Clinical trial NCT02989857
Conditions: Advanced Cholangiocarcinoma Metastatic Cholangiocarcinoma
Keywords: IDH1
Sponsor: Institut de Recherches Internationales Servier
Start date: 2017-02-20; Completion date: 2021-05-17
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study AG120-C-005 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of orally administered AG-120. Participants, all personnel involved in the evaluation of participants' response to treatment (e.g., Investigators, study coordinators, study pharmacists), and designated Sponsor team members will be blinded to study treatment. Participants are required to have a histologically-confirmed diagnosis of isocitrate dehydrogenase-1 (IDH1) gene-mutated cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative therapies prior to enrollment. IDH1 mutation testing will be performed at participating investigative sites. Participants must have progression of disease and have received at least 1 but not more than 2 prior treatment regimens for advanced disease (nonresectable or metastatic). All participants must have received either a gemcitabine or a 5 fluorouracil (5-FU) based chemotherapy regimen.

Detailed description:

Arms: arm 1: Participants received AG-120 500 mg, tablet, orally, once a day (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months. arm 2: Participants received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Participants who experienced disease progression and received placebo were allowed to cross over and receive AG-120. arm 3: Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
Interventions: intervention 1: AG-120 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet administered orally intervention 2: Tablet administered orally

Protocol documents:
Prot_002.pdf: 
 
Official Title: 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 
NCT Number: NCT02989857 
Document Date: Protocol Version 7: 23-June-2021 
 





















































































































































































































Prot_000.pdf: 
 
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  
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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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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  
1 1  
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 


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 2  
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  
A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 3  
A gi os P har mace uticals, I nc.  
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  


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A me n d me nt 5, Versi o n 6. 0  
C o nfi de ntial  
1 5  
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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  
1 6  
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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  
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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.  


St u d y A G 1 2 0 -C -0 0 5  
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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 


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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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, 
me dical, s ur gical, a n d me dicati o n hist or y, ra di o gra p hic e val u ati o n t o deter mi ne e xte nt of disease 


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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. 


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  
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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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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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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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1 1. 2. 3.  
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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1 1. 3.  
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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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.  


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  
8 5  
A gi os P har mace uticals, I nc.  
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).  


St u d y A G 1 2 0 -C -0 0 5  
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C o nfi de ntial  
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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 


St u d y A G 1 2 0 -C -0 0 5  
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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.  


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  
8 8  
A gi os P har mace uticals, I nc.  
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. 


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  
8 9  
A gi os P har mace uticals, I nc.  
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  
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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. 
 
 


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 1  
A gi os P har mace uticals, I nc.  
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. 

SAP_001.pdf: 
 
Official Title: 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 
NCT Number: NCT02989857 
Document Date: SAP Version 1: 01-April-2019 
 


 
 
STATISTICAL ANALYSIS PLAN 
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  
 
 
STUDY DRUG: 
 AG-120 
PROTOCOL NUMBER: 
 AG120-C-005 
 
SAP Version: 
Version 1.0 
Draft Date:  
01 April, 2019 
 
 
 
 
 
 
Prepared by: 
, Ph.D. 
AG-120-005 Biostatistician 
 
                     Date 
 
 
 
Approved by: 
, M.D. 
AG-120-005 
 
 
                                     
