G L P  
G o o d La b orat or y Practice  
H B V, H C V  
He patitis ( B/ C) vir us  
h C G  
H u ma n c h ori o nic g o na d otr o pi n  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H R  
Hazar d rati o  
H R Q O L  
Healt h -relate d q ualit y of life 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I D H, I D H 1, I D H 2 
Is ocitrate de h y dr o ge nase pr otei n, 1, 2 
I D M C 
I n de pe n de nt data m o nit ori n g c o m mittee 
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I R C 
I n de pe n de nt Ra di ol o g y Ce nter 
I T T 
I nte nt-t o-Treat  
I W R S 
I nteracti ve we b res p o nse s yste m 
L V E F  
Left ve ntric ular ejecti o n fracti o n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M RI  
Ma g netic res o na nce i ma gi n g  
m S v  
Millisie vert  
M T D  
Ma xi m u m t olerate d d ose  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
N Y H A  
Ne w Y or k Heart Ass ociati o n  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 2  
A gi os P har mace uticals, I nc.  
A b bre vi ati o n  
Defi niti o n  
O R R  
O bjecti ve res p o nse rate 
O S  
O verall s ur vi val  
P A S  
P har mac o ki netic a nal ysis set  
P D  
P har mac o d y na mic  
P F S  
Pr o gressi o n -free s ur vi val 
P F S 2  
T i me fr o m first d ose t o sec o n d o bjecti ve disease pr o gressi o n or deat h 
P GI -C  
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C)  
P GI -S  
Patie nt Gl o bal I m pressi o n of Se verit y ( P GI -S)  
P -g p  
P -gl yc o pr otei n  
PI  
Pri nci pal I n vesti gat or  
P K  
P har mac o ki netic  
P M L  
Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
P P S  
Per pr ot oc ol set  
P R  
Partial res p o nse  
P R E S  
P osteri or re versi ble e nce p hal o pat h y s y n dr o me  
P S  
Perf or ma nce stat us  
Q D  
O nce dail y  
Q T c B, Q T c F  
Heart -rate c orrecte d Q T i nter val ( usi n g Bazett’s / Fri dericia’s f or m ula) 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A S  
Safet y A nal ysis Set  
S D  
Sta ble disease  
t½  
Eli mi nati o n half -life 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T T R  
Ti me t o res p o nse  
U L N  
U p per li mit of n or mal  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 3  
A gi os P har mace uticals, I nc.  
5.  
I N T R O D U C TI O N 
5. 1.  
Cell ul ar Met a b olis m a n d C a ncer  
5. 1. 1.  
T he R ole of Is ocitr ate D e h y dr o ge n ase  
T he is ocitrate de h y dr o ge nase (I D H) pr ot ei ns are critical meta b olic e nz y m es t hat e xist as 3 
is of or ms: I D H 1, I D H 2, a n d I D H 3 (Fi g ure  1 ). All 3 catal yz e t he o xi dati ve decar b o x yl ati o n of 
is ocitrate t o pr o d uce car b o n di o xi de ( C O2) a n d al p ha-ket o gl utarate ( α -K G). I D H 1 a n d I D H 2 
pr o d uce a d e ni ne di n ucle oti de p h os p hate ( N A D P H) w here as I D H 3 o nl y pr o d uces N A D H.  
Ca ncer -ass ociate d m utati o ns ha ve bee n i de ntifie d i n I D H 1 a n d I D H 2; h o we ver t o date, n o 
m utati o ns ha ve bee n des cri be d i n I D H 3 (Ye n, et al. 2 0 1 0 ). O ne f u n da m e ntal differe nce b et wee n 
I D H 1 a n d I D H 2 is t he s u bcell ular l ocalizati o n of t he 2 pr otei ns. I D H 1 is l o calize d i n b ot h 
per o xis o mes a n d c yt os ol (Geis brec ht a n d G o ul d 1 9 9 9 ; Y os hi hara, et al. 2 0 0 1 ). I D H 2 is a 
mit oc h o n drial is of or m of I D H (Wa n g, et al. 2 0 1 3 ; Y os hi hara, et al. 2 0 0 1 ). 
T he ge nes e nc o di n g I D H 1 a n d I D H 2 are l ocate d o n c hr o m os o me 2 q 3 3. 3 a n d 1 5 q 2 6. 1, 
res pecti vel y. M utati o ns i n t hese I D H pr otei ns m ost c o m m o nl y lea d t o alterati o ns affecti n g 
ar gi ni ne-1 3 2 ( R 1 3 2 H or R 1 3 2 C) i n I D H 1,  a n d t he a nal o g o us ar gi ni ne resi d ue (ar gi ni ne -1 7 2 
m utate d t o l ysi ne [ R 1 7 2 K]) or ar gi ni ne -1 4 0 ( R 1 4 0 Q) i n I D H 2.  
Fi g ure  1 : 
T he Citric Aci d C ycle  
 
 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 4  
A gi os P har mace uticals, I nc.  
5. 1. 2.  
T u m ori ge nesis H y p ot hesis  
M uta nt I D H 1 a n d I D H 2 are n ot c atal yti call y i nacti ve e nz y mes, b ut rat her p ossess n o vel 
e nz y matic acti vities, c o nsiste nt wit h a gai n -of -f u ncti o n, rec o ncili n g t he het er oz y g o us nat ure of 
t he p oi nt m utati o ns (Da n g, et al. 2 0 0 9 ). T he m utat e d pr otei ns t he msel ves h a ve a 
gai n -of -f u ncti o n, ne o m or p hic acti vit y, catal yzi n g t he re d ucti o n of α -K G t o 2 -h y dr o x y gl ut arate 
( 2-H G) (Da n g , et al. 2 0 0 9). T he S p o ns or’s st u dies esta blis he d t hat p urifie d m uta nt pr otei n 
efficie ntl y catal yzes t h e pr o p ose d re d u cti o n of α -K G t o 2 -H G, w hile bei n g u na ble t o s y nt hesize 
is ocitrate (Da n g, et al. 2 0 0 9 ). M utati o ns i n I D H 1 a n d I D H 2 are al most al wa ys m ut uall y 
e x cl usi ve a n d occ ur at ver y earl y sta ges of t u m or de vel o p me nt s u g gesti n g t hat t he y pr o m ote 
f or mati o n a n d pr o gressi o n of t u m ors (Welc h, et al. 2 0 1 2 ). 
E vi de nce s u p p orts t hat c a ncer -ass oci ate d I D H m utati o ns bl oc k n or mal cell ular differe ntiati o n 
a n d pr o m ote t u m ori ge nesis via t he a b n or mal pr o d u cti o n of 2 -H G, a p ot e ntial o nc o meta b olit e. 
Hi g h le v els of 2 -H G h a v e bee n s h o w n t o i n hi bit K G de pe n d e nt di o x y ge nases i ncl u di n g 
hist o ne a n d de o x yri b o n u cle oti de de met h ylases, w hic h pla y a ke y r ol e i n re g ulati n g t he e pi ge netic 
state of cells (C h o w d h ur y, et al. 2 0 1 1 ; K oi v u ne n, et al. 2 0 1 2 ; X u, et al. 2 0 1 1 ). C o nsiste nt wit h 
2 -H G pr o m oti n g t u m ori ge nesis via a n effect o n c hr o mati n str uct ure, patie nts wit h I D H m utati o ns 
dis pla y a c yt osi n e -g ua ni n e di n ucle oti de ( C p G) isla n d met h ylat or p h e n ot y p e ( CI M P) a n d se veral 
st u dies ha ve s h o w n t hat o vere x pressi o n of I D H m uta nt e nz y mes ca n i n d uce hist o ne a n d 
de o x yri b o n ucleic aci d  (D N A) h y per m et h yl ati o n as well as i m pair n or mal cell ular differe ntiati o n 
(Fi g uer oa, et al. 2 0 1 0 ; L u, et al. 2 0 1 2 ; T urca n, et al. 2 0 1 2 ). 
Cli nical st u dies i n se veral t u m or t y p es i ncl u di n g gli o ma a n d ac ute m yel o ge n o us le u ke mia 
( A M L) ha v e f o u n d el e vate d le vels of 2 -H G i n cells wit h m uta nt I D H 1 a n d I D H 2 as c o m p are d t o 
cells wit h wil d -t y pe alleles (Gr oss, et al. 2 0 1 0 ; War d, et al. 2 0 1 0 ). I n n or m al cells, 2-H G is 
prese nt i n l o w le vels. H o we ver, I D H 1/I D H 2 m utati o ns i n ca ncer cells res ult i n t he e x cess 
acc u m ulati o n of 2 -H G t o e xtre mel y hi g h le vels, w hic h ca n alter a n u m ber of d o w nstrea m cell ular 
acti vities. T he ele vat e d le vels of 2 -H G als o are prese nt i n t he sera a n d uri ne of s o me affecte d 
patie nts. Eff orts are u n der wa y i n t he o n g oi n g P has e 1 st u d y ( A G 1 2 0 -C -0 0 2) t o e x pl ore t he 
ass ociati o n of plas ma a n d tiss ue 2 -H G wit h u n derl yi n g t u m or b ur de n a n d t u m or res p o nse i n 
c h ola n gi ocarci n o ma a n d ot her s oli d t u m ors.  
5. 1. 3.  
I D H M ut ati o ns i n C h ol a n gi oc arci n o m a a n d Ot her S oli d Tu m ors  
I D H 1 m utati o ns c o nti n ue t o be i de ntifie d i n a vari et y of s oli d t u m or s u bt y p es, i ncl u di n g gli o mas, 
c h o n dr osarc o mas, a n d i ntra he patic c h ola n gi ocarci n o mas. M utati o ns i n I D H 1 ha ve bee n f o u n d i n 
a p pr o xi matel y 7 0 % of Gra de 2 t o 3 gli o mas (Ya n, et al. 2 0 0 9 ), 5 0 % of c h o n dr osarc o mas 
(A mar y, et al. 2 0 1 1 ), a n d 2 0 % of i ntra he p atic c h ol a n gi o carci n o mas (B or ger, et al. 2 0 1 2 ) a n d a 
s maller perce nta ge of e xtra-he p atic c h ola n gi ocarci n o mas (Ki p p, et al. 2 0 1 2 ). 
I D H 1 m utati o ns are rele v a nt t hera pe utic t ar gets i n c h ola n gi ocarci n o ma as t h e y m a y pla y a r ol e i n 
t he pat h o ge nesis of t he disease b y bl oc ki n g t he differe ntiati o n of li ver pr o ge nit or cells a n d 
pr o m oti n g cell ular pr oliferati o n (Sa ha, et al. 2 0 1 4 ). T he maj orit y of a v aila ble data s u g gest I D H 1 
m utati o ns are n ot ass ociate d wit h pr o g n osis i n c h ola n gi ocarci n o ma u nli ke I D H 1 m utati o ns i n 
gli o ma, w hic h are ass oci ate d wit h i m pr o ve d o utc o mes (G o yal, et al. 2 0 1 5 ). 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
2 5  
A gi os P har mace uticals, I nc.  
5. 2.  
O ver vie w of C h ol a n gi oc arci n o m a  
Base d o n t h e a vaila bl e i nci de nce d ata, w hic h c o m bi nes i ntra he patic c h ola n gi ocarci n o ma wit h 
ca ncers arisi n g i n t he he p at oc yt es, a p pr o xi matel y 6 0 0 0 patie nts wit h c h ola n gi ocarci n o ma ( 1 5 % 
of 3 9, 2 3 0) are dia g n ose d eac h year i n t he U S (AJ C C 2 0 1 0 ; Sie gel, et al. 2 0 1 6 ). T he e x pecte d 
i nci de nce of c h ola n gi oc arci n o ma i n t he E ur o pea n U ni o n ( E U) is 0. 8 4/ 1 0 0, 0 0 0 (R A R E C A R E 
2 0 1 6 ). 
T he ma na ge m e nt of t his disease i ncl u des m ulti -m o dalit y treat me nt: biliar y dec o m pressi o n, 
s ur ger y, ra diati on a n d ot her i nter ve nti o ns f or l o cal disease c o ntr ol, li ver tr a ns pla ntati o n, a n d 
c he m ot hera p y. I n t he a d v a nce d, n o nresecta ble setti n g, t he diseas e is i nc ura ble a n d palliati ve 
c he m ot hera p y is t he pri mar y treat me nt o pti o n. M o n ot hera p y a n d c o m bi nati o n c he m ot he ra p y 
a p pr oac h es wit h ge mcita bi ne - or 5 -fl o ur o uracil-base d re gi me ns are ofte n c o nsi dere d i n t his 
setti n g. I n t he A B C-0 2 trial, a st u d y i n patie nts wit h a d va nce d biliar y ca n cers i ncl u di n g 
c h ola n gi ocarci n o ma, t he c o m bi nati o n of ge mcita bi ne a n d cis plati n i m pr o ve d pr o gressi o n -free 
s ur vi val ( P F S) ( hazar d rati o [ H R]: 0. 6 3, 8. 0 vs. 5. 0 m o nt hs, P < 0. 0 0 1) a n d o verall s ur vi val ( H R: 
0. 6 4, 1 1. 7 vs. 8. 1  m o nt hs, P < 0. 0 0 1) c o m pare d t o ge mcita bi ne al o ne (Valle, et al. 2 0 1 0 ). T h us t he 
c o m bi nati o n of ge mcita bi ne a n d cis plati n is a sta n dar d o pti o n i n t he first -li ne setti n g f or patie nts 
wit h a d va nce d n o nresect a ble disease.  
Sec o n d -li ne c he m ot hera p y re gi me ns pr o d uce a n i n cre me ntall y s maller be nefit wit h a n a vera ge 
me dia n P F S of 2 t o 3 m o nt hs (Briea u, et al. 2 0 1 5 ; La m arca, et al. 2 0 1 4 ). H o we ver, des pite 
c urre nt treat me nt o pti o ns, pr o g n osis f or t his p o p ulati o n re mai ns p o or wit h 5 -year s ur vi val rates 
ra n gi n g fr o m 2 % t o 3 0 % (A C S 2 0 1 4 ). 
Gi ve n t he o verall p o or o utc o mes ass ociate d wit h c o nsec uti ve c h e m ot hera p y re gi me ns i n patie nts 
wit h c h ola n gi o carci n o ma, t here is a n ur ge nt nee d f or t he de vel o p me nt of n o vel tar gete d t hera pies 
f or patie nts wit h t his seri o us a n d life-t hreate ni n g disease. 
5. 3.  
A G -1 2 0  
5. 3. 1.  
O ver vie w  
A G -1 2 0 is a p ote nt a n d s electi ve i n hi bit or of t he I D H 1 m uta nt  pr otei n wit h n o si g nifica nt off -
tar get acti vit y o bser ve d. T he c o m p o u n d has bee n de m o nstrate d t o re d u ce 2-H G le vels b y > 9 5 %, 
t o re verse gr o wt h f act or-i n de pe n de nt gr o wt h i n vitr o, a n d t o i n d uce differe ntiati o n i n le u ke mia 
cell m o dels. Preli mi nar y cli nical d ata i n patie nts wit h a d va nce d h e mat ol o gi c mali g n a ncies 
har b ori n g a n I D H 1 m utati o n ( A G 1 2 0 -C -0 0 1) a n d wit h a d va nce d s oli d t u m ors har b ori n g a n I D H 1 
m utati o n ( A G 1 2 0 -C -0 0 2) ha ve s h o w n t he c o m p o u n d t o be well t olerate d at t otal dail y d oses u p 
t o 1 2 0 0 m g wit h cli nical acti vit y o bser ve d i n b ot h s oli d a n d li q ui d t u m ors. T he 5 0 0 m g d os e 
le vel of A G-1 2 0 was e x pa n de d a n d sel ecte d f or f ut ure st u dies base d o n t he a vaila ble 
p har mac o ki netic ( P K)/ p h ar mac o d y n a mic ( P D), safet y pr ofile, a n d preli mi nar y cli nical acti vit y 
o bser v e d.  
5. 3. 2.  
S u m m ar y of N o ncli nic al I nf or m ati o n  
Details of t he n o ncli nical de vel o p me nt pr o gra m f or A G -1 2 0 are pr o vi d e d i n t he I n v esti gat or’s 
Br oc h ure. A s u m mar y of t he ke y i nf or mati o n is pr o vi de d bel o w.  

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5. 3. 2. 1.  
P h ar m a c o ki netic Dr u g I nter acti o ns  
A G -1 2 0 is mai nl y met a b olize d  b y C Y P 3 A 4, wit h mi n or c o ntri b uti o ns fr o m C Y P 2 B 6 a n d 
C Y P 2 C 8. T heref ore, c o -a d mi nistrati o n wit h C Y P 3 A 4 i n hi bit ors or i n d ucers c o ul d ha ve a n effect 
o n t he P K of A G -1 2 0.  
A G -1 2 0 is a n i n d ucer of h u ma n C Y P 3 A 4 a n d ma y als o be a n i n d ucer of C Y P 2 B 6, C Y P 2 C 8, a n d 
C Y P 2 C 9. T heref ore, t h ere is a p ossi bilit y of P K dr u g -dr u g i nteracti o ns w he n A G -1 2 0 is c o -
a d mi nistere d wit h se nsiti ve s u bstrates of C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4/ 5.  
A G -1 2 0 is a wea k direct i n hi bit or of C Y P 2 C 8, C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5 wit h I C 5 0 
val ues > 5 0 μ M a n d s h o ws little or n o e vi de nce of direct i n hi biti o n of C Y P 1 A 2, C Y P 2 B 6, or 
C Y P 2 C 9. A G -1 2 0 s h o ws n o ti me - or meta b olis m -de pe n de nt i n hi biti o n of a n y of t he C Y P 
e nz y mes e v al uate d. T h e li keli h o o d of i n hi biti o n of C Y P e nz y m es b y A G -1 2 0 is, t heref ore,  
e xtre mel y l o w.  
A G -1 2 0 is a s u bstrate of P -gl yc o pr ot ei n ( P -g p) b ut n ot breast ca n cer resista nce pr otei n ( B C R P). 
H o we ver, c oa d mi nistrati o n of itrac o naz ole (a str o n g P -g p i n hi bit or) ha d n o effect o n t he 
ma xi m u m c o nce ntrati o n ( C ma x ) of A G-1 2 0 i n h u m a n s u bject s, s u g gesti n g t h e i n v ol ve me nt of 
i ntesti nal P-g p i n A G -1 2 0 dis p ositi o n i n vi v o is li kel y t o be mi ni mal. A G -1 2 0 is n ot a s u bstrate 
of O A T P 1 B 1 or O A T P 1 B 3 tra ns p ort ers.  
A G -1 2 0 d oes n ot i n hi bit P -g p, B C R P, O A T P 1 B 1, O A T P 1 B 3, O A T 1, a n d O C T 2 at cli nicall y 
rele va nt c o n ce ntr ati o ns. A G-1 2 0 a p p ears t o be a wea k i n hi bit or of O A T P 1 B 1 a n d O A T P 1 B 3, 
wit h I C 5 0 val ues of 9. 5 6 a n d 2 2. 8 μ M, res pecti vel y. A G -1 2 0 d oes n ot i n hi bit t he O A T 1 - a n d 
O C T 2 -me diate d u pta ke of t he pr o be s u bstrate (I C 5 0 >  6 5  μ M) b ut i n hi bits O A T 3 
(I C5 0 ~ 0. 3 2 2  μ M).  
5. 3. 2. 2.  
S afet y P h ar m ac ol o g y a n d T o xic ol o g y  
T he t o xicit y pr ofile of A G -1 2 0 has bee n e val u ate d i n vitr o i n t he bacterial re verse m utati o n assa y 
a n d i n viv o i n S pra g ue D a wle y rats a n d c y n o m ol g us m o n ke ys. T h e c o m p o u n d was n ot m uta ge nic 
a n d was w ell t olerate d at esti mate d efficaci o us e x p os ures wit h a p ote ntial 4 -f ol d t hera pe utic 
wi n d o w.  
S afety p h ar m ac ol o gy  
I n di vi d ual a ni mals wit h p ossi ble ( ≥3 0 msec) a n d pr o ba ble ( ≥6 0 mse c) test article -relate d Q T 
pr ol o n gati o n c orrecte d f or heart rate usi n g Bazett’s f or m ula ( Q T c B) (M or ga nr ot h 2 0 0 1 ) ha v e 
bee n n ote d i n b ot h t he 2 8 -da y a n d 3 -m o nt h G o o d La b orat or y Practice ( G L P) c y n o m ol g us 
m o n ke y st u dies at free C ma x  val ues ≥0. 7 -f ol d t he C 2 D 1 5 0 0 m g free C ma x  h u ma n e x p os ure 
( 5 0 0 m g is t he d ose s electe d f or t he e x pa nsi o n p hase of t he o n g oi n g P hase 1 cli nical trial, St u d y 
A G 1 2 0 -C -0 0 1). I n a d diti o n, pr ol o n ge d Q Tc B was o bser ve d at t he 4 5 a n d 1 3 5  m g/ k g d ose le vels 
i n a n o n-G L P si n gle d os e m o n ke y C V safet y p har mac ol o g y st u d y, i n w hic h gr o u p m ea n C ma x 
val ues were si milar t o t hat of i n di vi d ual a ni mals i n t he 2 8 -da y a n d 3 -m o nt h re peat -d ose st u dies.  
T oxic ol o gy  
I n G L P 2 8-da y re peat -d ose t o xic ol o g y st u dies, oral d oses of A G -1 2 0 a d mi nistere d t wice d ail y 
( BI D) at t he pr ojecte d h u ma n effic aci o us e x p os ure were well t olerate d b y b ot h rats a n d m o n ke ys. 
I n rats, si g nifica nt fi n di n gs at 1 0 0 m g/ k g/ da y were li mite d t o mi ni mal alterati o ns i n cli nical 
pat h ol o g y para meters, li ver a n d t h yr oi d fi n di n gs c o nsiste nt wit h a ut oi n d ucti o n of meta b olis m, 

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a n d s ple nic e xtra me d ullar y h e mat o p oiesis. I n m o n ke ys, si g nifica nt fi n di n gs at 3 0 m g/ k g / da y 
were li mite d t o gastr oi ntesti nal cli nical o bser vati o ns a n d s p ora dic e mesis. I n b ot h s pecies, all 
si g nifica nt effects at pr oj ecte d effic aci o us e x p os ures were re v ersi ble o ver t he 1 4 -da y rec o v er y 
peri o d.  
I n t he G L P 2 8-da y rat st u d y, d ose -li miti n g t o xicity ( D L T) occ urre d at a d os a ge of 
2 0 0 0  m g/ k g/ da y. At t his d ose le vel, si g nifi ca ntl y re d uce d e x p os ures were o bser ve d, fr o m 1 5 -f ol d 
t he pr ojecte d effic aci o us e x p os ure o n Da y 0 t o 5. 4- t o 7. 8-f ol d o n Da y 2 7, w hic h were c o nsiste nt 
wit h a ut oi n d ucti o n of meta b olis m. T he maj orit y of t he u nsc he d ule d deat hs occ urre d earl y i n t he 
st u d y, bet w ee n D a ys 2 a n d 6, s u g gesti n g t hat t hes e earl y m ort alities were b ei n g dri v e n b y t he 
hi g her e x p os ures. T he ca use of t his earl y D L T was m ultifact orial a n d i ncl u de d m o derate, 
bri d gi n g, ce ntril o b ular he pat ocell ular de ge nerati o n a n d necr osis wit h a d diti o nal c o ntri b uti n g 
fact ors bei n g t u b ular necr osis i n t he ki d ne y; c ortical a n d me d ullar y t u b ular vac u olati o n i n t he 
ki d ne y; atr o p h y of s mall i ntesti nes; h y p ocell ularit y, he m orr ha ge a n d necr osi s of t he fe m oral 
a n d/ or ster nal b o ne m arr o w; a n d er osi o ns of t he gla n d ular st o mac h. W he n D L T o cc urre d lat er i n 
t he d osi n g peri o d (t he mi n orit y of t he earl y m ort alit y), it was d ue t o m uc os al atr o p h y of t he 
i ntesti nes, er osi o ns a n d ulcerati o ns of t he gla n d ular st o mac h a n d/ or rect u m, a n d l y m p h oi d 
de pleti o n a n d necr osis i n l y m p h oi d or ga ns wit h re nal t u b ular necr osis bei n g a n a d diti o nal 
c o ntri b uti n g fact or. E x p os ures at t his ti me were li kel y cl oser t o t he Da y 2 7 e x p os ures. T he 
Da y  2 7 A G -1 2 0 area u n d er t he c o n ce n tr ati o n × ti me c ur ve fr o m 0 t o 1 2 h o urs ( A U C0 -1 2 hr) val ue 
f or t his d osa ge was 6 9 5 0 0 a n d 1 0 1 0 0 0 hr• n g/ m L, i n males a n d fe mal es, res pecti vel y, w hic h is 
1. 2 - a n d 1. 8-f ol d t he h u m a n A U C0 -1 0 hr, res pecti vel y. T he n e xt l o wer d ose le vel teste d i n rats ( 5 0 0 
m g/ k g/ da y) res ulte d i n a n A U C 0 -1 2 hr val ues of 3 0 1 0 0 a n d 5 9 0 0 0 hr• n g/ m L i n males a n d fe m ales, 
res pecti vel y, w hi c h is 0. 5- a n d 1-f ol d t he h u ma n A U C0 -1 0. N o earl y m ort alit y occ urre d a n d t his 
e x p os ure le vel was t olerate d. All si g nifica nt fi n di n gs at t his d ose le vel w ere re versi ble. 
I n t he G L P 3-m o nt h rat st u d y, A G -1 2 0 was w ell t olerate d at d os a ge le vels of 2 0, 1 0 0, a n d 5 0 0 
m g/ k g/ da y i n rats a n d res ulte d i n n o test article -rel ate d deat hs. T est article-relate d effects were 
q ualitati vel y si milar at 1 0 0 a n d 5 0 0  m g/ k g/ da y. M ost fi n di n gs ha d res ol ve d d uri n g t he 4 -wee k 
rec o ver y peri o d. At 5 0 0 m g/ k g/ da y, t he Da y 9 0 mea n plas ma A U C0 -1 2 hr val ues were 2 9 0 0 0 a n d 
6 2 0 0 0 n g• hr/ m L i n males a n d fe males, res pecti vel y ( 0. 5 - a n d 1. 1-f ol d t he h u ma n A U C0 -1 0 hr 
val ue), a n d at 1 0 0 m g/ k g / da y w ere 1 2 1 0 0 a n d 2 0 0 0 0, res pecti vel y ( 0. 2- a n d 0. 3 -f ol d t he h u ma n 
A U C 0 -1 0 hr val ue). At 5 0 0  m g/ k g/ da y, t he Da y 9 0 mea n plas ma C ma x  val ues were 4 6 5 0 a n d 
9 7 1 0  n g/ m L i n males a n d fe males, r es pecti vel y, a n d at 1 0 0  m g/ k g/ da y were 2 7 7 0 a n d 
5 6 6 0  n g/ m L, res p ecti vel y. T he Da y 9 0 mea n plas ma A U C 0 -1 2 hr val ues at 2 0 m g/ k g/ da y were 
6 8 8 0 a n d 7 0 9 0  n g• hr/ m L  i n males a n d fe mal es, res pecti vel y ( 0. 1-f ol d t he h u ma n A U C0 -1 0 hr 
val ue) , a n d t he Da y 9 0 m ea n plas ma C ma x  val ues were 1 3 2 0 a n d 1 5 8 0 n g/ m L, res pecti vel y. T h e 
fi n di n gs obser ve d i n t he 3 -m o nt h rat st u d y are lar gel y c o nsiste nt wit h t h ose n ote d at t olera bl e 
d oses i n t he 2 8 -da y st u d y wit h t he e x ce pti o n of t he n o vel fi n di n g of a hi g her p otassi u m fracti o nal 
uri ne e x creti o n.  
I n t he G L P 2 8-da y m o n k e y st u d y, D L T occ urre d i n male m o n ke ys at a n A U C 0 -1 2 hr val ue of 
2 3 5 0 0 0 (at a d ose of 2 7 0 m g/ k g/ da y), w hic h is 4. 1 -f ol d t he h u ma n A U C0 -1 0 hr val ue. T he ca us e of 
D L T was ge n eral mal aise c haracterize d b y p o or b o d y c o n diti o n a n d gastr oi ntesti nal cli nical si g ns 
lea di n g t o e mesis a n d sec o n dar y as pirati o n. I n fe m ales at t he sa me d os e le vel, A G -1 2 0 was 
t olerate d a n d t he Da y 2 7 A U C0 -1 2 hr val ue was 1 0 9 0 0 0 hr• n g/ m L, w hic h is 1. 9 -f ol d t he h u ma n 
A U C 0 -1 0 hr val ue. T he d osa ge of 2 7 0 m g/ k g/ da y was ass ociate d wit h si g nifi ca nt wei g ht l oss a n d 
m ori b u n dit y; hi g her t otal, direct, a n d i n direct bilir u bi n a n d tri gl yceri des; l o wer he m o gl o bi n a n d 

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he mat ocrit val ues; l o wer p h os p h or o us le vels; l o wer al b u mi n a n d t otal pr otei n; hi g her mea n 
s pecific gra vit y a n d l o wer t otal uri ne v ol u me; ve ntric ular bi ge mi n y; pr ol o n ge d Q Tc B  i n fe mal es; 
hi g her li ver wei g hts; a n d he pat ocell ular h y p ertr o p h y. All si g nifica nt fi n di n gs w ere re versi ble 
f oll o wi n g t he rec o v er y p eri o d, wit h t he e x ce pti o n of t he car di o vasc ular fi n di n gs, f or w hic h 
rec o ver y was n ot assesse d beca use t h e affect e d a ni mals were assi g ne d t o t h e pri mar y necr o ps y.  
I n t he G L P 3-m o nt h m o n ke y st u d y, A G -1 2 0 at d osa ge le vels of 3 0, 9 0, a n d 1 8 0  m g/ k g/ da y f or 
u p t o 9 2  c o nsec uti ve da ys was well t olerate d at all d osa ge le vels a n d res ulte d i n n o test 
article-relate d d eat hs. Test article-relate d effects i ncl u de d diarr h ea i n males at ≥3 0  m g/ k g/ da y 
a n d fe males at 1 8 0  m g/ k g/ da y, a n d he pat o cell ular h y pertr o p h y a n d hi g her li ver wei g hts at 
≥3 0  m g/ k g/ d a y. Li kel y test article -relate d pr ol o n gati o ns of Q Tc B were n ot e d i n i n di vi d ual 
a ni mals i n t he 9 0 a n d 1 8 0  m g/ k g/ da y d ose gr o u ps at free C ma x  e x p os ure mar gi ns ≥1. 3 -f ol d t hat of 
t he h u ma n 5 0 0 m g Cma x  val ue. All test article -relate d c ha n ges res ol ve d d uri n g t he rec o v er y 
peri o d. T he 1 8 0  m g/ k g/ da y d os e le vel w as ass ociate d wit h ge n d er c o m bi ne d Da y 9 0 mea n 
pl as ma C ma x  a n d A U C 0 -1 2 hr val ues of 1 4 8 0 0  n g/ m L a n d 1 3 4 0 0 0  n g• hr/ m L, res pecti vel y ( 2. 3-f ol d 
t he h u ma n A U C0 -1 0 hr val ue) . T he fi n di n gs o bser ve d i n t he 3-m o nt h m o n ke y st u d y are lar gel y 
c o nsiste nt wit h t h ose n ote d at t olera ble d os es i n t he 2 8 -da y st u d y.  
5. 3. 3.  
S u m m ar y of Cli nic al D at a  
T he A G -1 2 0 cli nical de v el o p me nt pr o gra m w as i nitiate d i n Marc h 2 0 1 4 wit h 2 P hase 1 d ose 
escalati o n st u dies, A G 1 2 0 -C -0 0 1 a n d A G 1 2 0 -C -0 0 2. Refer t o t he I n v esti gat or’s Br oc h ure f or 
f urt her det ails o n eac h of t hese st u dies. 
5. 3. 3. 1.  
St u d y A G 1 2 0 -C -0 0 2  
St u d y A G 1 2 0 -C -0 0 2 is e val uati n g t he s afet y, P K, P D bi o mar ker patter ns, a n d cli nical acti vit y of 
A G -1 2 0 i n s u bjects wit h a d va nce d s oli d t u m ors, i ncl u di n g c h ol a n gi ocarci n o ma, wit h a n I D H 1 
m utati o n. T he pri mar y o bjecti ves of t he st u d y are t o assess t he safet y  a n d t olera bilit y of 
treat me nt wit h A G-1 2 0 a d mi nistere d dail y as a si n gle a ge nt d ose d orall y i n s u bjects wit h 
a d va nce d s oli d t u m ors, i ncl u di n g gli o ma, a n d t o deter mi ne t he ma xi m u m t olerate d d ose(s) 
( M T D[s]) a n d/ or t he rec o m me n de d P hase 2 d ose(s) of A G-1 2 0 i n t his p o p ulati o n. T he i nitial 
d osi n g re gi me n was 1 0 0 m g BI D a n d d os es u p t o 1 2 0 0 m g o nce dail y ( Q D) were assesse d i n a 
3 + 3 d ose escalati o n desi g n; base d o n t he fa v ora bl e P K pr ofile s h o wi n g a l o n g eli mi nati o n half -
life (t½ ), BI D d osi n g was disc o nti n ue d after t he first c o h ort a n d a Q D d osi n g re gi me n was 
i m ple me nte d. T he st u d y is di vi de d i nt o a d ose escalati o n p hase, f oll o we d b y a n e x pa nsi o n p hase 
t o all o w f or a m ore r o b ust e val uati o n of t he safet y pr ofile a n d preli mi nar y assess me nt of cli nical 
acti vit y. T hi s st u d y is c urre ntl y o n g oi n g. 
As of 1 6 J a n uar y 2 0 1 6, 1 2 2 s u bjects wit h s oli d t u m ors ha ve bee n treat e d i n St u d y A G 1 2 0 -C -0 0 2; 
6 9 of t he 1 2 2 s u bjects re mai n o n treat me nt. T hirt y -s e ve n of t he s u bjects i n St u d y A G 1 2 0-C -0 0 2 
ha ve a pri mar y mali g na n c y of c h ola n gi o carci n o ma.  
Treat me nt wit h A G -1 2 0 has bee n w ell t olerate d; n o D L Ts h a ve b ee n re p ort e d. O verall, 
1 0 1  ( 8 3 %) of 1 2 2 s u bjects ha ve re p orte d treat me nt-e mer ge nt a d verse e v e nts ( T E A Es). T o d ate, 
t he m ost c o m m o nl y re p orte d a d verse e v e nts ( A Es) ha ve bee n na us ea ( 2 0 %), fati g ue ( 1 2 %), 
diarr hea, ( 1 1 %), pr ol o n ge d Q T i nter val ( 1 0 %), a n d v o miti n g ( 1 0 %). T h ere was n o e vi de nce f or 
a n i ncrease i n t he i nci de n ce of t hes e c o m m o nl y re p orte d e ve nts wit h d ose.  

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T w o deat hs wit hi n 3 0 da ys of st u d y treat me nt ter mi nati o n ha ve bee n re p or te d i n t he 4 0 0 m g d ose 
c o h ort. O ne w as d ue t o a ne mia a n d t he ot her occ urre d d ue t o ac ute res pirat or y fail ure. B ot h 
deat hs were assess e d as u nrelate d t o st u d y treat me nt.  
A t otal of 2 0 ( 1 6 %) of t he 1 2 2  s u bjects ha ve e x perie nce d s eri o us A Es ( S A Es). N o i n di vi dual 
S A E was re p ort e d i n m ore t ha n 1 s u bject, a n d n o ne of t hese S A Es w ere ass esse d t o be rel ate d t o 
A G -1 2 0. T he o nl y S A E e x perie nce d b y m ore t ha n o ne s u bject was h ea dac h e ( 2  s u bjects, 2 %); 
a d diti o nal S A Es were re p orte d i n 1 s u bject eac h. O nl y a n e ve nt of s u pra ve ntric ular e xtras yst oles 
was assesse d as p ossi bl y relate d t o st u d y treat me nt.  
Preli mi nar y a nal ysis of P K data at t he 1 0 0 m g BI D a n d, 3 0 0, 4 0 0, 5 0 0, 6 0 0, 8 0 0, 9 0 0, a n d 
1 2 0 0  m g Q D d os e le vels de m o nstrate d e x celle nt oral A G -1 2 0 e x p os ure t hat o n C ycle 1, D a y 1 5 
( C 1 D 1 5) a n d C ycle 2, Da y 1 ( C 2 D 1) was a b o ve t he pre dicte d effi caci o us e x p os ure of 1 2. 9 
hr• μ g/ m L t hat was ass o ci ate d wit h 9 7 % t u m or 2 -H G i n hi biti o n ( direct I D H 1 pat h wa y i n hi biti o n 
P D bi o mar ker) i n n o ncli nical m o dels; mea n t ½  was fr o m 3 8. 4 t o 8 6. 2 h o ur s, w hic h e na bles a Q D 
oral d osi n g s c he d ule.  
E val uati o n of 2 -H G as a direct i n hi biti o n of t he I D H 1 pat h wa y P D bi o mar ker res p o ns e f oll o wi n g 
A G -1 2 0 d osi n g i n t he 1 0 0 m g BI D a n d 3 0 0, 4 0 0, 5 0 0, 6 0 0, 8 0 0, 9 0 0, a n d 1 2 0 0  m g Q D d os e 
c o h orts de m o nstrate d s ustai ne d r e d ucti o n i n 2 -H G plas ma le vels ( u p t o 1 0 0 % i n hi biti o n) b y 
C 2 D 1 at all d ose le vels.  
As of 1 4 A pril 2 0 1 6, 4 8 s u bjects wit h c h ola n gi ocarci n o ma ha ve b ee n tr eate d, i ncl u di n g 2 4 
s u bjects i n t he d ose escalati o n p hase a n d 2 4 i n t he e x pa nsi o n p hase. At t he ti me of t he data 
c ut off, 2 3 of t he 4 8 s u bjects re mai n o n treat me nt a n d 2 5 ha ve disc o nti n ue d ( 1 9 d ue t o disease 
pr o gressi o n a n d 2 eac h d ue t o A E, wit h dra wal of c o nse nt, a n d ot her reas o ns). T he o verall safet y 
pr ofile of A G -1 2 0 re m ai ns c o nsiste nt wit h t hat re p orte d i n t he m ost rece nt I n v esti gat or’s 
Br oc h ure. Of t he 4 8 c h ol a n gi o carci n o ma s u bjects, 3 8 were e val ua ble f or t h e a nal ysis of efficac y 
(ie, ha d a b aseli ne t u m or meas ure me nt a n d at least 1 p ost-baseli ne res p o ns e assess me nt or 
disc o nti n ue d earlier). T hree s u bjects  ( 8 %) wit h c h ola n gi ocarci n o ma recei vi n g A G-1 2 0 ( 1 at 3 0 0 
m g a n d 2 at 5 0 0 m g) ha d a n o bjecti ve partial res p o nse, as defi n e d b y t he Res p o nse E val uati o n 
Criteria i n S oli d T u m ors ( R E CI S T) v 1. 1 ( A p pe n di x  1 5. 9 ). I n a d diti o n, 2 2 s u bjects ( 5 8 %) ha d 
sta ble disease ( S D), 1 1 s u bjects ( 2 9 %) e x perie nce d disease pr o gressi o n as best res p o nse. T w o 
s u bjects ( 8 %) were n ot assesse d f or res p o nse ( dis c o nti n ue d treat me nt pri or t o a res p o nse 
assess me nt). At t he 6 -m o nt h ti me p oi nt, 6 0 % of s u bjects were pr o gressi o n free ( P F S 6) as 
assesse d b y t he Ka pla n -Meier met h o d. As of t he data c ut off, t hr ee s u bjects re mai ne d o n st u d y 
dr u g > 1 year wit h a n o verall best res p o nse of S D.  
T here w ere n o d os e li miti n g t o xicities. Base d o n t he a vaila ble p har mac o ki netic data (s u g gesti n g 
less t ha n d ose pr o p orti o n al i ncreas e i n e x p os ure b e y o n d 5 0 0 m g a n d ma xi mal plas ma 2-H G 
s u p pressi o n at 5 0 0 m g) a n d f oll o wi n g re vie w of data fr o m t he d ose escalati o n p hase of t his 
st u d y, A G-1 2 0 5 0 0  m g Q D was deter mi ne d t o be a safe a n d p ot e ntiall y effecti ve d ose f or f urt her 
st u d y. 
5. 3. 3. 2.  
St u d y A G 1 2 0 -C -0 0 1  
St u d y A G 1 2 0 -C -0 0 1 is e val uati n g t he s afet y, P K, P D bi o mar ker patter ns, a n d cli nical acti vit y of 
A G -1 2 0 i n s u bjects wit h a d va nce d A M L a n d relat e d he mat ol o gic mali g n a n cies t hat har b or a n 
I D H 1 m utati o n. T he pri mar y o bj ecti ves of t he st u d y are t o ass ess t he safet y a n d t olera bilit y of 

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treat me nt wit h A G-1 2 0 a d mi nistere d dail y i n s u bj ects wit h a d va nce d he mat ol o gic mali g na ncie s, 
t o deter mi ne t he M T D a n d/ or t he rec o m me n d e d P hase 2 d ose of A G -1 2 0 i n t his p o p ulati o n, a n d 
t o assess t he preli mi nar y cli nical acti vit y of A G-1 2 0 i n s u bjects wit h rela ps e d or refract or y A M L 
wit h a n I D H 1 m utati o n. T he i nitial d osi n g re gi me n was BI D; base d  o n t he fa v ora bl e P K pr ofile 
s h o wi n g a l o n g t ½ , BI D d osi n g was disc o nti n ue d after t he first c o h ort a n d a Q D d osi n g re gi me n 
was i m ple me nte d. Li ke t he A G 1 2 0 -C -0 0 2 st u d y, t his st u d y is di vi de d i nt o a d ose escalati o n 
p hase, f oll o we d b y a n e x pa nsi o n p hase t o al l o w f or a m ore r o b ust e val uati o n of t he safet y pr ofile 
a n d preli mi nar y ass ess me nt of cli nical acti vit y. T his st u d y is c urre ntl y o n g oi n g. A s u m mar y of 
t he data fr o m t his st u d y is pr o vi de d i n t he I n vesti gat or’s Br oc h ure f or A G-1 2 0.  
5. 4.  
I de ntifie d Ris ks of A G-1 2 0  
Cli nical safet y d ata f or A G -1 2 0 are descri be d i n Secti o n  5. 3. 3 . T he o nl y e x pecte d ris k of 
treat me nt wit h A G-1 2 0 i n patie nts wit h s oli d t u m ors, as de taile d i n t he I n v esti gat or’s Br oc h ure, 
is pr ol o n ge d Q T i nter val. Patie nts ma y be at i ncrease d ris k f or de vel o p me nt of Q T pr ol o n gati o n 
w he n treat e d wit h A G ‐1 2 0 i n c o m bi nati o n wit h fl u or o q ui n ol o nes, az ole a ntif u n gal a ge nts, or 
ser ot o ni n ( 5‐H T 3) a nta g o nists. I n vesti gat ors nee d t o be vi gila nt; refrai n fr o m a d mi nisteri n g 
c o nc o mita nt me dicati o ns ass ociate d wit h Q T pr ol o n gati o n a n d if n o ot h er t hera pe utic o pti o ns are 
a vaila ble, m o nit or patie nts recei vi n g A G ‐1 2 0 wit h t he c o m bi nati o n of t hese dr u gs, a n d e val u ate 
electr ocar di o gra m ( E C G) a n d electr ol ytes (i ncl u di n g p otassi u m, ma g nesi u m, a n d calci u m) 
partic ularl y i n patie nts pr ese nti n g wit h na usea, v o miti n g, or diarr hea. F or m ore i nf or mati o n, see 
Secti o n  9. 9 . 
Refer t o t he A G -1 2 0 I n v esti gat or’s Br oc h ure f or t he f ull details re gar di n g t he ris ks of A G -1 2 0 
t hera p y. 
5. 5.  
St u d y R ati o n ale  
A G -1 2 0 is a n o vel, first -i n-class c o m p o u n d tar gete d selecti vel y t o i n hi bit t he m utate d I D H 1 
e nz y me. S mall m olec ule i n hi biti o n of t he m uta nt I D H e nz y me re prese nts a n o vel, tar gete d 
a p pr oac h t o ca ncer treat me nt. Direct i n hi biti o n of t he gai n -of -f u ncti o n acti vit y of t he I D H 1 
m utate d pr otei n is i nte n de d t o i n hi bit t he pr o d ucti o n of t he o nc o ge nic m e ta b olite 2-H G. A G -1 2 0 
has bee n e xte nsi vel y e val uate d i n n o ncli nical st u dies a n d has bee n s h o w n i n vitr o a n d i n viv o t o 
effecti vel y i n hi bit t he gai n -of -f u ncti o n acti vit y of t he m utate d pr otei n lea di n g t o > 9 5 % i n hi biti o n 
of t he pr o d ucti o n of t he p ote ntial o nc o meta b olite 2 -H G. I n cli nical st u dies, u p t o 9 8 % i n hi biti o n 
of plas ma 2 -H G h as bee n o bser ve d i n s u bjects wit h s oli d t u m ors after Q D d osi n g of A G -1 2 0.  
T he preli mi nar y P hase 1 cli nical data (fr o m 1 4 A pril 2 0 1 6) wit h A G -1 2 0 i n t he p o p ulati o n of 
s u bjects wit h pre vi o usl y treate d I D H 1 m uta nt c h ola n gi ocarci n o ma h a ve s h o w n t he c o m p o u n d t o 
be well t olerate d wit h e vi de nce of cl i nicall y mea ni n gf ul acti vit y i ncl u di n g p artial res p o nses 
( R E CI S T v 1. 1) a n d d ura ble disease c o ntr ol wit h 6 0 % of s u bjects pr o gressi o n free at 6 m o nt hs 
( P F S 6). Base d o n t he s u p p orti ve effic ac y a n d safet y dat a (see Secti o n 5. 3. 3. 1 ), A G-1 2 0 ma y 
ser ve as a n o vel m olec ul arl y t ar get e d treat me nt o pti o n f or patie nts wit h pre vi o usl y treate d I D H 1 
m utate d c h ola n gi ocarci n o ma.  
St u d y A G 1 2 0 -C -0 0 5 is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y desi g n e d t o 
de m o nstrate t he efficac y a n d safet y of A G -1 2 0 i n s u bjects wit h a hist ol o gicall y -c o nfir me d 
dia g n osis of I D H 1 ge n e -m utate d c h ola n gi ocarci n o ma c o m pare d t o place b o. Patie nts eli gi ble f or 
t he st u d y are t h ose w ho h a ve diseas e pr o gressi o n f oll o wi n g at least 1 b ut n o m ore t ha n 2 pri or 

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treat me nt re gi me ns i n t he a d va nce d setti n g, i ncl u di n g 1 ge m cita bi ne or 5-fl ur o uracil ( 5-F U) -
c o ntai ni n g re gi me n, a n d w h o are n ot eli gi ble f or c urati ve res ecti o n, tra ns pl a ntati o n, or a b lati ve 
t hera pies. 
T here are n o sta n d ar d treat me nt o pti o ns f or patie nts w h o ha ve pr o gresse d o n a ge mcita bi ne - or 5 -
F U -b ase d c h e m ot hera p y re gi me n a n d palliati ve care is ofte nti mes i nstit ute d, t h us a place b o 
c o ntr ol is acce pta ble. T h e st u d y all o ws f or s u bject s i n t he place b o ar m t o cr oss o ver t o t he 
A G -1 2 0 ar m u p o n d o c u me nte d disease pr o gressi o n as l o n g as t he y meet eli gi bilit y criteri a 
deter mi ne d i n t he E O T Visit. Cr oss o ver s u bjects will f oll o w t he sa me assess me nt sc he d ule as 
fr o m C 1 D 1. 