 
                      Date 
  
Approved by: 
, Ph.D. 
, Biostatistics 
 
                      Date 
 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY OBJECTIVES ................................................................................................6 
2.1. 
Primary Objective .........................................................................................................6 
2.2. 
Secondary Objectives ...................................................................................................6 
2.3. 
Exploratory Objectives .................................................................................................6 
3. 
STUDY ENDPOINTS ..................................................................................................8 
3.1. 
Primary Endpoint ..........................................................................................................8 
3.2. 
Secondary Endpoints ....................................................................................................8 
4. 
OVERALL STUDY DESIGN ......................................................................................9 
5. 
SAMPLE SIZE ESTIMATION ..................................................................................10 
6. 
ANALYSIS POPULATIONS ....................................................................................11 
6.1. 
Intent-to-Treat Set (ITT) .............................................................................................11 
6.2. 
Safety Analysis Set (SAS) ..........................................................................................11 
6.3. 
Per-Protocol Set (PPS) ................................................................................................11 
6.4. 
Crossover Set (COS) ...................................................................................................11 
7. 
STATISTICAL ANALYSES .....................................................................................12 
7.1. 
Subject Disposition .....................................................................................................12 
7.2. 
Protocol Deviations ....................................................................................................12 
7.3. 
Demographics and Baseline Characteristics ...............................................................12 
7.3.1. 
Demographics .............................................................................................................13 
7.3.2. 
Baseline Characteristics ..............................................................................................13 
7.4. 
Prior Therapy and Medical History ............................................................................14 
7.4.1. 
Prior Systemic Anticancer Therapy ............................................................................14 
7.4.2. 
Prior Local-Regional Therapy ....................................................................................14 
7.4.3. 
Prior Surgery for Cholangiocarcinoma .......................................................................14 
7.4.4. 
Medical History ..........................................................................................................14 
7.5. 
Prior/Concomitant Medications and Procedures ........................................................14 
7.6. 
Exposure to Study Drug and Compliance ..................................................................15 
8. 
EFFICACY ANALYSIS ............................................................................................16 


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8.1. 
Progression-Free Survival (PFS) ................................................................................16 
8.1.1. 
Primary Analyses of PFS ............................................................................................16 
8.1.2. 
Additional Analyses of PFS ........................................................................................17 
8.2. 
Objective Response Rate (ORR) ................................................................................18 
8.3. 
Overall Survival (OS) .................................................................................................19 
8.4. 
Multiple Comparisons/Multiplicity Adjustment .........................................................20 
8.5. 
Time To Response (TTR) ...........................................................................................20 
8.6. 
Duration of Response (DOR) .....................................................................................20 
8.7. 
Health-Related Quality of Life (HRQOL) ..................................................................21 
8.7.1. 
Brief Descriptions of Questionnaires ..........................................................................21 
8.7.2. 
Statistical Analyses .....................................................................................................22 
8.8. 
Post Crossover ............................................................................................................24 
9. 
SAFETY ANALYSIS ................................................................................................25 
9.1. 
Adverse Events ...........................................................................................................25 
9.2. 
Adverse Events of Special Interest .............................................................................26 
9.3. 
On-Treatment Death ...................................................................................................26 
9.4. 
Laboratory Data ..........................................................................................................26 
9.4.1. 
Hematology .................................................................................................................26 
9.4.2. 
Clinical Chemistry ......................................................................................................27 
9.4.3. 
CA19-9 Level .............................................................................................................27 
9.4.4. 
Coagulation Analysis ..................................................................................................27 
9.4.5. 
Urinalysis ....................................................................................................................27 
9.4.6. 
Pregnancy Tests ..........................................................................................................27 
9.5. 
Physical Examination .................................................................................................27 
9.6. 
Vital Signs ..................................................................................................................27 
9.7. 
Electrocardiograms (ECGs) ........................................................................................28 
9.8. 
Left Ventricular Ejection Fraction (LVEF) ................................................................28 
9.9. 
ECOG Performance Status (PS) .................................................................................28 
9.10. 
Interim Analysis ..........................................................................................................28 
10. 
GENERAL METHODS .............................................................................................29 
10.1. 
General Rules ..............................................................................................................29 
10.2. 
Unscheduled Visits and Visit Windows .....................................................................29 


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10.3. 
Baseline Values ..........................................................................................................29 
10.4. 
Computing and Coding Standards ..............................................................................30 
10.5. 
Missing/Partial Dates in Adverse Events and Concomitant 
Medications/Therapies ................................................................................................30 
10.6. 
Missing/Partial Dates in On-study Anticancer Therapies ..........................................31 
10.7. 
Missing/Partial Dates at Screening Visits ...................................................................32 
11. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL ............................33 
12. 
APPENDICES ............................................................................................................34 
12.1. 
Appendix A: Best Overall Response Confirmation Rule ...........................................34 
12.2. 
Appendix B: One-Sided Cochran–Mantel–Haenszel (CMH) Test ............................34 
12.3. 
Appendix C: Overall Survival Analyses using Rank Preserving Structural 
Failure Time Model (RPSFT) .....................................................................................35 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analysis for Protocol AG-120-C-005, “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,” Amendment 4, Version 5.0, which was issued on 04 April 2018. It contains 
definitions of analysis populations, derived variables, and statistical methods for the analysis of 
efficacy and safety. 
This SAP provides a comprehensive and detailed description of the strategy, rationale, and 
statistical techniques to evaluate the necessary efficacy and safety endpoints. The purpose of this 
SAP is to ensure the credibility of the study findings by pre-specifying the statistical approaches 
to the analysis of study data prior to database lock. Pharmacokinetic (PK)/pharmacodynamic 
analysis and exploratory biomarker analyses are not in the scope of this SAP. This SAP will be 
finalized and approved prior to the database lock for the primary analysis. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is: 
• To demonstrate the efficacy of AG-120 based on progression-free survival (PFS) per 
Independent Radiology Center (IRC) assessment compared to placebo in subjects 
with nonresectable or metastatic cholangiocarcinoma with an isocitrate 
dehydrogenase 1 (IDH1) mutation. 
2.2. 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the safety and tolerability of AG-120 compared to placebo. 
• To evaluate PFS per Investigator assessment. 
• To compare the efficacy of AG-120 with placebo based on overall survival (OS), 
objective response rate (ORR), duration of response (DOR), and time to response 
(TTR), with response assessed per the Investigator and by the IRC. 
• To evaluate health-related quality of life (HRQOL) with AG-120 compared to 
placebo as assessed by the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaires (EORTC-QLQ-C30 and EORTC-QLQBIL21), 
the Patient Global Impression of Change (PGI-C), and the Patient Global Impression 
of Severity (PGI-S). 
• To evaluate health economic outcomes as assessed by the 5-level EuroQol five 
dimensions questionnaire (EQ-5D-5L). 
• To evaluate the pharmacokinetics (PK) of AG-120. 
• To evaluate the PK/pharmacodynamic relationship of AG-120 and 
2-hydroxyglutarate (2-HG) in blood samples. 
2.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To evaluate, for the subgroup of placebo subjects who have crossed over to the 
AG-120 arm, the time from first dose of AG-120 to second documented progression 
on AG-120 or death, whichever occurs first (PFS2). 
• To correlate baseline molecular and/or protein characteristics in tumor tissues with 
clinical response. 
• To correlate baseline 2-HG levels in plasma samples with clinical response. 
• To evaluate levels of mutant IDH1 and other genes in circulating tumor DNA 
obtained from plasma at baseline and over the course of the treatment. 


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• To correlate any PK variations with drug-metabolizing enzyme (DME) related genes, 
if the data are warranted. 
• To explore additional biomarkers in blood for morphologic, functional, biologic, 
epigenetic, and metabolic changes over the course of treatment. 


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3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint is PFS, defined as the time from date of randomization to date of first 
documented disease progression (as assessed by the IRC per RECIST v1.1), or date of death due 
to any cause. 
3.2. 
Secondary Endpoints 
• Adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation 
or death. The severity of AEs will be assessed by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. 
• Safety laboratory parameters, vital signs, 12-lead electrocardiograms (ECGs), 
evaluation of left ventricular ejection fraction (LVEF), Eastern Cooperative Oncology 
Group (ECOG) performance status (PS), and concomitant medications. 
• Secondary efficacy endpoints include: 
o OS, defined as the time from date of randomization to date of death. 
o ORR, defined as the proportion of subjects with a best overall response (BOR) 
defined as CR or PR, as assessed by the Investigator and by the IRC per 
RECIST v1.1. 
o DOR, defined as the time from date of first documented complete response 
(CR) or partial response (PR) to date of first documented disease progression 
or death due to any cause, as assessed by the Investigator and by the IRC per 
RECIST v1.1. 
o TTR, defined as the time from date of randomization to date of first 
documented CR or PR for responders, as assessed by the Investigator and by 
the IRC per RECIST v1.1. 
o PFS as determined by the Investigator. 
• HRQOL as assessed by validated instruments (EORTC-QLQ-C30, EORTC-
QLQBIL21, PGI-C, and PGI-S). 
• Health economic outcomes as assessed by the EQ-5D-5L instrument. 
• Serial or sparse blood sampling at specified time points for determination of plasma 
concentration-time profiles and PK parameters of AG-120. 
• Blood sampling at specified time points for determination of 2-HG levels to 
characterize the pharmacodynamic effects of AG-120. 