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6.  
T RI A L O B J E C TI V E S A N D  E N D P OI N T S  
6. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bje cti ve of t he st u d y is:  
 T o de m o nstrate t he effic ac y of A G -1 2 0 bas e d o n P F S per I n de p e n de nt Ra di ol o g y 
Ce nter (I R C) ass ess me nt c o m pare d t o place b o i n s u bjects wit h n o nresect a ble or 
metastatic c h ola n gi oc arci n o ma wit h  a n I D H 1 m utati o n.  
6. 2.  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are:  
 T o e val uate t he s afet y a n d t olera bilit y of A G -1 2 0 c o m pare d t o place b o.  
 T o e val uate P F S per I n vesti gat or ass ess me nt.  
 T o c o m pare t h e efficac y of A G -1 2 0 wit h place b o base d o n o verall s ur vi val ( O S), 
o bjecti ve res p o nse rate ( O R R), d urati o n of res p o nse ( D O R), a n d ti me t o res p o nse 
( T T R), wit h res p o nse assesse d per I n vesti gat or a n d b y t he I R C. 
 T o e val uate h ealt h -relate d q ualit y of life ( H R Q O L) wit h A G-1 2 0 c o m pare d t o 
place b o as asses se d b y t h e E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of 
Ca ncer Q u alit y of Life Q uesti o n naires ( E O R T C -Q L Q -C 3 0 a n d E O R T C -Q L Q -
BI L 2 1 ), t h e Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI -C), a n d t he Patie nt Gl o bal 
I m pr essi o n of Se verit y ( P GI-S) . 
 T o e val uate h e alt h ec o n o mic o utc o mes as assesse d b y t he 5 -le vel E ur o Q ol fi ve 
di me nsi o ns q uesti o n naire  ( E Q-5 D -5 L).  
 T o e val uate t he P K of A G -1 2 0.  
 T o e val uate t he P K/ P D relati o ns hi p of A G -1 2 0 a n d 2 -H G i n bl o o d sa m ples.  
6. 3.  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti v es of t he st u d y are: 
 T o e val uate, f or t he s u b gr o u p of place b o s u bjects w h o ha ve cr osse d o ver t o t he 
A G -1 2 0 ar m, t he ti me fr o m first d ose of A G -1 2 0 t o sec o n d d oc u me nte d pr o gressi o n 
o n A G -1 2 0 or deat h, w hi c he ver occ urs first ( P F S 2).  
 T o c orrel ate bas eli ne m olec ular  a n d/ or pr otei n c h aracteristics i n t u m or tiss ues wit h 
cli nical res p o nse.  
 T o c orrel ate bas eli ne 2 -H G le vels i n plas ma sa m ples wit h cli nical res p o nse.  
 T o e val uate le v els of m uta nt I D H 1 a n d ot h er ge n es i n circ ulati n g t u m or D N A 
o btai ne d fr o m plas ma at baseli ne  a n d o ver t he c o urse of t he tr eat me nt.  
 T o c orrel ate a n y P K vari ati o ns wit h dr u g -met a b olizi n g e nz y me ( D M E) rel ate d ge nes, 
if t he data are w arra nte d. 

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 T o e x pl ore a d diti o nal bi o mar kers i n bl o o d f or m or p h ol o gic, f u n cti o nal, bi ol o gic, 
e pi ge netic, a n d m eta b olic c ha n ges o ver t he c o urse of treat me nt.  
6. 4.  
St u d y E n d p oi nts  
6. 4. 1.  
Pri m ar y E n d p oi nt  
 T he pri mar y e n d p oi nt is P F S, defi ne d as t he ti me fr o m date of ra n d o mizati o n t o date 
of first d oc u me nte d disease pr o gressi o n (as assess e d b y t h e I R C per R E CI S T v 1. 1), or 
date of deat h d ue  t o a n y ca use. 
6. 4. 2.  
Sec o n d ar y E n d p oi nts  
 A Es, S A Es, A Es lea di n g t o disc o nti n uati o n or deat h. T he se verit y of A Es will be 
assesse d b y t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteri a f or A d verse 
E ve nts ( N CI C T C A E), v ersi o n 4. 0 3.  
 Safet y l a b orat or y p ara meters, vital si g ns, 1 2 -lea d E C Gs, e val uati o n of left ve ntric ular 
ejecti o n fracti o n ( L V E F), Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
perf or ma n ce stat us ( P S), a n d c o nc o mita nt me dicati o ns.  
 Sec o n dar y effic ac y e n d p oi nts i ncl u de:  
o  O S, defi ne d as t he ti me fr o m date of ra n d o mizati o n t o date of deat h.  
o  O R R, defi ne d as t he pr o p orti o n of s u bjects wit h a best o verall res p o ns e defi ne d as 
C R or P R, as assesse d b y t he I n v esti gat or a n d b y t he I R C p er R E CI S T v 1. 1.  
o  D O R, defi ne d as t h e ti me fr o m date of first d oc u m e nte d c o m plete res p o nse ( C R) 
or partial res p o ns e ( P R) t o date of first d oc u m e nte d disease pr o gressi o n or deat h 
d ue t o a n y ca us e, as ass esse d b y t he I n vesti gat or a n d b y t he I R C per R E CI S T 
v 1. 1.  
o  T T R, defi ne d as t he ti me fr o m date of ra n d o mizati o n t o date of first d oc u m e nte d 
C R or P R f or res p o n ders, as assesse d b y t he I n vesti gat or a n d b y t he I R C per 
R E CI S T v 1. 1.  
o  P F S as deter mi ne d b y t he I n v esti gat or.  
 H R Q O L as assess e d b y v ali date d i nstr u me nts ( E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -
BI L 2 1, P GI -C, a n d P GI -S) (E O R T C 1 9 9 5 ; Frie n d, et al. 2 0 1 1 ). 
 Healt h ec o n o mic o ut c o mes as assesse d b y t h e E Q -5 D -5 L i nstr u me nt (Sze n de 2 0 1 4 ). 
 Serial or s pars e bl o o d sa m pli n g at s pecifi e d ti me p oi nts f or deter mi nati o n of plas ma 
c o nce ntr ati o n -ti me pr ofiles a n d P K para meters of A G-1 2 0.  
 Bl o o d sa m pli n g at s pecifie d ti me p oi nts f or deter mi nati o n of 2 -H G le vels t o 
c haracteriz e t he P D effects of A G -1 2 0.  
6. 4. 3.  
E x pl or at or y E n d p oi nts  
 Baseli ne m olec ular a n d pr otei n pr ofili n g usi n g ba n ke d or fres h t u m or sa m ples . 

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 E val uati o n of m uta nt I D H 1 le vels a n d ot her ge nes i n circ ulati n g t u m or D N A usi n g 
serial plas ma sa m ples. 
 Serial bl o o d a n d/ or plas ma sa m ples f or m or p h ol o gic, f u n cti o nal, e pi ge n etic,  bi ol o gic, 
a n d meta b olic pr ofili n g.  
 C orrelati o n of ger mli ne D N A dr u g meta b olis m, cleara n ce relate d ge n e 
p ol y m or p his ms wit h P K varia nce, safet y, a n d/ or efficac y usi n g b u ccal s w a b ger mli ne 
D N A sa m ples, if t he d ata are warra nte d.  

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7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n  
T his is a P hase 3, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d efficac y a n d s afet y 
st u d y of orall y a d mi nistere d A G-1 2 0 i n s u bjects wit h a d va nce d c h ola n gi o carci n o ma 
( n o nresecta ble or m etastatic). S u bjects, all pers o n n el i n v ol ve d in t he e val uati o n of s u bjects’ 
res p o nse t o treat me nt (e g, I n v esti gat ors, st u d y c o or di nat ors, st u d y p h ar macists), a n d desi g n ate d 
S p o ns or tea m me m bers will be bli n de d t o st u d y treat me nt u ntil d oc u me nte d disease pr o gressi o n . 
S u bjects are re q uire d t o h a ve a his t ol o gi call y c o nsiste nt dia g n osis of I D H 1 ge n e-m utate d 
c h ola n gi ocarci n o ma t hat is n ot eli gi ble f or c urati v e resecti o n, tra ns pla ntati o n, or a blati ve 
t hera pies. S u bjects m ust ha ve d oc u me nt e d pr o gressi o n of disease a n d h a ve recei v e d treat me nt 
wit h at least 1  b ut n ot m ore t ha n 2 pri or treat me nt re gi me ns  f or a d va nce d disease ( n o nresecta ble 
or metastatic) . At le ast 1 of t he pri or re gi me ns m ust ha ve i ncl u de d ge mcita bi ne or 5-F U. 
S yste mic a dj u va nt c h e m ot hera p y will be c o nsi dere d a li ne of treat me nt if  t here is d oc u me nt e d 
disease pr o gressi o n d uri n g or wit hi n 6 m o nt hs of c o m pleti n g t he t hera p y, wit h S p o ns or a p pr o val.  
A t otal of a p pr o xi matel y 1 8 6 s u bjects will be ra n d o mize d i n a 2: 1 rati o t o t he A G -1 2 0 a n d 
place b o ar ms, res pecti vel y, stratifie d b y n u m b er of pri or t hera p ies ( 1 vs. 2). T he e nr oll me nt 
d urati o n will be a p pr o xi matel y 2 6 m o nt hs, ass u mi n g a n i nitial 5 s u bjects p er m o nt h e nr oll me nt 
rate f or t h e first 6 m o nt hs a n d 8 s u bjects per m o nt h t hereafter. T h e pri mar y a nal ysis of P F S will 
occ ur o nce 1 3 1 P F S e v e nts ha ve bee n d eter mi ne d b y I n v esti gat or assess me nt (a p pr o xi matel y 6 
m o nt hs after t he last s u bject is ra n d o mize d). O S will be a nal yze d t wice, o nce at t he ti me of P F S 
pri mar y a nal ysis a n d o n ce at t he occ urre nce of 1 5 0 O S e ve nts (a p pr o xi matel y 2 4 m o nt hs aft er 
t he last su bject is ra n d o miz e d).  
A n i n de pe n de nt dat a m o nit ori n g c o m mittee (I D M C) will re vie w t he safet y data o n a re g ular 
basis t o e ns ure t he safet y of treat me nt a n d pr o per c o n d uct of t he st u d y. T he first i nteri m safet y 
re vie w me eti n g will be c o n d ucte d w he n a p pr o xi matel y 2 0 s u bjects ha ve c o m plete d 2 c ycles of 
t hera p y or ha ve disc o nti n ue d earlier; t hereafter, meeti n gs will be c o n d ucte d e ver y 3-6  m o nt hs or 
o n a n a d h oc b asis. N o f or mal i nteri m a nal ysis f or efficac y will be c o n d u cte d bef ore t h e pri mar y 
a nal ysis.  
Eac h s ubject’s c o urse of treat me nt will be c o m prise d of t he f oll o wi n g peri o ds:  
Pre -Scree ni n g Peri o d ( O pti o n al) : A ba n ke d t u m or sa m ple (t he m ost rece nt o ne a vaila ble, 
prefera bl y c ollecte d wit hi n t he last 3 years) or fres h t u m or bi o ps y is re q uire d f or c o nfir m ati o n of 
I D H 1 ge n e m utati o n stat us b y ce ntral la b orat or y t esti n g, as p art of t he s u bj ect’s eli gi bilit y f or 
e nr oll me nt  ( R 1 3 2 C/ L/ G/ H/ S m utati o n varia nts teste d). P ote ntial s u bjects will si g n a 
pre -scree ni n g c o nse nt f or t he p ur p ose of deter mi ni n g I D H 1 m uta nt stat us. ( P ote ntial s u bjects 
w h o d o n ot pr o vi de a sa m ple at pre -scree ni n g will pr o vi de o ne at Scree ni n g.) 
Pre -Tre at me nt/ Scree ni n g Peri o d : F oll o wi n g i nf or me d c o nse nt, all s u bjects will u n der g o 
Scree ni n g pr oce d ures t o deter mi ne eli gi bilit y wit hi n 2 8 da ys pri or t o t he start of st u d y tr eat me nt 
o n C ycle 1, Da y  1 ( C 1 D 1),  wit h t he e x ce pti o n of baseli ne ra di o gra p hic sca ns, w hic h s h o ul d be 
perf or me d wit hi n 2 1 da ys pri or t o C 1 D 1 . If a t u m or sa m ple is n ot c ollecte d d uri n g t he pre-
scree ni n g p eri o d, a ba n k e d or fres h bi o ps y at Scree ni n g will be c ollecte d. A d diti o nal Scree ni n g 
pr oce d ures i ncl u de re vie w of e ntr y criteria, rec or di n g of de m o gra p hics a n d disease hist or y, 
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(c o m p ute d t o m o gra p h y [ C T] or ma g netic res o na n ce i ma gi n g [ M RI]), c o m plete p h ysic al 
e x a mi nati o n (i ncl u di n g hei g ht/ wei g ht), vital si g ns, E C O G P S, 1 2 -lea d E C G, ec h ocar di o gra p h y 
( E C H O) ( or ot h er met h o ds acc or di n g t o i nstit uti o nal practice) f or L V E F (acc or di n g t o 
i nstit uti o nal sta n dar d of care), a b uccal s wa b f or ger m-li ne m utati o n a n d D M E relate d ge n e 
p ol y m or p his m a nal ysis, plas ma sa m ple f or circ ul ati n g t u m or D N A, cli nical la b orat or y 
assess me nts ( he mat ol o g y, ser u m c he mistr y, c o a g ulati o n, uri nal ysis, a n d ser u m pre g n a nc y test), 
a n d bl o o d sa m ples f or e x pl orat or y bi o mar ker meas ure me nt.  
Tre at me nt Peri o d a n d E n d of Tre at me nt Visit : S u bjects w h o meet all st u d y eli gi bilit y criteria 
will be ra n d o ml y assi g n e d i n a 2: 1 rati o t o recei ve A G -1 2 0 orall y at a d ose of 5 0 0 m g Q D or 
A G -1 2 0 -matc h e d oral place b o Q D. Ra n d o mizati o n will be stratifie d b y n u m ber of pri or s yste mic 
t hera pies ( 1 vs 2). Dail y st u d y treat me nt will be gi n o n C 1 D 1. C ycles are 2 8 da ys ( +/-2 d a ys) i n 
d urati o n a n d d osi n g is c o nti n u o us. All s u bjects will c o nti n ue t o recei v e best s u p p orti ve care 
acc or di n g t o i nstit uti o nal practice t hr o u g h o ut t he st u d y, re gar dless of treat m e nt ar m. St u d y visits 
will be c o n d ucte d e v er y ot her wee k d uri n g C ycl es 1 -3 ( Da ys 1 a n d 1 5), a n d Da y 1 of eac h c ycle 
t hereafter. A n E n d of Treat me nt ( E O T) Visit will be perf or me d o n t he last da y of st u d y treat me nt 
( wit hi n 5 t o 3 3 da ys of last d ose, t o acc o m m o date f or p ote ntial d osi n g d ela ys of u p t o 2 8 da ys). 
Ra di o gra p hic assess me nt ( C T or M RI) f or e val uati o n of disease res p o nse will be c o n d ucte d 
e ver y 6 w ee ks ( ± 5 d a ys) f or t he first 8 ass ess me nts (ie, t hr o u g h wee k 4 8) a n d e ver y 8 wee ks 
( ± 5 da ys) t hereaft er fr o m C 1 D 1, i n de pe n de nt of d ose dela ys a n d/ or d os e i nterr u pti o ns, a n d/ or at 
a n y ti me w h e n pr o gressi o n of disease is s us pect e d. F or s u bjects w h o disc o nti n ue st u d y 
dr u g/ place b o f or reas o ns ot her t ha n disease pr o gressi o n or start of a n ot her a ntica ncer a ge nt, a n 
assess me nt will be c o n d u cte d at t he E O T Visit. U p o n re q uest b y t he I n v esti gat or, t h e s u bjects 
a n d site staff will be u n bli n de d t o treat me nt assi g n me nt after d oc u m e nte d disease pr o gressi o n (as 
assesse d b y t he I n v esti gat or) i n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or, a n d s u bjects 
ra n d o mize d t o t he place b o ar m w h o c o nti n ue t o m eet eli gi bilit y criteri a det er mi ne d i n t he E O T 
visit will be gi ve n t he o p p ort u nit y t o cr oss o ver t o t he acti ve treat me nt ar m a n d recei ve A G -1 2 0. 
F or t h ose s u bjects w h o cr oss o ver, place b o will n ot be c o u nte d as a pri or li ne of t hera p y f or t he 
p ur p ose of eli gi bilit y. If s u bjects cr oss o ver, t he y will start a gai n wit h st u d y pr oce d ures as at 
C 1 D 1. T hese s u bjects will c o nti n ue t o be e val uate d f or t u m or res p o nse b y t he I n vesti gat or. If t he 
treat me nt assi g n me nt is deter mi ne d t o be A G-1 2 0 u p o n ra di o gra p hic diseas e pr o gressi o n, t he 
I n v esti gat or ma y c o nsi der c o nti n ui n g tr eat me nt wit h A G-1 2 0, pr o vi de d  t he s u bject is cli nicall y 
be nefitti n g a n d t here is n o c o ntrai n dicati o n t o c o nti n ui n g treat me nt be y o n d pr o gressi o n (see 
Secti o n  9. 8  f or para meters f or treati n g be y o n d pr o gressi o n). Tar get a n d n o n-tar get lesi o n 
selecti o n a n d o bjecti ve t u m or res p o nse ass ess me nts per Res p o nse E val u ati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v 1. 1 will be perf or me d b y t h e i nstit uti o nal ra di ol o gist(s). A n i n de pe n d e nt 
ce ntral r e vie w of res p o ns e will be c o n d ucte d b y a n I n d e pe n de nt Ra di ol o g y Ce nter (I R C) per 
R E CI S T v 1. 1.  All sca ns will be se nt t o t he I R C as detaile d i n t he site -s pecific I ma gi n g C ore 
Ma n ual (see S ecti o n  1 0. 7. 2 ). 
H R Q O L assess me nts will be c o n d ucte d pre -d ose o n C 1 D 1 a n d o n Da y  1 of e ver y c ycle 
t hereafter u ntil E O T. Aft er E O T visit, t he H R Q O L will be c o n d u cte d e v er y 1 2 wee ks u ntil t he 
start of ne w a ntica ncer t h era p y. O n e a d diti o nal H R Q O L assess me nt will als o be c o n d ucte d at t he 
safet y f oll o w-u p visit. Healt h ec o n o mic o utc o mes assess me nts will occ ur pre -d ose o n C 1 D 1,  
C 3 D 1,  a n d at t he E O T Visit. C o m plia nce assess me nts will occ ur at C 1 D 1 5, Da y 1 of e v er y c ycle 

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t hereafter, a n d at t he E O T Visit. If s u bjects cr oss o ver, t he y will f oll o w t he sa me assess me nt 
sche d ule  as fr o m C 1 D 1 . 
S u bjects will be assesse d at e ver y visit f or A Es a n d c o nc o mita nt me dicati o ns, starti n g fr o m t he 
first d ose of st u d y treat m e nt. T o xicit y se v erit y will be gra de d acc or di n g t o t he N CI C T C A E 
versi o n 4. 0 3. He mat ol o g y a n d s er u m c h e mistr y wil l be assesse d o n Da ys 1 a n d 1 5 of C ycles 1-3, 
o n Da y 1 of eac h tr eat me nt c ycl e t hereafter, a n d at t he E O T Visit. Li mite d p h ysical e x a mi nati o ns 
a n d vital si g ns assess me nts will be perf or me d o n Da y 1 of eac h c ycle, wit h a c o m plete p h ysical 
e x a mi nati o n a n d vi tal si g ns c o n d ucte d at t he E O T Visit; vital si g ns will als o be assesse d o n 
C 1 D 1 5 a n d C 2 D 1 5. Uri n al ysis a n d c oa g ulati o n testi n g will o nl y be p erf or me d at Scree ni n g. 
E C O G P S will be assesse d o n C 1 D 1, Da y 1 of eac h treat me nt c ycl e t hereaft er, a n d at t he E O T 
V isit. E C Gs will be o btai ne d pre-d os e o n C 1 D 1 a n d C 2 D 1, 2 h o urs p ost -d ose o n C 1 D 1, C 1 D 1 5, 
a n d C 2 D 1, a n yti me o n Da y 1 of s u bse q ue nt c ycles, a n d at t he E O T Visit. E c h ocar di o gra p h y ( or 
ot her met h o ds acc or di n g t o i nstit uti o nal practice)  t o assess L V E F will be perf or me d (acc or di n g 
t o i nstit uti o nal sta n dar d of care) o nl y if cli nicall y i n dicate d. 
Bl o o d sa m ples f or P K/ P D assess me nts will be dra w n o ver a 4 -h o ur p eri o d o n C 1 D 1 a n d C 2 D 1. 
A d diti o nal bl o o d sa m ples f or P K/ P D assess me nts will be dra w n at 2 h o urs ( ± 1 0 mi n ut es) p ost 
d ose o n C 1 D 1 5, pre -d os e ( wit hi n 3 0 mi n utes) o n C 3 D 1 a n d Da y 1 of eac h treat me nt c ycl e 
t hereafter, a n d at a n y ti me d uri n g t h e E O T Visit. 
Bl o o d a n d plas ma sa m pl es will be o btai ne d f or e x pl orat or y bi o mar kers a n d c orrel ati ve st u dies at 
Scree ni n g, C 1 D 1 5 ( plas ma o nl y), Da y 1 of e ver y c ycle t hereafter, a n d at t he E O T Visit.  
S u bjects ma y c o nti n ue wit h t heir assi g ne d st u d y tr eat me nt u ntil disease pr o gressi o n, 
de vel o p me nt of u nacce pt a ble t o xicit y, c o nfir me d pre g na nc y, d eat h, wit h dra wal of c o ns e nt, t he 
s u bject is l ost t o f oll o w-u p, or t he S p o ns or u n bli n ds or  e n ds t he st u d y, w hic he ver occ urs first. 
S u bjects w h o are d eter mi ne d t o be o n A G -1 2 0 u p o n st u d y u n bli n di n g ma y c o nti n ue o n A G -1 2 0. 
F or s u bjects w h o are d eter mi ne d t o be o n A G -1 2 0 u p o n ra di o gra p hic diseas e p r o gressi o n a n d 
ha ve de m o nstrat e d cli nic al be nefit, Pri nci pal I n v esti gat ors ( PIs), wit h c o ns ult fr o m t he S p o ns or, 
ma y k ee p t he s u bjects o n A G -1 2 0 aft er t he dise ase pr o gressi o n.  ( See Secti o n  9. 6  f or a d diti o nal 
u n bli n di n g sce nari os. ) 
Pri m ar y E n d p oi nt Res ults a n d S u bse q ue nt St u d y U n bli n di n g:  O nce t he pri mar y e n d p oi nt of 
P F S ( base d o n ce ntral r a di ol o g y R E CI S T 1. 1 assess me nt) is statisti call y a n al yze d, t he S p o ns or 
will c o m m u nicate t he t o pli ne a g gre gat e res ults of t he st u d y via p u blic discl os ure, w hic h will 
i ncl u de partici pati n g st u d y te a ms. S h ortl y aft er p u blic discl os ure of t he t o pli ne a g gre gate res ults, 
t he S p o ns or will c o m m u nicate t o all sites t hat treat me nt assi g n me nts of all s u bjects will be 
u n bli n de d a n d will als o i nf or m sites w hic h of t he 2  f oll o wi n g sce nari os t o p urs ue f oll o wi n g 
u n bli n di n g.  
If t he pri mar y e n d p oi nt is statisticall y p ositi ve, all o n g oi n g s u bjects ( A G-1 2 0 a n d 
place b o -tr eat me nt assi g n e d s u bjects) will be gi ve n t he o p p ort u nit y  t o recei v e o pe n-la bel A G-1 2 0 
f oll o wi n g u n bli n di n g. U n bli n di n g will n o l o n ger be c o nti n ge nt u p o n d oc u m e nte d ra di o gra p hic 
disease pr o gressi o n. S u bjects w h o were alr ea d y recei vi n g A G -1 2 0 ma y c o nti n ue t o recei ve 
A G -1 2 0 o n t he sa me assess me nt sc he d ule. S u bjects w h o were recei vi n g place b o a n d c o nti n ue t o 
meet cr oss -o v er eli gi bilit y criteria will be gi ve n t h e o p p ort u nit y t o r ecei v e o pe n -la bel A G-1 2 0. 
F or s u bjects w h o cr oss o ver, place b o will n ot be c o u nte d  as a pri or li ne of t hera p y f or t he 
p ur p ose of eli gi bilit y. If s u bjects cr oss o ver, t he y will f oll o w t he sa me assess me nt sc he d ule as 

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fr o m C 1 D 1. Pri or t o cr ossi n g o ver, t h ese s u bjects will u n der g o a C T or M RI t hat will ser ve as t he 
ne w baseli ne a gai nst w hi c h all s u bse q ue nt R E CI S T v 1. 1 assess me nts will be perf or me d. If t h e 
s u bject has u n der g o n e a rece nt C T or M RI ( ≤3 wee ks pri or t o start of cr oss -o ver treat me nt), t he 
sca n d oes n ot nee d t o be re peat e d. Palliati ve ra di ot hera p y t o treat s y m pt o m atic pre -e xisti n g or 
ne w n o n -tar get lesi o ns ( per R E CI S T v 1. 1) t hat ca n n ot ot her wise be me dicall y ma na ge d will be 
per mitte d after u n bli n di n g has o cc urre d. A G -1 2 0 s h o ul d be hel d f or t he d urati o n of palliati ve 
ra di ot hera p y. A 2-w ee k was h o ut fr o m c o m pleti o n of ra di ot hera p y will  be re q uire d pri or t o 
starti n g or res u mi n g A G-1 2 0. F or s u bjects r ecei vi n g palliati ve ra di ot hera p y pri or t o t he first d ose 
of o pe n -la b el A G-1 2 0, a re peat C T or M RI will be perf or me d u p o n c o m pleti o n of t he 2 -wee k 
was h o ut peri o d t o d oc u m e nt t he area t hat was irra diate d a n d t o ser ve as t he ne w baseli ne. All 
decisi o ns t o p urs ue palliati ve ra di ot hera p y will re q uire S p o ns or a n d/ or Me dical M o nit or 
a p pr o val.  
If t he pri mar y e n d p oi nt is statisticall y ne gati ve, all o n g oi n g A G-1 2 0 s u bjects will be per mitte d t o 
c o nti n ue recei vi n g o p e n-l a bel A G-1 2 0 f oll o wi n g u n bli n di n g at t he discreti o n of t he treati n g 
i n vesti gat or. Palliati ve ra di ot hera p y will be all o we d f or s u bjects w h o c o nti n ue recei vi n g A G-1 2 0 
as descri be d i n t he prece di n g “statisticall y p ositi ve” para gra p h. S u bjects w h o were recei vi n g 
place b o will n ot be per mitte d t o recei ve o pe n -la bel A G-1 2 0 i n t his sce nari o a n d will c o me off 
st u d y. 
P ost -Tre at me nt F oll o w -u p Visit : A P ost -Treat me nt F oll o w -U p Visit f or s afet y will occ ur 
2 8  da ys ( n o m ore t ha n 3 3 da ys) after t he last d ose  of st u d y dr u g. E v er y eff ort m ust be ma de t o 
perf or m pr ot o c ol -s pecifi e d e val uati o ns u nless c o nse nt t o partici pate i n t he st u d y is wit h dra w n. 
Assess me nts t o be perf or me d at t he F oll o w -u p Visit i ncl u de E C O G P S a n d A E a n d c o nc o mita nt 
me dicati o n rec or di n g.  If a s u bject’s d ose is i nterr u pte d f or 2 8 da ys a n d t he n t he s u bject 
disc o nti n ues st u d y partici pati o n, t he E O T Visit will ser ve as t he P ost -Treat me nt F oll o w -u p Visit.  
P F S a n d S ur vi v al F oll o w -u p:  S u bjects w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n 
disease pr o gressi o n or wit h dra wal of c o nse nt will be f oll o we d i n P F S f oll o w -u p (e v er y 6 wee ks 
t hr o u g h w ee k 4 8, a n d e v er y 8 wee ks t hereafter) u ntil d oc u me nte d disease pr o gressi o n or t he 
i nitiati o n of ne w ca ncer t hera p y. If a s u bjects be gi ns a ne w a ntica ncer t hera p y d uri n g P F S 
f oll o w-u p, i nf or mati o n o n t he ne w a ntica ncer t hera p y will be c ollecte d.  
O S f oll o w -u p assess me nts will occ ur a p pr o xi matel y e v er y 1 2 wee ks after E O T u nless t he s u bject 
is i n P F S f oll o w-u p at t hat ti me. If a s u bject pr o gresses or d oes n ot c o m e b ac k f or s ca ns w hile i n 
P F S f oll o w -u p, t he n t he O S f oll o w -u p assess me nts will be gi n at t he ne xt pla n ne d O S f oll o w -u p 
ti me p oi nt, f oll o wi n g t he sc he d ule of e ver y 1 2 wee ks after E O T. O S f oll o w -u p will c o nti n ue 
u ntil all s u bjects ha ve die d, wit h dra w n c o n se nt, are l ost t o f oll o w-u p, or u ntil t he occ urre nce of 
1 5 0 O S e ve nts, w hic he v er occ urs first.  
E n d of St u d y:  E n d of st u d y is defi n e d as t he p oi nt i n ti me w he n all s u bjects ha ve die d, 
wit h dra w n c o nse nt, b ee n l ost t o f oll o w -u p, or u ntil 1 5 0 O S e ve nts ha ve o c c urre d. Fi nal a nal ysis 
f or O S will be c o n d ucte d at t he e n d of t he st u d y. 
7. 2.  
J ustific ati o n of t he St u d y Desi g n  
T he st u d y is desi g ne d as a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d efficac y a n d safet y 
st u d y. S u bjects will be ra n d o ml y assi g ne d i n a 2: 1 rati o t o recei ve A G-1 2 0 or A G -1 2 0 -m atc he d 
place b o. Ra n d o m assi g n me nt of s u bjects a v oi ds bias a n d hel ps e ns ure t hat b ot h k n o w n a n d 

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u n k n o w n ris k fact ors are distri b ute d e ve nl y b et wee n treat me nt gr o u ps. T h e st u d y i ncl u des a 
matc he d place b o ar m wit h bli n di n g of all site pers o n nel i n v ol ve d i n t he e val uati o n of s u bjects’ 
res p o nse t o treat me nt (e g, I n v esti gat ors, st u d y c o or di nat ors, st u d y p h ar macists); t his desi g n 
all o ws f or c o ntr ol of p ote ntial i nfl ue nces of t he n at ural c o urse of t he diseas e ot her t ha n t h ose 
relate d t o t he p har mac ol o gic acti o n of t he test dr u g, a n d re d uces bias i n s u bjecti ve assess me nts, 
i ncl u di n g b ot h efficac y a n d safet y e v al uati o ns. Eli gi ble s u bjects will c o nti n ue t o recei ve best 
s u p p orti ve care t hr o u g h o ut t he d urati o n of t he st u d y. 
A n I D M C will re vie w safet y d ata at s c he d ule d i nt er vals as o utli ne d i n Secti o n  1 0. 5. 1 . 
De m o nstrati o n of t he effi cac y of A G -1 2 0 as assess e d b y P F S is t he pri mar y o bject i ve of t he 
st u d y. Res p o nse ass ess me nts use d t o deter mi ne P F S will be base d o n sta n dar d res p o ns e criteria 
( R E CI S T v 1. 1) wit h t he pri mar y e n d p oi nt base d o n I R C res p o ns e assess me nts. 
Sec o n dar y e n d p oi nts i ncl u de safet y, O S, O R R, D O R, T T R, H R Q O L, a n d healt h ec o n o mic 
o utc o mes. P F S per I n v esti gat or assess me nt is als o a sec o n dar y e n d p oi nt. A nal yses of O R R, 
D O R, a n d T T R base d o n res p o nse ass ess me nts will be perf or m e d as det er mi ne d b y t he I R C a n d 
b y t he I n vesti gat or.  
7. 3.  
R ati o n ale f or t he D ose Selecte d  
Preli mi nar y d ata h a v e s h o w n A G -1 2 0 t o be well t olerate d at t otal dail y d os es u p t o 1 2 0 0  m g i n 
s oli d t u m ors ( A G 1 2 0-C -0 0 2) a n d i n he mat ol o gic mali g na n cies ( A G 1 2 0 -C -0 0 1); t he M T D was 
n ot reac h e d i n eit her st u d y. As of a 1 6  J a n uar y 2 0 1 6, 1 2 2  s u bjects ha ve bee n treate d wit h 
A G -1 2 0 i n t he A G 1 2 0 -C -0 0 2 st u d y, of w hic h 8 4  s u bjects recei ve d 5 0 0 m g Q D; 1 1 9  s u bjects 
ha ve bee n treat e d wit h A G -1 2 0 i n t he A G 1 2 0 -C -0 0 1 st u d y, of w hic h 8 9  s u bjects recei ve d 5 0 0 
m g Q D. Bas e d o n a re vie w of t he a vaila bl e safet y, P K/ P D, a n d cli nical acti vit y data  o bser ve d 
d uri n g d ose escalati o n , 5 0 0 m g Q D w as selecte d as t he A G-1 2 0 d ose f or t h e e x pa nsi o n p hases of 
b ot h of t hese trials.  
I n t hes e st u dies, t here h a ve bee n mi ni mal d ose i nterr u pti o ns, a n d wit h o ut a n a p pare nt d os e 
relati o ns hi p f or a n y c o m m o nl y re p orte d T E A Es or Gra d e ≥3 T E A Es. N o D L Ts ha v e bee n 
re p orte d i n St u d y A G 1 2 0-C -0 0 2. D ose -li miti n g t o xicities of Gra de 3 ras h a n d Gra de 3 Q T 
pr ol o n gati o n w ere o bs er ve d i n t he 1 2 0 0  m g Q D a n d 8 0 0  m g Q D c o h orts res pecti vel y i n 
St u d y  A G 1 2 0 -C -0 0 1; h o we ver, e x pa nsi o n of t h ese d ose c o h orts di d n ot res ult i n i de ntificati o n of 
t he M T D. 
Plas ma A G -1 2 0 e x p os ure i ncrease d i n a less t ha n pr o p orti o nal ma n ner acr oss d oses fr o m 1 0 0  m g 
BI D t o 1 2 0 0 m g Q D, n eari n g a pl atea u at 5 0 0 m g Q D, i n b ot h s oli d t u m ors a n d he mat ol o gic 
mali g na n cies.  S ustai ne d a n d c o nsiste nt plas ma 2 -H G i n hi biti o n was o bser ve d wit h plas ma 2 -H G 
le vels re d uce d t o t he n or mal ra n ge of healt h y v ol u nteers ( u p t o 9 8. 0 % i n hi biti o n i n s oli d t u m ors, 
9 9. 7 % i n he mat ol o gic m ali g na n cies) at all d oses, wit h n o a p pare nt d ose res p o nse . T he 5 0 0 m g 
Q D d ose has s h o w n a ma xi m u m P D effect base d o n 2 -H G le vels f or t he maj orit y of s u bjects.  
As of 1 4 A pril 2 0 1 6, A G -1 2 0 was ass oci ate d wit h cli nical acti vit y i n s u bjects wit h 
c h ola n gi ocarci n o ma, i ncl u di n g 3  s u bjects wit h best o verall res p o nse of P R a n d 2 2  s u bjects wit h 
best o verall res p o ns e of sta ble disease i n t he d ose escalati o n a n d e x pa nsi o n p hases of A G 1 2 0 -C -
0 0 2. Of t he 4 8 s u bjects wit h c h ola n gi ocarci n o ma ( b ot h d ose escalati o n a n d e x pa nsi o n p hases) i n 
St u d y A G 1 2 0 -C -0 0 2, 3 7  s u bjects recei ve d 5 00 m g Q D d oses of A G -1 2 0.  