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4. 
OVERALL STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled efficacy and safety 
study of orally administered AG-120 in subjects with advanced cholangiocarcinoma 
(nonresectable or metastatic). Subjects, all personnel involved in the evaluation of subjects’ 
response to treatment (eg, Investigators, study coordinators, study pharmacists), and designated 
Sponsor team members will be blinded to study treatment until documented disease progression. 
Subjects are required to have a histologically consistent diagnosis of IDH1 gene-mutated 
cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative 
therapies. Subjects must have documented progression of disease and have received treatment 
with at least 1 but not more than 2 prior treatment regimens for advanced disease (nonresectable 
or metastatic). At least 1 of the prior regimens must have included gemcitabine or 5-FU. 
Systemic adjuvant chemotherapy will be considered a line of treatment if there is documented 
disease progression during or within 6 months of completing the therapy, with Sponsor approval. 
A total of approximately 186 subjects will be randomized in a 2:1 ratio to the AG-120 and 
placebo arms, respectively, stratified by number of prior therapies (1 vs. 2). The primary analysis 
of PFS will occur once 131 PFS events have been determined by Investigator assessment. 
Overall survival will be analyzed twice, once at the time of PFS primary analysis and once at the 
occurrence of 150 OS events. 
Subjects who meet all study eligibility criteria will be randomly assigned in a 2:1 ratio to receive 
AG-120 orally at a dose of 500 mg once daily (QD) or AG-120-matched oral placebo QD. Daily 
study treatment will begin on C1D1. Cycles are 28 days (+/-2 days) in duration and dosing is 
continuous. Study visits will be conducted every other week during Cycles 1-3 (Days 1 and 15), 
and Day 1 of each cycle thereafter. Radiographic assessment (computed tomography [CT] or 
magnetic resonance imaging [MRI]) for evaluation of disease response will be conducted every 
6 weeks (±5 days) for the first 8 assessments (ie, through week 48) and every 8 weeks (±5 days) 
thereafter from C1D1, independent of dose delays and/or dose interruptions, and/or at any time 
when progression of disease is suspected. 
Upon request by the Investigator, the subject and site staff will be unblinded to treatment 
assignment after documented disease progression (as assessed by the Investigator and after 
consultation with the Sponsor Medical Monitor), and subjects randomized to the placebo arm 
who continue to meet eligibility criteria determined in the End of Treatment (EOT) visit will be 
given the opportunity to cross over to the active treatment arm and receive AG-120. For those 
subjects who cross over, placebo will not be counted as a prior line of therapy for the purpose of 
eligibility. If subjects cross over, they will start again with study procedures as at C1D1. These 
subjects will continue to be evaluated for tumor response by the Investigator. 
An independent data monitoring committee (IDMC) will review the safety data on a regular 
basis to ensure the safety of treatment and proper conduct of the study. The first interim safety 
review meeting will be conducted when approximately 20 subjects have completed 2 cycles of 
therapy or have discontinued earlier; thereafter, meetings will be conducted every 3-6 months or 
on an ad hoc basis. No formal interim analysis for efficacy will be conducted before the primary 
analysis. 


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5. 
SAMPLE SIZE ESTIMATION 
A total of approximately 186 subjects will be needed for the study. 
The primary objective of the study is to demonstrate the improvement in PFS by IRC assessment 
for subjects receiving treatment with AG-120 as compared to subjects receiving placebo. 
Assuming a hazard ratio (HR) of 0.5 for PFS (equivalent to a median PFS of 3 months in the 
placebo arm vs. 6 months in the AG-120 arm, assuming an exponential distribution), a total of 
131 PFS events are required to provide 96% power at a 1-sided alpha of 0.025 level of 
significance to reject the null hypothesis using a stratified log-rank test. Based on this, a total of 
approximately 186 subjects will need to be randomized in a 2:1 ratio to the AG-120 and placebo 
arms, respectively, assuming approximately a 22% dropout rate, an approximate 26-month 
randomization period, and an additional 6-month follow-up for PFS after the last subject is 
randomized. Therefore, the primary analysis of PFS will occur at approximately 6 months after 
the last subject is randomized. 
Overall survival will be analyzed twice, once at the time of the final analysis for PFS and once at 
the occurrence of 150 OS events (final analysis for OS, which will occur at approximately 
24 months after the last subject is randomized). Assuming an HR of 0.67 for OS (median OS of 
8 months in the placebo arm vs. 12 months in the AG-120 arm, assuming an exponential 
distribution), a total of 150 OS events will provide 64% power at a 1-sided alpha of 0.025. 


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6. 
ANALYSIS POPULATIONS 
The following subject populations (ie, analysis sets) will be evaluated and used for presentation 
of the data: 
• Intent-to-Treat Set (ITT) 
• Safety Analysis Set (SAS) 
• Per-Protocol Set (PPS) 
• Crossover Set (COS) 
6.1. 
Intent-to-Treat Set (ITT) 
All subjects who are randomized, with the treatment group designated according to the 
randomization. The ITT will be the primary analysis set for all analyses except for safety. 
6.2. 
Safety Analysis Set (SAS) 
All subjects who receive at least one dose of study drug (AG-120 or placebo). Subjects will be 
analyzed according to the actual treatment received. The SAS will be the primary analysis set for 
all safety analyses. 
6.3. 
Per-Protocol Set (PPS) 
All subjects in ITT who do not violate the terms of the protocol in a way that would significantly 
affect the study outcome, with treatment group designated according to the randomization.  
In general, subjects who meet the following criteria will be excluded from this analysis set: 
• Do not have histopathologically diagnosed nonresectable or metastatic 
cholangiocarcinoma 
• Do not have documented IDH1 gene-mutated disease based on central laboratory 
testing 
• Do not have any measurable lesion at baseline as defined by RECIST v1.1 as 
determined by IRC 
• Three or more prior systemic therapy in an advanced setting (nonresectable or 
metastatic) 
• Have received a prior IDH inhibitor. 
6.4. 
Crossover Set (COS) 
A subset of placebo subjects who cross over and receive AG-120 upon the radiographic 
documented progression (PD). The COS will be the analysis set for analyzing post-crossover 
data. 


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7. 
STATISTICAL ANALYSES 
Unless specified otherwise, longitudinal data will be presented by “before crossover” and “after 
crossover” periods, defined as: 
• “After crossover” contain data collected after placebo subjects crossed over to 
AG-120. COS will be the analysis set. 
• “Before crossover” contain AG120 arm data and the Placebo arm data up till 
crossover. 
7.1. 
Subject Disposition 
The disposition table of subjects will include the following categories: 
• Number and percentage of subjects who are randomized (ITT set) 
o Number and percentage of subjects who are randomized but not dosed 
o Number and percentage of subjects who are randomized and dosed 
• An end-of-treatment disposition (still on treatment vs. discontinued from treatment) 
based on SAS set. The primary reason for treatment discontinuation will also be 
included. 
• An end-of-study disposition (still on study vs. discontinued from study) based on ITT 
set. The primary reason for study discontinuation will also be included. 
• Placebo subjects who crossed over to AG-120 based on COS set. An end-of-treatment 
disposition (still on AG-120 vs. discontinued from AG-120) and the primary reason 
for discontinuing AG-120 will be summarized. 
A listing of subjects who failed screening, including the reason for screen failures will be 
provided. 
A listing of subjects including the date of first dose, date of last dose, date of crossover (if any), 
reason of treatment discontinuation, date of death, cause of death, end of study date, and the 
reason of study discontinuation will be provided. 
7.2. 
Protocol Deviations 
A subject-level protocol deviation listing will be provided by site and subject based on ITT set. 
Major subject-level protocol deviations will be summarized, including: 
• Number and percentage of subjects with at least 1 major protocol deviation. 
• Subjects by number of major protocol deviations (1, 2, ≥3). 
• Number and percentage of subjects within each major protocol deviation category. 
7.3. 
Demographics and Baseline Characteristics 
Baseline/demographics-related tables will be presented per randomization (ITT). 