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7. 4.  
Criteri a f or St u d y Ter mi n ati o n  
T his st u d y ma y be pre mat urel y ter mi nate d, if i n t h e o pi ni o n of t he S p o ns or, t here is s ufficie ntl y 
reas o na bl e ca us e. I n t he e ve nt of s uc h acti o n, writte n n otificati o n d oc u me nti n g t he reas o n f or 
st u d y ter mi nati o n will be pr o vi de d t o eac h I n vesti gat or.  
T he st u d y will be ter mi nate d if a n y of t h e f oll o wi n g cir c u msta nces occ ur:  
 Deter mi nati o n of u ne x pecte d, si g nifi ca nt, or u nacce pta ble ris k t o s u bjects. ( A n I D M C 
will re vie w t he safet y dat a o n a re g ul ar basis t o e ns ure t he ris k/ be nefit rati o.) 
 Fail ure t o e nt er s u bjects at a n acce pta ble rate.  
 I ns ufficie nt a d h ere n ce t o pr ot oc ol re q uire m e nts. 
 Pla ns t o m o dif y, s us p e n d, or disc o nti n ue t he de vel o p me nt of t he st u d y tr eat me nt.  
 Ot her a d mi nistrati ve reas o ns.  
If t he st u d y is ter mi nate d earl y f or a n y reas o n ot her t ha n u nacce pta ble t o xicit y, S p o ns or will 
c o nti n ue t o pr o vi de dr u g t o s u bjects w h o are b e nefiti n g fr o m treat me nt. S h o ul d t he st u d y be 
cl ose d pre mat urel y d ue t o u nacce pta ble t o xicit y, all st u d y mat erials m ust be ret u r ne d t o t he 
S p o ns or or S p o ns or’s desi g nee.  

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8.  
S T U D Y P O P U L A TI O N  
8. 1.  
N u m ber of S u bjects  
A t otal of a p pr o xi matel y 1 8 6 s u bjects will be ra n d o mize d i n a 2: 1 rati o, stratifie d b y n u m ber of 
pri or s yste mic tr eat me nt re gi me ns f or a d va nce d disease ( 1 or 2) i nt o t he 2 treat me nt ar ms, 
i ncl u di n g a p pr o xi matel y 1 2 4 s u bjects i n t he A G-1 2 0 ar m a n d 6 2 s u bjects i n t he place b o ar m.  
8. 2.  
I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g criteria t o be e nr olle d i n t he st u d y:  
1.  Be ≥1 8 years of a ge.  
2.  Ha ve a hist o pat h ol o gical dia g n osis (fres h or ba n ke d t u m or bi o ps y sa m ple, prefera bl y 
c ollecte d wit hi n t he last 3 years) c o nsiste nt wit h n o nresect a ble or metast atic 
c h ola n gi ocarci n o ma a n d are n ot eli gi ble f or c urati ve resecti o n, tra ns pla ntati o n, or a blati ve 
t hera pies. 
3.  Ha ve d oc u m e nte d I D H 1 ge n e-m utate d disease (fr o m a fres h t u m or bi o ps y or t he m ost 
rece nt b a n ke d t u m or tiss ue a vaila ble) base d o n ce ntral la b orat or y testi n g 
( R 1 3 2 C/ L/ G/ H/ S m utati o n varia nts teste d). 
4.  Ha ve a n E C O G P S sc ore of 0 or 1 ( A p pe n di x  1 5. 1 ). 
5.  Ha ve a n e x pecte d s ur vi v al of ≥3 m o nt hs.  
6.  Ha ve at least o ne e v al ua ble a n d meas ura ble lesi o n as defi ne d b y R E CI S T v 1. 1. S u bjects 
w h o ha ve recei v e d pri or l ocal t hera p y (i ncl u di n g b ut n o t li mite d t o e m b olizati o n, 
c he m oe m b olizati o n, ra di ofre q ue n c y a blati o n, or ra diati o n t hera p y) are eli gi ble pr o vi de d 
meas ura ble disease falls o utsi de of t he treat me nt fiel d or wit hi n t he fiel d a n d has s h o w n 
≥2 0 % gr o wt h i n siz e si nce p ost -treat me nt ass ess me nt. 
7.  Ha ve d oc u m e nte d diseas e pr o gressi o n f oll o wi n g at least 1 a n d n o m ore t ha n 2 pri or 
s yste mic re gi me ns f or a d va nce d dise ase ( n o nresecta ble or metastatic). S u bj ects m ust 
ha ve recei ve d at least 1 ge mcita bi ne - or 5 -F U -c o nt ai ni n g re gi me n f or a d va n ce d 
c h ola n gi oc arci n o ma. S yste mic a dj u va nt c he m ot hera p y will be c o nsi dere d a li ne of 
treat me nt if t here is d oc u me nte d disease pr o gressi o n d uri n g or wit hi n 6 m o nt hs of 
c o m pleti n g t he t hera p y.  
8.  Ha ve rec o vere d fr o m t o xicities ass ociate d wit h pri or a ntica ncer t hera p y t o b asel i ne u nless 
sta bilize d u n der me dical ma na ge me nt. 
9.  Ha ve a d e q uate b o n e marr o w f u ncti o n as e vi de nce d b y:  
a. A bs ol ute ne utr o p hil c o u nt ≥1, 5 0 0/ m m 3 or 1. 5  × 1 0 9/ L 
b.  He m o gl o bi n ≥8  g/ d L  
c. Platelets ≥1 0 0, 0 0 0/ m m 3 or 1 0 0  ×  1 0 9/ L 
1 0.  Ha ve a d e q uate h e patic f u ncti o n as e vi de nce d b y:  
a. Ser u m t otal bilir u bi n ≤2  × u p per li mit of n or mal ( U L N), u nless c o nsi dere d d ue t o 
Gil bert’s disease  
b.  As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤5  ×  U L N  

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1 1.  Ha ve a d e q uate re nal f u ncti o n as e vi de nce d b y:  
a. Ser u m creati ni ne < 1. 5  ×  U L N  
O R  
b.  Creati ni ne cleara n ce ≥5 0 m L/ mi n base d o n t he C o c kcr oft -Ga ult gl o mer ular filtrati o n 
rate ( G F R) esti mati o n: 
( 1 4 0  A ge)   ( wei g ht i n k g)  ( 0. 8 5 if fe mal e)/ 7 2  ser u m creati ni ne 
1 2.  Be a bl e t o u n dersta n d a n d willi n g t o si g n t he i nf or me d c o nse nt f or m a n d t o c o m pl y wit h 
sc he d ule d visits, treat me nt pla ns, pr oce d ures, a n d la b orat or y tests, i ncl u di n g serial 
peri p heral bl o o d sa m pli n g a n d uri ne sa m pli n g, d uri n g t he st u d y. A le gall y a ut h orize d 
re pres e ntati ve ma y c o ns e nt o n be half of a s u bject w h o is ot her wise u na ble t o pr o vi de 
i nf or me d c o nse nt if acce pta ble t o a n d a p pr o ve d b y t he site’s I nstit uti o nal Re vie w B o ar d 
(I R B)/I n d e pe n d e nt Et hics C o m mittee (I E C). ( S u bjects w h o d o n ot s pea k o ne of t he 
la n g u a ges t hat t he Q L Q -C 3 0, Q L Q -BI L 2 1, P GI -C, P GI -S, or E Q -5 D -5 L are pr o vi d e d i n 
at t his ti me will be per mitte d t o e nr oll a n d n ot c o m plete t hese H R Q O L/ healt h ec o n o mic 
o utc o me i nstr u me nts, ass u mi n g all ot her eli gi bilit y criteria are met.)  
1 3.  Fe male s u bjects wit h re pr o d ucti ve p ote ntial m ust ha ve a n e gati ve ser u m pre g n a nc y test 
pri or t o t he start of t hera p y, or a c o nfir m ati o n fr o m a n o bstetricia n i n cas e of e q ui v ocal 
ser u m pre g na nc y res ults. Fe males of re pr o d ucti ve p ote ntial are defi ne d as s e x uall y 
mat ure w o me n w h o h a ve n ot u n der g o ne a h ysterect o m y, bilateral o o p h orect o m y, or t u bal 
occl usi o n or w h o ha v e n ot bee n nat urall y p ost me n o pa usal (ie, w h o ha ve n ot me nstr uate d) 
f or at least 2 4 c o ns ec uti v e m o nt hs (ie, ha ve n ot ha d me nses at a n y ti me i n t he prece di n g 
2 4  c o nsec uti ve m o nt hs). W o me n of re pr o d ucti ve p ote ntial, as well as fertile me n wit h 
part n ers w h o are fe male wit h re pr o d ucti ve p ote nti al, m ust a gree t o use 2 effecti ve f or ms 
of c o ntrace pti o n (i ncl u di n g at least 1 barri er f or m) fr o m t he ti me of gi vi n g i nf or me d 
c o nse nt t hr o u g h o ut t he st u d y a n d f or 9 0 da ys ( b ot h fe males a n d m ales) f oll o wi n g t he la st 
d ose of st u d y dr u g. Effecti ve f or ms of c o ntrace pti o n are defi ne d as h or m o nal oral 
c o ntrace pti ves, i njecta bles, patc hes, i ntra uteri ne de vices, i ntra uteri ne h or m o ne -rel easi n g 
s yste ms, bilateral t u bal li gati o n, c o n d o ms wit h s per mici de, or male p art ner ster ilizati o n. 
8. 3.  
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will n ot be e nr olle d i n t he st u d y:  
1.  Recei ve d a pri or I D H i n hi bit or.  
2.  Recei ve d s yste mic a ntica ncer t hera p y or i n vesti gati o nal a ge nt < 2 wee ks pri or t o Da y 1 
( was h o ut fr o m pri or i m m u ne base d a ntica ncer t hera p y is 4 w ee ks). I n a d diti o n, t he first 
d ose of st u d y tr eat me nt s h o ul d n ot occ ur bef ore a peri o d ≥5 half -li ves of t h e 
i n vesti gati o nal a ge nt has ela pse d. 
3.  Recei ve d ra di ot hera p y t o metastatic sites of diseas e < 2 wee ks pri or t o D a y 1.  
4.  U n der we nt he patic ra diati o n, c he m oe m b olizati o n, a n d ra di ofre q ue n c y a blati o n < 4 wee ks 
pri or t o Da y 1.  
5.  Ha ve k n o w n s y m pt o matic brai n metastas es re q uiri n g ster oi ds. S u bjects wit h pre vi o usl y 
dia g n ose d brai n metastas es are eli gi ble if t h e y ha v e c o m plete d t heir tre at me nt a n d ha ve 

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rec o vere d fr o m t he ac ute effects of ra di ati o n t hera p y or s ur ger y pri or t o st u d y e ntr y, ha ve 
disc o nti n ue d c ortic oster oi d treat me nt f or t hes e metastases f or at least 4 wee ks a n d ha ve 
ra di o gra p hic all y sta bl e disease f or at least 3 m o nt hs pri or t o st u d y e ntr y. N ote: u p t o 1 0 
m g per da y of pre d nis o ne e q ui vale nt will be all o we d.  
6.  Ha ve a hist or y of a n ot her pri mar y ca n cer, wit h t he e x ce pti o n of: a) c urati vel y res ecte d 
n o n -mela n o ma s ki n ca n cer; b) c urati vel y treat e d cer vical carci n o ma i n sit u; or c) o t her 
pri mar y s oli d or li q ui d t u m or wit h n o k n o w n acti ve disease prese nt t hat, i n t he o pi ni o n of 
t he I n v esti gat or, will n ot affect s u bject o utc o me i n t he setti n g of c urre nt 
c h ola n gi ocarci n o ma dia g n osis.  
7.  U n der we nt maj or s ur ger y wit hi n 4 wee ks of Da y 1 or ha v e n ot r ec o vere d fr o m p ost -
s ur ger y t o xicities. 
8.  Are pre g na nt or breastf ee di n g.  
9.  Are ta ki n g k n o w n str o n g C Y P 3 A 4 i n d ucers or se nsiti ve C Y P 3 A 4 s u bstrate me dicati o ns 
wit h a narr o w t h era p e utic wi n d o w  ( A p p e n di x 1 5. 2 ), u nless t he y ca n b e tra nsferre d t o 
ot her me dicati o ns wit hi n ≥5 half -li ves pri or t o d osi n g. 
1 0.  E x cl usi o n criteri o n 1 0 re m o ve d i n Pr ot oc ol A me n d me nt 4, Versi o n 5. 0.  
1 1.  Ha ve a n acti ve i nf ecti o n re q uiri n g s yst e mic a nti-i nfecti ve t hera p y or wit h a n u ne x plai ne d 
fe ver > 3 8. 5° C wit hi n 7 da ys of Da y 1 (at t he discreti o n of t he I n vesti gat or, s u bjects wit h 
t u m or fe ver ma y b e e nr olle d). 
1 2.  Ha ve a n y k n o w n h y pers e nsiti vit y t o a n y of t h e c o m p o ne nts of A G -1 2 0 or t he matc he d 
place b o.  
1 3.  Ha ve si g nifica nt acti ve car diac dise ase wit hi n 6 m o nt hs pri or t o t he start of st u d y 
treat me nt, i ncl u di n g Ne w Y or k Heart Ass ociati o n ( N Y H A) Class III or I V c o n gesti ve 
heart fail ure ( A p p e n di x  1 5. 3 ); m y ocar dial i nfarcti o n; u nsta ble a n gi n a; a n d/ or str o ke. 
1 4.  Ha ve L V E F < 4 0 % b y E C H O sca n ( or b y ot h er m et h o ds acc or di n g t o i nstit uti o nal 
practice) o btai ne d wit hi n 2 8 da ys pri or t o t he start of st u d y tr eat me nt.  
1 5.  Ha ve a h eart -rate c orrect e d Q T i nter val ( usi n g Fri dericia’s f or m ula) ( Q Tc F) 
(A p pe n di x  1 5. 4 ) ≥4 5 0 msec or ot her fact ors t hat i ncreas e t he ris k of Q T pr ol o n gati o n or 
arr h yt h mic e v e nts (e g, heart fail ure, h y p o k ale mia, fa mil y hist or y of l o n g Q T i nter val 
s y n dr o me). B u n dl e bra n c h bl oc k a n d pr ol o n ge d Q Tc F i nter val are per mitte d wit h 
a p pr o val of t he M e dical M o nit or.  
1 6.  Are ta ki n g me dicati o ns t hat are k n o w n t o pr ol o n g t he Q T i nter val ( A p p e n di x  1 5. 5 ), 
u nless t he y ca n be tr a nsf erre d t o ot her me dicati o ns wit hi n ≥5 half -li ves pri or t o d osi n g or 
u nless t he me dicati o ns ca n be pr o perl y m o nit ore d d uri n g t he st u d y. (If e q ui vale nt 
me dicati o n is n ot a vaila ble, Q Tc F s h o ul d b e cl osel y m o nit ore d.)  
1 7.  Ha ve k n o w n acti ve he p atitis B ( H B V) or he p atitis C ( H C V) i nfecti o ns, k n o w n p ositi ve 
h u ma n i m m u n o deficie nc y vir us ( HI V ) a nti b o d y res ults, or ac q uire d i m m u n o deficie nc y 
s y n dr o me ( AI D S) relate d ill ness. S u bjects wit h a s ustai ne d viral res p o nse t o H C V or 
i m m u nit y t o pri or H B V i nfecti o n will be per mitte d. S u bjects wit h c hr o nic H B V t hat is 
a de q uatel y s u p pr esse d per i nstit uti o na l practice will be per mitte d. 

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1 8.  Ha ve a n y ot h er ac ute or c hr o nic me dical or ps yc hiatric c o n diti o n, i ncl u di n g rece nt 
( wit hi n 1 2 m o nt hs of Da y 1) or acti ve s uici d al i deati o n or be ha vi or, or a la b orat or y 
a b n or malit y t hat ma y i n crease t h e ris k ass ociat e d wit h st u d y partici pati o n or 
i n vesti gati o nal pr o d u ct a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of st u d y 
res ults a n d, i n t he j u d g m e nt of t he I n vesti gat or, w o ul d ma ke t he s u bject i na p pr o priate f or 
e ntr y i nt o t his st u d y.  
1 9.  Ha ve k n o w n acti ve i nfla m mat or y ga str oi ntesti nal disease, c hr o ni c diarr hea, pre vi o us 
gastri c res ecti o n or la p b a n d d ys p h a gia, s h ort -g ut s y n dr o me, gastr o paresis, or ot her 
c o n diti o ns t hat li mit t he i n gesti o n or gastr oi ntesti nal a bs or pti o n of dr u gs a d mi nistere d 
orall y. G astr oes o p h a geal refl u x  disease u n der me dical treat me nt is all o we d (ass u mi n g n o 
dr u g i nteracti o n p ote ntial).  
2 0.  Ha ve bee n c o m mitte d t o a n i nstit uti o n b y virt ue of a n or der iss ue d eit her b y t he j u dicial 
or a d mi nistrati ve a ut h orities.  
2 1.  Are de p e n de nt o n t he S p o ns or, I n vesti gat or, or st u d y site, per l ocal i nstit uti o n re g ul ati o ns. 
2 2.  Ha ve k n o w n me di cal hist or y of pr o gressi ve m ultif ocal le u k oe n ce p hal o pat h y ( P M L).  
8. 4.  
S u bject I de ntific ati o n a n d Re gistr ati o n  
S u bjects w h o are ca n di dates f or e nr oll me nt i nt o t he st u d y will be e v al uate d f or eli gi bili t y b y t he 
I n v esti gat or t o e ns ure t h at t he i ncl usi o n a n d e x cl usi o n criteria (see Secti o n 8. 2  a n d Secti o n  8. 3 , 
res pecti vel y) ha ve b ee n s atisfie d a n d t hat t he s u bject is eli gi ble f or p artici pati o n i n t his cli nical 
st u d y. T he M e dical M o nit or will c o nfir m eli gi bilit y f or all s u bjects pri or t o ra n d o miz ati o n. 
8. 5.  
S u bject Wit h dr a w al Criteri a  
S u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n. A s u bject’s 
disc o nti n uati o n of st u d y treat me nt or wit h dra wal fr o m t he st u d y will n ot je o par dize t he 
relati o ns hi p wit h t heir healt hcare pr o vi ders or affect t heir f ut ure care. S u bjects ma y c h o ose t o 
disc o nti n ue st u d y treat me nt b ut a gree t o re mai n o n st u d y f or f oll o w -u p c o ntact. T his decisi o n 
m ust be rec or de d i n writi n g b y t he st u d y site.  
S h o ul d a s u bject deci de t o wit h dra w, all eff orts will be ma d e t o c o m plete a n d re p ort t he 
pr ot oc ol -defi ne d st u d y o bser vati o ns as c o m pletel y as p ossi ble a n d t o deter mi ne t he reas o n f or 
wit h dra wal.  
I n t he e ve nt a s u bj ect disc o nti n ues st u d y treat me nt or wit h dra ws fr o m t he st u d y, t he Me dical 
M o nit or m ust be i nf or me d. If  t here is a me dical r eas o n f or wit h dra wal, t he s u bject will re mai n 
u n der t he s u per visi o n of t he I n vesti gat or u ntil satisfact or y h ealt h has ret ur ne d.  
W he n a s u bject disc o nti n ues st u d y tr eat me nt or wit h dra ws fr o m t he st u d y, t he pri mar y reas o n f or 
disc o nti n ua ti o n or wit h dra wal m ust be rec or de d i n t he a p pr o priat e secti o n of t he electr o nic cas e 
re p ort f or m (e C R F) a n d all eff orts will be ma de t o c o m plete a n d re p ort fi nal st u d y o bser vati o ns 
as t h or o u g hl y as p ossi ble.  
8. 5. 1.  
Wit h dr a w al fr o m St u d y Tre at me nt  
S u bjects ma y di sc o nti n ue or be disc o nti n ue d fr o m st u d y treat me nt at a n y ti me. I n t his sit uati o n, a 
s u bject wit h o ut d oc u me nte d pr o gressi ve dise ase b y t he I n v esti gat or s h o ul d be f oll o we d f or t u m or 

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assess me nts u ntil t he de vel o p me nt of pr o gressi ve disease a n d/ or s ur vi val. S u bjects will be 
disc o nti n ue d fr o m st u d y treat me nt f or t he f oll o wi n g reas o ns:  
 Wit h dra wal of c o nse nt  
 Certai n a d vers e e v e nts (as descri be d i n Secti o n  9. 8 ) i ncl u di n g i nsta nces of Gra de 4 
Q Tc F pr ol o n gati o n.  
 A c o nfir me d dia g n osis of P M L ( Secti o n  1 1. 3. 1 ) or G uillai n-Barre s y n dr o m e 
( Secti o n 1 1. 3. 2 ). 
 Disease pr o gressi o n (s u bjects w h o are, i n t he o pi ni o n of t he I n vesti gat or, b e nefitti n g 
fr o m treat me nt [ e g, sl o w pr o gressi o n] ma y b e all o we d t o c o nti n ue o n st u d y treat me nt 
wit h a p pr o val of t he Me dical M o nit or)  
 Deat h  
 I n v esti gat or decisi o n 
 S u bject decisi o n t o wit h dra w fr o m treat me nt (s u bj ect ma y c o nti n ue wit h P F S a n d/ or 
s ur vi val f oll o w-u p)  
 Pr ot oc ol vi olati o n: n o n -a d here nce t o st u d y tr eat m e nt re gi me n  or pr ot o c ol 
re q uire me nts 
 C o nfir me d pre g na n c y (st u d y t hera p y s h o ul d be i m me diatel y i nterr u pte d bas e d u p o n a 
p ositi ve uri nar y h u m a n c h ori o nic g o n a d otr o pi n [ h C G] test, a n d per ma ne ntl y 
disc o nti n ue d if c o nfir me d b y a s er u m β -h C G test)  
 L ost t o f oll o w -u p  
All A Es  s h o ul d be f oll o we d u ntil res ol uti o n or f or a peri o d of 2 8 d a ys fr o m t he last d ose of st u d y 
treat me nt, w hic he v er is s h orter. If t h e s u bject wit h dre w fr o m treat me nt beca use of a n A E, e v er y 
eff ort m ust be ma d e t o perf or m pr ot o c ol -s pecifi e d safet y f oll o w-u p p r oce d ures. 
8. 5. 2.  
St u d y Ter mi n ati o n  
S u bjects w h o disc o nti n ue treat me nt wit h o ut diseas e pr o gressi o n or d eat h will c o nti n ue t o be 
f oll o we d f or P F S e v er y 6 wee ks after t he E O T Visit ( ± 5 da ys) f or t he first 8 assess me nts (ie, 
t hr o u g h w ee k 4 8), a n d t h e n e ver y 8 wee ks ( ± 5 da ys) t hereafter u ntil diseas e pr o gressi o n, deat h, 
start of s u bse q ue nt a ntic a ncer t hera p y, or wit h dra wal of c o nse nt. After s u bjects ha ve 
disc o nti n ue d treat me nt  b eca use of diseas e pr o gressi o n , t he y will be c o ntact e d a p pr o xi matel y 
e ver y 1 2 w ee ks t o asse ss s ur vi val stat us ( O S) a n d t o d oc u me nt recei pt of s u bse q ue nt a ntica n cer 
t hera p y u nless c o ns e nt t o partici pate is wit h dra w n. S u bjects will be ter mi nate d fr o m t he st u d y f or 
t he f oll o wi n g reas o ns: 
 Deat h  
 Wit h dra wal of c o nse nt  
 L oss t o f oll o w -u p  
 Occ urre nce of 1 5 0 O S e v e nts  
 S p o ns or ter mi nati o n of t he st u d y  

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If s u bjects are ter mi nat e d fr o m t he st u d y b eca us e of t he occ urre n ce of 1 5 0 O S e ve nts or S p o ns or 
decisi o n, S p o ns or will c o nti n ue t o pr o vi de dr u g t o s u bjects w h o are be nefiti n g fr o m treat me nt.  

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9.  
S T U D Y T R E A T M E N T  
9. 1.  
De scri pti o n of St u d y Tre at me nt 
A G -1 2 0 will be a d mi nistere d orall y at a d ose of 5 0 0 m g ( pr o vi d e d as 2 5 0 m g stre n gt h ta blets).  
Place b o will be s u p plie d as matc he d ta blets t o be a d mi nistere d orall y.  
9. 2.  
St u d y Tre at me nt P ac k a gi n g a n d L a beli n g  
A G -1 2 0 a n d mat c he d pla c e b o will be s u p plie d i n a p pr o priate c o ntai ners wit h c hil d resista nt 
cl os ures a n d will be la b ele d a p pr o pri atel y as i n vesti gati o nal pr o d uct f or t his st u d y.  
Pac ka gi n g a n d la b eli n g will be pre pare d t o meet all re g ulat or y re q uire me nts.  
9. 3.  
St u d y Tre at me nt St or a ge  
A G -1 2 0 ta blets a n d mat c he d place b o t a blets m ust be st ore d acc or di n g t o t h e pac k a ge la bel.  
All st u d y treat me nt pr o d ucts m ust be st ore d i n a sec ure, li mite d -access l ocati o n a n d ma y be 
dis pe nse d o nl y b y t he I n vesti gat or or b y a me m ber of t he staff s p ecificall y  a ut h orize d b y t he 
I n v esti gat or. 
9. 4.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt  
S u bjects w h o meet all st u d y eli gi bilit y criteria will be ra n d o ml y assi g ne d i n a 2: 1 rati o, stratifie d 
b y n u m ber of pri or s yste mic treat me nt re gi me ns f or a d va nce d diseas e ( 1 or 2), t o recei ve 
A G -1 2 0 orall y Q D or A G -1 2 0 -matc h e d place b o orall y Q D.  
T he ra n d o mizati o n sc he d ule will be ge nerate d b y a n i n de pe n de nt statistical gr o u p. T h e 
ra n d o mizati o n assi g n me nt will be i m ple me nte d b y a n i nteracti ve we b res p o nse s yste m (I W R S). 
9. 5.  
Bli n di n g  
T he s u bjects, I n vesti gat ors, t he cli nical res earc h u nit staff w h o deal directl y wit h s u bjects, a n d 
t he S p o ns or will be bli n de d t o st u d y treat me nt assi g n me nt u ntil d oc u me nte d disease pr o gressi o n. 
T he I W R S will assi g n eac h s u bject s pecifi c Me dicati o n I D -la bel e d st u d y dr u g c o nt ai ners. A G-
1 2 0 a n d place b o will be pac ka ge d a n d la bele d i de nticall y s o t hat t he st u d y p har macist will 
re mai n bli n de d t o treat m e nt assi g n me nt. 
T he s u bjects, cli nical r es earc h u nit staff, a n d S p o ns or will re mai n bli n de d f or t he d urati o n of t h e 
st u d y u nless e mer ge nc y u n bli n di n g is re q uire d (see Secti o n  9. 6 ). U p o n re q uest b y t he 
I n v esti gat or, s u bjects a n d staff will be u n bli n de d at t he ti me of disease pr o gressi o n as c o nfir m e d 
b y st u d y s p o ns or.  
A n I D M C will re vie w u n bli n de d safet y a n d ot her cli nical data at sc h e d ule d meeti n gs; t he 
u n bli n de d s u m maries will be pre pare d b y a n i n d e p e n de nt statistical ce nter ( Secti o n  1 0. 5. 1 ). 
9. 6.  
U n bli n di n g  
T he nee d t o u n bli n d st u d y treat me nt s h o ul d first be disc usse d wit h t he S p o ns or’s Me dical 
M o nit or ( or Res p o nsi ble Me dical Offi cer), if at all p ossi ble. I n t he e v e nt of a me dical e mer ge n c y 

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or pre g na n c y i n a fe male s u bject or i n t he se x ual part ner of a male s u bject, i n w hic h k n o wle d ge 
of t he i n vesti gati o nal pr o d uct is critical t o t he s u bject’s ma na ge me nt, t he st u d y treat me nt ma y be 
u n bli n de d f or t hat s u bject b y t he treati n g I n vesti gat or. I n v esti gat ors are e n c o ura ge d t o disc uss a 
pla n t o brea k t he bli n di n g c o d e wit h t he Me dical M o nit or.  
I n case of a n e m er ge n c y, t he I n v esti gat or ma y access t he I W R S t o re veal t he i de ntit y of t he 
treat me nt f or t hat s u bject. O nce t he d ecisi o n t o u n bli n d has bee n ma de, t he I n v esti gat or m ust 
rec or d t h e nat ure of t he e mer ge nc y t hat re q uire d t he u n bli n di n g, al o n g wit h t he date a n d ti me of 
t he u n bli n di n g o n t he pr o per s o urce d oc u me ntati o n a n d n otif y t he S p o ns or’s Me dical M o nit or ( or 
Res p o nsi ble  Me dical Officer) of t h e u n bli n di n g.  
I n t he e ve nt t hat a s u bj ect’s treat me nt assi g n me nt is u n bli n de d, eit her acci de ntall y or i n t he cas e 
of e mer ge nc y u n bli n di n g, t he s u bject will be all o we d t o c o nti n ue st u d y treat me nt. I n t h e cas e of 
e mer ge n c y u n bli n di n g, if t he s u bject is recei vi n g place b o, cr oss o ver t o A G-1 2 0 will n ot be 
per mitte d u ntil d oc u me nte d pr o gressi o n.  
U p o n re q uest b y t he I n vesti gat or, t he s u bject a n d site staff will be u n bli n de d t o treat me nt 
assi g n me nt after d oc u me nte d disease pr o gressi o n (as as sesse d b y t h e I n vesti gat or a n d aft er 
c o ns ultati o n wit h t he S p o ns or Me dical M o nit or), a n d s u bjects ra n d o mize d t o t he place b o ar m 
w h o still meet eli gi bilit y criteria will be gi ve n t he o p p ort u nit y t o cr oss o ver t o t he acti ve 
treat me nt ar m a n d recei v e A G-1 2 0. F or t h ose s u bj ects w h o cr oss o v er, place b o will n ot be 
c o u nte d as a pri or li ne of t hera p y f or t h e p ur p ose of eli gi bilit y. If s u bjects cr oss o ver, t he y will 
f oll o w t he sa me assess m e nt sc he d ule as fr o m C 1 D 1. T hese s u bjects will c o nti n ue t o be e val uate d 
f or tu m or res p o nse b y t h e I n vesti gat or. If t he treat me nt assi g n me nt is deter mi ne d t o be A G-1 2 0 
u p o n ra di o gra p hic diseas e pr o gressi o n, t he I n vesti gat or m a y c o nsi der c o nti n ui n g A G -1 2 0, 
pr o vi de d t he s u bject a p p ears t o be cli nicall y b e nefitti n g a n d t here is n o c o nt rai n dicati o n t o 
c o nti n ui n g treat me nt be y o n d pr o gressi o n (see Secti o n  9. 8  f or para met ers f or treati n g be y o n d 
pr o gressi o n).  
Palliati ve ra di ot hera p y t o treat s y m pt o matic n o n-tar get lesi o ns per R E CI S T v 1. 1 t hat ca n n ot 
ot her wise be me di call y ma na ge d will be per mitte d after disease pr o gressi o n has bee n verifie d 
a n d u n bli n di n g has occ urre d (see Secti o n  9. 8. 1. 3 ). A G -1 2 0 s h o ul d be hel d f or t he d urati o n of 
palliati ve ra di ot hera p y.  P alliati ve ra di ot hera p y a n d a n y ot h er a nti -ca ncer t hera p y will n ot be 
per mitte d d uri n g t h e bli n de d p orti o n of t his st u d y. A n y d ecisi o n t o p urs ue palliati ve ra di ot hera p y 
will re q uire Me dic al M o nit or a p pr o val. After palliati ve ra di ot hera p y, t here will be a 2 -wee k 
was h o ut peri o d bef ore t h e start or res u m pti o n of A G -1 2 0 treat me nt. F or s u bjects ra n d o mize d t o 
place b o w h o recei ve pallia ti ve ra di ot hera p y bef ore cr ossi n g o ver t o A G-1 2 0, a re peat C T or M RI 
will be perf or me d at t he e n d of t he 2 -w ee k was h o ut peri o d, w hic h will ser ve as t he ne w baseli ne 
f or c o m paris o n f or all s u bse q ue nt sca ns i n or der t o assess P F S 2 (see Secti o n 1 2. 1 2. 1 ). F or 
s u bjects per mitte d t o c o nti n ue o n o pe n-la bel A G-1 2 0 be y o n d d o c u me nte d ra di o gra p hic 
pr o gressi o n, a ne w baseli ne i ma gi n g assess me nt will n ot be re q uire d a n d t h e i ma gi n g 
assess me nts will c o nti n ue o n t he c urre nt sc he d ul e.  
Pri m ar y E n d p oi nt Res ults a n d S u bse q ue nt St u d y U n bli n di n g:  O nce t he pri mar y e n d p oi nt of 
P F S ( base d o n ce ntral r a di ol o g y R E CI S T 1. 1 assess me nt) is statisticall y a n al yze d, t he S p o ns or 
will c o m m u nicate t he t o pli ne a g gre gat e res ults of t he st u d y via p u blic discl os ure, w hic h will 
i ncl u de partici pati n g st u d y te a ms. S h ortl y aft er p u blic discl os ure of t he t o pli ne a g gre gate res ults, 
t he S p o ns or will c o m m u nicate t o all sites t hat treat me nt assi g n me nts of all s u bjects will be 

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u n bli n de d a n d will als o i nf or m sites w hic h of t he 2  f oll o wi n g sce nari os t o p urs ue f oll o wi n g 
u n bli n di n g.  
If t he pri mar y e n d p oi nt is statisticall y p ositi ve, all o n g oi n g s u bjects ( A G-1 2 0 a n d 
place b o -tr eat me nt assi g n e d s u bjects) will be gi ve n t he o p p ort u nit y  t o recei v e o pe n-la bel A G-1 2 0 
f oll o wi n g u n bli n di n g. U n bli n di n g will n o l o n ger be c o nti n ge nt u p o n d oc u me nte d ra di o gra p hic 
disease pr o gressi o n. S u bjects w h o were alr ea d y recei vi n g A G -1 2 0 ma y c o nti n ue t o recei ve  
A G -1 2 0 o n t he sa me assess me nt sc he d ule. S u bjects w h o were recei vi n g place b o a n d c o nti n ue t o 
meet cr oss -o v er eli gi bilit y criteria will be gi ve n t h e o p p ort u nit y t o r ecei v e o pe n -la bel A G-1 2 0. 
F or s u bjects w h o cr oss o ver, place b o will n ot be c o u nte d as a pri or li ne of t hera p y f or t he 
p ur p ose of eli gi bilit y. If s u bjects cr oss o ver, t he y will f oll o w t he sa me assess me nt sc he d ule as 
fr o m C 1 D 1. Pri or t o cr ossi ng o ver, t h ese s u bjects will u n der g o a C T or M RI t hat will ser ve as t he 
ne w baseli ne a gai nst w hi c h all s u bse q ue nt R E CI S T v 1. 1 assess me nts will be perf or me d. If t h e 
s u bject has u n der g o n e a rece nt C T or M RI ( ≤3 wee ks pri or t o start of cr oss -o ver treat me nt), t he 
sca n d oes n ot nee d t o be re peat e d. Palliati ve ra di ot hera p y t o treat s y m pt o m atic pre -e xisti n g or 
ne w n o n -tar get lesi o ns ( per R E CI S T v 1. 1) t hat ca n n ot ot her wise be me dicall y ma na ge d will be 
per mitte d after u n bli n di n g has o cc urre d. A G -1 2 0 s h o ul d be hel d f o r t he d urati o n of palliati ve 
ra di ot hera p y. A 2-w ee k was h o ut fr o m c o m pleti o n of ra di ot hera p y will be re q uire d pri or t o 
starti n g or res u mi n g A G-1 2 0. F or s u bjects r ecei vi n g palliati ve ra di ot hera p y pri or t o t he first d ose 
of o pe n -la b el A G-1 2 0, a re peat C T or M RI will be perf or me d u p o n c o m pleti o n of t he 2 -wee k 
was h o ut peri o d t o d oc u m e nt t he area t hat was irra diate d a n d t o ser ve as t he ne w baseli ne. All 
decisi o ns t o p urs ue palliati ve ra di ot hera p y will re q uire S p o ns or a n d/ or Me dical M o nit or 
a p pr o val.  
If t he pri mar y e n d p oi nt is statisticall y ne gati ve, all o n g oi n g A G-1 2 0 s u bjects will be per mitte d t o 
c o nti n ue recei vi n g o p e n -l a bel A G-1 2 0 f oll o wi n g u n bli n di n g at t he discreti o n of t he treati n g 
i n vesti gat or. Palliati ve ra di ot hera p y will be all o we d f or s u bjects w h o c o ntin ue recei vi n g A G -1 2 0 
as descri be d i n t he prece di n g “statisticall y p ositi ve” para gra p h. S u bjects w h o were recei vi n g 
place b o will n ot be per mitte d t o recei ve o pe n -la bel A G-1 2 0 i n t his sce nari o a n d will c o me off 
st u d y. 
9. 7.  
St u d y Tre at me nt Pre p ar ati o n a n d A d mi nist r ati o n 
Dail y tr eat me nt wit h A G -1 2 0 or place b o will be gi n o n C 1 D 1; cli nical o bser vati o ns will be 
c o n d ucte d o ver 4 h o urs f oll o wi n g t he first d ose of st u d y treat me nt o n C 1 D 1. D osi n g is 
c o nti n u o us; t here are n o pla n ne d i nter -c ycle rest p eri o ds. S u bjects s h o ul d  be i nstr ucte d t o ta ke 
t heir Q D d ose at a p pr o xi matel y t he s a me ti me eac h da y. 
S u bjects s h o ul d be i nstr ucte d t o s wall o w ta blets w h ole a n d t o n ot c he w t he ta blets. S u bjects ma y 
ta ke A G-1 2 0 or place b o ta blets wit h or wit h o ut f o o d. S u bjects s h o ul d be a d vise d t hat if 
A G -1 2 0/ place b o ta blets are ta ke n wit h f o o d, t h e s u bject s h o ul d a v oi d gra pefr uit or gra pefr uit 
pr o d ucts a n d a v oi d c o ns u mi n g a hi g h -fat meal. Please refer t o e x a m ples of l o w-fat a n d hi g h-fat 
meals i n A p pe n di x  1 5. 7 . 
If t he s u bject f or gets t o ta ke t he dail y d ose, t he n t he y s h o ul d ta ke A G-1 2 0 or place b o wit hi n 
1 2  h o urs after t h e misse d d ose. If m ore t h a n 1 2 h o urs ha ve el a pse d, t he n t h at d ose s h o ul d be 
o mit te d, a n d t he s u bject s h o ul d res u me treat me nt wit h t he ne xt sc he d ule d d ose. 

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S u bjects will c o nti n ue t o recei v e best s u p p orti ve care t hr o u g h o ut t he st u d y, re gar dl ess of 
treat me nt ar m. 
S u bjects ma y c o nti n ue wit h t heir assi g ne d st u d y tr eat me nt u ntil disease pr o gressi o n, 
de vel o p me nt of u nacce pt a ble t o xicit y, c o nfir me d pre g na nc y, d eat h, wit h dra wal of c o ns e nt, t he 
s u bject is l ost t o f oll o w-u p, or t he S p o ns or u n bli n ds or e n ds t he st u d y, w hic he ver occ urs first. 
S u bjects w h o are d eter mi ne d t o be o n A G -1 2 0 u p o n st u d y u n bli n di n g ma y c o nti n ue o n A G -1 2 0. 
F or s u bjects w h o are d eter mi ne d t o be o n A G -1 2 0 u p o n ra di o gra p hic diseas e pr o gressi o n a n d 
ha ve de m o nstrat e d cli nic al be nefit, PIs, wit h c o ns ult fr o m t he S p o ns or, ma y kee p t he s u bjects o n 
A G -1 2 0 aft er t he dise ase pr o gressi o n.  ( See Secti o n  9. 6  f or a d diti o nal u n bli n di n g sce n ari os.) 
9. 8.  
Criteri a f or D ose M o dific ati o n, Disc o nti n u ati o n of St u d y Tre at me nt, 
C o nti n u ati o n Be y o n d R a di o gr a p hic Pr o gressi o n, a n d All o w a nce of 
P alli ati ve R a di ot her a p y  
9. 8. 1.  
St u d y Tre at me nt D ose M o dific ati o n a n d St o p pi n g Criteri a  
9. 8. 1. 1.  
D ose M o dific ati o ns a n d Del a ys  
F or a n y A E, i ncl u di n g A Es n ot s pecificall y me nti o ne d i n Ta ble 1 , t he I n v esti gat or ma y d eci de t o 
dela y d osi n g or m o dif y t he d ose of A G -1 2 0/ place b o base d o n cli nical j u d g me nt. T hese decisi o ns 
s h o ul d be disc usse d wit h t he Me dical M o nit or pri or t o i m ple me ntati o n. D ose m o dificati o ns of 
A G -1 2 0/ place b o fr o m 5 0 0 m g t o 2 5 0 m g will be per mitte d o n st u d y f or ma na ge me nt of A Es 
(Ta ble 1 ). If m ore t h a n o ne A E occ urs t hat w o ul d re q uire a d ose m o dificati o n, u p o n res ol uti o n of 
all A Es t o baseli ne or Gra de 1, A G -1 2 0/ place b o s h o ul d be d ose re d u ce d t o 2 5 0 m g. Re -
escalati o n ma y be all o we d wit h a p pr o val fr o m t he Me dical M o nit or.  
D ose dela ys are disc o ura ge d, e x ce pt as nee d e d f or ma na ge me nt of A Es, d ose h ol ds d uri n g 
palliati ve ra di ot hera p y, a n d was h o ut fr o m palliati ve ra di ot hera p y. D ose d ela ys u p t o 2 8  da ys will 
be per mitte d at t he discreti o n of t he I n v esti gat or i n c o ns ultati o n wit h t he Me dical M o nit or f or 
reas o ns i ncl u di n g ma nage me nt of A Es a n d f or miti gati n g cir c u msta nces (e g, pla n ne d 
pr oce d ures). Palliati ve ra di ot hera p y deli vere d i n t he u n bli n de d o pe n -la bel cr oss o ver p eri o d or i n 
t he setti n g of c o nti n uati o n of A G-1 2 0 be y o n d dis ease pr o gressi o n will re q uire a 2 -wee k was h o ut 
pe ri o d after ra di ot hera p y bef ore t h e res u m pti o n of A G-1 2 0 treat me nt  (see S ecti o n 9. 8. 1. 3 ). 
Palliati ve biliar y dec o m pressi o n pr oce d ures will b e per mitt e d o n st u d y a n d will n ot re q uire 
i nterr u pti o n of A G-1 2 0/ place b o.  
If t he s u bject ca n n ot res u me A G -1 2 0/ place b o wit hi n 2 8 da ys, t he s u bject s h o ul d be disc o nti n ue d 
fr o m st u d y me dicati o n. Ot her reas o ns f or tr eat me nt ter mi nati o n are pr o vi d e d i n Secti o n  8. 5 . If 
A G -1 2 0 or pla ce b o is disc o nti n ue d, t he s u bject will c o m plete t he E O T a n d F oll o w -u p Visits, a n d 
t he n e nter P F S f oll o w-u p (if disease h as n ot pr o gresse d) a n d s ur vi val f oll o w -u p. E x e m pti o ns 
ma y b e c o nsi dere d f or t h ose s u bjects w h o are deter mi ne d b y t he I n vesti gat or t o ha ve recei v e d 
cli nical be nefit fr o m t reat me nt. If a d ose is del a ye d f or t he ma na ge me nt of a n A E, t he s u bject 
s h o ul d res u me t he st u d y at t he ne xt pla n ne d visit wit hi n a d osi n g c ycl e (e g, if t he s u bject di d n ot 
start d osi n g at C 3 D 1 d ue t o ma na ge me nt of a n A E, t he n d osi n g w o ul d be res u me d at C 3 D 1 u p o n 
res ol uti o n of t he A E, n ot C 3 D 1 5).  