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7.3.1. 
Demographics 
Demographic and other baseline variables will be summarized for each treatment arm based on 
all randomized subjects (ITT set) and for the two treatment arms combined (total). 
Subject demographic data, including age, gender, race, regions, and ethnicity (if available) will 
be obtained during screening. 
Age (years), height (cm), weight (kg), body mass index (BMI) (weight [kg]/height [m2]), and 
other continuous baseline characteristics will be summarized descriptively (number of subjects, 
mean, standard deviation [SD], median, minimum, and maximum). Age category (<45, ≥45 -
<65, and ≥65 years), sex, race, and ethnicity and other categorical variables will be summarized 
by frequency tabulations (count, percent). 
If age is not collected in the database, it will be calculated as follows: age = [ICF year – birth 
year]. 
Body mass index will be calculated as follows: BMI (kg/m2) = weight in kg / (height in m)2. 
7.3.2. 
Baseline Characteristics 
The following baseline characteristics will be summarized by treatment arms and for the two 
arms combined (total) based on ITT set. The variables will include: 
• Number and percentage of subjects within each randomization strata (1 vs. 2 prior 
lines of therapy per randomization)  
• IDH1 allele types per central IDH1 testing 
• ECOG at baseline 
• Cholangiocarcinoma type at diagnosis (Intrahepatic Cholangiocarcinoma, 
Extrahepatic Cholangiocarcinoma, Perihilar Cholangiocarcinoma, Unknown) 
• T/N/M stage at initial diagnosis (Tx, Nx, Mx) 
• Grade at initial diagnosis (Well differentiated, Moderately differentiated, Poorly 
differentiated, Undifferentiated, Unknown) 
• Extent of disease at Screening 
• Liver cirrhosis at Screening 
• Presence of Biliary Stent at Screening 
• Presence of Ascites at Screening 
• Ascites related to Cholangiocarcinoma within the past 3 months 
• Paracentesis with the past 3 months 
• Pleural effusion related to Cholangiocarcinoma within the past 3 months 
• Thoracentesis within the past 3 months 
Baseline characteristic listing will be provided. 


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7.4. 
Prior Therapy and Medical History 
7.4.1. 
Prior Systemic Anticancer Therapy 
Prior therapies will be summarized for each treatment arm and for the two treatment arms 
combined (total) based on the ITT set. It will be summarized continuously as well as 
categorically. Types of therapies (adjuvant, palliative, etc.) will also be summarized. 
This is the actual prior lines of systemic anticancer therapy subjects received in advanced setting 
in order to determine the study eligibility, not the stratification factor entered at the 
randomization. In majority of cases these two should match. However, it does not preclude the 
likelihood of mismatch due to mis-stratification, etc. A table will be provided to summarize the 
discrepancy between these two. 
Duration of last line of therapy (in months) in advanced setting will be summarized, calculated as 
(end date of the last line of therapy – start date of the last line of therapy + 1)/(30.4375). 
In case there are multiple drugs within 1 line of therapy, the outer window rule will be applied to 
calculate the duration: the earliest start date of all drugs will be the start date, and the latest end 
date will be the end date for that line. 
The imputation of partial/missing dates is described in Section 10.6. 
A data listing will be provided and the line that is contributed to the eligibility will be flagged. 
7.4.2. 
Prior Local-Regional Therapy 
A data listing will be provided for prior local-regional therapy, including the type of prior local-
regional therapy, anatomical location, start date, end date, therapy setting, best response, and 
date of progression. 
7.4.3. 
Prior Surgery for Cholangiocarcinoma 
A data listing will be provided for prior surgery, including procedure, location, pathology 
finding, date of procedure, whether disease recur or progress after the procedure, and date of 
recurrence or progression. 
7.4.4. 
Medical History 
Medical history will be summarized by System Organ Class (SOC) and Preferred Term (PT), 
and sorted alphabetically in SOC and in PT. Medical history will be summarized by treatment 
arms and by both treatment arms combined (total) based on ITT set. A listing of medical history 
will also be provided. 
7.5. 
Prior/Concomitant Medications and Procedures 
A summary table of concomitant medications will be provided by treatment arms and total. 
Concomitant medications are those medications that were ongoing at the time of first dose or that 
were initiated after first dose but prior to last dose plus 28 days (inclusive). If an end date is 
missing or the medication is ongoing, the medication will be included as concomitant 
medications. Concomitant medications will be tabulated by anatomic therapeutic class (ATC; 