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T a ble 1 : 
M a n a ge me nt of A d vers e E ve nts  
A d verse E ve nts  
Acti o n  
Gra de 2 na usea or 
v o miti n g (relate d or 
u nrelate d)  
 
C o nsi der h ol di n g d ose of A G -1 2 0/ place b o u ntil res ol uti o n of A E t o Gra de 
≤1 wit hi n 2 8 da ys of s u p p orti ve t hera p y.  
 
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of 
care. 
 
Ma y res u me A G 1 2 0/ place b o at sa me d ose.  
Gra de 3 a d verse e ve nts 
(relate d, first e ve nt) 
 
H ol d d ose of A G -1 2 0/ place b o u ntil res ol uti o n t o Gra d e ≤1 or baseli ne 
wit hi n 2 8 da ys of s u p p orti ve t hera p y a n d t he n res u me d ose.  
 
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of 
care. 
 
If t he Gra de 3 A E rec urs (a sec o n d ti me), c o nsi der re d uci n g A G-
1 2 0/ place b o t o 2 5 0 m g i n c o ns ultati o n wit h t he Me dical M o nit or. Re -
escalati o n ma y be per mitte d after disc ussi o n wit h t he Me dical M o nit or.  
 
If t he Gra de 3 A E rec urs (a t hir d ti me) des pite d ose re d ucti o n of A G-
1 2 0/ place b o, t he n c o nsi der disc o nti n ui n g A G -1 2 0/ place b o i n c o ns ultati o n 
wit h t he Me di cal M o nit or. 
Gra de 4 a d verse e ve nts 
(relate d, first e ve nt) 
 
H ol d A G -1 2 0/ place b o.  
 
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of 
care. 
 
If t he A E res ol ves t o Gra de ≤1 or baseli ne wit hi n 2 8 da ys, t he n restart A G -
1 2 0/ place b o d osi n g a t 2 5 0 m g i n c o ns ultati o n wit h t he Me dical M o nit or.  
 
If t he A E d oes n ot res ol ve t o Gra de ≤1 or baseli ne wit hi n 2 8 da ys, c o nsi der 
disc o nti n ui n g st u d y treat me nt i n c o ns ultati o n wit h t he Me dical M o nit or.  
 
If t he Gra de 4 A E rec urs (a sec o n d ti me), des pite d ose re d ucti o n, A G-
1 2 0/ place b o s h o ul d be disc o nti n ue d i n c o ns ultati o n wit h t he Me dical 
M o nit or.  
* See T a ble  2  f or s pecific d ose m o dificati o ns f or Q T c F pr ol o n gati o n. 
9. 8. 1. 2.  
C o nti n u ati o n of Tre at me nt Be y o n d R a di o gr a p hic Pr o gressi o n  
I n t he e ve nt of ra di o gra p hic pr o gressi o n per R E CI S T v 1. 1 b ut i n t he a bse nce of cli nical 
deteri orati o n, w ors e ni n g E C O G perf or ma nce stat us, or disease pr o gressi o n t hat ma y c o m pr o mise 
or ga n f u ncti o n, t he s u bject ma y c o nti n ue t o recei v e st u d y tr eat me nt wit h A G -1 2 0 at t he 
discreti o n of t he treati n g p h ysicia n i n c o ns ultati o n wit h t he S p o n s or Me dical M o nit or. If t here is 
cli nical deteri orati o n or c o nti n ue d ra di o gra p hic pr o gressi o n d oc u me nte d o n s u bse q ue nt i ma gi n g, 
treat me nt will be disc o nti n ue d a n d t he s u bject will c o m plete t he E O T a n d F oll o w -u p Visits, a n d 
e nter s ur vi val f oll o w -u p.  
9. 8. 1. 3.  
P alli at i ve R a di ot her a p y After U n bli n di n g After Dise ase Pr o g ressi o n 
Palliati ve ra di ot hera p y t o treat s y m pt o matic pre -e xisti n g or ne w n o n -tar get lesi o ns ( per R E CI S T 
v 1. 1) t hat ca n n ot ot her wise be me dicall y ma na ge d will be per mitte d after disease pr o gressi o n has 
bee n c o nfir me d a n d u n bli n di n g has occ urre d. A G -1 2 0 s h o ul d be hel d f or t h e d urati o n of 
palliati ve ra di ot hera p y. A 2 -wee k was h o ut fr o m c o m pleti o n of ra di ot hera p y will be re q uire d 
pri or t o starti n g or res u mi n g A G -1 2 0. F or s u bj ects ra n d o mize d t o place b o w h o recei ve palliati ve 
ra di ot hera p y b ef ore cr ossi n g o ver t o A G-1 2 0, a re peat C T or M RI will be p erf or me d u p o n 
c o m pleti o n of t he 2 -wee k was h o ut peri o d t o d oc u me nt t he area t hat was irra diate d a n d t o ser ve 
as t he ne w bas eli ne a gai nst w hic h all s u bse q ue nt R E CI S T v 1. 1 assess me nts will be perf or me d, 

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f or t he p ur p ose of d oc u m e nti n g P F S 2 d uri n g t he u n bli n de d o pe n -la bel cr oss o ver peri o d (s ee 
Secti o n  1 2. 1 2. 1 ). F or s u bjects per mitte d t o c o nti n ue o n o pe n -la bel A G-1 2 0 be y o n d d o c u me nte d 
ra di o gra p hic pr o gressi o n, a ne w bas eli ne i ma gi n g assess me nt will n ot be re q uire d a n d t he 
i ma gi n g assess me nts will c o nti n ue o n t he c urre nt s c he d ule. All decisi o ns t o p urs ue palliati ve 
ra di ot hera p y will re q uire Me dical M o nit or a p pr o val. 
9. 8. 1. 4.  
Bili ar y Tr act O bstr ucti o n D uri n g Tre at me nt  
I n t he e ve nt of t h e de vel o p me nt of o bstr ucti ve ja u n dice d ue t o biliar y tract o bstr ucti o n, t he 
a p pr o priate m eas ur es will be ta ke n t o dia g n ose a n d relie ve t he o bstr ucti o n.  St u d y treat me nt 
i nterr u pti o n is n ot re q uire d, b ut will be per mitte d at t he discreti o n of t he I n vesti gat or. 
9. 9.  
G ui deli nes f or M a n a ge me nt of Q T Pr ol o n g ati o n  
T he disc ussi o n of t he e mer ge ncy m a n a ge me nt of T ors a des de p oi ntes a n d its he m o dy n a mic 
c o nse q ue nces is b ey o n d t he sc o pe of t his g ui deli ne.  
E ve nts of Q Tc F pr ol o n gati o n ≥Gra de 2 s h o ul d be re p orte d as A Es of s pecial i nterest ( A E SIs) t o 
t he S p o ns or wit hi n 2 4 h o urs, acc or di n g t o e x pe dite d re p orti n g pr oce d ures (see Secti o n  1 1. 2. 3 ). 
T he f oll o wi n g are g ui d eli nes f or t he ma n a ge me nt of A Es of s pecial i nterest base d o n t he A G -1 2 0 
n o n -cli nical a n d cli nic al safet y fi n di n gs i n s u bjects wit h s oli d t u m ors t o date.  
Pr ol o n gati o n of Q Tc F i nt er val has b ee n o bser ve d i n m o n ke ys at relati vel y hi g h d oses of A G -1 2 0 
(see Secti o n  5. 3. 2. 2 ) a n d has bee n i de ntifie d as a n e x pecte d ris k of treat me nt wit h A G-1 2 0 (see 
t he I n v esti gat or’s Br oc h ure). As of 1 6 J a n uar y 2 0 1 6, 1 2 ( 1 0 %) of 1 2 2 s u bjects i n St u d y 
A G 1 2 0 -C -0 0 2 a n d 1 9  ( 1 6 %) of 11 9  s u bjects i n St u d y A G 1 2 0-C -0 0 1 ha v e e x perie nce d Q T 
pr ol o n gati o n w hile recei vi n g A G -1 2 0.  
S u bjects ma y be at i ncrease d ris k f or t he d e vel o p me nt of Q T pr ol o n gati o n w he n treate d wit h 
A G -1 2 0 i n c o m bi nati o n wit h fl u or o q ui n ol o nes, az ole a ntif u n gal a ge nts, or se r ot o ni n ( 5‐H T 3) 
a nta g o nists. I n v esti gat ors nee d t o be vi gila nt; refrai n fr o m a d mi nisteri n g c o nc o mita nt 
me dicati o ns ass ociate d wit h Q T pr ol o n gati o n a n d if n o ot her t hera pe utic o pti o ns are a v aila ble, 
m o nit or s u bjects recei vi n g st u d y treat me nt wit h t he c o m bi n ati o n of t hese dr u gs, a n d e val uate 
E C G a n d electr ol ytes (i ncl u di n g p otassi u m, ma g n esi u m, a n d calci u m) p artic ularl y i n s u bjects 
prese nti n g wit h na usea, v o miti n g, or diarr hea. S yste mic a d mi nistrati o n of a m o derate or str o n g 
C Y P 3 A 4 i n hi bit or re q uires caref ul m o nit ori n g of Q Tc F (see Secti o n  9. 1 3. 2 ). 
S u bjects w h o e x perie nce pr ol o n gati o n of t h e Q Tc F i nter val t o > 4 8 0 msec ( C T C A E Gra de ≥2) 
w hile recei vi n g st u d y treat me nt, s h o ul d be pr o m ptl y e v al uate d f or ca us alit y of t he Q Tc F 
pr ol o n gati o n a n d m a na ge d acc or di n g t o t he f oll o wi n g g ui deli nes a n d T a ble  2 : 
 Le v els  of ele ctr ol ytes ( p otassi u m, calci u m, a n d ma g nesi u m) s h o ul d be c hec ke d a n d 
s u p ple me ntati o n gi ve n t o c orrect a n y val u es o utsi de t he n or mal r a n ge.  
 C o nc o mita nt t hera pies s h o ul d be re vie we d a n d a dj uste d as a p pr o pri ate f or 
me dicati o ns wit h k n o w n Q T pr ol o n gi n g e ffects. 
 If n o ot her ca use is i de ntifie d a n d t he I n v esti gat or belie ves it is a p pr o priate, 
partic ularl y if Q T c F re m ai ns ele vate d (after a b o v e meas ures ha ve b ee n i m ple me nte d, 
or as deter mi ne d b y t h e I n vesti gat or), st u d y tr eat me nt ma y b e i nterr u pte d, a n d a n 
E C G s h o ul d be rec h ec ke d i n a p pr o xi matel y 1 wee k after t he Q Tc F pr ol o n gati o n was 

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first o bser ve d or m ore fre q ue ntl y as cli nicall y i n di cate d. If Q Tc F has rec o v ere d or 
i m pr o ve d a n d t he I n v esti gat or b elie ves it is safe t o d o s o, re-c h alle n ge wit h st u d y 
treat me nt s h o ul d be c o nsi dere d if hel d. 
 E C Gs s h o ul d be c o n d uct e d at least wee kl y (e g, at e ver y sc h e d ule d visit) f or 2  wee ks 
f oll o wi n g Q Tc F re d ucti o n ≤4 8 0 msec. 
T a ble  2 : 
M a n a ge me nt of Q T Pr ol o n g ati o n b y C T C A E Gr a de  
C T C A E Gr a de  
M a n a ge me nt  
Gra de 2  
( Q Tc F > 4 8 0 a n d ≤5 0 0 msec) 
 
T he d ose of st u d y treat me nt ma y be re d uce d t o 2 5 0 m g Q D 
wit h o ut i nterr u pti o n of d osi n g. T he d ose of st u d y treat me nt 
ma y be re -escalate d t o t he pri or d ose i n ≥1 4  da ys after Q T 
pr ol o n gati o n has decrease d t o ≤Gra de 1.  
Gra de 3  
( Q Tc F > 5 0 0 msec o n at least t w o 
se parate E C Gs) 
 
 
H os pitalizati o n f or c o nti n u o us car diac m o nit ori n g a n d 
e val uati o n b y a car di ol o gist s h o ul d b ot h be c o nsi dere d.  
 
D osi n g wit h st u d y treat me nt will be i nterr u pte d. If Q T c F 
ret ur ns t o wit hi n 3 0 msec of baseli ne or < 4 5 0 msec f or 
males a n d < 4 7 0  msec f or fe males wit hi n 1 4 da ys, treat me nt 
ma y be res u me d at a re d uce d d ose of 2 5 0 m g.  
 
T he d ose of st u d y treat me nt ca n n ot be re -escalate d 
f oll o wi n g d ose re d ucti o n f or Gra de 3 Q T c F pr ol o n gati o n 
u nless t he pr ol o n g ati o n was ass ociate d wit h a n electr ol yte 
a b n or malit y or c o nc o mita nt me dicati o n.  
Gra de 4  
( Q Tc F > 5 0 0 msec or > 6 0 msec 
c ha n ge fr o m baseli ne wit h T orsa des 
de p oi ntes or p ol y m or p hic 
ve ntric ular tac h ycar dia or 
si g ns/s y m pt o ms of seri o us 
arr h yt h mia) 
 
S u bj ects s h o ul d be a d mitte d t o a h os pital f or c o nti n u o us 
car diac m o nit ori n g a n d disc har ge d o nl y after re vie w b y a 
car di ol o gist. 
 
D osi n g wit h st u d y treat me nt s h o ul d be per ma ne ntl y 
disc o nti n ue d.  
9. 1 0.  
D ur ati o n of S u bject P artici p ati o n  
9. 1 0. 1.  
Tre at me nt D ur ati o n  
Treat me nt wit h A G -1 2 0 or place b o will c o nti n ue u ntil disease pr o gressi o n, de vel o p me nt of ot her 
u nacce pta ble t o xicit y, c o nfir me d pre g n a nc y, deat h, wit h dra wal of c o nse nt, t he s u bject is l ost t o 
f oll o w-u p, or t he S p o ns or u n bli n ds or e n ds t he st u d y, w hic h e ver occ urs first. S u bjects  w h o are 
deter mi ne d t o be o n A G -1 2 0 u p o n st u d y u n bli n di n g ma y c o nti n ue o n A G -1 2 0. F or s u bjects w h o 
are det er mi ne d t o be o n A G -1 2 0 u p o n ra di o gra p hic disease pr o gressi o n a n d ha ve de m o nstrat e d 
cli nical be nefit, PIs, wit h c o ns ult fr o m t he S p o ns or, ma y k ee p t he  s u bj ects o n A G-1 2 0 aft er t he 
disease pr o gressi o n.  ( See Secti o n  9. 6  f or a d diti o nal u n bli n di n g sce nari os.) 
F oll o wi n g disc o nti n uati o n of st u d y tr eat me n t, s u bjects are t o atte n d a F oll o w-u p Visit at least 
2 8  da ys a n d n o m ore t ha n 3 3 da ys after t he last d ose f or st u d y assess me nts. W he n st u d y 
treat me nt is wit h hel d fr o m a s u bject i n or der t o res ol ve t o xicit y a n d t he s u bject d oes n ot 
s u bse q ue ntl y restart treat me nt, E O T is defi ne d as t he date w h e n t he st u d y dr u g was first hel d. 

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S u bjects s h o ul d pr ocee d wit h E O T assess me nts, safet y, P F S, a n d s ur vi v al f oll o w -u p. If t he 
decisi o n t o n ot restart st u d y treat me nt occ urs o utsi de of t he 2 8 -d a y safet y f oll o w -u p wi n d o w, t h e 
s u bject s h o ul d pr ocee d wit h P F S a n d s ur vi val f oll o w-u p.  
S u bjects will be c o ntacte d a p pr o xi matel y e ver y 1 2 wee ks after E O T t o ass ess s ur vi val stat us, 
H R Q O L ( u ntil t he start of ne w a ntica ncer t hera p y), a n d t o d oc u me nt recei pt of s u bse q ue nt 
a ntica ncer t hera p y  u nless c o nse nt t o partici pate is wit h dra w n . 
9. 1 1.  
Tre at me nt C o m pli a nce  
S u bjects will be dis pe nse d t he a p pr o priat e n u m ber of S p o ns or -pac k a ge d, la bele d b ottle(s) f or at 
least 2 8 da ys of d osi n g o n Da y 1 of eac h c ycle. T he s u bject will be as ke d t o ret ur n all b ott les a n d 
u n use d ta blets ( or e m pt y b ottles) o n Da y 1 of eac h c ycle or at t heir ne xt st u d y visit f or 
assess me nt of c o m plia nce wit h t he d osi n g re gi me n.  
S u bjects will be gi ve n a S p o ns or - a n d I R B -a p pr o ve d d osi n g diar y f or eac h treat me nt c ycl e. T he y 
s h o ul d rec or d rele va nt i nf or mati o n re gar di n g t heir st u d y treat me nt i n t he diar y (e g, c o nfir mati o n 
t hat eac h d ail y d ose was ta ke n, reas o ns f or misse d d oses). Treat me nt c o m plia nce will be ass esse d 
base d o n ret ur n of u n use d dr u g a n d t he d osi n g diar y.  
9. 1 2.  
St u d y Tre at me nt Acc o u nt a bilit y  
Acc o u nta bilit y f or t he st u d y treat me nt at t he st u d y site is t he res p o nsi bilit y of t he I n vesti gat or. 
T he I n vesti gat or will e ns ure t hat t he st u d y treat me nt is use d o nl y i n acc or da nce wit h t his 
pr ot oc ol. W here all o we d, t he I n v esti gat or ma y c h o ose t o  assi g n dr u g acc o u nta bilit y 
res p o nsi bilities t o a p har macist or ot her a p pr o priate i n di vi d ual. 
T he I n vesti gat or or d ele gate will mai ntai n acc urat e dr u g acc o u nta bilit y rec or ds i n dicati n g t he 
dr u g’s deli ver y d ate t o t he site, i n ve nt or y at t he site, use b y eac h s u bject, a n d ret ur n t o t he 
S p o ns or or its desi g nee ( or dis p osal of t he dr u g, if a p pr o ve d b y t he S p o ns or). T hese rec or ds will 
a de q uatel y d o c u me nt t hat t he s u bjects were pr o vi de d t he d oses as s pecifie d i n t he pr ot oc ol a n d 
s h o ul d rec o ncile all st u d y treat ment recei ve d fr o m t he S p o ns or. Acc o u nta bilit y rec or ds will 
i ncl u de dates, q ua ntities, batc h/serial n u m bers, e x pirati o n dates (if a p plica ble), a n d s u bject 
n u m bers. T he S p o ns or or its desi g nee will re vie w dr u g acc o u nt a bilit y at t he site o n a n o n g oi n g 
basis d u ri n g m o nit ori n g visits. 
St u d y treat me nt m ust n ot be use d f or a n y p ur p ose ot her t ha n t he prese nt st u d y. St u d y treat me nt 
t hat has bee n dis pe nse d t o a s u bject a n d ret ur ne d u n use d m ust n ot be re-dis pe nse d t o a differe nt 
s u bject. 
S u bjects will recei ve i nstr ucti o ns f or h o me a d mi nistrati o n of st u d y treat me nt al o n g wit h a diar y 
t o rec or d t he d ate a n d ti me of eac h d ose, as well as t he n u m ber of ta bl ets ta ke n. 
All u n use d a n d use d st u d y treat me nt s h o ul d be ret ai ne d at t he site u ntil t he y are i n ve nt ori e d a n d 
verifie d b y st u d y site pers o n nel a n d/ or t he st u d y m o nit or. All use d, u n use d, or e x pire d st u d y 
treat me nt will be ret ur n e d t o t he S p o ns or or its desi g nee or if a ut h orize d, dis p ose d of at t he st u d y 
site per t he site’s Sta n dar d O perati n g Pr oce d ures ( S O Ps) a n d d oc u me nte d . All material 
c o ntai ni n g A G -1 2 0 a n d/ or matc he d place b o will b e treate d a n d dis p ose d of as hazar d o us waste i n 
acc or da nce wit h g o v er ni n g re g ulati o ns.  

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9. 1 3.  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d Tre at me nts  
9. 1 3. 1.  
Pri o r Me dic ati o ns a n d Pr o ce d ures  
All me dicati o ns a d mi niste re d a n d pr oce d ures c o n d ucte d wit hi n 2 8 da ys pri or t o t he first da y of 
st u d y treat me nt a d mi nistrati o n are t o be rec or de d o n t he e C R F. I n a d diti o n, all pri or treat me nts 
f or t he u n derl yi n g mali g na nc y s h o ul d be rec or de d. 
9. 1 3. 2.  
C o nc o mit a nt T her a p y Re q uiri n g C aref ul M o nit ori n g  
C o nc o mita nt use of dr u gs wit h a p ote ntial Q T pr ol o n gati o n s h o ul d be a v oi de d a n d re pl ace d wit h 
alter nati ve treat me nts. If t his is n ot p ossi ble, s u bjects recei vi n g t hes e dr u gs s h o ul d be a de q uatel y 
m o nit ore d.  
T hese me dicati o ns i ncl u de b ut are n ot l i mite d t o: 
 Fl u or o q ui n ol o nes s uc h as ci pr ofl o x aci n a n d m o xifl o x aci n  
 Az ole a ntif u n gals s uc h as fl uc o naz ole a n d p osac o naz ole  
 Ser ot o ni n  ( 5-H T 3) a nta g o nists  s uc h as gra nisetr o n a n d o n da nsetr o n 
Ot her e x a m ples of dr u gs k n o w n t o pr ol o n g t he Q T i nter val are liste d i n A p pe n di x  1 5. 5 . 
S yste mic a d mi nistrati o n of m o derate or str o n g C Y P 3 A 4 i n hi bit ors ( A p pe n di x  1 5. 6 ) re q uires 
caref ul m o nit ori n g of t h e Q Tc (see Secti o n  9. 1 3. 4 ). 
9. 1 3. 3.  
Pr o hi bite d C o nc o mit a nt T her a p y  
A ntica ncer t hera p y ot her t ha n t he treat me nt o utli ne d i n t he pr ot oc ol is n ot per mitte d d uri n g t h e 
st u d y. If alter nati ve t h era p y is re q uire d f or treat me nt of t he s u bject’s diseas e, t he s u bject s h o ul d 
be disc o nti n ue d fr o m t he st u d y treat me nt.  
9. 1 3. 4.  
Dr u g -Dr u g I nter a cti o ns 
A G -1 2 0 is mai nl y met a b olize d b y C Y P 3 A 4 a n d, t heref ore, s u bjects s h o ul d n ot use str o n g 
C Y P 3 A 4 i n d ucers ( A p pe n di x  1 5. 2 ) d uri n g treat me nt wit h A G -1 2 0.  
A G -1 2 0 cli nical trials a n d p h ysi ol o gicall y base d p har mac o ki netic ( P B P K) si m ulati o ns ha ve 
s h o w n t hat A G-1 2 0 plas ma c o nce ntr ati o ns i ncrease wit h c o -a d mi nistrati o n of a str o n g or 
m o derate C Y P 3 A 4 i n hi bit or, a n d i ncrease d A G -1 2 0 plas ma c o nce ntrati o ns ma y i ncreas e t he ris k 
of Q Tc pr ol o n gati o n. T heref ore, alter nati ve t hera pies t hat are n ot str o n g or m o derate C Y P 3 A 4 
i n hi bit ors s h o ul d be c o nsi dere d d uri n g treat me nt wit h A G-1 2 0. If c o nc o mita nt use of str o n g or 
m o derate C Y P 3 A 4 i n hi bit ors is u na v oi da ble, s u bjects s h o ul d be m o nit ore d f or i ncrease d ris k of 
Q Tc pr ol o n gati o n.  
A G -1 2 0 is a n i n d ucer of h u ma n C Y P 3 A 4/ 5 a n d ma y als o i n d uce C Y P 2 B 6, C Y P 2 C 8, a n d 
C Y P 2 C 9. T heref ore, m e dicati o ns of se nsiti ve C Y P 3 A 4 s u bstrates wit h a narr o w t hera pe utic 
wi n d o w ( A p pe n di x  1 5. 2 ) s h o ul d be a v oi de d u nless t he s u bject ca n b e tra nsferre d t o ot her 
me dicati o ns pri or t o e nr olli n g. C o nsi der alter nati ve t hera pies t h at are n ot s e n siti ve s u bstrates of 
C Y P 2 C 9 (e g, p he n yt oi n, warfari n). M o nit or i nter nati o nal n or malize d rati o (I N R) le vels m ore 
fre q ue ntl y i n s u bjects r ecei vi n g w arfari n (a C Y P 2 C 9 s u bstrate) d uri n g i nitiati o n or 
disc o nti n uati o n of A G -1 2 0.  

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A G -1 2 0 is a n i n hi bit or of O A T 3. A  P B P K si m ulati o n pre dicte d a n i ncreas e ( < 3 0 %) i n t he A U C 
of a se nsiti ve O A T 3 s u bstrate, s u g gesti n g t h at t he p ote ntial f or cli nicall y rel e va nt dr u g 
i nteracti o ns d ue t o t he i n hi biti o n of O A T 3 a p pears t o be l o w. 
C oa d mi nistrati o n of A G -1 2 0 ma y d ecrease t h e c o n ce ntrati o ns of h or m o n al c o ntrace pti ves.  
9. 1 3. 5.  
All o w e d C o nc o mit a nt Me dic ati o ns, Pr oce d ures, a n d Tre at me nts  
Me dicati o ns a n d treat me nts ot her t ha n t h ose s pecifie d a b o ve are p er mitte d d uri n g t he st u d y. All 
i nterc urre nt me dical c o n diti o ns a n d c o m plicati o ns of t he u n derl yi n g mali g na nc y will be treate d 
at t he discreti o n of t he I n vesti gat or acc or di n g t o acce pta bl e l ocal sta n dar ds of me dical care.  
If cli nicall y i n dicate d, p alliati ve biliar y dec o m pressi o n pr oce d ures will be per mitte d o n-st u d y 
after disc ussi o n wit h t he Me di cal M o nit or. 
S u bjects s h o ul d recei ve a nal gesics, a ntie metics, a nti -i nfecti ves, a nti p yretics, bl o o d pr o d ucts, a n d 
a n y ot h er best s u p p orti ve care m eas ur es (e x cl u di n g a ntica ncer t hera p y) as necessar y, ass u mi n g 
n o dr u g i nteracti o n p ote ntial.  
Palliati ve ra di ot hera p y f or s y m pt o matic n o n-tar get lesi o ns t hat ca n n ot ot her wise be me dicall y 
ma na ge d will be per mitte d after Me di cal M o nit or a p pr o val after disease pr o gressi o n has bee n 
verifie d a n d u n bli n di n g h as occ urre d, a n d i n t he s etti n g of c o nti n uati o n of A G-1 2 0 be y o n d 
disease pr o gressi o n, as d escri be d i n Secti o n  9. 8. 1. 3 . 
Gr o wt h fact ors ( gra n ul oc yt e c ol o n y -sti m ulati n g fact or [ G-C S F], gra n ul oc yt e -macr o p ha ge 
c ol o n y-sti m ulati n g fact or [ G M-C S F]) ca n be use d t o s u p p ort s u bjects w h o ha ve de v el o pe d d ose -
li miti n g Gra de 4 ne utr o pe nia or Gra de 3 n e utr o pe nia wit h fe ver a n d/ or i nfecti o n. T he use of 
er yt hr o p oiesis sti m ulati n g a ge nts is per mitte d acc or di n g t o t he A merica n S ocie t y of Cli nical 
O nc ol o g y G ui deli nes (Riz z o, et al. 2 0 1 0 ). 
All c o nc o mita nt me dicat i o ns a n d a n y pr oce d ures perf or me d d uri n g t he st u d y, i ncl u di n g t h ose 
use d t o treat A Es, are t o be re p ort e d o n t he e C R F.  

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1 0.  
S T U D Y A S S E S S M E N T S  
1 0. 1.  
Sc he d ule of E ve nts  
Ta ble  3  pr o vi des t he s c he d ule of assess me nts f or t his st u d y. Pre -scree ni n g or scree ni n g f or 
I D H 1 m will occ ur at a ce ntral la b usi n g eit her t he m ost rece nt ba n ke d t u m or sa m ple ( prefera bl y 
fr o m wit hi n t he last 3 years) or a fres h bi o ps y. P ote ntial s u bjects will si g n a pre -s cree ni n g or 
scree ni n g c o nse nt f or m f or t he p ur p ose of deter mi ni n g I D H 1 m uta nt stat us ( R 1 3 2 C/ L/ G/ H/ S 
m utati o n varia nts teste d). After o btai ni n g writte n i nf or me d c o ns e nt f or t he st u d y o verall, all 
s u bjects will u n der g o Scree ni n g pr oce d ures t o det er mi ne eli gi bilit y wit hi n 2 8  da ys pri or t o t he 
start of st u d y tr eat me nt o n C 1 D 1, wit h t he e x ce pti o n of baseli ne ra di o gra p hic sca ns, w hic h 
s h o ul d be perf or m e d wit hi n 2 1 da ys pri or t o C 1 D 1. S u bjects are t o atte n d st u d y ce nter visits as 
o utli ne d i n t he Sc he d ule of Assess me nts ( Ta ble  3 ). 
St u d y ce nter visits will be c o n d ucte d o n a n o ut patie nt basis w he ne ver p ossi ble. S u bjects are t o 
re mai n at t he st ud y ce nter f or 4 h o urs f oll o wi n g t h e C 1 D 1 a n d C 2 D 1 d oses f or P K/ P D a n d E C G 
assess me nts ( Ta ble  4 ). After t he Scree ni n g Visit, a s y m pt o m-directe d, li mite d p h ysic al e xa m 
s h o ul d be perf or m e d at e ac h C ycle, Da y 1 visit, per i nstit uti o n sta n dar ds of care.  
A n E O T Visit will be c o n d ucte d as s o o n as p ossi ble after disc o nti n ui n g st u d y treat me nt ( wit hi n 
5  da ys of last d ose of st u d y treat me nt, if st u d y dr u g d osi n g has  n ot bee n del a ye d); i n a d diti o n, 
s u bjects are t o atte n d a F oll o w-u p Visit 2 8  da ys ( n o m ore t ha n 3 3 da ys) after t he last d ose of 
st u d y treat me nt f or fi nal safet y assess me nts. If a s u bject’s d ose is hel d a n d it is s u bse q ue ntl y 
deci de d t o disc o nti n ue tr eat me n t, t he E O T Visit s h o ul d be c o n d ucte d as s o o n as p ossi ble, wit hi n 
2 8 da ys (a n d n o m or e t ha n 3 3 da ys) aft er t he last d ose of st u d y dr u g.  
O S f oll o w -u p assess me nts will occ ur a p pr o xi matel y e v er y 1 2 wee ks after E O T u nless t he s u bject 
is i n P F S f oll o w-u p at t hat  ti me. If a s u bject pr o gresses or d oes n ot c o m e b ac k f or s ca ns w hile i n 
P F S f oll o w -u p, t he n t he O S f oll o w -u p assess me nts will be gi n at t he ne xt pla n ne d O S f oll o w -u p 
ti me p oi nt, f oll o wi n g t he sc he d ule of e ver y 1 2 wee ks after E O T. O S f oll o w -u p will assess 
s ur vi val stat us a n d d oc u me ntati o n of recei pt a n d t y pe of s u bs e q ue nt a ntica ncer t hera p y u nless 
c o nse nt t o partici pate is wit h dra w n. If a s u bject b e gi ns a n e w a ntica ncer t h era p y d uri n g P F S 
f oll o w-u p, i nf or mati o n o n t he ne w t hera p y will nee d t o be e ntere d. O S f oll o w -u p will c o nti n ue 
u ntil all s u bjects ha ve die d, wit h dra w n c o nse nt, are l ost t o f oll o w -u p, or u ntil t he occ urre nce of 
1 5 0 O S e ve nts, w hic he v er occ urs first. H R Q O L ( u ntil t he start of ne w a ntica ncer t h era p y) 
assess me nts will be c ollecte d e ver y 1 2 wee ks after E O T.  
S u bjects w h o cr oss o ver fr o m t he place b o ar m t o t he acti ve ar m after d oc u me nte d disease 
pr o gressi o n, m ust c o nti n ue t o meet eli gi bilit y crit eria deter mi ne d i n t he E O T visit a n d will start 
a gai n wit h st u d y pr oce d ures as at C 1 D 1. F or t h ose s u bjects  w h o cr oss o ver, place b o will n ot be 
c o u nte d as a pri or li ne of t hera p y f or t h e p ur p ose of eli gi bilit y. T h ese s u bjects will c o nti n ue t o be 
e val uate d f or t u m or res p o nse b y t h e I n vesti gat or. F or s u bjects w h o recei ve palliati ve 
ra di ot hera p y after u n bli n di n g an d d uri n g t he cr oss o ver peri o d, t here will b e a 2 -wee k was h o ut 
peri o d after ra di ot hera p y bef ore t h e start of A G -1 2 0 treat me nt (see Secti o n 9. 8. 1. 3 ). A re p eat C T 
or M RI will be p erf or me d at t he e n d of t he 2 -wee k was h o ut peri o d t o d oc u me nt t he area t hat was 
irra diate d a n d t o ser ve as t he ne w baseli ne a gai nst w hic h all s u bse q ue nt R E CI S T v 1. 1 
assess me nts will be perf or me d, f or t he p ur p ose of d oc u me nti n g P F S 2 d uri n g t he u n bli n de d o p e n -
la bel cr oss o ver peri o d (s ee Secti o n  1 2. 1 2. 1 ). 

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Palliati ve ra di ot hera p y d eli vere d i n t he setti n g of c o nti n uati o n of A G -1 2 0 be y o n d dis ease 
pr o gressi o n will re q uire a 2 -wee k was h o ut peri o d after ra di ot hera p y bef ore t he res u m pti o n of 
A G -1 2 0 treat me nt (see S ecti o n 9. 8. 1. 3 ). I ma gi n g s h o ul d c o nti n ue o n sc he d ule per pr ot oc ol f or 
t hese s u bjects a n d n o a d diti o nal C T or M RI will be re q uir e d at t he e n d of t he 2-wee k was h o ut 
peri o d.  
A G -1 2 0 s h o ul d be hel d f or t he d urati o n of palliati ve ra di ot hera p y.  
O nce t he pri mar y e n d p oi nt of P F S  ( base d o n ce ntr al ra di ol o g y R E CI S T 1. 1 assess me nt) is 
statisticall y a nal yz e d, t he S p o ns or will u n bli n d t he treat me nt assi g n me nts of all s u bjects. 
S u bjects w h o were alrea d y recei vi n g A G -1 2 0 ma y  c o nti n ue t o r ecei ve A G -1 2 0 o n t he sa me 
assess me nt sc he d ule as b ef ore u n bli n di n g. I n t he s etti n g of a st atisticall y p ositi ve pri mar y 
e n d p oi nt, s u bjects w h o w ere recei vi n g place b o a n d c o nti n ue t o meet eli gi bilit y criteria will be 
gi ve n t he o p p ort u nit y t o cr oss o ver t o o pe n -la bel A G-1 2 0. S u bjects w h o cr oss o ver f oll o wi n g 
u n bli n di n g will f oll o w t he sa me assess m e nt sc he d ule as fr o m C 1 D 1.  
He mat ol o g y, s er u m c h e mistr y, circ ul ati n g t u m or D N A, a n d e x pl orat or y bi o mar ker assess me nts 
are re q uire d at b ot h t he E O T visit a n d at t he cr oss o ver C 1 D 1 visit. If t he cr oss o ver C 1 D 1 visit 
occ urs wit hi n 3 da ys of t he E O T visit, t hese la b orat or y assess me nts nee d n ot be re peate d.  