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level 4) and preferred term (PT). If the concomitant medication starts on or after the start of 
AG-120 upon crossover, it will be summarized in the “after crossover” table. 
A summary table of concomitant procedures will be summarized by indication and preferred 
term. If the concomitant procedure starts on or after the start of AG-120 upon crossover, it will 
be summarized in the “after crossover” table. 
In addition, the following data listings will be provided: 
• A listing for prior and concomitant medications, with a flag to indicate prior vs. 
concomitant 
• A listing of concomitant procedures 
7.6. 
Exposure to Study Drug and Compliance 
Extent of exposure will be summarized for each treatment arm based on SAS. The following 
variables will be summarized: 
• Duration of treatment (in months): (Date of the last dose – Date of the first dose + 
1)/30.4375 
o For subjects who are still on treatment at a data cut-off date, the data cut-off 
date will be the date of the last dose. 
o Duration of treatment will be summarized as a continuous as well as a discrete 
variable (≥1 month, ≥3 months, ≥6 months, ≥9 months, ≥12 months) 
• Actual Dose Intensity (mg/day): Actual Total Dose/ Duration of Treatment (days) 
• Relative Dose Intensity (%): Actual Dose Intensity/Planned Dose Intensity, where the 
planned total daily dose is the dose assigned at the study entry. 
• Dose modifications (dose decreased, dose held) and the reasons for dose 
modifications. 
In addition, a separate table for placebo subjects who crossed-over and received AG-120 will be 
provided by using the same analysis method.  


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8. 
EFFICACY ANALYSIS 
For PFS, best overall response (BOR), ORR, DOR and other endpoints based on progression 
and/or response status, the primary analyses will be based on the independent central review by 
IRC. The endpoints based on Investigator assessment will be used as secondary analyses. 
Efficacy data after crossover will be analyzed separately. 
After unblinding at local PD per Investigator assessment, subjects on AG-120 are allowed to stay 
on AG-120 if the treating Investigator deems they are clinically benefiting. The IRC will read all 
scans up to the discontinuation of AG-120. Subjects on placebo will no longer stay on placebo 
after radiographic disease progression and unblinding, hence no further scans will be read by 
IRC beyond the initial locally assessed disease progression imaging time point. Because of that, 
there is a potential systematic bias that subjects on the AG-120 arm could have PD called by IRC 
later than the locally assessed PD date; however, subjects on the placebo arm would 
systematically be censored by IRC analysis at the time of local PD if not concordant with local 
PD. To alleviate the potential imbalance between two arms, IRC assessments after the local PD 
from both arms will be excluded from the primary analysis of scan-related endpoints per IRC 
read. A sensitivity analysis by including all the scans read by IRC will be conducted. 
All efficacy analyses will be based on the ITT set unless stated otherwise. If analyses are 
performed on more than one analysis set, the analyses on the ITT set will be considered primary. 
For each period, once the PD occurred, or the new anticancer therapy was initiated, all the 
subsequent tumor/response assessments will not be included in the tumor/response related 
summary analyses, but it will be included in the data listings. 
Data after crossover (such as PFS) will be analyzed in a similar manner. 
Listings for all efficacy endpoints will be provided. 
8.1. 
Progression-Free Survival (PFS) 
8.1.1. 
Primary Analyses of PFS 
The primary analysis of PFS will be based on IRC assessment for ITT set. 
Progression-free survival (PFS) is defined as the time in months from the randomization date to 
the date of the first documentation of disease progression as determined by the IRC per 
RECIST v1.1 or death due to any cause, whichever occurs first. 
PFS = (Earliest Date of Disease Progression or Death – Randomization Date + 1) / 30.4375. 
The approach regarding handling of missing response assessments and censoring is presented in 
Table 1: 
Handling of Missing Response Assessment and Censoring for the Primary Analysis 
of PFS. 
A stratified log-rank test (one-sided) will be used to compare PFS of the AG-120 arm against the 
placebo arm at the time when 131 investigator-assessed events have occurred, with the one-sided 
significance level controlled at 0.025. The HR (AG-120/placebo) and the corresponding 2-sided 
95% confidence interval (CI) will be estimated using a stratified Cox regression model. For both 
the stratified log-rank test and stratified Cox regression model, the strata will be those used for 
stratified randomization, that is, the number of prior lines of therapy at randomization.  