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Visit/ C ycle:  
Pre -
Scree ni n g  
Scree ni n g  
C ycle 1  
( +/-2 d a ys)  
C ycle 2  
( +/-2 d a ys)  
C ycle 3  
( +/-2 d a ys)  
C ycle 4 +  
( +/-2 d a ys)  
 
E O T 1 
S afet y  
F oll o w -
u p 2 
P F S 
F oll o w - 
u p 3 
S ur vi v al 
F oll o w -
u p  
St u d y D a y:  
 
D -2 8  
D 1 4 
D 1 5  
D 1 4 
D 1 5  
D 1  
D 1 5  
D 1  
 
D + 2 8  
 
 
C o nc o mita nt Me dicati o ns a n d 
Pr oce d ures  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
S ur vi val Stat us a n d Ne w 
A ntica ncer T hera p y C hec k  
 
 
 
 
 
 
 
 
 
 
 
 
X 2 8 
A b bre viati o ns: D = Da y; D N A = de o x yri b o n ucleic aci d; E C G = electr ocar di o gra m, E C H O = ec h ocar di o gra p h y; E C O G = Easter n C o o pera ti ve O nc ol o g y Gr o u p; 
E O T = e n d of treat me nt; L V E F = left ve ntric ular ej ecti o n fr acti o n; P D = p har mac o d y na mi c; P F S = pr o gressi o n -free s ur vi val; P K = p har mac o ki netic; 
P S  =  perf or ma nce stat us; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors  
N ote: all c ycles are 2 8 da ys ( +/- 2 da ys) i n d urati o n, t here ar e n o pla n ne d rest peri o ds bet wee n c ycles. 
* Res ults fr o m t he li mite d p h ysical e xa ms will be ca pt ure d i n s o urce d oc u me ntati o n, b ut t here is n o e C R F f or t hese e xa ms.  
1 Assess me nts t o be c o n d ucte d o n t he last d a y of st u d y treat me nt ( wit hi n 5 t o 3 3 da ys of last d ose of st u d y treat me nt). F or s u b j ects w h o cr oss o ver fr o m place b o 
ar m t o A G -1 2 0  after d oc u me nte d disease pr o gressi o n  or S p o ns or u n bli n di n g of t he st u d y , t heir eli gi bilit y t o cr oss o ver will be deter mi ne d base d o n pr oce d ures 
c o n d ucte d i n t he E O T Visit. If s u bj ects cr oss o ver, t he y will f oll o w t he sa me assess me nt sc he d ule as fr o m C 1 D 1.  
2 At least 2 8 da ys, a n d n o m ore t ha n 3 3 da ys after disc o nti n uati o n of treat me nt, s u bj ects will ret ur n t o u n der g o re vie w of c o nc o mita nt me dicati o ns, E C O G P S, 
a n d assess me nt f or res ol uti o n of a n y treat me nt -relate d t o xicit y.  
3 S u bj ects w h o disc o nti n ue s t u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n or wit h dra wal of c o nse nt will b e f oll o we d e ver y 6 wee ks after t he EO T 
Visit ( ± 5 da ys) f or t he first 8 assess me nts (ie, t hr o u g h wee k 4 8), a n d t he n e ver y 8 wee ks ( ± 5 da ys) t hereafter f or ra di o gra p h ic assess me nts u ntil d oc u me nte d 
disease pr o gressi o n, deat h, start of s u bse q ue nt a ntica ncer t hera p y, or wit h dra wal of c o nse nt.  
4 S u bj ects are t o re mai n at t he st u d y ce nter f or 4 h o urs f oll o wi n g t he C 1 D 1 a n d C 2 D 1 d oses f or P K/ P D a n d E C G assess me nts.  
5 Hei g ht is  t o be o btai ne d o nl y at t he Scree ni n g assess me nt. 
6 O n C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nt s h o ul d be c o n d ucte d pre -d ose.  
7 S yst olic a n d diast olic bl o o d press ure, heart rate, res pirat or y rate, a n d te m perat ure. Assess me nts s h o ul d be c o n d ucte d w hil e t he s u bj ect is seate d or s u pi ne. O n 
C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nts s h o ul d be c o n d uct e d pre -d ose.  
8 Pr oce d ure is t o be c o n d ucte d at Scree ni n g. T he sa me pr oce d ure t o e val uate L V E F s h o ul d be c o n d ucte d t hereafter o nl y if cli nica ll y i n dicate d. 
9 S u bj ects wil l ha ve m ost rece nt ba n ke d t u m or ( prefera bl y wit hi n t he last 3 years) or fres h bi o ps y sa m ples a vaila ble f or I D H 1 m c o nfir mati o n ( R 1 3 2 C/ L/ G/ H/ S 
m utati o n varia nts teste d) b y ce ntral la b orat or y pri or t o recei vi n g t heir first d ose of st u d y tre at me nt (see Secti o n  1 0. 4 ). T his sa m ple ca n be c ollecte d at eit her 
Pre -scree ni n g or t he Scree ni n g Visit. At least 1 0 0 micr o ns of f or mali n -fi xe d paraffi n-e m b e d de d tiss ue or a t u m or tiss ue bl oc k wit h c orres p o n di n g pat h ol o g y 
re p ort s h o ul d be a vaila ble f or s hi p me nt t o a la b orat or y desi g nate d b y t he S p o ns or. T hese sa m ples will be s u bj ecte d t o a d diti o nal e x pl orat or y bi o mar ker 
a nal yses. Date of t u m or tiss ue c ollecti o n f or eit her  ba n ke d or fres h t u m or sa m ples s h o ul d be rec or de d base d o n t he pat h ol o g y re p ort. Detaile d i nstr ucti o ns f or 
t u m or tiss ue c ollecti o n a n d s hi p pi n g f or ce ntral testi n g will be pr o vi de d i n a se parate la b ma n ual. 
1 0 He m o gl o bi n, re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C) c o u nt a n d differe ntial ( % ne utr o p hils, % ba n ds), a n d platelet c o u nt. N o nee d t o re p eat o n 
C 1 D 1 if baseli ne assess me nt p erf or me d wit hi n 3 da ys pri or t o t hat date, or o n cr oss o ver C 1 D 1 if E O T assess me nt p erf or me d wit hi n 3 da ys pri or t o t hat  date. 
O n C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nts s h o ul d be c o n d ucte d pre -d ose.  
1 1 S o di u m, p otassi u m, calci u m, ma g nesi u m, p h os p h or us, al b u mi n, gl uc ose, bl o o d urea nitr o ge n ( B U N), creati ni ne, uric aci d, lactat e de h y dr o ge nase ( L D H), 
al kali ne p h os p hatase ( A L P),  ala ni ne a mi n otra nsferase ( A L T), as partate a mi n otra nsferase ( A S T), t otal bilir u bi n, a n d direct bilir u bi n. N o nee d t o re p eat o n  C 1 D 1 

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if baseli ne assess me nt p erf or me d wit hi n 3 da ys pri or t o t hat date, or o n cr oss o ver C 1 D 1 if E O T assess me nt p erf or me d wit hi n 3 da ys pri or t o t hat date. C A 1 9 -9 
will als o be c ollecte d at Scree ni n g, C 1 D 1, Da y 1 of e ver y ot her c ycle, a n d at E O T. N o nee d t o re peat C A 1 9 -9 o n C 1 D 1 or cr oss o ver C 1 D 1 if a n assess me nt 
was perf or me d wit hi n 3 da ys pri or t o t hat date. O n C 1 D 1 a n d cr oss o ver  C 1 D 1, assess me nts s h o ul d be c o n d ucte d pre -d ose.  
1 2 Pr ot hr o m bi n ti me ( P T), acti vate d partial t hr o m b o plasti n ti me (a P T T), a n d i nter nati o nal n or malize d rati o (I N R).  
1 3 C ol or, a p peara nce, p H, s pecifi c gra vit y, ket o nes, pr otei n, gl uc ose, bilir u bi n, nitrite, u r o bili n o ge n, occ ult bl o o d, a n d micr osc o pic i ns pecti o n of se di me nt. 
1 4 A ser u m pre g na nc y test will b e perf or me d at Scree ni n g a n d a uri ne pre g na nc y test will be c o n d ucte d o n C 1 D 1 a n d c o nfir me d ne ga ti ve pri or d osi n g, a n d o n Da y 
1 of all s u bse q ue nt c ycles. O n C 1 D 1 a n d cr oss o ver C 1 D 1, t he test s h o ul d be c o n d ucte d pre -d ose.  
1 5 Assi g n s u bj ect n u m ber a n d ra n d o mizati o n all ocati o n f or eli gi ble s u bj ects.  
1 6 T he m or ni n g d oses o n C 1 D 1, C 1 D 1 5, C 2 D 1, C 3 D 1, a n d Da y 1 of all s u bse q ue nt c ycles are t o occ ur i n cli nic t o all o w f or pre -d ose assess me nts ( C 1 D 1) a n d t o 
acc o m m o date P K/ P D sa m pli n g (see Secti o n  1 0. 8  a n d Secti o n  1 0. 9 ). 
1 7 Treat me nt c o m plia nce is t o be assesse d base d o n ret ur n of u n use d dr u g as well as s u bj ect diaries (see Secti o n  9. 1 1 ). 
1 8 T u m or assess me nts will i ncl u de all k n o w n or s us pecte d dise ase sites. C T i ma gi n g of t he c hest, a b d o me n, a n d  pel vis ( T ors o) wit h tri p hasic I V c o ntrast s h o ul d 
be perf or me d at baseli ne a n d o n st u d y. F or s u bj ects wit h all er g y t o I V i o di ne c o ntrast, C T c hest wit h o ut I V c o ntrast a n d M RI a b d o me n wit h I V c o ntrast s h o ul d 
be perf or me d at baseli ne a n d o n st u d y. Brai n sca n s wit h C T or M RI s h o ul d be perf or me d at baseli ne i n s u bj ects wit h k n o w n treate d brai n metastases a n d o n 
st u d y at t he sa me i ma gi n g ti me p oi nts as T ors o i ma gi n g. B o ne sca ns will be perf or me d at baseli ne if disease is s us pecte d a n d o n st u d y at t he sa me i ma gi n g ti me 
p oi nts as T ors o i ma gi n g. Ra di o gra p hic assess me nt ( C T or M RI) f or e val uati o n of disease res p o nse t o be c o n d ucte d at Scree ni n g ( Da y -2 1), e ver y 6 we e ks 
( ± 5 da ys) f or t he first 8 assess me nts (ie, t hr o u g h wee k 4 8), a n d t he n e ver y 8 wee ks ( ± 5 da ys) t here after i n de p e n de nt of d ose dela ys a n d/ or d ose i nterr u pti o ns, 
a n d/ or at a n y ti me w he n pr o gr essi o n of disease is s us pecte d. F or s u bj ects ra n d o mize d t o place b o w h o recei ve palliati ve r a di ot hera p y after u n bli n di n g a n d 
d uri n g t he cr oss o ver peri o d, a re p eat C T o r M RI will be perf or me d at t he e n d of t he 2-wee k was h o ut peri o d after ra di ot hera p y  t o d oc u me nt t he area t hat was 
irra diate d a n d t o ser ve as t he ne w baseli ne a gai nst w hic h all s u bse q ue nt R E CI S T v 1. 1 assess me nts will be perf or me d, f or t he pur p ose of d oc u me nt i n g P F S 2 
d uri n g t he u n bli n de d o pe n -la b el cr oss o ver peri o d (see Secti o n  1 2. 1 2. 1 ). F or s u bj ects per mitte d t o c o nti n ue o n o pe n-la bel A G-1 2 0 be y o n d d oc u me nte d 
ra di o gra p hic pr o gressi o n, a ne w baseli ne i ma gi n g assess me nt will n ot be re q uire d a n d t he i ma gi n g assess me nts will c o nti n ue o n  t he c urre nt sc he d ule. A n y 
a ncillar y fi n di n gs o n t he ra di o gra p hic assess me nts will be c o m m u nicate d t o t he a p pr o priate p h ysic ia n f or n otificati o n t o t he s u bj ect. All sca ns o btai ne d will b e 
se nt t o t he I R C, as detaile d i n t he site-s pecific I ma gi n g C ore Ma n ual (see Secti o n  1 0. 7. 2 ). 
1 9 E xte nt of disease will be assesse d base d o n R E CI S T v 1. 1.  
2 0 Res p o nse t o treat me nt is t o be assesse d at t his visit if t he s u bj ect disc o nti n ues treat me nt f or reas o ns ot her t ha n disease pr o gressi o n or start of a n ot her a ntica ncer 
t hera p y. 
2 1  If a s u bj ect g oes off treat me nt f or reas o ns ot her t ha n disease pr o gressi o n, res p o nse assess me nts will be c o n d ucte d at t he E O T Visit a n d e ver y 6 wee ks ( ± 5 da ys) 
f or t he first 8 assess me nts (ie, t hr o u g h wee k 4 8), a n d t he n e ver y 8 wee ks ( ± 5 da ys) t hereaft er until wit h dra wal of c o nse nt, disease pr o gressi o n, deat h, t he 
s u bj ect is l ost t o f oll o w-u p, or u ntil t he e n d of st u d y/st u d y ter mi nati o n.  
2 2 E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, a n d P GI -S ( p h ysical f u ncti o n, a p petite l oss, a n d pai n ) t o be c o n d ucte d pre-d ose o n C 1 D 1 a n d cr oss o ver C 1 D 1; 
P GI -C is n ot c ollecte d o n C 1 D 1 or cr oss o ver C 1 D 1 . After E O T visit, t he H R Q O L will b e c o n d ucte d e ver y 1 2 wee ks u ntil t he start of ne w a ntica ncer t hera p y.  
2 3 E Q -5 D -5 L t o be c o n d ucte d pre -d ose o n C 1 D 1 a n d cr oss o ver C 1 D 1.  
2 4 F or all s u bj ects, plas ma sa m pl es will be o btai ne d f or e val uati o n of I D H m utati o ns a n d ot her ge nes  i n circ ulati n g t u m or D N A at Scree ni n g, o n C 1 D 1 5, o n Da y 1 
of e ver y c ycle t hereafter, a n d at E O T. N o nee d t o re peat o n cr oss o ver C 1 D 1 if E O T assess me nt perf or me d wit hi n 3 da ys pri or t o t hat date.  
2 5 F or all s u bj ects, bl o o d sa m ples m ust b e o btai ne d at Scree ni n g, o n Da y 1 of e ver y c ycle t hereafter, a n d at E O T. N o nee d t o re p eat o n cr oss o ver C 1 D 1 if E O T 
assess me nt p erf or me d wit hi n 3 da ys pri or t o t hat date.  
2 6 A b uccal s w a b f or ger m -li ne m utati o n a nal ysis will be o btai ne d at Scree ni n g.  
2 7 A d verse e ve nts will be gra d e d acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts v 4. 0 3 . After i nf or me d c o nse nt has 
bee n o btai ne d b ut pri or t o i niti ati o n of st u d y dr u g, o nl y seri o us a d verse e ve nts ( S A Es) ca us e d b y a pr ot oc ol -ma n date d i nt er ve nti o n s h o ul d be re p orte d. After 

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i nitiati o n of st u d y dr u g, all A Es a n d S A Es re gar dless of attri b uti o n will be c ollecte d. A n y S A Es t hat are assesse d as relat e d t o stu d y treat me nt t hat occ ur > 2 8 
da ys p ost -treat me nt als o are t o be re p orte d. 
2 8 After a s u bj ect disc o nti n ues tr eat me nt d ue t o pr o gressi o n of disease, t he y will be c o ntacte d e ver y 1 2  wee ks ( ± 7 da ys) t hereafter f or assess me nt of s ur vi val 
stat us ( O S), H R Q O L, a n d a nti ca ncer t hera pies u ntil deat h, wit h dra wal of c o nse nt, t he s u bj ect is l ost t o f oll o w -u p, t he occ urre nce of 1 5 0 O S e ve nts, or u ntil t he 
e n d of st u d y/st u d y ter mi nati o n, u nless c o nse nt t o partici pate is wit h dra w n.  
 
T a ble 4 : 
P h ar m a c o ki netic/ P h ar m a c o d y n a mic S a m pli n g ( 2 -H G) a n d Electr oc a r di o gr a m Sc he d ule *  
Visit/ C ycle:  
Scree ni n g  
C ycle 1  
C ycle 2  
C ycle 3 +  
E O T 1 
S afet y F/ U  
St u d y D a y:  
D -2 8  
D 1  
D 1 5  
D 1  
D 1  
D + 2 8  
 
Assess me nt  
E C G  
Bl o o d  
E C G 2 Bl o o d  E C G 2 
Bl o o d  
E C G 2  
Bl o o d  
E C G 2  
Bl o o d  
E C G 2 
E C G  
Pre -d ose 3 
X  
X  
X  
 
 
X  
X  
X 4 
 
 
 
 
P ost -d ose  
 
 
 
 
 
 
 
 
 
 
 
 
  A n yti me  
  
 
 
 
 
 
 
 
X  
X  
X  
X  
  0. 5 hr 5 
 
X  
 
 
 
X  
 
 
 
 
 
 
  2 hr 5 
 
X  
X 6 
X  
X 6 
X  
X 6 
 
 
 
 
 
  4 hr 5 
 
X  
 
 
 
X  
 
 
 
 
 
 
A b bre viati o ns: D = da y, E C G = electr ocar di o gra m, E O T = e n d of treat me nt, F/ U = f oll o w -u p.  
N ote: All 1 2 -lea d E C Gs are t o be c o n d ucte d after 3 mi n utes of rec u m be nc y or se mi-rec u m be nc y. A 1 2-lea d si n gle E C G s h o ul d als o be o btai ne d as cli nicall y 
i n dicate d.  
* T he sa me sc he d ule s h o ul d be use d f or place b o s u bj ects w h o cr oss o ver t o A G -1 2 0 after d oc u m e nte d disease pr o gressi o n  or S p o ns or u n bli n di n g of t he st u d y . 
1 Assess me nts t o be c o n d ucte d o n t he last d a y of st u d y treat me nt ( wit hi n 5 da ys of last d ose of st u d y dr u g).  
2 1 2 -lea d E C Gs are t o be o btai ne d at Da y 1 of C ycles 1 a n d 2, a n d o n C 1 D 1 5. E C Gs s h o ul d be d o ne bef ore P K sa m pli n g o n t hese da ys. A n E C G will be 
c ollecte d o n C 3 D 1 a n d o n Da y 1 of all c ycles t here after. E C Gs are t o be o btai ne d wit hi n ± 1 5 mi n utes of s pecifie d ti me.  
3 T o be o btai ne d wit hi n 3 0 mi n utes bef ore d ose; ca n be d o ne a n y ti me d uri n g Scree ni n g.  
4 Bl o o d sa m ples t o be c ollecte d at C ycle 3 a n d be y o n d, u ntil E O T.  
5 Bl o o d sa m ples t o be o btai ne d wit hi n ± 1 0 mi n utes of s pecifie d ti me. Bl o o d sa m ples t o be c ollecte d wit hi n 1 0 mi n utes aft er c o m pleti o n of t he E C G.  
6 E C G t o be o btai ne d wit hi n ± 1 5 mi n utes of s pecifie d ti me.  
 

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1 0. 2.  
I nf or me d C o nse nt 
A c o m plete descri pti o n of t he st u d y is t o be prese nte d t o eac h p ote ntial s u bj ect a n d a si g ne d a n d 
date d i nf or me d c o nse nt is t o be o btai ne d bef ore a n y st u d y s pecific pr oce d ures are perf or me d. 
S u bject s will si g n a pre-scree ni n g a n d/ or scree ni n g c o ns e nt f or m de pe n di n g o n w he n t heir 
I D H 1 m testi n g is perf or me d. A le gall y a ut h orize d re pres e ntati ve ma y c o nse nt o n be half of a 
s u bject w h o is ot her wise u na ble t o pr o vi de i nf or m e d c o nse nt if acce pta ble t o a n d a p pr o ve d b y 
t he site’s I nstit uti o nal Re vie w B oar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C). 
1 0. 3.  
De m o gr a p hic D at a a n d Me dic al, S ur gic al, a n d Me dic ati o n Hist or y  
S u bject de m o gra p hic dat a, i ncl u di n g ge n der, date of birt h, a ge, race, a n d et h nicit y, will be 
o btai ne d d uri n g Scree ni n g, acc or di n g t o a p plica bl e l ocal re g ul ati o ns.  
A c o m plete me dic al a n d s ur gic al hist or y, i n cl u di n g t he site of u n d erl yi n g c h ola n gi ocarci n o ma 
a n d t he date of c o nfir mati o n of t he hist ol o gic dia g n osis of t he u n derl yi n g c h ola n gi ocarci n o ma, 
will be o btai ne d d uri n g S cree ni n g. T h e me dical hist or y is t o i ncl u de all rele va nt pri or me dical 
hist or y as w ell as all c urre nt me dical c o n diti o ns.  
All me dicati o ns a d mi nistere d a n d pr oce d ures c o n d ucte d wit hi n 2 8 da ys pri or t o C 1 D 1 s h o ul d be 
re p orte d i n t he e C R F. I n a d diti o n, all pri or treat me nt re gi me ns f or t he u n derl yi n g mali g n a nc y 
will be re p orte d.  
1 0. 4.  
Ge ne M ut ati o n A n al ysis a n d M olec ul ar C h ar acteriz ati o n  
Tiss ue fr o m a pre -treat me nt fres h or ba n ke d t u m or bi o ps y will be re q uire d f or all scree ne d 
s u bjects f or ce ntral lab orat or y I D H 1 m c o nfir mat or y testi n g  ( R 1 3 2 C/ L/ G/ H/ S m utati o n varia nts 
teste d). W he n s u bjects are e nr olle d f or t he st u d y, t hese sa m ples ca n be use d f or f urt her m olec ular 
a n d/ or pr otei n a n al ys es t o gai n i nsi g hts i nt o A G -1 2 0 res p o nse or resista nce bi o mar kers. 
C orres p o n di n g p at h ol o g y re p ort is als o re q uir e d. I nstr ucti o ns f or t u m or tiss ue c ollecti o n a n d 
s hi p pi n g f or ce ntral testi n g will be det aile d i n a se parate st u d y ma n ual. 
A b uccal s w a b f or ger m -li ne m utati o n a nal ysis will be o btai ne d at Scree ni n g t hat ca n be use d as 
a ger mli ne c o ntr ol f or s o matic m utati o n as well as e x pl ori n g a c orrelati o n b et wee n P K variati o n 
wit h D M E relate d ge n e p ol y m or p his ms.  
F or all s u bjects, plas ma s a m ples will be o btai ne d f or e val uati o n of I D H m utati o ns a n d ot her 
ge n es i n circ ul ati n g t u m or D N A at Scree ni n g, o n C 1 D 1 5, o n Da y 1 of e v er y c ycle t hereafter, a n d 
at t he E O T Visit.  
1 0. 5.  
S afet y Assess me nts  
1 0. 5. 1.  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
Safet y a n d ot her cli nical data will be re vie we d re g ularl y b y a n I D M C t o e ns ure t he safet y of 
t hera p y. T he first safet y re vie w meeti n g will be c o n d ucte d w he n a p pr o xi matel y 2 0 s u bjects h a ve 
c o m plete d 2 c ycles of t hera p y or ha v e disc o nti n ue d earlier; t hereafter, meeti n gs will be 
c o n d ucte d a p pr o xi matel y e ver y 3 -6 m o nt hs ( or o n a n a d h oc b asis) u ntil t he st u d y is u n bl i n de d 
f or t he pri mar y effi cac y a nal ysis. T here will be n o f or mal a nal ysis of efficac y. Me m b ers of t he 

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I D M C will be e xter nal t o t he S p o ns or a n d will f oll o w a c harter t hat o utli nes t heir r oles a n d 
res p o nsi bilities. T he S p o ns or will re mai n bli n de d t o t he data u ntil t he pri mar y efficac y a nal ysis.  
All s u m maries a n d a nal yses b y tr eat me nt ar m f or t he I D M C re vie w will be pre pare d b y a n 
i n de pe n de nt statistical gr o u p. T he safet y d ata will i ncl u de de m o gra p hic dat a, A Es, S A Es, a n d 
rele va nt la b orat or y dat a. F oll o wi n g t heir d ata re vi e w, t he I D M C will pr o vi de a rec o m me n dati o n 
as t o w het her t he st u d y ma y c o nti n ue, w het her a me n d me nt(s) t o t he pr ot o c ol s h o ul d be 
i m ple me nte d, or w het her t he st u d y s h o ul d be st o p pe d. T he fi nal d ecisi o n will rest wit h t he 
S p o ns or.  
T he re q uir e me nt s of t hes e re vie ws will be s pecifie d i n t he I D M C c harter. 
1 0. 5. 2.  
P h ysic al E x a mi n ati o n a n d E C O G Perf or m a nce St at us  
A c o m plete p h ysical e x a mi nati o n, i ncl u di n g assess me nt of wei g ht, will be o btai ne d at Scree ni n g 
a n d at t he E O T Visit. A li mite d p h ysi cal e xa mi nati o n s h o ul d be c o m plete d o n Da y  1 of eac h 
treat me nt c ycl e. Hei g ht will be o btai ne d at t he Scree ni n g Visit o nl y. S u bjects s h o ul d be 
m o nit ore d f or ras h at p h ysical e x a mi nati o ns a n d d uri n g ass ess me nts of a d v erse reacti o ns.  
Deter mi nati o n of E C O G P S will be perf or me d at Scree ni n g, o n Da y  1 of eac h treat me nt c ycle 
t hereafter, at t he E O T Visit, a n d at t he Safet y F oll o w-u p V isit. See A p pe n di x 1 5. 1  f or E C O G P S 
sc ori n g. O n C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nt s h o ul d be c o n d ucte d pre-d ose.  
1 0. 5. 3.  
Vit al Si g ns  
Vital si g ns, i ncl u di n g  s yst olic a n d diast olic bl o o d press ure, h eart rate, res pirat or y rat e, a n d 
te m perat ur e, will be o btai ne d at Scree ni n g, Da ys 1 a n d 1 5 of C ycles 1 a n d 2, o n Da y 1 of eac h 
treat me nt c ycl e t hereafter, a n d at t he E O T Visit. Assess me nts s h o ul d be c o n d ucte d w hile t he 
s u bject is seate d or s u pi n e. O n C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nts s h o ul d be c o n d ucte d 
pre -d ose.  
1 0. 5. 4.  
Electr oc a r di o gr a m a n d Assess me nt of Left Ve ntric ul ar Ejecti o n Fr acti o n  
T he 1 2 -lea d E C Gs are t o be o btai ne d at Scree ni n g, pre-d ose o n Da y 1 of C ycles 1 a n d 2, 2 h o urs 
p ost -d ose o n Da ys 1 a n d 1 5 of C ycl e 1 a n d o n Da y 1 of C ycl e 2, a n yti me o n Da y 1 of C ycle 3 
a n d be y o n d, a n d at t he E O T a n d at Safet y F oll o w -u p Visits. W he n t he ti mi n g of a bl o o d sa m ple 
c oi nci des wit h t he ti mi n g of a n E C G meas ure me nt, t he E C G w ill be c o m plete d bef ore t he 
c ollecti o n of t he bl o o d sa m ple ( wit hi n 1 0 mi n utes).  
All E C Gs s h o ul d be o btai ne d f oll o wi n g 3  mi n utes of rec u m b e nc y or se mi -rec u m be nc y. 
S u bjects are t o ha v e L V E F deter mi ne d b y E C H O ( or b y ot h er met h o ds acc or di n g t o i nstit uti o nal 
p ractice) as cli nic all y i n dicate d. 
1 0. 5. 5.  
S afet y L a b or at or y Assess me nts  
Cli nical la b orat or y e val u ati o ns are t o be perf or m e d b y t he site’s l ocal la b orat or y. Pri or t o starti n g 
t he st u d y, t he I n v esti gat or will pr o vi de t o t he S p o ns or ( or its desi g n ee) c o pies of all la b orat or y 
certificati o ns a n d n or mal ra n ges f or all la b orat or y para meters t o be perf or m e d b y t h at la b orat or y.  
Cli nical la b orat or y e val u ati o ns are t o be c o n d ucte d acc or di n g t o t he Sc h e d ule of Assess me nts 
(Ta ble  3 ). Cli nical la b orat or y e v al uati o ns ma y be c ollecte d u p t o 2 4 h o urs pri or t o st u d y visit as 

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l o n g as t he la bs were c oll ecte d wit hi n t he visit wi n d o w ( +/-2 da ys). I n a d diti o n, all cli nicall y 
si g nifica nt la b orat or y a b n or malities n ote d o n testi n g will be f oll o we d b y re peat testi n g a n d 
f urt her i n vesti gate d acc or di n g t o t he j u d g me nt of t he I n vesti gat or. 
T he safet y la b orat or y p ara meters t o be e val uate d b y t he I n v esti gat or are:  
He m at ol o g y : 
He m o gl o bi n, re d b l o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C) c o u nt 
a n d differe ntial ( % n e utr o p hils, % ba n ds), platelet c o u nt  
C he mistr y : 
S o di u m, p otassi u m, calci u m, ma g nesi u m, p h os p h or us, al b u mi n, gl uc ose, 
bl o o d urea nitr o ge n ( B U N), creati ni ne, uric aci d, lactate de h y dr o g e nas e 
( L D H), al kali ne p h os p hatase ( A L P), A S T, A L T, t otal bilir u bi n, direct 
bilir u bi n  
C o a g ul ati o n St u dies : Pr ot hr o m bi n ti me ( P T), acti vate d partial t hr o m b o plasti n ti me (a P T T), 
i nter nati o nal n or malize d rati o (I N R) 
Uri n al ysis : 
C ol or a n d a p peara nce; p H, s pecif ic gra vit y, k et o n es, pr otei n, gl uc ose, 
bilir u bi n, nitrite, ur o bili n o ge n, a n d occ ult bl o o d; a n d micr osc o pic 
i ns pecti o n of se di me nt. 
Bl o o d f or h e mat ol o g y a n d c he mistries is t o be o btai ne d at Scree ni n g, o n Da ys 1 a n d 1 5 of C ycles 
1 -3, o n Da y 1 of e ver y tr eat m e nt c ycle t h ereafter, a n d at t he E O T Visit. If assess me nts f or 
he mat ol o g y a n d ser u m c he mistr y w ere p erf or me d wit hi n 3  da ys pri or t o C 1 D 1, t hese d o n ot nee d 
t o be re peate d at t he C 1 D 1 Visit. If assess me nts f or he mat ol o g y a n d ser u m c he mistr y at E O T 
were p erf or me d wit hi n 3  da ys pri or t o cr oss o ver C 1 D 1, t hese d o n ot nee d t o be re peate d at t he 
cr oss o ver C 1 D 1 Visit. O n C 1 D 1 a n d cr oss o ver C 1 D 1, assess me nts s h o ul d be c o n d ucte d pre -
d ose.  
C A 1 9 -9 will als o be c ollecte d at Scree ni n g, C 1 D 1, Da y 1 of e v er y ot her c ycle  starti n g wit h 
C ycle  3, a n d at E O T. If assess me nt of C A 1 9 -9 was perf or me d wit hi n 3  da ys pri or t o C 1 D 1, it 
d oes n ot nee d t o be re peate d at t he C 1 D 1 Visit. If assess me nt of C A 1 9-9 at E O T was perf or me d 
wit hi n 3  da ys pri or t o cr oss o ver C 1 D 1, t his d oes n ot nee d t o be re p eate d at t he cr oss o ver C 1 D 1 
Visit. O n C 1 D 1 a n d cr oss o ver C 1 D 1, t he test s h o ul d be c o n d ucte d pre -d os e.  
Bl o o d sa m ples f or c oa g ulati o n st u dies a n d uri nal ysis are t o be o btai ne d at Scree ni n g o nl y.  
Pre g n a nc y Test:  
All w o me n of c hil d -beari n g p ote nti al m ust ha ve a ne gati ve pre g n a nc y test 
t o be eli gi ble. A s er u m pre g n a nc y test will be perf or me d at Scree ni n g; a 
uri ne pre g n a nc y test m ust be c o n d ucte d a n d c o nfir me d ne gati ve o n t he 
first da y of st u d y treat me nt a d mi nistrati o n bef ore d osi n g a n d o n Da y 1 of 
ever y c ycle. O n C 1 D 1 a n d cr oss o ver C 1 D 1, t he t est s h o ul d be c o n d ucte d 
pre -d ose.  
1 0. 5. 6.  
A d verse E ve nts  
All A Es will be gra de d usi n g t he N CI C T C A E versi o n 4. 0 3 gra di n g s yste m ( A p pe n di x  1 5. 8 ). 
C o m plete details o n A E m o nit ori n g are pr o vi de d i n Secti o n  1 1 . 

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1 0. 6.  
E x pl or at or y Bl o o d S a m ples  
Bl o o d a n d/ or pr ocesse d bl o o d will be re q ueste d f or e x pl orat or y bi o mar kers a n d c orrelati ve 
st u dies fr o m all s u bjects t o assess m olec ular, e pi ge netic, a n d pr ote o mic c ha n ges at Scree ni n g, o n 
Da y 1 of e v er y c ycle t hereafter, a n d at t he E O T Visit. If sa m ples f or e x pl orat or y bi o mar kers a n d 
c orrel ati ve st u dies at E O T were c ollecte d wit hi n 3  da ys pri or t o cr oss o ver C 1 D 1, t hese d o n ot 
nee d t o be re peat e d at t he cr oss o ver C 1 D 1 Visit. O n C 1 D 1 a n d cr oss o ver C 1 D 1, sa m ples 
s h o ul d be o btai ne d pre-d ose.  
I nstr u cti o ns f or t he sa m ple c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt of sa m ples f or ce ntral 
a nal ysis will be d etaile d i n a se parate st u d y ma n ual.  
1 0. 7.  
Effic ac y Assess me nts  
1 0. 7. 1.  
Res p o nse t o Tre at me nt  
T he effi cac y of A G -1 2 0 will be e val uate d b y assessi n g res p o ns e t o treat me nt acc or di n g t o 
R E CI S T v 1. 1 (Eise n ha u er, et al. 2 0 0 9 ) (A p pe n di x  1 5. 9 ). 
Ra di o gra p hic assess me nts ( C T or M RI) t o o btai n t u m or meas ure me nts are t o be c o n d ucte d at 
Scree ni n g, e v er y 6 w ee ks f or t he first 8 ass ess me nts (ie, t hr o u g h wee k 4 8), a n d e ver y 8 wee ks 
t hereafter ( ± 5 d a ys) fr o m C 1D 1, i n de pe n de nt of d ose -dela ys a n d/ or d ose i nterr u pti o ns , a n d/ or at 
a n y ti me w h e n pr o gressi o n of disease is s us pect e d. C T i ma gi n g of t he c h est, a b d o me n, a n d pel vis 
( T ors o) wit h tri p hasic I V c o ntrast ( 3 0 millisie verts  [ m S v] per sca n) s h o ul d be perf or me d at 
baseli ne a n d o n st u d y. F or s u bjects wit h aller g y t o I V i o di ne c o ntrast, C T of t he c hest wit h o ut I V 
c o ntrast a n d M RI of t he a b d o me n wit h I V c o ntr ast s h o ul d be perf or me d at baseli ne a n d o n st u d y. 
Brai n sc a ns wit h C T ( 2 m S v per sca n) or M RI s h o ul d be perf or m e d at bas eli ne i n s u bjects wit h 
k n o w n treate d brai n metastases a n d o n st u d y at t he sa me i ma gi n g ti me p oi nts as T ors o i ma gi n g. 
B o ne sca ns ( 4 m S v per s ca n) will be perf or m e d at baseli ne if diseas e is s us pecte d a n d o n st u d y as 
a p pr o priate as t he sa me i ma gi n g t i me p oi nts as T ors o i ma gi n g. A n y a ncillar y fi n di n gs o n t he 
ra di o gra p hic assess me nts will be c o m m u nicate d t o t he a p pr o priat e p h ysi cia n f or n otificati o n t o 
t he s u bject. T he sa me m et h o d ( C T or M RI) s h o ul d be use d c o nsiste ntl y f or a n y gi v e n s u bject. 
F or s u bjec ts r a n d o mize d t o place b o w h o recei v e p alliati ve ra di ot hera p y aft er u n bli n di n g a n d 
d uri n g t he cr oss o ver peri o d, a re peat C T or M RI will be perf or me d at t he e n d of t he 2 -wee k 
was h o ut peri o d after ra di ot hera p y t o d oc u me nt t he area t h at was irra diate d a n d t o ser ve as t he 
ne w baseli ne a gai nst w hi c h all s u bse q ue nt R E CI S T v 1. 1 assess me nts will be perf or me d, f or t h e 
p ur p ose of d oc u m e nti n g P F S 2 d uri n g t he u n bli n d e d o pe n -la bel cr oss o ver peri o d (see 
Secti o n  1 2. 1 2. 1 ). T he rea di n g ra di ol o gist(s) s h o ul d be pr o vi de d t he dat es a n d l ocati o n of t he 
i nter ve ni n g ra diati o n w h e n perf or mi n g t he ne w baseli ne assess me nt. F or s u bjects per mitte d t o 
c o nti n ue o n o pe n -la b el A G-1 2 0 be y o n d d oc u m e nte d ra di o gra p hic pr o gressi o n or st u d y 
u n bli n di n g, a ne w b aseli ne i ma gi n g assess me nt will n ot be re q uire d a n d t h e i ma gi n g assess me nts 
will c o nti n ue o n t he c urre nt sc he d ule. F or s u bjects w h o disc o nti n ue st u d y dr u g f or reas o ns ot her 
t ha n disease pr o gressi o n, a n assess me nt will be c o n d ucte d at t he E O T Visit a n d e ver y 6 wee ks 
t hr o u g h w ee k 4 8, t he n e v er y 8 wee ks t hereafter ( wit h t he e x ce pti o n of t h ose s u bjects w h o i nitiate 
a ne w ca ncer t hera p y aft er disc o nti n ui n g st u d y treat me nt) u ntil wit h dra wal of c o nse nt, diseas e 
pr o gressi o n, deat h, t he s u bject is l ost t o f oll o w -u p, or u ntil t he e n d of st u d y/st u d y ter mi nati o n.  
O S f oll o w -u p assess me nts will occ ur a p pr o xi matel y e v er y 1 2 wee ks after E O T u nless t he s u bject 
is i n P F S f oll o w-u p at t hat ti me. If a s u bj ect pr o gresses or d oes n ot c o m e b ac k f or s ca ns w hile i n 

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P F S f oll o w -u p, t he n t he O S f oll o w -u p assess me nts will be gi n at t he ne xt pla n ne d O S f oll o w -u p 
ti me p oi nt, f oll o wi n g t he sc he d ule of e ver y 1 2 wee ks after E O T. O S f oll o w -u p will assess 
s ur vi val stat us a nd d oc u me ntati o n of recei pt a n d t y pe of s u bs e q ue nt a ntica ncer t hera p y u nless 
c o nse nt t o partici pate is wit h dra w n. If a s u bject b e gi ns a n e w a ntica ncer t h era p y d uri n g P F S 
f oll o w-u p, i nf or mati o n o n t he ne w t hera p y will nee d t o be e ntere d. O S f oll o w -u p will c o nti n ue 
u ntil all s u bjects ha ve die d, wit h dra w n c o nse nt, are l ost t o f oll o w -u p, or u ntil t he occ urre nce of 
1 5 0 O S e ve nts, w hic he v er occ urs first. H R Q O L ( u ntil t he start of ne w a ntica ncer t h era p y) 
assess me nts will be c ollecte d e ver y 1 2 wee ks after E O T.  
All s ca ns s h o ul d be se nt t o t he I R C, as d etaile d i n t he site -s pecifi c I ma gi n g C ore Ma n ual (s ee 
Secti o n  1 0. 7. 2 ). A ce ntr al re vie w of c ollecte d i ma ges ma y be c o n d u cte d b y a n i n de pe n de nt 
re vie w c o m mittee. T his i n de pe n de nt r e vie w will n ot be use d f or tr eat me nt decisi o ns. 
1 0. 7. 2.  
I n de pe n de nt R a di ol o g y Ce nter 
A n i n de pe n de nt r a di ol o g y re vie w will be c o n d u ct e d at a n i n de p e n de nt ra di ol o g y ce nter. T h e I R C 
will be c hartere d t o e v al uate res p o nse assess me nt i n de pe n de ntl y per R E CI S T v 1. 1. 
A detaile d st u d y -s pecific I ma gi n g C ore Ma n ual will be ma de a vaila ble t o sites re gar di n g sca n 
ac q uisiti o n re q uire me nts. All ra di ol o gical sca ns ac q uire d at all sc he d ul e d ti me p oi nts a n d a n y 
a d dit i o nal ( u nsc he d ule d) ra di ol o gic al i ma ges ac q uire d t o e val uate f or p ote ntial metastatic disease 
als o m ust be se nt t o t he I R C.  
1 0. 7. 3.  
He alt h -Rel ate d Q u alit y of Life I nstr u me nts  
S u bjects will c o m plete t he E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, a n d P GI -S i nstr u me nts 
pri or t o  d osi n g o n C 1 D 1 ; su bjects will c o m plete t he E O R T C -Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, 
P GI -C, a n d P GI -S pri or t o d osi n g o n Da y 1 of e ver y c ycle t hereafter u ntil E O T. After E O T visit, 
H R Q O L s h o ul d b e assesse d e ver y 1 2  wee ks u ntil t he start of ne w a ntica ncer t hera p y. O n e 
a d diti o nal H R Q O L assess me nt will als o be c o n d ucte d at t he safet y f oll o w -u p visit.  If s u bjects 
cr oss o ver, t he y will f oll o w t he sa me ass ess me nt sc he d ule  as fr o m C 1 D 1 . C o m pleti o n of t he 
q uesti o n naires ta kes a p pr o xi matel y 1 2 t o 1 7  mi n utes. D uri n g t he f oll o w -u p peri o d ( P F S a n d/ or 
O S), sites s h o ul d f oll o w u p wit h s u bjects t o e nc o ura ge t he m t o c o m plete t h e H R Q O L 
q uesti o n naires. D uri n g t his ti me, t he H R Q O L i nstr u me nts will be a vaila ble o nli ne as a mea ns t o 
mi ni mize missi n g e ntries a n d l ost data. If a s u bj ect d o es n ot s pea k o ne of t h e pr o vi de d la n g ua ges 
f or t he E O R T C-Q L Q -C 3 0, E O R T C -Q L Q -BI L 2 1, P GI -C, or P GI -S , t he s u bject will n ot be 
re q uire d t o c o m plet e t he i nstr u me nts. ( See Secti o n 1 2. 8. 1  f or t he statistical as pects f or m a na gi n g 
s uc h missi n g data.) 
T he E O R T C -Q L Q -C 3 0 is a vali date d ge n eral q u esti o n naire a d mi nistere d t o assess H R Q O L i n 
s u bjects wit h ca ncer. T he E O R T C -Q L Q -BI L 2 1 was s pecificall y d esi g n e d t o me as ure s u bject -
re p orte d iss ues r elate d t o s y m pt o ms, disease, a n d treat me nt i n s u bjects wit h c h ola n gi ocarci n o ma 
a n d gall bla d der ca ncer. T he P GI -C is a self-rate d e val uati ve i nstr u me nt f or assess me nt of c h a n ge 
fr o m baseli ne acr oss 3 d o mai ns a n d t he P GI-S is a self-rat e d e val u ati ve i nstr u me nt f or c urre nt 
se verit y of s y m pt o ms acr oss t he sa me 3 d o mai ns. F or b ot h t he P GI-C a n d P GI -S, s u bjects will be 
as ke d t o res p o n d t o 3  d o mai n f u ncti o ns ( p h ysi cal f u ncti o n, a p petite l oss, a n d pai n) f or a t otal of 6 
q uesti o ns.  

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1 0. 7. 4.  
He a lt h Ec o n o mic O utc o mes Assess me nt 
S u bjects will c o m plete t he E Q -5 D -5 L pri or t o d osi n g o n C 1 D 1, C 3 D 1, a n d at t he E O T Visit. If 
s u bjects cr oss o ver, t h e y will f oll o w t he sa me assess me nt sc he d ule as fr o m C 1 D 1.  T here are 
i n de x-base d val ues (“ utilities”) t hat are a maj or feat ure of t he E Q -5 D -5 L i nstr u me nt, facilitati n g 
t he calc ulati o n of q u alit y-a dj uste d life years ( Q A L Ys) t hat are use d t o i nf or m ec o n o mic 
e val uati o ns of healt hcare i nter ve nti o ns.  
T he E Q -5 D -5 L is a  vali d ate d ge neric healt h stat us meas ure use d i n cli nical trials i n ca ncer t hat 
c o nsists of 2 parts: t he E Q -5 D descri pti ve s yst e m a n d t he E Q vis ual a n al o g ue scale. T he 
descri pti ve s yste m c o m prises fi ve di me nsi o ns ( m o bilit y, self -care, us u al acti vit y, 
pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n). T he fi ve -le vel versi o n of t he des cri pti ve s yste m will be 
use d i n t his st u d y ( n o pr o ble ms, sli g ht pr o ble ms, m o derate pr o bl e ms, se vere pr o ble ms, or 
e xtre me pr o ble ms). T he E Q vis ual a nal o g ue scale rec or ds t he p atie nt’s sel f-rate d healt h o n a 
vertical vis ual a nal o g u e s cale, w h ere t he e n d p oi nts are la belle d “ T he b est he alt h y o u ca n 
i ma gi ne ” a n d “ T h e w orst healt h y o u ca n i ma gi ne.” 
1 0. 8.  
P h ar m ac o ki netic Assess me nts  
Serial or s pars e bl o o d sa m ples will be dra w n bef ore a n d after d osi n g of st u d y treat me nt i n or der 
t o deter mi ne circ ul ati n g plas ma c o nce ntrati o ns of A G-1 2 0. T he bl o o d sa m ples will als o be use d 
f or t he deter mi nati o n of 2-H G c o n ce ntrati o ns a n d meta b olic pr ofili n g (see Secti o n  1 0. 9 ). 
Bl o o d sa m ples will be dra w n o n Da y 1 of C ycl es 1 a n d 2 at t he f oll o wi n g ti me p oi nts: pre -d ose 
( wit hi n 3 0 mi n utes), 3 0 mi n utes, a n d 2, a n d 4 h o urs ( ± 1 0 mi n utes) p ost-d ose. A d diti o nal bl o o d 
sa m ples f or P K/ P D assess me nts will be dra w n at 2  h o urs ( ± 1 0 mi n utes) p ost -d ose o n C 1 D 1 5, 
pre -d ose ( wit hi n 3 0 mi n utes) o n C 3 D 1 a n d Da y 1 of eac h treat me nt c ycle t hereafter, a n d a n yti me 
d uri n g t he E O T Visit.  
W he n t he ti mi n g of a bl o o d sa m ple c oi nci des wit h t he ti mi n g of a n E C G m eas ure m e nt, t he E C G 
will be c o m plete d bef ore t he c ollecti o n of t he bl o o d sa m ple s uc h t hat t he bl o o d sa m ple is 
c ollecte d at t he n o mi nal ti me ( ± 1 0 mi n utes). 
1 0. 9.  
P h ar m ac o d y n a mic Assess me nts  
Plas ma sa m ples o btai ne d at Scree ni n g will be e v al uate d f o r 2-H G le vels. Serial or s parse bl o o d 
sa m ples will be dra w n at t he sa me ti me as P K sa m ples (see Secti o n  1 0. 8 ) i n or der t o deter mi ne 
circ ulati n g c o nc e ntrati o ns of 2 -H G.  
1 0. 1 0.  
S a m ple Pr ocessi n g, St or a ge, a n d S hi p me nt  
I nstr u cti o ns f or t he pr o cessi n g, st ora ge, a n d s hi p me nt of all st u d y sa m ples f or ce ntr al a nal ysis 
will be pr o vi de d i n a se p arate st u d y ma n ual.  

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1 1.  
A D V E R S E E V E N T S  
M o nit ori n g of A Es will b e c o n d ucte d t h r o u g h o ut t he st u d y ( o nce s u bjects ha ve recei ve d st u d y 
dr u g); S A Es t hat are assesse d as relat e d t o st u d y tr eat me nt t hat occ ur > 2 8 d a ys p ost tr eat me nt 
als o are t o be re p ort e d. All A Es s h o ul d be m o nit ore d u ntil t he y are res ol ve d or are clearl y 
deter mi ne d t o b e d ue t o a s u bject’s sta ble or c hr o nic c o n diti o n or i nterc urre nt ill ness(es).  
A d verse E ve nt Re p orti n g Peri o d  
I n v esti gat ors will see k i nf or mati o n o n A Es at eac h s u bject c o ntact, as o utli n e d bel o w. All A Es, 
w het her re p orte d b y t he s u bject or n ote d b y st u d y p ers o n nel, will be rec or de d i n t he s u bject’s 
me dical rec or d a n d o n t h e A d vers e E ve nt e C R F.  
 After i nf or m e d c o nse nt h as bee n o btai ne d b ut pri or t o i nitiati o n of st u d y dr u g, o nl y 
S A Es ca use d b y a pr ot oc ol -ma n date d i nter v e nti o n s h o ul d be re p orte d (e g, S A Es 
relate d t o i n vasi ve st u d y pr oce d ures s uc h as bi o psies). 
 After i nitiati o n of st u d y dr u g, all A Es a n d S A Es re gar dless of attri b uti o n will be 
c ollecte d at e v er y visit u ntil 2 8 da ys f oll o wi n g t he last a d mi nistrati o n of st u d y 
treat me nt or u ntil st u d y disc o nti n uati on/ter mi nati o n or u ntil i nitiati o n of s u bse q ue nt 
a ntica ncer t hera p y, w hic he ver occ urs first. S u bjects will be assesse d at t he F oll o w -U p 
Visit t o deter mi ne if a n y ne w A Es ha v e occ urre d. After t his peri o d, I n v esti gat ors 
s h o ul d re p ort o nl y S A Es t hat are c o nsi dere d t o be relate d t o st u d y treat me nt 
( A G-1 2 0/ place b o).  
1 1. 1.  
Defi niti o n of A d verse E ve nts  
1 1. 1. 1.  
A d verse E ve nt  
A n A E (als o r eferre d t o as a n a d vers e e x perie nce) is a n y u nt o w ar d me dical occ urre nce ass ociat e d 
wit h t he use of a dr u g i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. A n A E ca n t heref ore 
be a n y of t he f oll o wi n g:  
 A n y u nfa v ora ble a n d u ni nte n de d si g n (e g, a n a b n or mal la b orat or y 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 dr u g, w het her or n ot c o nsi dere d 
relate d t o t he dr u g. 
 A n y n e w di seas e or e x acer bati o n of a n e xisti n g disease (a w ors e ni n g i n t he c haracter, 
fre q ue n c y, or se v erit y of a k n o w n c o n diti o n). 
 Rec urre n ce of a n i nter mitte nt me dical c o n diti o n (e g, h ea d ac he) n ot prese nt at 
baseli ne.  
 A n y d eteri or ati o n i n a la b orat or y val ue or ot h er cli nical test (e g, E C G, X -ra y) t hat is 
ass ociate d wit h s y m pt o ms or lea ds t o a c h a n ge i n st u d y treat me nt or c o nc o mita nt 
treat me nt or disc o nti n uati o n fr o m st u d y treat me nt. 
 A d verse e ve nts t hat are relate d t o a pr ot oc ol -ma n date d i nter ve nti o n, i ncl u di n g t h os e 
t hat occ ur pri or t o assi g n me nt of st u d y treat me nt ( e g, s cree ni n g i n vasi ve pr oce d ures 
s uc h as bi o psies). 

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A n A E ca n arise fr o m a n y use of t he dr u g (e g, off -la bel use, use i n c o m bi n ati o n wit h a n ot her 
dr u g) a n d fr o m a n y r o ute of a d mi nistrati o n, f or m ulati o n, or d ose, i ncl u di n g a n o ver d ose.  
Disease pr o gressi o n or d eat h d ue t o c h ola n gi o carci n o ma pr o gressi o n will n ot be c o nsi dere d a n 
A E ( or a n S A E) i n t his st u d y, b ut will be c ollecte d as a n o utc o me or reas o n f or disc o nti n uati o n, 
as a p pr o priat e. A d verse e ve nts ( or  S A Es) c o nsi dere d as c o m plicati o ns of disease pr o gressi o n 
s h o ul d be re p orte d. See Secti o n  1 1. 2. 7  f or m ore d etaile d i nstr ucti o ns re gar di n g t he re p orti n g of 
disease pr o gressi o n a n d deat hs d ue t o disease pr o gressi o n.  
1 1. 1. 2.  
Rel ate d A d vers e E ve nt  
A relate d A E is a n y A E f or w hic h t here is a reas o na ble p ossi bilit y t h at t he dr u g ca use d t h e A E.  
Assess me nt of C a us alit y of A d verse E ve nts  
I n v esti gat ors s h o ul d use t heir k n o wle d ge of t he s u bject, t he circ u msta n ces s urr o u n di n g t h e e ve nt, 
a n d a n e v al uati o n of a n y p ote ntial alter nati ve ca us es t o deter mi ne w het her or n ot a n A E is 
c o nsi dere d t o be relate d t o t he st u d y treat me nt, i n dicati n g " yes" or " n o" acc or di n gl y ( T a ble  5 ). 
T he f oll o wi n g g ui d a nce s h o ul d be ta ke n i nt o c o nsi derati o n:  
 Te m p oral rel ati o ns hi p of e ve nt o nset t o t he i nitiati o n of st u d y tr eat me nt  
 C o urse of t he e v e n t, c o nsi deri n g es peci all y t he effects of d ose re d ucti o n, 
disc o nti n uati o n of st u d y treat me nt, or rei ntr o d ucti o n of st u d y tr eat me nt ( w here 
a p plica ble)  
 K n o w n ass ociati o n of t he e ve nt wit h t he st u d y tr eat me nt or wit h si milar treat me nts  
 K n o w n ass ociati o n of t he  e ve nt wit h t he disease u n der st u d y  
 Prese nce of ris k fact ors i n t he s u bject or use of c o nc o mita nt me dicati o ns k n o w n t o 
i ncreas e t he occ urre nce of t he e ve nt 
 Prese nce of n o n -tr eat me nt-relate d fact ors t hat are k n o w n t o be ass ociate d wit h t he 
occ urre nce of t he  e v e nt  
T a ble  5 : 
C a us al Attri b uti o n G ui d a nce  
Is t he a d verse e ve nt s us pecte d t o be c a use d b y t he st u d y tre at me nt o n t he b asis of f acts, e vi de nce, 
scie nce-b ase d r ati o n ales, a n d cli nic al j u d g me nt ?  
Y E S  T here is a pla usi ble te m p oral relati o ns hi p bet wee n t he o nset of t he a d verse e ve nt a n d 
a d mi nistrati o n of t he st u d y treat me nt, a n d t he A E ca n n ot be rea dil y e x plai ne d b y t he s u bject’s 
cli nical state, i nterc urre nt ill ness, or c o nc o mita nt t hera pies; a n d/ or t he A E f oll o ws a k n o w n 
patter n of res p o nse t o t he st u d y treat me nt; a n d/ or t he A E a bates or res ol ves u p o n 
disc o nti n uati o n of t he st u d y treat me nt or d ose re d ucti o n a n d, if a p plica ble, rea p pears u p o n re -
c halle n ge. 
N O  
A d verse e ve nts will be c o nsi dere d relate d, u nless t he y f ulfill t he criteria  as s pecifie d bel o w:  
E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y treat me nt (e g, pree xisti n g 
me dical c o n diti o n, u n derl yi n g disease, i nterc urre nt ill ness, or c o nc o mita nt me dicati o n); a n d/ or 
t he A E has n o pla usi ble te m p oral relati o ns hi p to a d mi nistrati o n of t he st u d y treat me nt (e g, 
ca ncer dia g n ose d 2  da ys after first d ose of st u d y treat me nt).  
 

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Seri o us A d verse E ve nt  
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d seri o us (a n S A E) if, i n t he vie w of eit her t he 
I n v esti gat or or S p o ns or, it res ults i n a n y of t h e f oll o wi n g o utc o mes: 
 Fatal (ie, t h e A E act uall y ca uses or lea ds t o deat h).  
 Lif e -t hreate ni n g. Life-t hr eate ni n g mea ns t hat t he s u bject was at i m me diate ris k of 
deat h fr o m t he reacti o n as it occ urre d, ie, it d oes n ot i ncl u de a reacti o n t h at 
h y p ot hetic all y mi g ht ha v e ca use d d eat h ha d it occ urre d i n a m ore se vere f or m.  
 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. H os pitalizati o n 
a d missi o ns a n d/ or s ur gic al o perati o ns sc he d ul e d t o occ ur d uri n g t he st u d y peri o d, b ut 
p la n ne d pri or t o st u d y e ntr y are n ot c o nsi dere d A Es if t he ill ness or diseas e e xiste d 
bef ore t h e s u bject was e nr olle d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n 
u ne x pecte d ma n ner d uri n g t he st u d y (e g, s ur ger y p erf or me d earlier t ha n pla n ne d).  
 A  persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or mal life f u ncti o ns.  
 C o n ge nital a n o mal y/ birt h defect i n a n e o nate/i nf a nt b or n t o a m ot her or fat her 
e x p ose d t o st u d y tr eat me nt.  
 I m p ort a nt me dical e v e nt. A n i m p orta nt me dical e ve nt is a n e ve nt t hat ma y n ot res ult 
i n deat h, be life-t hr eate ni n g, or re q uire h os pitalizati o n b ut ma y be c o nsi dere d a n S A E 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y je o par dize t he s u bject a n d 
ma y re q uire m e dical or s ur gical i nter ve n ti o n t o pr e ve nt o ne of t he o ut c o mes liste d i n 
t he defi niti o ns f or S A Es. E x a m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n -pa tie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g d e p e n de nc y or dr u g a b us e.  
T he ter ms “se v ere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y refers t o t he i nte nsit y of a n A E 
(rate d as mil d, m o derate, or se vere, or acc or di n g t o N CI C T C A E criteria); t h e e ve nt itself ma y b e 
of relati vel y mi n or me dic al si g nifica nce (s uc h as s e vere h ea d ac he wit h o ut a n y f urt her fi n di n gs).  
Se verit y a n d seri o us ness nee d t o be i n de p e n de ntl y assesse d f or eac h A E rec or de d o n t he e C R F.  
1 1. 2.  
Pr oce d ures f or Re p orti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  
All A Es (seri o us a n d n o n -seri o us) s p o nta ne o usl y re p orte d b y t he s u bject a n d/ or i n res p o nse t o a n 
o pe n q uesti o n fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e xa mi nati o n, or ot her 
dia g n ostic pr o ce d ures will be rec or de d o n t he a p pr o priate pa ge of t he e C R F. A n y cli nicall y 
rele va nt det eri orati o n i n l a b orat or y assess me nts or ot her cli nical fi n di n gs is c o nsi dere d a n A E 
a n d m ust be rec or de d o n t he a p pr o priat e pa ges of t he e C R F. W he n p ossi ble, si g ns a n d s y m pt o ms 
i n dicati n g a c o m m o n u n derlyi n g p at h ol o g y s h o ul d be n ote d as o ne c o m pre h e nsi ve e ve nt (i e, a 
dia g n osis).  
F or re p orts of S A Es, I n v esti gat ors s h o ul d rec or d all case det ails t hat ca n b e gat here d pr o m ptl y o n 
t he A E e C R F a n d s u b mit via t he Electr o nic Data Ca pt ure ( E D C) s yste m. All S A Es are t o be 
re p orte d wit hi n 2 4 h o urs fr o m t he p oi nt i n ti me w he n t he I n vesti gat or b ec o mes a ware of t he 

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S A E. All S A Es m ust be re p orte d w het h er or n ot t h e y are c o nsi dere d ca us all y relate d t o A G -
1 2 0/ place b o. Seri o us a d v erse e v e nt f or ms will be c o m plete d a n d t he i nf or mati o n c ollecte d will 
i ncl u de s u bject n u m ber, a narrati ve descri pti o n of t he e ve nt, a n d a n assess me nt b y t he 
I n v esti gat or as t o t he se v erit y of t he e v e nt a n d rel ate d ness t o st u d y dr u g. F oll o w-u p i nf or mati o n 
o n t he S A E ma y b e re q u este d b y t h e S p o ns or or  Me dical M o nit or.  
I n t he e ve nt t hat t he E D C s yste m is u na vaila ble, a pa per S A E a n d fa x c o vers heet s h o ul d be 
c o m plete d a n d fa x e d/e maile d t o A gi os P har m ace uticals, I n c. ( A gi os) wit hi n n o m ore t ha n 
2 4  h o urs after l ear ni n g of t he e ve nt usi n g t h e fa x n u m bers pr o vi de d t o I n vesti gat ors i n t he 
Seri o us A d verse E v e nt Re p ort F or m C o m pleti o n G ui deli nes.  
If t here are seri o us, u ne x pecte d relate d A Es ass ociate d wit h t he use of A G-1 2 0/ place b o, t he 
S p o ns or will n otif y t h e a p pr o priate re g ulat or y a ge nc y(i es) a n d all partici pa ti n g I n vesti gat ors o n 
a n e x pe dite d basis. T he l ocal I nstit uti o nal Re vie w B oar d (I R B)/I n de p e n de nt Et hics C o m mittee 
(I E C) will be pr o m ptl y n otifie d base d o n l ocal r e g ulati o ns w here re q uire d b y t he I R B/I E C of all 
seri o us, u ne x pecte d rel ate d A Es i n v ol vi n g ris k t o h u ma n s u bjects. 
All A Es, w het her seri o us or n ot, will be descri be d i n t he s o urce d oc u m e nts a n d o n t he A E pa ge 
of t he e C R F. All ne w e ve nts, as well as t h ose t hat w orse n i n se verit y or fre q ue nc y rel ati ve t o 
baseli ne, w hic h occ ur aft er s u bjects ha v e recei ve d at least o ne d ose of st u d y treat me nt t hr o u g h 
2 8  da ys f oll o wi n g t he l ast d ose of st u d y tr eat me nt, m ust be rec or de d. A d verse e ve nts t hat are 
o n g oi n g at t he ti me of tr eat me nt disc o nti n uati o n s h o ul d be f oll o we d t hr o u g h t he 2 8 -da y p ost -
treat me nt assess me nt. I n a d diti o n, S A Es t hat are assesse d b y t h e I n vesti gat or as relat e d t o st u d y 
dr u g m ust be re p orte d a n y ti me t he I n v esti gat or bec o mes a ware of s uc h a n e ve nt, e ve n if t his 
occ urre nce is m ore t ha n 2 8 da ys after t h e last d ose of st u d y treat me nt.  
I nf or mati o n t o be re p orte d i n t he descri pti o n of eac h A E i ncl u des:  
 A me dical dia g n osis of t he e ve nt (if a me dical dia g n osis ca n n ot b e deter mi ne d, a 
descri pti o n of eac h si g n or s y m pt o m c haract erizi n g t he e ve nt s h o ul d be rec or de d)  
 T he date of o ns et of t he e ve nt  
 T he date o f res ol uti o n of t he e ve nt 
 W het her t he e ve nt is seri o us or n ot  
 Se verit y of t he e v e nt (see bel o w f or defi niti o ns)  
 Relati o ns hi p of t he e ve nt t o st u d y treat me nt (s ee b el o w f or defi niti o ns)  
 Acti o n ta ke n: n o ne; c h a n ge i n t he st u d y tr eat me nt a d mi nistrati o n (e g, t e m p orar y 
i nterr u pti o n i n d osi n g); dr u g tr eat me nt r e q uire d; n o n-dr u g treat me nt re q uir e d; 
h os pitaliz ati o n or pr ol o n gati o n of h os pitalizati o n re q uire d (c o m plete S A E pa ge); 
dia g n ostic pr o ce d ure perf or me d; s u bject disc o nti n ue d fr o m t he st u d y (c o m plete E n d 
of St u d y Visit)  
 O utc o me: s u bject rec o vere d wit h o ut se q uelae; s u bject rec o v ere d wit h se q uelae; e ve nt 
o n g oi n g; s u bject die d ( n otif y t he Me di cal M o nit or wit hi n 2 4 h o urs, a n d c o m plete t he 
S A E f or m)  

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Se verit y  of all A Es, i ncl u di n g cli nicall y si g nifica nt treat me nt -e me r ge nt la b orat or y a b n or malities, 
will be gra de d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3 ( A p pe n di x  1 5. 8 ). A d verse e ve nts n ot 
liste d b y t he N CI C T C A E will be gra de d as f oll o ws:  
 Mil d: t he e ve nt is n oticea ble t o t he s u bject b ut d oes n ot i nterfere wit h r o uti ne acti vit y.  
 M o derate: t he e ve nt i nterferes wit h r o uti ne acti vit y b ut res p o n ds t o s y m pt o matic 
t hera p y or rest. 
 Se vere: t he e v e nt si g nifi ca ntl y li mits t he s u bject’s a bilit y t o perf or m r o uti ne acti vities 
des pite s y m pt o matic t hera p y.  
 Lif e -t hreate ni n g: a n e v e nt i n w hic h t he s u bject was at ris k of deat h at t he ti me of t he 
e ve nt.  
 Fatal: a n e ve nt t hat res ults i n t he deat h of t he s u bject.  
1 1. 2. 1.  
Di a g n osis vers us Si g ns a n d S y m pt o ms  
A dia g n osis (if k n o w n) s h o ul d be rec or de d o n t he A d verse E v e nt e C R F rat her t ha n i n di vi d ual 
si g ns a n d s y m pt o ms (e g, rec or d o nl y li ver fail ure or he patitis rat her t h a n ja u n dice, asteri xis, a n d 
ele vate d tra nsa mi nases). H o we ver, if a c o nst ellati o n  of si g ns a n d/ or s y m pt o ms ca n n ot be 
me dicall y c haracterize d as a si n gle dia g n osis or s y n dr o me at t he ti me of re p orti n g, eac h 
i n di vi d ual e ve nt s h o ul d be rec or de d o n t he A d verse E ve nt e C R F. If a dia g n osis is s u bse q ue ntl y 
esta blis he d, all pre vi o usl y re p orte d a d verse e ve nts base d o n si g ns a n d s y m pt o ms s h o ul d be 
n ullifie d a n d re pla ce d b y 1 A E re p ort b ase d o n t he si n gle dia g n osis, wit h a starti n g dat e t hat 
c orres p o n ds t o t he starti n g dat e of t he first s y m pt o m of t he e ve nt ual dia g n osis.  
1 1. 2. 2.  
A d verse E ve nts Occ urri n g Se c o n d ar y t o Ot her E ve nts  
I n ge neral, A Es occ urri n g sec o n dar y t o ot her e ve nts (e g, casca de e ve nts or cli nical se q uelae) 
s h o ul d be i de ntifie d b y t h eir pri mar y ca use, wit h t he e x ce pti o n of se vere or seri o us sec o n dar y 
e ve nts. H o we v er, me dic all y si g nifi ca nt A Es occ urri n g sec o n dar y t o a n i nitiati n g e v e nt t hat are 
se parat e d i n ti me s h o ul d be rec or de d as i n de pe n de nt e ve nts o n t he A d verse E ve nt e C R F. F or 
e x a m ple:  
a. If v o miti n g res ults i n mil d de h y drati o n wit h n o a d diti o nal treat me nt i n a healt h y a d ult, 
o nl y v o miti n g s h o ul d be re p orte d o n t he e C R F.  
b.  If v o miti n g res ults i n se v ere de h y drati o n a n d re q uires treat me nt, b ot h e v e nts s h o ul d 
be re p ort e d se paratel y o n t he e C R F.  
c. If a se v ere gastr oi ntesti nal he m orr ha ge lea ds t o re nal fail ure, b ot h e ve nts s h o ul d be 
re p orte d se p aratel y o n t he e C R F.  
d.  If diz zi ness lea ds t o a fall a n d s u bse q ue nt fract ur e, all 3 e ve nts s h o ul d be re p orte d 
se parat el y o n t h e e C R F. 
e. If ne utr o pe ni a is acc o m pa nie d b y a mil d, n o n-seri o us i nfecti o n, o nl y n e utr o pe nia 
s h o ul d be re p orte d o n t he e C R F. 
f. If ne utr o pe ni a is acc o m pa nie d b y a se v ere or seri o us i nfecti o n, b ot h e ve nts s h o ul d be 
re p orte d se p aratel y o n t he e C R F. 
All A Es s h o ul d be rec or de d se paratel y o n t he A d v erse E ve nt e C R F if it is u nclear as t o w het her 
t he e ve nts are ass oci ate d. 

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A d verse E ve nts of S peci al I nterest  
A n A E SI ca n b e seri o us or n o nseri o us a n d is a n e ve nt of s pecial i nterest t o t he S p o ns or. O n g oi n g 
m o nit ori n g a n d ra pi d c o m m u nicati o n ( wit hi n 2 4 h o urs) b y t he I n vesti gat or t o t he S p o ns or is 
re q uire d t o all o w f or f urt her c haracterizati o n a n d re p orti n g t o r e gulat or y a ut h orities.  
1 1. 2. 3. 1.  Q Tc F Pr ol o n g ati o n  
A n y Q T pr ol o n gati o n e v e nt assesse d as Gra d e 2 or w orse (e. g., Q Tc F i nter val l o n ger t ha n 
4 8 0  msec or 6 0 msec or l o n ger t ha n t he rea di n g at baseli ne wit h T orsa d e de p oi ntes or 
p ol y m or p hic ve ntric ular t ac h ycar dia or si g n s/s y m pt o ms of seri o us arr h yt h mia), irres p ecti ve of 
t he seri o us ness of t he e ve nt, s h o ul d be re p orte d as a n A E SI t o t he S p o ns or wit hi n 2 4 h o urs. See 
Secti o n  9. 9  f or f urt her details o n ma na gi n g s u bjects wit h Q Tc F Pr ol o n gati o n. See A p pe n di x 1 5. 4  
f or Fri dericia’s f or m ula. 
1 1. 2. 4.  
Persiste nt or Rec u rre nt A d verse E ve nts  
A persiste nt A E is o ne t h at e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n s u bject e val u ati o n 
ti me p oi nts. T he i nitial se verit y of t he e v e nt s h o ul d be rec or de d, a n d t he se v erit y s h o ul d be 
u p date d t o refl ect t he m ost e xtre me se verit y a n y ti me t he e ve nt w ors e ns i n i nte nsit y or gra de.  
W he n a n A E bec o mes s eri o us (re gar dless of c h a n ges i n gra de or se verit y), t he e C R F s h o ul d be 
u p da te d t o refl ect t his. As s uc h, a ne w A E (seri o us e ve nt wit h o nset date f or w he n A E b eca m e 
seri o us) s h o ul d be a d d e d t o t he e C R F. 
H o we ver t he sa me d o es n ot h ol d tr ue f or A Es t hat c ha n ge fr o m seri o us t o n o n -seri o us e ve nts. 
W he n a n A E d oes n ot res ol ve b ut is d o w n gra de d fr o m a seri o us t o a n o n -s eri o us e ve nt, a ne w 
A E is n ot re q uire d t o be ca pt ure d o n t he e C R F. A res ol uti o n date is re q uire d t o be e ntere d o n t h e 
S A E f or m o nce a n A E c h a n ges fr o m a s eri o us t o n o n -seri o us e ve nt si nce t his w o ul d res ult i n t he 
S A E res ol vi n g.  
A rec urre nt A E is o n e t hat res ol ves bet w ee n s u bject e val uati o n ti me p oi nts a n d s u bse q ue ntl y 
rec urs. Eac h rec urre n ce of a n A E s h o ul d be rec or de d se paratel y o n t he A d v erse E ve nt e C R F. 
1 1. 2. 5.  
A b n or m al L a b or at or y V al ues  
N ot e ver y la b orat or y a b n or malit y q ualifie s as a n A E. A la b orat or y test res ult s h o ul d be re p orte d 
as a n A E if it meets a n y of t he f oll o wi n g criteri a:  
a. Acc o m pa nie d b y cli nical s y m pt o ms  
b.  Res ults i n a c ha n ge i n st u d y treat me nt (e g, d os a ge m o dificati o n, treat me nt 
i nterr u pti o n, or treat me nt disc o nti n uatio n)  
c. Res ults i n a me dical i nter ve nti o n (e g, p otassi u m s u p ple me ntati o n f or h y p o k ale mia) or 
a c ha n ge i n c o nc o mita nt t hera p y  
d.  Cli nicall y si g nifica nt i n t he I n vesti gat or’s j u d g me nt  
It is t he I n v esti gat or’s r es p o nsi bilit y t o re vi e w all la b orat or y fi n di n gs. Me di cal a n d scie ntific 
j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her a n is olate d la b orat or y a b n or malit y s h o ul d be 
classifie d as a n A E.  

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If a cli nic all y si g nifica nt la b orat or y a b n or malit y is a si g n of a diseas e or s y n dr o me (e g, A L P a n d 
bilir u bi n 5 × U L N ass oci a te d wit h c h olec ystitis), o nl y t he dia g n osis (ie, c h olec ystitis) s h o ul d be 
rec or de d o n t he A d v erse E ve nt e C R F. 
If a cli nic all y si g nifica nt la b orat or y a b n or malit y is n ot a si g n of a disease or s y n dr o me, t h e 
a b n or malit y itself s h o ul d be rec or de d o n t he A d vers e E ve nt e C R F, al o n g wit h a descri pt or 
i n dicati n g if t he test r es ult is a b o ve or bel o w t he n or mal ra n ge. 
1 1. 2. 6.  
De at hs  
Deat hs occ urri n g d uri n g t he pr ot oc ol -s pecifie d A E re p orti n g peri o d (Secti o n  1 1. 2 ) t hat are 
attri b ute d b y t he I n vesti gat or s olel y t o pr o gressi o n of c h ola n gi ocarci n o ma s h o ul d be rec or de d 
o nl y o n t he Treat me nt a n d St u d y Disc o nti n uati o n e C R Fs. All ot her o n -treat me nt deat hs, 
re gar dl ess of rel ati o nshi p t o st u d y treat me nt, m ust be rec or de d o n t he A d verse E ve nt e C R F a n d 
re p orte d t o t he S p o ns or wit hi n 2 4 h o urs. 
Deat h s h o ul d be c o nsi dere d a n o utc o me a n d n ot a disti nct e ve nt. T he u n derl yi n g me dical 
dia g n osis or s us pecte d di a g n osis t hat ca use d or c o ntri b ut e d t o t he fatal o utc o me s h o ul d be 
rec or de d as t he si n gle me dical c o nce pt o n t he A d verse E ve nt e C R F. Ge n erall y, o nl y 1 s u c h e ve nt 
s h o ul d be re p orte d. T h e t er m “s u d de n d eat h” s h o ul d o nl y be use d f or t he occ urre n ce of a n a br u pt 
a n d u ne x pecte d deat h d ue t o pre s u me d car diac ca uses i n a s u bject wit h or wit h o ut pree xisti n g 
heart diseas e, wit hi n 1 h o ur of t he o nset of ac ute s y m pt o ms or, i n t he cas e of a n u n wit nesse d 
deat h, wit hi n 2 4 h o urs after t he s u bject w as last see n ali ve a n d sta ble. If t he ca use of deat h is 
u n k n o w n a n d ca n n ot b e ascertai ne d at t he ti me of re p orti n g, “ u ne x plai ne d deat h” s h o ul d be 
rec or de d o n t he A d v erse E ve nt e C R F. If t he ca us e of deat h later bec o mes a vaila ble (e g, after 
a ut o ps y), “ u ne x plai ne d d eat h” s h o ul d be re place d b y t he esta blis he d ca us e o f deat h. 
All deat hs will be c ollect e d. All o n -treat me nt d eat hs ( wit hi n t he 2 8 da ys aft er last d ose of st u d y 
treat me nt) s h o ul d ha ve a n ass ociate d S A E ca pt ure d f or t he e v e nt t hat le d t o deat h, e xce pt i n t he 
e ve nt of diseas e pr o gressi o n (see Secti o n  1 1. 2. 7 ). 
D uri n g p ost -tr eat me nt s ur vi val f oll o w-u p, all deat hs will c o nti n ue t o be c ollecte d, b ut o nl y t h ose 
u nrelate d t o diseas e pr o gressi o n will be classifie d as S A Es.  
1 1. 2. 7.  
Pr o g ressi o n of C h ol a n gi oc arci n o m a  
Pr o gressi o n of c h ola n gi o carci n o ma s h o ul d n ot be re p orte d as a n A E if it is clearl y c o nsiste nt 
wit h t he s us pecte d pr o gressi o n of t he u n derl yi n g ca ncer as d efi ne d b y R E CI S T v 1. 1 
(A p pe n di x  1 5. 9 ). Cli nical s y m pt o ms of pr o gressi o n ma y b e re p orte d as A Es if t he s y m pt o ms 
ca n n ot be det er mi ne d as e x cl usi vel y d u e t o t he pr o gressi o n of t he s u b ject’s u n derl yi n g 
c h ola n gi ocarci n o ma, or d oes n ot fit t he e x pecte d patter n of pr o gressi o n f or t he disease.  
If t here is a n y u ncertai nt y a b o ut a n A E bei n g d ue o nl y t o t he diseas e u n der st u d y, it s h o ul d be 
re p orte d as a n A E or S A E. 
1 1. 2. 8.  
Pre -e xisti n g Me dic al C o n dit i o ns 
A pree xisti n g me dical c o n diti o n is o ne t hat is prese nt at t he Scree ni n g Visit f or t his st u d y. S uc h 
c o n diti o ns s h o ul d be rec or de d o n t he Me dical Hist or y e C R F.  

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A pree xisti n g me dical c o n diti o n s h o ul d be rec or de d as a n A E o nl y if t he fre q ue nc y, se verit y, or 
c haracter of t he c o n diti o n w orse ns d uri n g t he st u d y. W he n rec or di n g s uc h e ve nts o n t he A d verse 
E ve nt e C R F, it is i m p orta nt t o c o n ve y t he c o n ce pt t hat t he pree xisti n g c o n diti o n has c ha n ge d b y 
i ncl u di n g a p plica ble descri pt ors (e g, “ m or e fre q ue nt hea dac h es”).  
1 1. 2. 9.  
H os pit aliz ati o n  or Pr ol o n ge d H os pit aliz ati o n  
A n y A E t hat res ults i n h os pitaliz ati o n or pr ol o n ge d h os pitalizati o n s h o ul d be d oc u me nte d a n d 
re p orte d as a n S A E ( per t he defi niti o n of S A E i n Secti o n  1 1. 1. 3 ), e x ce pt as o utli ne d bel o w. 
T he f oll o wi n g h os pitaliz ati o n sce nari os are n ot c o nsi dere d  t o be S A Es: 
 H os pitalizati o n f or res pite care  
 Sta n dar d pr oce d ure f or pr ot oc ol t hera p y a d mi nistrati o n; h o we ver, h o s pitali zati o n or 
pr ol o n ge d h os pitaliz ati o n f or a c o m plicati o n of t hera p y a d mi nistrati o n will be 
re p orte d as a n S A E 
 R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n  
 A d mi nistrati o n of bl o o d or plate let tra nsf usi o n as r o uti ne treat me nt of st u di e d 
i n dicati o n; h o we ver, h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n 
of s uc h tra nsf usi o n r e mai ns a re p orta bl e S A E  
 A pr oce d ure f or pr ot oc ol/ disease -relate d i n vesti gati o ns (e g, s ur ger y, sca ns, 
en d osc o p y, sa m pli n g f or la b orat or y tests, b o ne marr o w sa m pli n g); h o we v er, 
h os pitaliz ati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n of s uc h pr oce d ures 
re mai ns a re p orta ble S A E 
 H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n f or tec h nical, practical , or s ocial 
reas o ns, i n a bse n ce of a n A E 
 A pr oce d ure t hat is pla n n e d (ie, pla n ne d pri or t o start of treat me nt o n st u d y); m ust be 
d oc u me nte d i n t he s o urce d oc u me nt a n d t he e C R F; h os pitalizati o n or pr ol o n ge d 
h os pitaliz ati o n f or a c o m plicati o n re mai ns a re p or ta ble S A E 
 A n electi ve tr eat me nt of or a n electi ve pr oce d ure f or a pre -e xisti n g c o n diti o n, 
u nrelate d t o t he st u die d i n dicati o n, t hat has n ot w orse ne d fr o m baseli ne  
1 1. 2. 1 0.  
O ver d ose or I nc orrect A d mi nistr ati o n  
St u d y treat me nt o ver d ose is t he acci de ntal or i nte nti o na l use of t he dr u g i n a n a m o u nt hi g her t h a n 
t he d ose bei n g st u die d. A n o ver d ose or i n c orrect a d mi nistrati o n of st u d y tr eat me nt is n ot a n A E 
u nless it res ults i n u nt o war d me dical effects.  
A n y st u d y treat me nt o ver d ose or i nc orrect a d mi nistrati o n of st u d y tr ea t me nt s h o ul d be n ote d o n 
t he St u d y Dr u g A d mi nistrati o n e C R F. 
All A Es ass ociate d wit h a n o ver d ose or i nc orrect a d mi nistrati o n of st u d y tr eat me nt s h o ul d be 
rec or de d o n t he A d v erse E ve nt e C R F. If t he ass ociate d A E f ulfills seri o us criteria, t he e v e nt 
s h o ul d be re p orte d t o t he S p o ns or b y t he I n v esti gat or wit hi n 2 4 h o urs after l ear ni n g of t he e ve nt.  

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Ot her P ote nti al Ris ks  
1 1. 3. 1.  
Le u k oe nce p h al o p at h y  
Le u k o e nce p hal o pat h y is a p ote ntial ris k ass ociate d wit h A G -1 2 0 treat me nt base d o n cli nical 
safet y fi n di n gs o bser v e d acr oss t he A G-1 2 0 cli nical de vel o p me nt pr o gra m. Pr o gressi ve 
m ultif ocal le u k oe nce p h al o pat h y ( P M L) a n d p osteri or re versi ble e nce p hal o p at h y s y n dr o m e 
( P R E S), b ot h Gra de 3 S A Es, ha ve eac h b ee n re p orte d i n 1 s u bject wit h u n derl yi n g h e mat ol o gi c 
mali g na n cies.  
T he si g ns a n d/ or s y m pt o ms of P M L ma y be gi n gra d uall y, us u all y w orse n ra pi dl y, a n d v ar y 
de pe n di n g o n w hic h part of t he brai n is i nfecte d. Si g ns a n d s y m pt o ms ma y i ncl u de diffic ult y 
wit h wal ki n g a n d ot h er m o ve me nts, pr o gressi ve wea k ness, d ecli ne i n me ntal f u ncti o n, vis u al 
fiel d deficits, a n d s peec h a n d la n g ua ge dist ur ba nces. Rarel y, hea d ac hes a n d seiz ures occ ur. 
S u bjects s h o ul d be m o nit ore d f or o ns et of si g ns or s y m pt o ms s u g gesti ve of P M L. Dia g n ostic 
e val uati o ns ma y i ncl u de c o ns ultati o n wit h a ne ur ol o gist, M RI of t he bra i n, l u m bar p u nct ure, 
a n d/ or brai n bi o ps y as cli nicall y w arra nte d. T he I n vesti gat or s h o ul d i m me di atel y c o ntact t he 
St u d y M e dical M o nit or w he n P M L is a s us p ecte d or c o nfir me d dia g n osis. Treat me nt wit h 
A G -1 2 0 s h o ul d be s us pe n de d i n t he setti n g of s us pecte d P M L a n d per ma n e ntl y disc o nti n ue d i n 
s u bjects wit h c o nfir me d P M L. 
P osteri or re versi ble e nce p hal o pat h y s y n dr o me is a rare cli nic o -ra di ol o gi cal ne ur ol o gical 
s y n dr o me (Li n da  a n d v o n Heij ne , 2 0 1 5 ). Cli nical c haracteristics ma y i ncl u de s u b-ac ut e o nset of 
hea dac he, h y perte nsi o n, seiz ures, altere d me ntal  stat us, vis ual dist ur ba nces, a n d occasi o nall y 
ot her f ocal ne ur ol o gical si g ns. Ra di ol o gi call y, si g ns of vas o ge nic e de ma are us ua ll y see n 
bilaterall y i n t he w hite matter of t he p ariet o -occi pital l o bes, b ut c ha n ges ca n als o be see n i n 
fr o ntal a n d te m p oral l o bes, brai nste m, cere bell u m, a n d i n c ortical as well as dee p gra y m atter. 
S u bjects s h o ul d be m o nit ore d f or o ns et of ne ur ol o gical si g ns a n d/ or s y m pt o ms t hat are cli nicall y 
ass ociate d wit h P R E S. Dia g n ostic e v al uati o ns ma y i ncl u de c o ns ultati o n wit h a ne ur ol o gist, M RI 
of t he brai n, a n d ot h er rec o g niz e d sta n dar d of care meas ures as cli nicall y warra nte d. 
A d diti o nall y, t he I n vesti gat or s h o ul d c o ns ult wit h t he St u d y Me dical M o nit or f or ma na ge me nt 
g ui deli nes t o be utiliz e d i n t he setti n g of s us pecte d or c o nfir me d P R E S.  
Refer t o Secti o n 6. 5. 8. 1 ( P M L) a n d Secti o n 6. 5. 8. 2 ( P R E S) i n t he A G -1 2 0 I n v esti gat or’s 
Br oc h ure  f or f urt h er details o n t hese e ve nts.  
1 1. 3. 2.  
Se ns ori m ot or Ne ur o p at h y/ P ol y ne ur o p at h y  
Se ns ori m ot or ne ur o pat h y/ p ol y ne ur o pat h y is a p ote ntial ris k ass ociate d wit h A G -1 2 0 treat me nt 
base d o n safet y fi n di n gs o bser ve d acr oss t he A G -1 2 0 cli nical de vel o p me nt pr o gra m. 
G uillai n -Barre s y n dr o m e ( Gra d e 2 S A E i n 1  s u bject; Gra de 3 S A E i n 1  s u bject, b ot h wit h 
u n derl yi n g h e mat ol o gi c mali g na n cies) a n d l u m b osacral ple x o pat h y ( Gra de 2 S A E i n 1  s u bject 
wit h u n derl yi n g he m at ol o gic mali g na n c y) are rare, seri o us s y n dr o mes t hat affect t he ce nt ral a n d 
peri p heral ner v o us s yste ms.  
S u bjects s h o ul d be m o nit ore d f or o ns et of ne w si g ns or s y m pt o ms of m ot or a n d/ or se ns or y 
ne ur o pat h y s uc h as u nilateral or bilateral wea k ness, se ns or y alterati o ns, or parest hesia. If a 
s u bject e x perie nces si g ns or s y m pt o ms s u g gesti ve of se ns ori m ot or ne ur o pat h y, G uillai n-Barre 
s y n dr o me, or l u m b osacral ple x o pat h y, dia g n ostic e val uati o n ma y i ncl u de a c o ns ultati o n wit h a 

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ne ur ol o gist, l u m bar p u nct ure, a n d ele ctr o m y o gra p h y. T he I n vesti gat or s h o ul d i m me diatel y 
c o ntact t he St u d y M e dical M o nit or w he n G uillai n -Barre s y n dr o m e is a s us pecte d or c o nfir me d 
dia g n osis. A G -1 2 0 s h o ul d be per ma n e ntl y disc o nti n ue d i n s u bjects wit h a c o nfir me d dia g n osis of 
G uillai n -Barre s y n dr o m e. Refer t o Secti o n 6. 5. 6 ( Se ns ori m ot or Ne ur o pat h y/ P ol y n e ur o pat h y) i n 
t he A G-1 2 0 I n v esti gat or’s Br oc h ure f or f urt her det ails o n t hese e ve nts. 
1 1. 4.  
Pre g n a nc y Re p orti n g  
Pre g n a nc y is neit her a n A E n or a n S A E, u nless a c o m plicati o n relati n g t o t he pre g na n c y occ urs 
(e g, s p o nta ne o us a b orti o n, w hic h ma y q ualif y as a n S A E). 
Pre g n a ncies  a n d s us pecte d pre g na nci es (i ncl u di n g a p ositi ve pre g na n c y test re gar dl ess of a ge or 
disease state) of a fe male s u bject or part ner of a m ale s u bject occ urri n g w hile t he s u bject is o n 
st u d y treat me nt, or wit hi n 2 8 da ys of t he s u bject’s last d ose of st u d y tr eat m e nt, are c o nsi dere d 
i m me diatel y re p orta ble e ve nts. If a fe male p art ner of a male s u bject ta ki n g i n vesti gati o nal 
pr o d uct bec o mes pre g na nt, t he male s u bject ta ki n g st u d y treat me nt s h o ul d n otif y t he 
I n v esti gat or, a n d t he pre g na nt fe male p art ner s h o ul d be a d vise d t o call her healt hcare pr o vi der 
i m me diatel y. I n pre g na nt fe male s u bjects, st u d y tr eat me nt is t o be disc o nti n ue d i m me diatel y a n d 
t he s u bject i nstr ucte d t o ret ur n a n y u n use d st u d y dr u g t o t he I n vesti gat or. T he pre g na n c y, 
s us pecte d pre g na nc y, or p ositi ve pre g n a nc y test m ust be re p orte d i m me di atel y usi n g t he 
pre g na nc y re p orti n g f or m. T he I n vesti gat or m ust f oll o w -u p a n d d oc u me nt t he c o urse a n d 
o utc o me of all pre g n a nci es e ve n if t he s u bject was disc o nti n ue d fr o m t he st u d y or if t h e st u d y 
has fi nis he d. T he  fe male s u bject or part ner of a m ale s u bject s h o ul d recei v e a n y necessar y 
c o u nseli n g re gar di n g t h e ris ks of c o nti n ui n g t he pre g n a nc y a n d t he p ossi ble effects o n t he fet us. 
M o nit ori n g s h o ul d c o nti n ue u ntil c o ncl usi o n of t he pre g na nc y.  
All o utc o mes of pre g na n c y (fr o m a fe mal e s u bject or t he se x ual part ner of a male s u bject) m ust 
be re p ort e d b y t he I n vesti gat or t o t he S p o ns or or Me dical M o nit or o n a pre g n a nc y re p orti n g f or m 
wit hi n 2 8 da ys after he/s he has gai ne d k n o wle d ge of t he deli ver y or electi v e a b orti o n.  
A n y S A E t hat o cc urs d uri n g pre g n a nc y m ust be rec or de d o n t he S A E re p ort f or m (e g, mater nal 
seri o us c o m plicati o ns, s p o nta ne o us or t hera pe utic a b orti o n, ect o pic pre g na n c y, still birt h, 
ne o natal deat h, c o n ge nital a n o mal y, or birt h defect) a n d re p orte d wit hi n 2 4 h o urs i n acc or da nce 
wit h t he pr oce d ure f or re p orti n g S A Es.  
Fe males of re pr o d ucti ve p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test pri or t o t he start of 
t hera p y, or a c o nfir m ati o n fr o m a n o bstetricia n i n case of e q ui v ocal ser u m pre g na nc y res ults. 
W o m e n of re pr o d ucti ve p ote ntial, as well as fertile me n wit h part ners w h o are fe male wit h 
re pr o d ucti ve p ot e ntial, m ust a gree t o use 2 effecti ve f or ms of c o ntrace pti o n (i ncl u di n g at least 1 
barrier f or m) fr o m t he ti me of gi vi n g i nf or m e d c o nse nt t hr o u g h o ut t he st u d y a n d f or 9 0 da ys 
( b ot h fe males a n d m ales) f oll o wi n g t he last d ose of st u d y dr u g. Fe m ales of re pr o d ucti ve p ot e ntial 
are defi ne d as s e x uall y mat ure w o me n w h o ha ve n ot u n der g o ne a h ysterect o m y or bilateral 
o o p h orect o m y or w h o h a ve n ot bee n nat ur all y p ost me n o pa usal (ie, w h o ha ve n ot me nstr uate d at 
all) f or at least 2 4 c o nsec uti ve m o nt hs (ie,  has ha d me nses at a n y ti me i n t he prece di n g 2 4 
c o nsec uti ve m o nt hs).  
Males wit h part ners w h o are fe male wit h r e pr o d ucti ve p ote ntial m ust a gree t hat t he y or t h eir 
part ners will use 2  effecti ve f or ms of c o ntrace pti o n (i ncl u di n g at least 1 barrier f or m) w he n 

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e n ga gi n g i n re pr o d ucti ve se x ual acti vit y t hr o u g h o ut t he st u d y, a n d will a v oi d c o ncei vi n g f or 9 0 
da ys after t h e last d ose of st u d y treat me nt.  
Effecti ve f or ms of c o ntrace pti o n are d efi ne d as h or m o nal oral c o ntrace pti v es, i njecta bles, 
patc hes, i ntra uteri ne de vi ces, i ntra uteri n e h or m o ne -releasi n g s yste ms, bilateral t u bal li gati o n, 
c o n d o ms wit h s per mici de, or male part ner sterilizati o n. Please refer t o Secti o n  9. 1 3. 4  f or f urt her 
details o n p ote ntial dr u g -dr u g i nteracti o ns wit h h or m o nal c o ntrace pti ves.  
1 1. 5.  
F oll o w -u p of S u bjects After A d verse E ve nts  
1 1. 5. 1.  
I n vesti g at or F oll o w-U p  
T he I n vesti gat or s h o ul d f oll o w eac h A E u ntil t he e ve nt has res ol ve d t o bas eli ne gra de or better, 
t he e ve nt is assesse d as sta ble b y t he I n vesti gat or, t he s u bject is l ost t o f oll o w-u p, or t he s u bject 
wit h dra ws c o nse nt. E v er y eff ort s h o ul d be ma d e t o f oll o w  all S A Es c o nsi dere d relate d t o st u d y 
treat me nt or trial-relate d pr oce d ures u ntil a fi nal o utc o me ca n b e re p orte d. 
All pre g n a ncies re p ort e d d uri n g t he st u d y s h o ul d b e f oll o we d u ntil pre g na n c y o ut c o me. If t h e 
E D C s yste m is n ot a vaila ble at t he ti me of pre g n a nc y o ut c o me, f oll o w re p orti n g i nstr ucti o ns 
pr o vi de d i n S ecti o n 1 1. 4 . 
1 1. 5. 2.  
S p o ns or F oll o w -u p  
F or S A Es, A Es of s p ecial i nterest, a n d pre g n a ncies, t he S p o n s or or a desi g nee ma y f oll o w-u p b y 
tele p h o ne, fa x, electr o nic mail, a n d/ or a m o nit ori n g visit t o o btai n a d diti o nal case details a n d 
o utc o me i nf or mati o n (e g, fr o m h os pital disc har ge s u m maries, c o ns ulta nt re p orts, a ut o ps y 
re p orts) i n or d er t o perf or m a n i n depe n de nt me dical assess me nt of t he re p orte d cas e.  
1 1. 5. 3.  
P ost -st u d y A d verse E ve nts 
At t he treat me nt disc o nti n uati o n visit, t he I n vesti gat or s h o ul d i nstr uct eac h s u bject t o re p ort t o 
t he I n v esti gat or a n y s u bs e q ue nt A Es t hat t he s u bject’s pers o nal p h ysicia n b elie ves c o ul d be 
relate d t o pri or st u d y treat me nt or st u d y pr oce d ures. 
T he I n vesti gat or s h o ul d n otif y t he S p o ns or of a n y deat h, S A E, or ot her A E of c o ncer n occ urri n g 
at a n y ti me after a s u bject has disc o nti n ue d st u d y partici pati o n if t he e ve nt is belie ve d t o be 
relate d t o pri or st u d y treat me nt or st u d y pr oce d ures. T he S p o ns or s h o ul d als o be n otifie d if t he 
I n v esti gat or bec o m es a w are of t h e de vel o p me nt of ca ncer or a c o n ge nital a n o mal y/ birt h defect i n 
a s u bse q ue ntl y c o ncei ve d offs pri n g of a s u bject t hat partici pate d i n t his st u d y.  

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1 2.  
S T A TI S TI C A L M E T H O D S  
1 2. 1.  
Ge ner al Met h o ds  
S u m maries will be pr o d uce d f or dis p ositi o n, de m o gra p hic a n d b aseli ne dise ase c haracteristics, 
safet y a n d t olera nce, p har mac o ki netics, P D bi o mar kers, a n d efficac y v aria bles, as a p pr o pri ate.  
Cate g orical da ta will be s u m mariz e d b y fre q ue n c y distri b uti o ns ( n u m ber a n d perce nt a ges of 
s u bjects). C o nti n u o us data will be s u m marize d b y descri pti ve statistics ( mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma xi m u m). Ti me -t o-e ve nt e n d p oi nts will be esti mate d usi n g 
Ka pla n -Mei er met h o ds. P oi nt esti mates a n d 9 5 % CIs will be pr o vi de d w here a p pr o priate, a n d 
esti mates of t he me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -m o nt h, 6 -
m o nt h, a n d 1 2 -m o nt h rates) will be pr o d uce d.  
All data will be pr o vi de d i n  b y -s u bject listi n gs. 
T he st u d y d ata will be a n al yze d a n d re p ort e d i n t he pri mar y cli nical st u d y re p ort ( C S R) base d o n 
all s u bjects’ data u p t o t h e ti me w he n 1 3 1 P F S e ve nts ha ve bee n d eter mi ne d b y I n v esti gat or 
assess me nt. A n y a d diti o nal data f or s ur vi val f oll o w -u p a n d f or s u bjects c o nti n ui n g t o recei ve 
st u d y treat me nt past t he data c ut off d ate f or t he C S R u ntil t he occ urre nce of 1 5 0 O S e ve nts will 
be re p ort e d at t he e n d of t he st u d y i n t he fi nal C S R.  
1 2. 2.  
S a m ple Size Esti m ati o n  
A t otal of a p pr o xi matel y 1 8 6 s u bje cts will be nee d e d f or t he st u d y.  
T he pri mar y o bje cti ve of t he st u d y is t o de m o nstrate t he i m pr o ve me nt i n P F S b y I R C assess me nt 
f or s u bjects recei vi n g treat me nt wit h A G-1 2 0 as c o m pare d t o s u bjects r ecei vi n g place b o. 
Ass u mi n g a hazar d rati o ( H R) of 0. 5 f or P F S (e q ui vale nt t o a me dia n P F S of 3  m o nt hs i n t he 
place b o ar m vers us 6 m o nt hs i n t he A G -1 2 0 ar m, ass u mi n g a n e x p o ne ntial distri b uti o n), a t otal 
of 1 3 1 P F S e ve nts are re q uire d t o pr o vi de 9 6 % p o wer at a 1 -si de d al p ha of 0. 0 2 5 le vel of 
si g nifica n ce t o r eject t he n ull h y p ot hesis (Secti o n  1 2. 7. 1 ) usi n g a str atifie d l o g-ra n k test. Base d 
o n t his, a t otal of a p pr o xi matel y 1 8 6  s u bjects will nee d t o be ra n d o mize d i n a 2: 1 rati o t o t he A G-
1 2 0 a n d place b o ar ms, res pecti vel y, ass u mi n g a p pr o x i matel y a 2 2 % dr o p o ut rate, a n a p pr o xi mate 
2 6 -m o nt h ra n d o mizati o n peri o d, a n d a n a d diti o nal 6 -m o nt h f oll o w -u p f or P F S after t h e last 
s u bject is ra n d o mize d. T heref ore, t he pri mar y a n al ysis of P F S will occ ur at a p pr o xi matel y 6 
m o nt hs after t he last s u bject i s ra n d o mize d. 
O verall s ur vi val will be a nal yze d t wic e, o nce at t he ti me of t he fi nal a n al ysis f or P F S a n d o nce at 
t he occ urre nce of 1 5 0 O S e ve nts (fi nal a n al ysis f or O S, w hic h will occ ur at a p pr o xi matel y 2 4 
m o nt hs after t he last s u bject is ra n d o mize d). Ass u mi n g a n H R of 0. 6 7 f or O S ( me dia n O S of 8 
m o nt hs i n t he place b o ar m vs. 1 2 m o nt hs i n t he A G -1 2 0 ar m, ass u mi n g a n e x p o ne ntial 
distri b uti o n), a t otal of 1 5 0 O S e ve nts will pr o vi de 6 4 % p o wer at a 1 -si de d al p ha of 0. 0 2 5. 
1 2. 3.  
A n al ysis Sets  
T he f oll o wi n g a nal ysis s ets will be e val uate d a n d use d f or prese ntati o n of t he data:  
 I nte n d-t o-Treat A nal ysis Set (I T T): All s u bjects w h o were ra n d o mize d. S u bjects will 
be classifie d acc or di n g t o t he assi g n e d treat me nt ar m. T he I T T will be use d f or t he 
pri mar y efficac y a nal yses, a n d is t he defa ult a n al ysis set u nless ot her wise s pecifie d.  

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 Safet y A nal ysis Set ( S A S): All s u bjects w h o recei ve d at least o ne d ose of st u d y 
treat me nt. S u bjects will be classifie d acc or di n g t o t he treat me nt r ecei v e d. T h e S A S 
will be t he pri mar y set f or t he a nal ysis of safet y data, u nless ot her wise s pecifie d.  
 Cr oss o ver Set ( C O S): A s u bset of s u bjects i nitiall y assi g ne d t o recei ve place b o w h o 
cr osse d o ver a n d recei v e d A G -1 2 0.  
 Per -Pr ot oc ol Set ( P P S): All s u bjects i n t he I T T w h o ha d n o maj or pr ot oc ol vi olati o ns.  
A d diti o nal efficac y a n al yses ma y b e pr o d u ce d usi n g t he P P S. R ules f or maj or 
pr ot oc ol vi olati o ns will be s pecifie d i n t he statistical a nal ysis pla n ( S A P).  
 P har mac o ki netic A n al ysis Set ( P A S): All s u bjects w h o ha ve at least 1 bl o o d sa m ple 
p ost -d ose pr o vi di n g  e val ua ble P K data f or A G -1 2 0.  
1 2. 4.  
R a n d o miz ati o n a n d Str atific ati o n  
Eli gi ble s u bjects will be ra n d o mize d i n a 2: 1 rati o t o recei ve A G -1 2 0 or place b o, stratifie d b y 
n u m ber of pri or t hera pies ( 1 vs 2). T he ra n d o mizati o n sc he me will be ge nerate d b y a n 
i n de pe n de nt statistical gr o u p. T he ra n d o mizati o n assi g n me nt will be i m ple me nte d b y a n 
i nteracti ve w e b res p o ns e s yste m (I W R S). 
1 2. 5.  
Dis p ositi o n  
A ta b ulati o n of t he dis p ositi o n of s u bjects will be prese nte d b y tr eat me nt ar m, i ncl u di n g t he 
n u m ber ra n d o mize d, t he n u m ber treat e d, t he reas o ns f or treat me nt disc o nti n uati o n, a n d t he 
reas o ns f or st u d y disc o nti n uati o n. E ntr y criteria a n d pr ot oc ol de viati o ns will be liste d. 
1 2. 6.  
B aseli ne E v al u ati o ns  
De m o gra p hic a n d baseli n e disease c haracteristic data will be s u m marize d b y treat me nt ar m. Data 
t o be ta b ulate d will i ncl u de se x, a ge, a n d race a n d et h nicit y, as w ell as disease-s pecifi c 
i nf or mati o n. 
1 2. 7.  
Effic ac y A n al yses  
Res p o nse t o treat me nt will be assesse d b y t he site I n v esti gat ors a n d b y t he I R C usi n g R E CI S T 
v 1. 1 (see Secti o n  1 0. 7 ). 
T o c o ntr ol t he o verall T y pe I err or rate at t he 5 % le vel, t he fi x e d se q ue nce t esti n g pr oce d ure 
(Westfall a n d Kris he n 2 0 0 1 ) will be use d t o a dj ust f or m ulti ple statistical testi n g of t he pri mar y 
a n d selecte d s ec o n d ar y efficac y e n d p oi nts. T hese e n d p oi nts will be teste d i n t he f oll o wi n g or der:  
• 
P F S base d o n I R C  
• 
O S  
• 
O R R base d o n I R C  
N o a dj ust me nt t o t he α le vel will be ma de f or t h e ot her a nal yses.  

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A n al ysis f or t he Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of P F S is defi ne d as t he ti me fr o m t he dat e of ra n d o mizati o n t o t he date of 
first d oc u me ntati o n of disease pr o gressi o n as det er mi ne d b y t he I R C p er R E CI S T v 1. 1 or d eat h 
d ue t o a n y ca us e, w hic he ver occ urs first.  
S u bjects wit h o ut d oc u me ntati o n of disease pr o gressi o n or deat h at t he ti me of t he pri mar y 
a nal ysis of P F S will be ce ns ore d at t he d ate of t he last res p o nse assess me nt pri or t o t he start of 
alter nate t hera p y. If disease pr o g ressi o n or d eat h is d oc u me nte d aft er 1 si n gle missi n g res p o ns e 
assess me nt, t he act u al e v e nt date of disease pr o gressi o n/ deat h will be use d f or t he P F S e ve nt 
date. If disease pr o gressi o n is d oc u me nte d after 2 or m ore missi n g res p o ns e assess me nts, t he P F S 
time of t hese s u bjects will be ce ns or e d at t he dat e of t he last res p o nse assess me nt ( C R or P R or 
S D) pri or t o 2 or m ore missi n g res p o nse assess me nts. Detaile d ce ns ori n g r ules will be s pecifie d 
i n t he S A P. 
T he pri mar y effic ac y a n al ysis will be t he c o m paris o n of t he distri b uti o n of P F S bet wee n t he t w o 
treat me nt ar ms usi n g a l o g-ra n k test stratifie d b y t he ra n d o mizati o n stratificati o n fact or at o ne-
si de d 2. 5 % le vel of si g nifica nce. Ass u mi n g a pr o p orti o nal hazar d m o del f or P F S, t he n ull 
h y p ot hesis will be teste d:  
H 0 1 ( n ull h y p ot heses): Θ1 ≥ 0 vs. H a 1 (alter nati ve h y p ot heses): Θ1 < 0  
w here Θ 1is t he l o g hazar d rati o of P F S i n t he A G-1 2 0 (i n vesti gati o nal treat me nt) ar m vs. place b o 
(c o ntr ol) ar m. 
A C o x re gressi o n m o del stratifie d b y t h e ra n d o mi zati o n stratificati o n fact or will be use d t o 
esti mate t he H R of P F S  c o m pari n g t he A G -1 2 0 ar m wit h t he place b o ar m , al o n g wit h t he 9 5 % 
CI.  
Ka pla n -Mei er esti mates of P F S, i ncl u di n g esti mat es of t he me dia n a n d ot her q ua ntiles, as w ell as 
i n di vi d ual ti me p oi nts (e g, 3-m o nt h, 6 -m o nt h, a n d 1 2 -m o nt h rates), will be prese nte d f or eac h 
treat me nt ar m. Patter ns of ce ns or e d data will be e x a mi ne d bet wee n t he treat me nt ar m a n d 
place b o ar m b y s u m marizi n g t he n u m ber of P F S e ve nts t hat are ce ns ore d a n d b y ta b ulati n g t he 
reas o ns f or ce ns ore d o bs er vati o ns. 
T here will be n o i nteri m a nal ysis f or P F S. T he a n al ysis of P F S will be perf or me d w he n 1 3 1 
I n v esti gat or-ass esse d P F S e ve nts ha ve occ urre d, e x pecte d at a p pr o xi matel y 3 2 m o nt hs after t he 
first s u bject is ra n d o mize d i n t he st u d y. T he pri mar y a nal ysis  of P F S will be base d o n I R C 
res p o nse ass ess me nts. 
Se nsiti vit y a n al ys es f or P F S ma y i n cl u de b ut are n ot li mite d t o t he tests liste d bel o w. P F S ma y be 
a nal yze d usi n g:  
1.  Stratifie d l o g -ra n k test usi n g t he P P S base d o n I n v esti gat or assess me nts; 
2.  Stratifie d l o g -ra n k test usi n g t he P P S base d o n I R C assess me nts;  
3.  U nstratifie d l o g -ra n k t est usi n g t he I T T base d o n I n vesti gat or assess me nts; 
4.  U nstratifie d l o g -ra n k t est usi n g t he I T T base d o n I R C assess me nts. 
Ot her se nsiti vit y a n al ys es f or P F S ma y be c o n d u cte d a n d will be s pecifi e d i n t he S A P. 

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S u b gr o u p a n al ys es will be perf or me d o n eac h le vel of t he stratificati o n fact or. T he a n al ys es will 
i ncl u de Ka pla n-M eier s u m maries, u nstratifie d l o g -ra n k tests a n d H Rs (t o get her wit h ass ociate d 
9 5 % CIs) fr o m C o x re gressi o n m o dels. Ot her  s u b gr o u p a nal yses f or P F S, i ncl u di n g b ut n ot 
li mite d t o l ocall y a d va nce d vs. metastatic ca ncer, ma y b e c o n d uct e d a n d will be s pecifie d i n t he 
S A P.  
1 2. 7. 2.  
A n al yses f or t he Sec o n d ar y Effic ac y E n d p oi nts  
1 2. 7. 2. 1.  O ver all S ur vi v al  
O verall s ur vi val is defi n e d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h d ue t o a n y 
ca use. S u bjects w h o are ali ve at t he a nal ysis c ut off date will be ce ns ore d at t he date of last 
c o ntact.  
Ass u mi n g a n H R of 0. 6 7 f or O S ( me dia n O S of 8  m o nt hs i n t he place b o ar m vs. 1 2 m o nt hs i n t he 
A G -1 2 0 ar m, ass u mi n g a n e x p o ne ntial distri b uti o n), a t otal of 1 5 0 O S e ve nts will pr o vi de 6 4 % 
p o wer at a 1 -si de d al p ha of 0. 0 2 5. Wit h a sa m ple siz e of 1 8 6, a d diti o nal O S f oll o w-u p of 
a p pr o xi matel y 2 4 m o nt hs after last s u bject is ra n d o mize d will be nee de d t o o bta i n 1 5 0 O S 
e ve nts. Ass u mi n g a n H R of 0. 6 1 5 ( me dia n O S of 8 m o nt hs i n t he place b o ar m vs. 1 3 m o nt hs i n 
t he A G-1 2 0 ar m, ass u mi n g a n e x p o ne ntial distri b uti o n), a t otal of 1 5 0 O S e ve nts will pr o vi de 
8 0 % p o wer at a 1 -si de d al p ha of 0. 0 2 5. 
D ue t o t he all o wa n ce of  cr oss o ver of s u bjects w h o pr o gress o n t he place b o ar m t o t he 
A G -1 2 0  ar m, it is a ntici p ate d t hat t he  tr ue effect of A G-1 2 0 o n s ur vi val as c o m pare d t o place b o 
will n ot be a ble t o be me as ure d, a n d t h at t he trial will n ot be p o were d t o detect a mea ni n gf ul 
s ur vi val effect. 
O S will be c o m pare d bet wee n t he t w o treat me nt ar ms, pr o vi de d t he pri mar y e n d p oi nt P F S is 
statisticall y si g nifica nt fa v ori n g t he A G-1 2 0 ar m. A hierarc hical testi n g pr oce d ure will be 
a d o pte d i n t his st u d y a n d t he O S a nal yses will be perf or me d o nl y if t h e pri mar y effi cac y 
e n d p oi nt P F S is statisticall y si g nifi ca nt. O S will be a nal yz e d base d o n t h e data fr o m t he I T T, 
acc or di n g t o t he tr eat me nt ar m t o w hic h s u bjects were ra n d o mize d a n d t he strata t he y were 
assi g ne d at ra n d o mizati o n. T he distri b uti o n f u ncti o n of O S will be esti mate d usi n g t he Ka pla n -
Meier met h o d. T he me di a n O S al o n g wit h 9 5 % CIs will be prese nte d b y tr eat me nt ar m.  
Ass u mi n g a pr o p orti o nal hazar ds m o del f or O S, t h e n ull h y p ot hesis will be teste d:  
H 0 2 ( n ull h y p ot heses): Θ2 ≥ 0 vs. H a 2 (alter nati ve h y p ot heses): Θ2 < 0  
w here Θ 2 is t he l o g hazar d rati o of O S i n t he A G-1 2 0 (i n vesti gati o nal treat me nt) ar m vs. place b o 
(c o ntr ol) ar m. 
T w o a nal yses are pla n n e d f or O S: 1) a n i nteri m a nal ysis at t he pr oj ecte d ti me of t he fi nal 
a nal ysis f or P F S ( p r o vi de d P F S is si g nifica nt); 2) a fi nal a nal ysis f or O S w h e n 1 5 0 deat hs are 
o bser ve d. O v erall s ur vi v al at t he i nteri m will be teste d wit h t he al p ha bei n g det er mi ne d usi n g t he 
ga m ma s p e n di n g f u ncti o n ( ga m ma = -8), a n d t he o verall t y p e I err or rate will be c o n tr olle d at t he 
1 -si de d 0. 0 2 5 le vel. T he l o g-ra n k test stratifie d b y ra n d o mizati o n stratificati o n fact or will be 
use d t o c o m pare O S bet wee n t he t w o treat me nt ar ms. T he u nstratifie d l o g -ra n k test will als o be 
c o n d ucte d.  

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Ka pla n -Mei er esti mates of O S will be p rese nte d f or eac h treat me nt ar m, i ncl u di n g esti mates of 
t he me dia n a n d ot her q u a ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3-m o nt h, 6 -m o nt h, a n d 1 2 -
m o nt h rates). T he H R of O S wit h 9 5 % CI c o m p ari n g A G -1 2 0 wit h place b o will be esti mate d 
fr o m a C o x pr o p orti o nal hazar ds m o del stratifie d b y ra n d o mizati o n stratificati o n fact or. 
D urati o n of f oll o w -u p will als o be prese nte d.  
Se nsiti vit y a n al ys es f or O S, s uc h as ta ki n g i nt o acc o u nt t he fact or of cr oss o ver, will be s pecifi e d 
i n t he S A P. 
1 2. 7. 2. 2.  Pr o g ressi o n Free S ur vi v al  per I n vesti g at or  
T he sec o n d ar y e n d p oi nt of P F S is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first occ urre nce 
of d oc u me nte d dise ase pr o gressi o n as deter mi ne d b y t he I n vesti gat or a n d t h e i nstit uti o nal 
ra di ol o gist(s) p er R E CI S T v 1. 1 or deat h fr o m a n y ca use, w hic h e ver occ urs first. 
T he sa me ce ns ori n g r ules as t he pri mar y e n d p oi nt of P F S will be a p plie d t o P F S per I n vesti gat or.  
A l o g -ra n k test stratifie d b y t he ra n d o mizati o n stratificati o n fact or will be use d t o c o m pare t h e 
P F S bet wee n t he A G -1 2 0 vs. place b o ar m. A C o x re gressi o n m o del stratifi e d b y t h e 
ra n d o mizati o n stratificati o n fact or will be use d t o esti mate t he H R of P F S c o m pari n g t he A G -1 2 0 
ar m wit h t he place b o ar m , al o n g wit h t he 9 5 % CI. 
Ka pla n -Mei er esti mates of  P F S, i ncl u di n g esti mat es of t he me dia n a n d ot her q ua ntiles, as w ell as 
i n di vi d ual ti me p oi nts (e g, 3-m o nt h, 6 -m o nt h, a n d 1 2 -m o nt h rates), will be prese nte d f or eac h 
treat me nt ar m. 
1 2. 7. 2. 3.  O bjecti ve R es p o nse R ate  
F or t he sec o n dar y efficac y e n d p oi nts of O R R, D O R, a n d T T R, a nal ys es will be perf or m e d usi n g 
I n v esti gat or- a n d I R C -assesse d res p o nse.  
O bjecti ve res p o ns e rat e is defi ne d as t he rate of c o nfir me d C R a n d P R per R E CI S T v 1. 1.  
A s u m mar y of best o bjecti ve res p o nse b y ar m will be pr o d uce d. A C oc hra n -Ma ntel -Hae nszel  
( C M H) test will be use d t o c o m pare O R R bet w ee n t he 2 treat me nt ar ms. A l o gistic re gressi o n 
m o del ma y b e use d t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o a n d 
its ass ociate d 9 5 % CIs will be prese nte d. 
1 2. 7. 2. 4.  D ur ati o n of Res p o nse  
A m o n g res p o n ders w h o ac hie ve c o nfir me d C R or P R, D O R will be calc ulate d fr o m t he date of 
t he first occ urre nce of res p o nse t o t he date of first d oc u me nte d diseas e pr o gressi o n or deat h. 
Ka pla n -Mei er met h o ds will be use d t o esti mate D O R; s u bjects wit h o ut pr o gress i o n or deat h will 
be ce ns or e d at t he last r es p o nse assess me nt date. Detaile d ce ns ori n g r ules will be i ncl u de d i n t he 
S A P.  
Ka pla n -Mei er esti mates of D O R will be prese nt e d b y ar m, i ncl u di n g esti mates of t he me dia n a n d 
ot her q ua ntiles, as well as i n di vi d ual t i me p oi nts (e g, 3-m o nt h, 6 -m o nt h, a n d 1 2 -m o nt h rates).  

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1 2. 7. 2. 5.  Ti me t o Res p o nse  
A m o n g res p o n ders, ti me t o res p o nse will be assess e d fr o m t he dat e of ra n d o mizati o n t o t he date 
of first occ urre n ce of c o nfir me d res p o ns e per R E CI S T v 1. 1. T T R will be ta b ulate d b y ar m.  
1 2. 8.  
A n al yses of He alt h -Rel ate d Q u alit y of Life a n d He alt h Ec o n o mic 
O utc o mes  
1 2. 8. 1.  
He alt h -Rel ate d Q u alit y of Life A n al yses  
T he E O R T C -Q L Q -C 3 0, E O R T C -BI L 2 1, P GI -C, a n d P GI -S  q uesti o n naires will be use d t o 
c ollect data o n t he s u bject’s f u ncti o ni n g, dise ase -relate d s y m pto ms, H R Q O L, a n d h ealt h stat us. 
If a s u bject is n ot a ble t o s pea k a n y la n g u a ge t hat is c o vere d b y t h e E O R T C -Q L Q -C 3 0, E O R T C -
Q L Q -BI L 2 1, P GI -C, or P GI -S , t he d ata fr o m t h ose i nstr u me nts will be missi n g t hr o u g h o ut t he 
d urati o n of t hat s u bject’s i n v ol ve me nt i n t he st u d y. T he n u m ber a n d p erce nt a ge of s u bjects wit h 
t he e ntire q uesti o n nair e missi n g will be s u m marize d b y treat me nt. Details i ncl u di n g t he missi n g 
data ha n dli n g will be s pecifie d i n t he S A P.  
Descri pti ve statistics (e g, mea ns a n d me dia ns) will be use d t o s u m marize t he i n di vi d ual ite ms 
a n d s u b-scale s c ores of H R Q O L d ata as w ell as P GI-C a n d P GI -S sc ores at eac h sc h e d ule d 
assess me nt ti me p oi nt b y treat me nt. A d diti o nall y, c ha n ge fr o m baseli ne i n t he d o mai n sc ores at 
t he ti me of eac h assess m e nt will be s u m marize d b y treat me nt. A re peate d meas ure me nts a n al ysis 
m o del ma y b e use d t o c o m pare t he t w o treat me nt gr o u ps wit h res pect t o c h a n ges i n t he H R Q O L 
d o mai n  sc ores as w ell as t he P GI-C a n d P GI -S sc ores l o n git u di nall y o ver ti me. I n a d diti o n, 
a nc h or-b ase d met h o d will be use d t o a nal yz e t he ke y d o m ai ns wit h t he s pecific a nc h or q u esti o ns 
( P GI-C a n d P GI -S).  
Detaile d a n al ysis pla n will be s pecifie d i n t he S A P.  
1 2. 8. 2.  
He al t h Ec o n o mic O utc o mes A n al yses 
E Q -5 D -5 L s c ores will be s u m mariz e d b y descri pti ve statistics f or treat me nt ar ms.  
1 2. 9.  
E x p os ure a n d S afet y A n al yses  
Safet y will be e val uat e d b y t he i nci d e nce of A Es, ca usalit y, s e verit y, seri o us ness, a n d t y p e of 
A Es, a n d b y t he s u bj ect’s vital si g ns, E C O G perf or ma nce s c ores, cli nical la b orat or y test res ults, 
E C G, a n d L V E F d ata (as cli nicall y i n dicat e d).  
A s u m mar y of st u d y dr u g e x p os ure, i ncl u di n g t otal d ose, d urati o n of tr eat me nt, d ose i nte nsit y, 
a n d t he pr o p orti o n of s u bjects wit h d ose m o dificati o ns will be s u m marize d b y treat me nt ar m. 
Reas o ns f or d ose m o dificati o ns will be liste d b y s u bject a n d s u m marize d.  
C o nc o mita nt me dicati o ns will be liste d b y s u bject a n d will be s u m marize d b y treat me nt ar m.  
All safet y data will be liste d b y s u b je ct a n d s u m marize d b y tr eat me nt ar m. 
1 2. 9. 1.  
A d verse E ve nts  
S u m mar y ta bles a n d listi n gs f or a d verse e v e nts will i ncl u de treat me nt -e mer ge nt a d verse e ve nts 
( A Es), w here A E is d efi n e d as a n y A E t h at occ urre d bet wee n t he first d ose of a n y st u d y dr u g a n d 
2 8 da ys f oll o wi n g t he l ast d ose of a n y st u d y dr u g. T he i nci de nce of A Es ( ne w or w orse ni n g fr o m 

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baseli ne) will be s u m mariz e d acc or di n g t o t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) b y s yste m or ga n class a n d/ or preferre d ter m, se verit y ( base d o n N CI C T C A E v 4. 0 3 
gra di n g as assess e d b y t he I n vesti gat or), s eri o us ness, a n d relati o n t o st u d y treat me nt. T he 
f oll o wi n g s u m maries will be pr o d uce d: 
 All A Es  
 A Es lea di n g t o d ose m o dificati o ns  
 Treat me nt -relate d A Es 
 Gra de 3 or hi g h er A Es  
 Gra de 3 or hi g h er tr eat m e nt-relat e d A Es 
 T he m ost c o m m o nl y re p orte d A Es (ie, t h ose e ve nts re p orte d b y ≥1 0 % of all s u bjects)  
 S A Es  
 Disc o nti n uati o ns d ue t o A Es  
B y -s u bject listi n gs will be pr o vi de d f or o n-treat me nt deat hs ( o n-tr eat me nt is defi ne d as t he 
peri o d starti n g fr o m t he first d ose t o 2 8 da ys after t he last d ose), A Es, S A Es, a n d A Es lea di n g t o 
disc o nti n uati o n of treat me nt.  
1 2. 9. 2.  
L a b or at or y A b n or m alities  
F or la b orat or y tests i ncl u de d i n t he N CI C T C A E versi o n 4. 0 3, la b orat or y d ata will be gra d e d 
acc or di n gl y; a Gra d e 0 will be assi g ne d f or all n o n -missi n g val ues n ot gra d e d as 1 or hi g her. F or 
la b orat or y tests w here gra des are n ot defi ne d b y N CI C T C A E, res ults will be gra de d b y t h e 
l o w/ n or mal/ hi g h classificati o ns base d o n la b orat or y n or mal ra n ges. 
T he f oll o wi n g s u m maries will be ge n e rat e d se paratel y f or he m at ol o g y, ser u m c he mistr y a n d 
c oa g ulati o n st u dies, a n d uri nal ysis la b orat or y tests:  
 Descri pti ve statistics f or t he act ual val ues a n d/ or c ha n ge fr o m b aseli ne of cli nical 
la b orat or y para meters o v er ti me. 
 S hift ta bles usi n g N CI C T C A E gr a des t o c o m pare baseli ne t o t he w orst o n -treat me nt 
val ue (f or l a b orat or y t ests w here N CI C T C A E gra des are n ot d efi ne d, s hift ta bles 
usi n g t he l o w/ n or mal/ hi g h/[l o w a n d hi g h] classificati o n t o c o m pare bas eli ne t o t he 
w orst o n -treat me nt ma y be ge nerate d). 
 Lis ti n g of all la b orat or y data wit h val ues fla g ge d t o s h o w t he c orres p o n di n g N CI 
C T C A E gra des a n d t he classificati o ns relati ve t o t he la b orat or y n or mal ra n ges.  
I n a d diti o n t o t he a b o ve me nti o ne d ta bles a n d listi n gs, gra p hi cal dis pla ys of ke y safet y 
para meters , s uc h as s catt er pl ots of act ual or c ha n ge i n la b orat or y tests o ver ti me or b o x pl ots 
ma y b e s pecifi e d i n t he S A P.  
1 2. 9. 3.  
Ot her S afet y D at a  
Descri pti ve statistics f or t he act ual val ues a n d/ or t he c ha n ges fr o m bas eli ne of vital si g ns 
(i ncl u di n g s yst olic a n d di astolic bl o o d press ure, heart rate, res pirat or y rate, a n d te m perat ure) 
o ver ti me will be s u m mariz e d.  

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Descri pti ve statistics of E C O G P S o ver ti me will be s u m marize d b y fre q u e nc y. S hift ta bles ma y 
be pr o vi de d f or E C O G P S fr o m baseli ne t o w orst val ue of p ost -bas eli ne assess me nts.  
Cate g orical a n al ysis of Q Tc F i nter vals ma y be perf or me d. Ma xi m u m Q Tc F i nter vals a n d 
ma xi m u m c ha n ges fr o m baseli ne ma y als o be s u m marize d si milarl y i n a se parate dis pla y. E C G 
a b n or malities if c ollecte d will be prese nte d i n a d ata listi n g.  
A d diti o nal safet y a nal yses ma y be perf or me d if dee me d necessar y.  
1 2. 1 0.  
P h ar m ac o ki netic A n al yses  
A p o p ulati o n p har mac o ki netics a p pr oac h will be p erf or me d t o assess t y pical a n d i n di vi d ual 
s u bject P K para met ers. Descri pti ve statistics will be use d t o s u m marize P K c o nce ntr ati o ns at 
differe nt n o mi nal ti me p oi nts acr oss s u bjects.  
1 2. 1 1.  
P h ar m ac o d y n a mic A n al yses  
Descri pti ve statistics will be use d t o s u m marize 2 -H G c o nce ntrati o ns at differe nt n o mi nal ti me 
p oi nts acr oss s u bjects. T he p ote ntial relati o ns hi p bet wee n plas ma e x p os ure of A G -1 2 0 a n d 
plas ma 2 -H G le v els will be e x pl ore d wit h descri pti ve a n d gra p hical met h o ds as a p pr o priat e.  
1 2. 1 2.  
E x pl or at or y A n al yses  
1 2. 1 2. 1.  
A n al ysis of P F S 2  
F or s u bjects w h o cr oss o ver fr o m t he place b o ar m t o t he A G -1 2 0 ar m, P F S 2 will be calc ulate d 
fr o m first d ose of A G -1 2 0 t o sec o n d d oc u me nte d disease pr o gressi o n per I n vesti gat or ( or deat h).  
T he ne w bas eli ne f or res p o nse assess me nt f or s u bjects w h o cr osse d o v er will be t he pr o gressi ve 
disease sca n pri or t o cr oss o ver. F or s u bjects w h o cr oss o ver w h o recei ve palliat i ve ra di ot hera p y 
after u n bli n di n g a n d d uri n g t he cr oss o ver peri o d, t he ne w baseli ne f or res p o nse assess me nt will 
be t he M RI or C T sca n o btai ne d at t he e n d of t h e 2 -wee k was h o ut peri o d after ra di ot hera p y. I n 
t he e ve nt t hat m ore t ha n 1 sca n is o btai ne d, t he lat est sca n pri or t o t he first d ose of A G-1 2 0 will 
be use d as t he n e w bas eli ne. Ka pla n -M eier esti mates of P F S 2 will be prese nte d, i ncl u di n g 
esti mates of t he me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -m o nt h, 
6  m o nt h, a n d 1 2 -m o nt h rates). 
1 2. 1 2. 2.  
Ot her E x pl or at or y A n al yses  
All s u bjects wit h e val ua ble sa m ple meas ure me nts will be i ncl u de d i n t he data a nal ysis. Act ual 
val ues or c h a n ges/s hifts fr o m baseli ne of e x pl orat or y P K or P D bi o mar ker data will be 
s u m marize d o ver ti me a n d ma y b e dis pla ye d gra p hicall y.  
All e x pl orat or y P K or P D bi o mar ker data c ollecte d will be liste d i n f ull, a n d ot her e x pl orat or y 
a nal ys es ma y be c o n d uct e d de pe n di n g o n t he data. If feasi ble, t hese ma y i n cl u de e x pl orat or y 
P K/ P D a nal yses a n d e x pl orat or y c orrelati o n a nal yses wit h cli nical res p o nse or o utc o mes.  
T here ma y b e cir c u msta n ces w he n a decisi o n is ma de t o st o p c ollecti o n, n ot perf or m, or 
disc o nti n ue t he a nal ysis of P D bi o mar ker sa m ples d ue t o eit her practical or strate gic reas o ns (e g, 
i na de q uate sa m ple n u m b ers, iss ues relat e d t o t he q ualit y of sa m ples, or iss ues relate d t o t he assa y 
t hat precl u des t he a nal ysis of sa m ples). U n der s uc h circ u msta nces, t he sa m ple size ma y be t o o 
s mall t o perf or m a n y dat a a nal ysis a n d t he a vaila ble data will o nl y b e liste d. 

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All e x pl orat or y a n al ys es i nte n de d t o be disc usse d i n t he C S R will be defi ne d i n t he S A P. 
A d diti o nal a nal ys es ma y be pla n ne d a n d re p ort e d se parat el y fr o m t his st u d y.  
1 2. 1 3.  
Pr oce d ures f or H a n dli n g Missi n g, U n use d, a n d S p uri o us D at a  
N o i m p utati o n will be perf or me d f or missi n g data ele me nts u nless s pecifie d ot her wise.  
W he n ta b ulati n g A E dat a, partial dates will be i m p ute d. R ules of i m p utati o n will be s pecifie d i n 
t he S A P. 
F or t he p ur p os es of re p orti n g, s u bjects w h o ha v e n o disease pr o gressi o n ( or deat h) b y data c ut off 
date will ha ve ti me-t o-e v e nt data (e g, D O R a n d P F S) ce ns ore d at t he d ate of last d oc u me nte d 
disease assess me nt pri or t o t he data c ut off d ate. F urt her details of ce ns ori n g r ules f or a n al yses of 
effic ac y will be d oc u m e nte d i n t he S A P.  
S u bjects w h o ha ve diseas e pr o gressi o n a n d c o nti n ue t o recei ve treat me nt after pr o gressi o n will 
be c o nsi dere d as ha vi n g d oc u me nte d pr o gressi ve disease at t he ti me of first pr o gressi o n a n d will 
be c o u nte d as pr o gressi v e disease at t hat ti me i n pri mar y cli nical acti vit y a nal yses. All res p o nse 
assess me nts occ urri n g aft er d oc u me nte d pr o gressi o n ma y b e liste d a n d a nal yz e d se paratel y, 
e x ce pt f or s u bjects w h o were o n t he pl ace b o ar m a n d cr osse d o v er t o t he A G -1 2 0 ar m after 
d oc u me nte d diseas e pr o gressi o n, w h ose res p o nse assess me nt after cr oss o v er will be use d t o 
calc ulate P F S 2.  
1 2. 1 4.  
I nteri m A n al yses 
I nteri m safet y re vie ws of u n bli n de d data will be c o n d ucte d b y t he I D M C as o utli ne d i n t he 
I D M C c harter. N o f or mal i nteri m efficac y a nal ysis will be c o n d ucte d pri or t o t he pri mar y 
a nal ysis f or t his st u d y.  

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1 3.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  
1 3. 1.  
G o o d Cli nic al Pr actice  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he I nter n ati o nal C o u ncil f or Har m o nisati o n 
(I C H) f or G o o d Cli nical Practice ( G C P) a n d t he a p pr o priate re g ulat or y re q uire me nt(s). T he 
I n v esti gat or will be t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he st u d y treat me nt as 
descri be d i n t he pr ot o c ol a n d I n vesti gat ors’ Br oc h ure. Esse ntial cli nical d o c u me nts will be 
mai ntai ne d t o de m o nstrate t he vali dit y of t h e st u d y a n d t he i nte grit y of t he d ata c ollecte d. M aster 
files s h o ul d be esta blis he d at t he be gi n ni n g of t he st u d y, mai ntai ne d f or t he d urati o n of t he st u d y, 
a n d retai ne d acc or di n g t o t he a p pr o priat e re g ulati o ns.  
1 3. 2.  
Et hic al C o nsi der ati o ns  
T he st u d y will be c o n d ucte d i n acc or da nce wit h et hical pri nci ples f o u n de d i n t he Declarati o n of 
Helsi n ki (W M A 1 9 9 6 ). 
T he I n vesti gat or m ust o btai n I R B/I E C a p pr o v al f or t he i n vesti gati o n a n d m ust s u b mit writte n 
d oc u me ntati o n of t he a p pr o val t o t he S p o ns or bef ore he or s he ca n e nr oll a n y s u bject i nt o t he 
st u d y. T he I R B/I E C will re vie w all a p pr o priate st u d y d oc u m e ntati o n i n or der t o safe g u ar d t he 
ri g hts, safet y, a n d w ell-bei n g of t h e s u bjects. T he st u d y will o nl y be c o n d u cte d at sites w here 
I R B/I E C a p pr o v al has bee n o btai ne d. T he pr ot oc ol, I n vesti gat or’s Br oc h ure, i nf or me d c o ns e nt, 
a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he s u bjects (i ncl u di n g diar y car ds), 
safet y u p dates, a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hese d oc u me nts will be pr o vi de d t o 
t he I RB/I E C. T he I R B/I E C is t o be n otifie d of a n y a me n d me nt t o t he pr ot oc ol i n acc or da n ce wit h 
l ocal re q uir e me nts. Pr o gress re p orts a n d n otificati o ns of seri o us u ne x pecte d a d verse dr u g 
reacti o ns are t o be pr o vi de d t o t he I R B/I E C acc or di n g t o l ocal r e g ulati o ns a nd g ui deli nes.  
1 3. 3.  
S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
T he I n vesti gat or at eac h ce nter will e ns ure t hat t h e s u bject is gi v e n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris ks, a n d be nefits of t he st u d y. S u bjects 
m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he s u bject 
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d.  
After t he st u d y has b ee n f ull y e x plai ne d, writte n i nf or me d c o ns e nt will be o btai ne d fr o m eit her 
t he s u bject or his/ her le gal re prese ntati ve pri or t o st u d y partici p ati o n. 
T he s u bject’s si g ne d a n d date d i nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y -
relate d pr oce d ures. T he I n vesti gat or m ust mai ntai n t he ori gi nal, si g ne d c o nse nt f or m. A c o p y of 
t he si g ne d f or m m ust be gi ve n t o t he s u bject. 
T he met h o d of o btai ni n g a n d d oc u me nti n g t he i nf or me d c o nse nt a n d t h e c o nte nts of t he c o nse nt 
will c o m pl y wit h I C H -G C P a n d all a p plica ble re g ulat or y re q uire m e nt(s).  
1 3. 4.  
S u bj ect C o nfi de nti alit y  
I n or der t o mai ntai n s u bj ect pri vac y, all s o urce d o c u me nts/e C R Fs, st u d y tr eat me nt acc o u nta bilit y 
rec or ds, st u d y re p orts a n d c o m m u nicati o ns will i de ntif y t he s u bj ect b y t he assi g ne d s u bj ect 

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n u m ber. T he I n v esti gat or will gra nt m o nit or(s) a n d a u dit or(s) fr o m t he S p o ns or or its desi g n ee 
a n d re g ulat or y a ut h orit y(ies) access t o t he s u bject’s ori gi nal me dical rec or ds f or verificati o n of 
data gat here d o n t he s o urce d oc u me nts/e C R Fs a n d t o a u dit t he data c ollecti o n pr ocess. T he 
s u bject’s c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u blicl y a vaila ble t o t he e xte nt 
per mitte d b y t he a p plica ble la ws a n d re g ulati o ns.  
1 3. 5.  
Pr ot oc ol C o m pli a nce  
T he I n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol. M o dificati o ns t o t he 
pr ot oc ol s h o ul d n ot be ma de wit h o ut a gree me nt of b ot h t he I n v esti gat or a n d t he S p o ns or. 
C ha n ges t o t he pr ot oc ol will re q uire writte n I R B/I E C a p pr o val/fa v ora ble o pi ni o n pri or t o 
i m ple me ntati o n, e x ce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o 
s u bjects. T he I R B/I E C m a y pr o vi de, if a p plica ble, w here re g ulat or y a ut h orit y(ies) per mit, 
e x pe dite d re vie w a n d a p pr o val/fa v ora ble o pi ni o n f or mi n or c ha n ge(s) i n o n g oi n g st u dies t hat 
ha ve t he a p pr o val/fa v ora ble o pi ni o n of t he I R B/I E C. T he S p o ns or or desi g n ee will s u b mit all 
pr ot oc ol m o dificati o ns t o t he re g ulat or y a ut h orit y(ies) i n acc or da nce wit h t he g o v er ni n g 
re g ulati o ns. 
W he n i m me diate de viati o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate a n i m me diate hazar d(s) t o 
s u bjects, t he I n vesti gat or will c o ntact t he S p o ns or or Me dical M o nit or, if circ u msta nces p er mit, 
t o disc uss t he pla n ne d c o urse of acti o n. A n y de part ures fr o m t he pr ot oc ol m ust be f ull y 
d oc u me nte d i n t he s o urce d oc u me nts/e C R F.  
1 3. 6.  
D at a M a n a ge me nt  
All data f or t he s u bjects r ecr uite d f or t he trial wil l be e ntere d o nt o t he e C R Fs via a n E D C s yst e m 
pr o vi de d b y t he S p o ns or or desi g n ee. O nl y a ut h orize d staff ma y e nter data o nt o t he e C R Fs. If a n 
e ntr y err or is ma de, t he c orrecti o ns t o t he e C R Fs will be ma de acc or di n g t o e C R F g ui d eli nes b y 
a n a ut h orize d me m be r of t he site staff. 
Electr o nic case re p ort f or ms will be c hec ke d f or c orrect n ess a gai nst s o urce d oc u me nt data b y t he 
S p o ns or’s m o nit or. If a n y e ntri es i nt o t he e C R F are i nc orrect or i n c o m plete, t he m o nit or will as k 
t he I n v esti gat or or t he st u d y site staff t o ma ke a p pr o priate c orrecti o ns, a n d t he c orrecte d e C R F 
will a gai n b e re vie we d f or c o m plete ness a n d c o nsiste nc y. A n y discre pa ncies will be n ote d i n t he 
e C R F s yste m b y me a ns of electr o ni c data q ueries. A ut h orize d site staff will be as ke d t o r es p o n d 
t o all electr o nic q ueries acc or di n g t o t he e C R F g ui deli nes.  
1 3. 7.  
S o urce D oc u me nt/ C ase Re p ort F or m C o m pleti o n  
S o urce d oc u me nts/e C R Fs will be c o m plete d f or eac h st u d y s u bj ect. It is t he I n vesti gat or’s 
res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, a n d ti meli ness of t he data re p orte d i n t he 
s u bject’s s o urce d oc u me nt/e C R F. T he s o urce d o c u me nt/e C R F s h o ul d i n dicate t he s u bject’s 
partici pati o n i n t he st u d y a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr oce d ures, A Es, 
a n d s u bject stat us.  
T he I n vesti gat or, or d esi g n at e d re prese ntati ve, s h o ul d c o m plete t he s o urce d oc u me nt/e C R F as 
s o o n as p ossi ble after i nf or mati o n is c ollecte d, prefera bl y o n t he s a me da y t hat a st u d y s u bject is 
see n f or a n e x a mi nati o n, treat me nt, or a n y ot h er st u d y pr oce d ure. A n y o utst a n di n g e ntries m ust 

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be c o m plete d i m me diatel y after t he fi nal e xa mi nati o n. A n e x pla nati o n s h o ul d be gi ve n f or all 
missi n g data.  
T he I n vesti gat or m ust si g n a n d date t he I n v esti gat or’s State me nt at t he e n d of t he s o urce 
d oc u me nt/e C R F t o e n d orse t he rec or de d d ata.  
T he I n vesti gat or will ret ai n all c o m plete d s o urce d oc u me nts.  
1 3. 8.  
Direct Access t o S o urce D at a  
T he st u d y will be m o nit ore d b y t he S p o ns or or its desi g nee. M o nit ori n g will be d o ne b y pers o nal 
visits fr o m a re pres e ntati ve of t he S p o ns or (site m o nit or) a n d will i ncl u de o n -site re vie w of t he 
s o urce d oc u m e nts/e C R Fs f or c o m plete ness a n d clarit y, cr oss-c hec ki n g wit h s o urce d oc u m e nts, 
a n d clarifi cati o n of a d mi nistrati ve matters. T he re vie w of me dical rec or ds will be perf or me d i n a 
ma n ner t o e ns ur e t hat s u bject c o nfi de ntialit y  is mai ntai ne d. 
T he site m o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o pr ot oc ol desi g n a n d 
re g ulat or y re q uire me nts b y fre q ue nt c o m m u nicati o ns (letter, tele p h o ne, e-mail, a n d fa x).  
All u n use d st u d y treat me nt a n d ot her st u d y m ateri als s h o ul d be destr o ye d or ret ur ne d t o t he 
S p o ns or or desi g n ee after t he st u d y has b ee n c o m plete d.  
Re g ulat or y a ut h orities, t he I R B/I E C, a n d/ or t h e S p o ns or’s cli nical q ualit y ass ura nce gr o u p or 
desi g nee ma y re q uest a ccess t o all s o urce d oc u m e nts, e C R Fs, a n d ot h er st u d y d oc u m e ntati o n f or 
a n o n-site a u dit or i ns pecti o n. Direct access t o t hese d oc u me nts m ust be g u ara ntee d b y t he 
I n v esti gat or, w h o m ust pr o vi de s u p p ort at all ti mes f or t hese acti vities. 
1 3. 9.  
Rec or d Rete nti o n  
T he I n vesti gat or will mai ntai n all st u d y rec or d s acc or di n g t o I C H-G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s). Rec or ds will be retai ne d f or at least 2 years aft er t he last m ar keti n g a p plicati o n 
a p pr o val or 2 years after f or mal disc o nti n uati o n of t he cli nical de vel o p me nt of t he i n vesti gati o nal 
pr o d uct or acc or di n g t o a p plica ble re g ulat or y re q uire me nt(s). If t he I n vesti gat or wit h dra ws fr o m 
t he res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o 
acce pt t he res p o nsi bilit y. T he S p o ns or m ust be n otifie d i n writi n g if a c ust o dial c ha n ge o cc urs. 
1 3. 1 0.  
Li a bilit y a n d I ns ur a nce  
T he S p o ns or has s u bscri be d t o a n i ns ura nce p olic y c o v eri n g, i n its ter ms a n d pr o visi o ns, its le gal 
lia bilit y f or i nj uries ca us e d t o partici pati n g pers o ns a n d arisi n g o ut of t his researc h perf or me d 
strictl y i n acc or da n ce wit h t he scie ntific pr ot oc ol as well as wit h a p plica ble la w a n d pr ofessi o nal 
sta n dar ds. 
1 3. 1 1.  
P u blic ati o n of St u d y Fi n di n gs a n d Use of I nf or m ati o n  
All i nf or mati o n re gar di n g A G -1 2 0 s u p plie d b y t he S p o ns or or desi g nee t o t he I n v esti gat or is 
pri vi le ge d a n d c o nfi de ntial i nf or mati o n. T he I n v esti gat or a grees t o use t his i nf or mati o n t o 
acc o m plis h t he st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut c o nse nt fr o m t he S p o ns or. It 
is u n derst o o d t hat t here is a n o bli gati o n t o pr o vi de t he S p o ns or wit h c om plete data o btai ne d 
d uri n g t he st u d y. T he i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he 

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de vel o p me nt of A G -1 2 0 a n d a c o m pa ni o n dia g n ostic de vice a n d ma y be dis cl ose d t o re g ulat or y 
a ut h orit y(i es), ot her I n vesti gat ors, c or p orate part n ers, t he p u blic, or c o ns ult a nts as re q uir e d.  

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1 4.  
LI S T O F R E F E R E N C E S  
A C S. Bile D uct Ca ncer ( C h ola n gi ocarci n o ma). 2 0 1 4: A merica n Ca n cer S o ciet y.  
 
AJ C C, e d.  2 0 1 0  AJ C C Ca ncer Sta gi n g M a n ual: 7t h e diti o n: A merica n J oi nt C o m mittee o n 
Ca ncer.  
 
A mar y  M F, Bacsi K, Ma g gia ni F, Da mat o S, Hal ai D, Beris h a F, et al. I D H 1 a n d I D H 2 
m utati o ns are fre q ue nt e v e nts i n ce ntral c h o n dr osarc o ma a n d ce ntr al a n d peri osteal c h o n dr o mas 
b ut n ot i n ot her mese nc h y m al t u m o urs. J P at h ol. 2 0 1 1; 2 2 4( 3): 3 3 4 -4 3.  
 
B or ger D R, Ta n a b e K K, Fa n K C, L o pez H U, Fa nti n V R, Strale y K S, et al. Fre q u e nt m utati o n of 
is ocitrate de h y dr o ge nase (I D H) 1 a n d I D H 2 i n c h ola n gi o carci n o ma i de ntifie d t hr o u g h br oa d-
base d t u m or ge n ot y pi n g. O nc ol o gist.  2 0 1 2; 1 7( 1): 7 2 -9.  
 
Briea u B, Da ha n L, De R yc k e Y, B o ussa ha  T, Vasse ur P, T o u ger o n D, et al. Sec o n d -li ne 
c he m ot hera p y f or a d v a nce d biliar y tract ca ncer after fail ure of t he ge mcita bi ne -plati n u m 
c o m bi nati o n: A lar ge m ultice nter st u d y b y t h e Ass ociati o n des Gastr o -E nt er ol o g ues O n c ol o g ues. 
C a ncer.  2 0 1 5; 1 2 1( 1 8): 3 2 9 0 -7 . 
 
C h o w d h ur y R, Y e o h K K, Tia n Y M, Hillri n g ha us L, Ba g g E A, R ose N R, et al. T he 
o nc o meta b olite 2 -h y dr o x y gl utarate i n hi bits hist o ne l ysi ne d e met h yl ases. E M B O Re p.  
2 0 1 1; 1 2( 5): 4 6 3 -9.  
 
Da n g L, W hite D W, Gr oss S, Be n nett B D, Bitti n ger M A, Dri g gers E M, et al. Ca ncer -ass ociat e d 
I D H 1 m utati o ns pr o d uce 2-h y dr o x y gl ut arate. N at ure.  2 0 0 9; 4 6 2( 7 2 7 4): 7 3 9 -4 4.  
 
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 ns e  
e val uati o n criteri a i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne ( v ersi o n 1. 1). E ur J C a ncer.  
2 0 0 9; 4 5( 2): 2 2 8 -4 7.  
 
E O R T C. E O R T C Q L Q -C -3 0 Sc ori n g Ma n u al, V ersi o n 3. 0. E O R T C Q O L Gr o u p.  1 9 9 5.  
 
Fi g u er oa M E, A b del -Wa ha b O, L u C, War d P S, Patel J, S hi h A, et al. L e u k e mic I D H 1 a n d I D H 2 
m utati o ns res ult i n a h y p er met h yl ati o n p he n ot y pe, disr u pt T E T 2 f u ncti o n, a n d i m pair 
he mat o p oietic differe ntiati o n. C a ncer Cell.  2 0 1 0; 1 8( 6): 5 5 3 -6 7.  
 
Frie n d E, Ya de garfar G, B yr ne C, J o h ns o n C D, Sezer O, P ucciarelli S, et al. De vel o p me n t of a 
q uesti o n naire ( E O R T C m o d ule) t o meas ure q u alit y of life i n p atie nts wit h c h ola n gi ocarci n o ma 
a n d gall bla d der ca ncer, t he E O R T C Q L Q -BI L 2 1. Br J C a ncer.  2 0 1 1; 1 0 4( 4): 5 8 7 -9 2.  
 
Geis brec ht B V, a n d G o ul d SJ. T he h u ma n PI C D ge ne e n c o des a c yt o pl as mic a n d per o xis o mal 
N A D P( +) -de pe n d e nt is ocitrate de h y dr o ge nas e. J Bi ol C he m.  1 9 9 9; 2 7 4( 4 3): 3 0 5 2 7 -3 3.  
 

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G o yal L, G o vi n da n A, S het h R A, Nar di V, Blasz k o ws k y L S, Faris J E, et al. Pr o g n osis a n d 
Cli nic o pat h ol o gic Feat ur es of Patie nts Wit h A d va nce d Sta ge Is o citrate De h y dr o ge nase (I D H) 
M uta nt a n d I D H Wil d -T y p e I ntra h e patic C h ola n gi ocarci n o ma. O nc ol o gist.  2 0 1 5; 2 0( 9): 1 0 1 9 -2 7.  
 
Gr oss S, Cair ns R A, Mi n de n M D, Dri g gers E M, Bitti n ger M A, J a n g H G, et al. Ca ncer -
ass ociate d meta b olite 2 -h y dr o x y gl utarate acc u m ul ates i n ac ute m yel o ge n o us  le u ke mia wit h 
is ocitrate de h y dr o ge nase 1 a n d 2 m utati o ns. J Ex p Me d.  2 0 1 0; 2 0 7( 2): 3 3 9 -4 4.  
 
Ki p p B R, V oss J S, Kerr S E, Barr Fritc h er E G, Gra ha m R P, Z ha n g L, et al. Is o citrate 
de h y dr o ge nas e 1 a n d 2 m utati o ns i n c h ola n gi ocarci n o ma. H u m P at h ol.  2 0 1 2; 4 3( 1 0): 1 5 5 2 -8.  
 
K oi v u ne n P, Lee S, D u nca n C G, L o p ez G, L u G, Ra m kiss o o n S, et al. Tra nsf or mati o n b y t he 
( R)-e na nti o mer of 2 -h y dr o x y gl utarate li n ke d t o E G L N acti vati o n. N at ure.  2 0 1 2; 4 8 3( 7 3 9 0): 4 8 4 -
8.  
 
La m arca A, H u b n er R A, Da vi d R y d er W, a n d Valle J W. Sec o n d -li ne c he mot hera p y i n a d va n ce d 
biliar y ca ncer: a s yste matic re vie w. A n n O nc ol.  2 0 1 4; 2 5( 1 2): 2 3 2 8 -3 8.  
 
Li n da H, v o n Heij ne A. A case of p osteri or re versi ble e nce p hal o p at h y s y n dr o me ass ociate d wit h 
gile n ya (fi n g oli m o d) treat me nt f or m ulti ple scler osis. Fr o ntiers i n Ne ur ol o gy. 2 0 1 5; 6: 3 9 . 
 
L u C, War d P S, Ka p o or G S, R o hle D, T urca n S, A b del -Wa ha b O, et al. I D H m utati o n i m pairs 
hist o ne de met h ylati o n a n d res ults i n a bl oc k t o cell differe ntiati o n. N at ure.  2 0 1 2; 4 8 3( 7 3 9 0): 4 7 4 -
8.  
 
M or ga nr ot h J. F oc us o n iss ues i n meas uri n g a n d i nter preti n g c h a n ges i n t he Q Tc i nter val 
d urati o n. E ur J He art S u p pl.  2 0 0 1; 3( S u p pl K): K 1 0 5 -K 1 1 1.  
 
R A R E C A R E. S ur veilla nce of rare ca n cers i n E ur o pe: C h ola n gi ocarci n o m a. 2 0 1 6.  
 
Rizz o J D, Br o u wers M, H urle y P, Sei de nfel d J, Arcas o y M O, S pi va k J L, et al. A merica n S oci et y 
of He mat ol o g y/ A merica n S ociet y of Cli nical O n c ol o g y cli nical pr actice g ui deli ne u p date o n t he 
use of e p oeti n a n d d ar be p oeti n i n a d ult patie nts wit h ca ncer. Bl o o d.  2 0 1 0; 1 1 6( 2 0): 4 0 4 5 -5 9.  
 
Sa ha S K, Parac h o ni a k C A, G ha nta K S, Fita m a nt J, R oss K N, Naje m M S, et al. M uta nt I D H 
i n hi bits H N F-4al p ha t o bl oc k he pat oc yte differe ntiati o n a n d pr o m ote biliar y ca ncer. N at ure.  
2 0 1 4; 5 1 3( 7 5 1 6): 1 1 0 -4.  
 
Sie gel R L, Miller K D, a n d J e mal A . Ca ncer statistics, 2 0 1 6. C A C a ncer J Cli n.  2 0 1 6; 6 6( 1): 7 -3 0.  
 
Sze n de A, J a nsse n, B., Ca bases, J., e d.  2 0 1 4  Self -Re p orte d P o p ulati o n Healt h: A n 
I nter nati o nal Pers p ecti ve base d o n E Q-5 D: S pri n ger Net herla n ds.  
 
T urca n S, R o hle D, G o e n ka A, Wals h L A, Fa n g F, Yil maz E, et al. I D H 1 m utati o n is s ufficie nt 
t o esta blis h t he gli o ma h y p er met h yl at or p he n ot y p e. N at ure.  2 0 1 2; 4 8 3( 7 3 9 0): 4 7 9 -8 3.  
 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
9 6  
A gi os P har mace uticals, I nc.  
Valle J, Wasa n H, Pal mer D H, C u n ni n g h a m D, A nt h o ne y A, M ara v e yas A, et al. Cis plati n pl us 
ge m cita bi ne vers us ge mcita bi ne f or bil iar y tract ca ncer. N E n gl J Me d.  2 0 1 0; 3 6 2( 1 4): 1 2 7 3 -8 1.  
 
Wa n g F, Tra vi ns J, De La Barre B, Pe nar d -Lacr o ni q ue V, Sc hal m S, Ha nse n E, et al. Tar gete d 
I n hi biti o n of M uta nt I D H 2 i n Le u k e mia Cells I n d u ces Cell ular Differe ntiati o n. Scie nce.  2 0 1 3;I n 
press.  
 
War d P S,  Patel J, Wise D R, A b del -Wa ha b O, Be n nett B D, C oller H A, et al. T he c o m m o n feat ure 
of le u ke mia -ass ociate d I D H 1 a n d I D H 2 m utati o ns is a ne o m or p hic e nz y m e acti vit y c o n verti n g 
al p ha-ket o gl utarate t o 2 -h y dr o x y gl utarate. C a ncer Cell.  2 0 1 0; 1 7( 3): 2 2 5 -3 4.  
 
Welc h J S, Le y TJ, Li n k D C, Miller C A, Lars o n D E, K o b ol dt D C, et al. T he ori gi n a n d e v ol uti o n 
of m utati o ns i n ac ute m yel oi d le u ke mia. Cell.  2 0 1 2; 1 5 0( 2): 2 6 4 -7 8.  
 
Westfall P H, a n d Kris he n A. O pti mall y wei g hte d, fi x e d se q ue nce a n d gate kee per m ulti ple testi n g 
pr oce d ur es. J o ur n al of St atistic al Pl a n ni n g a n d I nfere nce.  2 0 0 1; 9 9( 1): 2 5 -4 0.  
 
W M A. W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki: Et hical pri nci ples f or me dical 
researc h i n v ol vi n g h u m a n s u bjects. 1 9 9 6. 
htt ps:// w w w. me d u ni graz. at/et hi k k o m missi o n/ F or u m/ D o w nl oa d/ Files/ D o H 1 9 9 6
E N. p df . 
 
X u W, Ya n g H, Li u Y, Ya n g Y, Wa n g P, Ki m S H, et al. O nc o meta b olite 2 -h y dr o x y gl utarate is a 
c o m petiti ve i n hi bit or of al p ha -ket o gl utarate -de p e n de nt di o x y ge n ases. C a ncer Cell.  
2 0 1 1; 1 9( 1): 1 7 -3 0.  
 
Ya n H, Pars o ns D W, Ji n G, Mc Le n d o n R, Ras hee d B A, Y u a n W, et al. I D H 1 a n d I D H 2 
m utati o ns i n gli o mas. N E n gl J Me d.  2 0 0 9; 3 6 0( 8): 7 6 5 -7 3.  
 
Ye n K E, Bitti n ger M A, S u S M, a n d Fa nti n V R. Ca ncer -ass ociate d I D H m ut ati o ns: bi o mar ker 
a n d t hera p e utic o p p ort u nities. O nc o ge ne.  2 0 1 0; 2 9( 4 9): 6 4 0 9 -1 7.  
 
Y os hi hara T, Ha ma m ot o T, M u na kata R, Tajiri R, O hs u mi M, a n d Y o k ota S. L ocalizati o n of 
c yt os olic N A D P -de pe n d e nt is ocitrate de h y dr o ge n ase i n t he per o xis o mes of rat li ver cells: 
bi oc he mical a n d i m m u n oc yt o c he mical st u dies. J Hist oc he m Cyt oc he m.  2 0 0 1; 4 9( 9): 1 1 2 3 -3 1.  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
9 7  
A gi os P har mace uticals, I nc.  
1 5.  
A P P E N DI C E S  
1 5. 1.  
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us Sc ori n g  
Gr a de  
S y m pt o m at ol o g y  
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 wa ki n g 
h o urs  
4  
C o m pletel y disa ble d. Ca n n ot 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  
S o urce: O ke n M M, Creec h R H, T or me y D C, H ort o n J, Da vis T E, Mc Fa d de n E T, 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 -6 5 5.  
1 5. 2.  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
P r o hi bite d me dic ati o ns a n d cert ai n f o o ds are n ot all o we d i n t his st u d y w hile s u bjects are 
recei vi n g st u d y dr u g.  
Str o n g C Y P 3 A I n d ucers  
C Y P 3 A S u bstr ates wit h a N arr o w T her a pe utic 
Wi n d o w  
A vasi mi be, car ba maze pi ne, e nzal uta mi de, 
mit ota ne, p he n yt oi n, rifa m pi n, rifa b uti n, St. 
J o h n’s w ort 
Alfe nta nil, aste miz ole 1, c ycl os p ori ne, 
di h y dr oer g ota mi ne, er g ota mi ne, fe nta n yl, 
pi m ozi de, q ui ni di ne, e ver oli m us, sir oli m us, 
tacr oli m us, terfe na di ne1 
N ote t hat t his is n ot a n e x ha usti ve list. F or a n u p date d list, se e t he f oll o wi n g li n k: 
htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ D e vel o p me nt Res o urces/ Dr u gI nt eracti o ns La beli n g/ uc m 0 8
0 4 9 9. ht m  
“ C Y P  s u bstrates wit h a narr o w t hera p e utic wi n d o w” refers t o dr u gs w h ose e x p os ure-res p o nse relati o ns hi p i n dicates 
t hat s mall i ncreases i n t heir e x p os ure le vels b y t he c o nc o mit a nt use of C Y P i n hi bit ors ma y lea d t o seri o us safet y 
c o ncer ns (e g, T orsa d es de P oi ntes).  
1 Wit h dra w n fr o m t he U nite d States mar ket beca use of safet y reas o ns.  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
9 8  
A gi os P har mace uticals, I nc.  
1 5. 3.  
Ne w Y or k He art Ass oci ati o n Cl assific ati o n  
Cl ass  
S y m pt o m at ol o g y  
I 
N o li mitati o n of p h ysical acti vit y. Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
II 
Sli g ht li mitati o n of p h ysical acti vit y. C o mf orta ble at rest, b ut or di nar y p h ysical acti vit y 
res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
III 
Mar ke d li mitati o n of p h ysical acti vit y. C o mf orta ble at rest, b ut less t ha n or di nar y 
acti vit y res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.  
I V 
U na ble t o carr y o n a n y p h ysical acti vit y wit h o ut disc o mf ort. S y m pt o ms at rest. If a n y 
p h ysical acti vit y is u n derta ke n, disc o mf ort is i ncrease d.  
S o urce: T he Criteria C o m mitt ee of t he Ne w Y or k Heart Ass ociati o n. N o me nclat ure a n d Criteria f or Dia g n osis of 
Diseases of t he Heart a n d Great Vessels. 9t h e d. B ost o n, Mass: Little, Br o w n & C o; 1 9 9 4: 2 5 3 -2 5 6.  
1 5. 4.  
Fri derici a’s F or m ul a  
Q Tc F = Q T/ R R 1/ 3 
1 5. 5.  
Me dic ati o ns K n o w n t o Pr ol o n g t he Q T I nter v al  
a mi o dar o ne 
d ofetili de  
gre pafl o xaci n  
m o xifl o xaci n  
q ui ni di ne  
aste miz ole 
d olasetr o n  
hal ofa ntri ne  
n orfl o xaci n  
se v ofl ura ne  
azit hr o m yci n  
d o m peri d o ne  
hal o peri d ol  
ofl o xaci n  
s otal ol  
be pri dil  
dr o peri d ol  
i b utili de  
o n da nsetr o n  
s parfl o xaci n  
c hl or o q ui ne 
er yt hr o m yci n  
itrac o naz ole 
pal o n osetr o n  
terfe na di ne  
c hl or pr o mazi ne 
escital o pra m 
ket oc o naz ole  
pe nta mi di ne  
t hi ori dazi ne  
ci pr ofl o xaci n 
flecai ni de 
le v ofl o xaci n 
pi m ozi de  
v oric o naz ole  
cital o pra m 
gatifl o xaci n  
le v o met ha d yl 
p osac o naz ole  
 
clarit hr o m yci n  
ge mifl o xaci n  
mes ori dazi ne  
pr o b uc ol  
 
dis o p yra mi de  
gra nisetr o n  
met ha d o ne  
pr ocai na mi de  
 
F or a c o m plete a n d u p date d ( o n g oi n g) list of me dicati o ns, please use t he f oll o wi n g li n k: 
htt ps://cre di ble me ds. or g/ healt hcare -pr o vi ders/  

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
9 9  
A gi os P har mace uticals, I nc.  
1 5. 6.  
E x a m ples of Str o n g a n d M o der ate C Y P 3 A 4 I n hi bit ors  
M o der ate C Y P 3 A 4 I n hi bit ors  
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  
Str o n g C Y P 3 A 4 I n hi bit ors  
B oce pre vir, clarit hr o m yci n, c o ni va pta n, gra pefr uit j uice, i n di na vir, itrac o naz ole  
Ket oc o naz ole, l o pi na vir/rit o na vir, mi befra dil, nefaz o d o ne, nelfi na vir, p osac o naz ole 
Rit o na vir, sa q ui na vir, tela pre vir, telit hr o m yci n, v oric o naz ole  
N ote: B ase d o n F D A g ui deli nes; I n vesti gat ors s h o ul d f oll o w l ocal i nstit uti o nal g ui deli nes, w here a p pr o priate.  
1 5. 7.  
Re prese nt ati ve E x a m ples of L o w -F at a n d Hi g h -F at, Hi g h -C al orie 
Me als  
L o w -fat br ea kfast: 
A) 2 slices of w hite brea d t oast, 1 ta bles p o o n li g ht fat mar gari n e, 1 ta bles p o o n of jell y, a n d 8 
o u nces of s ki m mil k ( 3 1 9 cal ories a n d 8. 2 gra ms of fat).  
B) 1 c u p of cer eal, 1 slice of t oast wit h ja m, 8 o u nces of s ki m mil k, a n d 1 c u p of decaffei n ate d 
c offee or tea ( 5 2 0 cal ories a n d 2 gra ms of fat).  
A hi g h -fat brea kfast c o nsists of t he f oll o wi n g a n d ma y b e a da pt e d t o t he l ocal re gi o nal 
prefere nce: 2 e g gs frie d i n b utter, 2  stri ps of bac o n, 2 slices of w hite brea d wit h b utter, 1 
cr oissa nt wit h 1 slice of c heese, a n d 8 o u nces of w h ole mil k. T his re prese nt ati ve hi g h -fat 
brea kfast c o ntai ns a p pr o xi matel y 1 0 0 0 cal ories a n d 5 8 gra ms of fat.  
1 5. 8.  
N ati o n al C a ncer I nstit ute C o m m o n Ter mi n o l o g y Criteri a f or 
A d verse E ve nts  
T he N CI C T C A E, versi o n 4. 0 3, ca n be accesse d usi n g t he f oll o wi n g li n k:  
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0 -0 6 -1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df  
1 5. 9.  
R E CI S T v 1. 1  
T u m or lesi o ns are t o be cate g orize d as meas ura ble vers us n o n -meas ura ble a n d tar get vers us n o n -
tar get base d o n R E CI S T v 1. 1 (Eise n ha uer, et al. 2 0 0 9 ). 
Me as ur a ble Lesi o ns : 
T u m or lesi o ns:  M ust be acc urat el y m eas ure d i n at least 1 di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:  
 1 0  m m b y C T sca n ( C T s ca n slice t hic k ness n o greater t ha n 5 m m).  
 1 0  m m cali per meas ur e m e nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h c ali pers s h o ul d be rec or de d as n o n -meas ura bl e).  
 2 0  m m b y c hest X -ra y. 

St u d y A G 1 2 0 -C -0 0 5  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 0 0  
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M ali g n a nt ly m p h n o des : T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l y m p h n o de 
m ust be ≥1 5 m m o n t he s h ort a x is w he n assesse d b y C T sca n. 
N o n -me as ur a ble Lesi o ns:  
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h n o des 
wit h ≥1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y n o n -meas ura bl e lesi o ns, i ncl u di n g 
le pt o me ni n geal disease, ascites, ple ural or pericar dial eff usi o n, i nfla m mat or y breast disease, 
l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, a b d o mi nal masses/a b d o mi nal or ga n o m e gal y i de ntifie d 
b y p h ysic al e x a m t hat is n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues.  
T ar get Lesi o ns:  
W he n m ore t ha n 1 meas ura ble lesi o n is prese nt at baseli ne all lesi o ns u p t o a ma xi m u m of 5  t otal 
(a n d a ma xi m u m of 2 lesi o ns per or ga n) re prese nt ati ve of all i n v ol ve d or ga ns s h o ul d be 
i de ntifie d as tar get lesi o ns a n d meas ure d at baseli n e. 
Tar get lesi o ns s h o ul d be selecte d o n t he b asis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re pres e ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts. 
Pat h ol o gical l y m p h n o des t hat are defi ne d as me as ura ble a n d i de ntifie d as tar get lesi o ns m ust 
ha ve a s h ort a xis of ≥1 5 m m b y C T sca n. O nl y t h e s h ort a xis of t hese n o des c o ntri b utes t o t he 
baseli ne s u m.  
A s u m of t he dia meters (l o n gest f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p ort e d as t he bas eli ne s u m dia meters. T he b aseli ne s u m 
dia meters will be use d as refere nce t o f urt her c h aracterize a n y o bjecti ve t u m or re gressi o n i n t he 
meas ura ble di me nsi o n of t he disease.  
N o n -t ar get Lesi o ns: 
All ot her  lesi o ns ( or sites of disease) i n cl u di n g p at 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 s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot r e q uire d a n d 
t hese lesi o ns s h o ul d be f oll o we d as ‘ prese nt’, ‘a bse nt’ or ‘ u ne q ui v o cal pr o gressi o n.’  
T he f oll o wi n g criteri a o utli ne d i n Ta ble 6  a n d Ta ble 7  will be use d t o assess res p o nse t o 
treat me nt. 
 
 

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A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 0 1  
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T a ble 6 : 
Dise ase Res p o nse Crit eri a f or T ar get a n d N o n -t ar get Lesi o ns 
C ate g or y  
Res p o nse Criteri a  
T ar g et Lesi o ns  
N o n -T ar get Lesi o ns/ T u m or M ar kers  
C o m plete Res p o nse 
( C R) 
Disa p peara nce of all tar get lesi o ns. A n y 
pat h ol o gical l y m p h n o des ( w het her tar get 
or n o n -tar get) m ust ha ve re d ucti o n i n s h ort 
a xis t o < 1 0 m m  
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).  
P artial Res p o nse ( P R)  
A ≥3 0 % decrease i n t he s u m  of t he 
dia meter of tar get lesi o ns, ta ki n g as 
refere nce t he baseli ne s u m dia meter 
N/ A  
Sta ble Disease ( S D) / 
I nc o m plete Res p o nse 
Neit her s ufficie nt s hri n ka ge t o q ualif y f or 
partial res p o nse n or s ufficie nt i ncrease t o 
q ualif y f or pr o gressi ve disease, ta ki n g  as 
refere nce t he s mallest s u m dia meter si nce 
t he treat me nt starte d 
P ersiste nce of 1 or m ore n o n -t ar get 
lesi o n(s) a n d/ or 
Mai nte na nce of t u m or mar ker le vels 
a b o ve t he n or mal li mits  
Pr o gressi ve Disease  
A ≥2 0 % i ncrease i n t he s u m of t he dia meter 
of tar get lesi o ns, ta ki n g as refere nce t he 
s mallest s u m dia meter rec or de d si nce t he 
treat me nt starte d. 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 ncre ase of at least 
5  m m, or  
T he a p peara nce of 1 or m ore ne w lesi o ns  
A p pear a nce of 1 or m ore ne w lesi o ns, 
a n d/ or  
U ne q ui v ocal pr o gressi o n of e xisti n g 
n o n -tar get lesi o ns 
T a ble 7 : 
O ver all Dise ase Res p o nse Criteri a  
T ar g et Lesi o ns  
N o n -T ar g et Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
I nc o m plete res p o nse/ S D 
N o  
P R  
P R  
I nc o m plete res p o nse/ N o n- 
Pr o gressi ve disease  
N o  
P R  
S D  
I nc o m plete res p o nse/ N o n-
Pr o gressi ve disease  
N o  
S D  
Pr o gressi ve disease  
A n y  
Yes or n o  
Pr o gressi ve disease  
A n y  
Pr o gressi ve disease  
Yes or n o  
Pr o gressi ve disease  
A n y  
A n y  
Yes  
Pr o gressi ve disease  
A b bre viati o ns: C R  =  c o m plete res p o nse; P R  =  partial res p o nse; S D  =  sta ble disease.