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Number of subjects with events, types of events (progression or death), and number of subjects 
censored, number of subjects for each reason of censoring, Kaplan-Meier estimates, and 95% CIs 
for the 25th percentile, median, and the 75th percentile for PFS will be presented by treatment 
group. Probabilities of event free at selected time points, such as 3-month, 6-month, 9-month, 
and 12-month, will be presented by treatment arms. Kaplan-Meier curves of PFS will be 
provided for each treatment arm with the number of subjects at risk over time included. 
8.1.2. 
Additional Analyses of PFS  
The following analyses of PFS will be performed by treatment arms: 
For IRC assessments: 
• Stratified log-rank test and Cox regression based on all scans read by IRC prior to 
crossover, including the scans after local PD from subjects who were originally 
assigned to AG-120 and continued to stay after unblinding. 
• Stratified log-rank test and Cox regression based on PPS set. 
• Unstratified log-rank test (one-sided) to compare the two treatment arms. An 
unstratified Cox regression will be used to estimate the HR (AG-120/placebo) with its 
95% CI. 
• Subgroup analysis with unstratified log-rank test and unstratified Cox regression 
model. The HR (AG-120/placebo) with its 95% CI will be displayed for all subgroups 
graphically in a forest plot. The subgroups will include: 
o The actual number of prior line of therapies in advanced setting (1 vs. ≥2) 
o Gender (female vs. male) 
o Extent of disease at screening (locally advanced vs. metastatic) 
 If subject had both local and metastatic, it would be considered as 
metastatic 
o Intrahepatic vs. extrahepatic 
 Perihilar will be included in extrahepatic category 
o ECOG at baseline (0 vs. >=1) 
o Regions (North America vs. Europe vs. Asia) 
In addition, the following exploratory analyses may be performed: 
o PFS analysis by excluding subjects who progressed early (≤47 days within 
randomization date, i.e., 6 weeks + 5 days of scan visit window). 
o The Cox regression model by including treatment, sum of target lesions at 
baseline, and other possibly related parameters in covariates. 
For Investigator assessments: 
• Stratified log-rank test (one-sided) will be utilized to compare the two treatment arms. 
A stratified Cox regression model will be used to estimate the HR (AG-120/placebo) 


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with its 95% CI. The same censoring rule as described for the primary PFS based on 
IRC assessment will be used. 
In addition, the concordance of PFS between investigator and IRC assessment will also be 
summarized by treatment arms and overall. 
Table 1: 
Handling of Missing Response Assessment and Censoring for the Primary 
Analysis of PFS 
Situation 
Date of Censoring 
No baseline assessment and no death. 
Date of the randomization 
Alternate anticancer systemic treatment started before 
documented progression (PD) or death. 
Date of last adequate assessment prior 
to the start of anticancer treatment1 
No adequate post-baseline assessment and no death. 
Date of the randomization 
No documented PD or death before data cutoff date. 
Date of last adequate assessment1 
Documented PD or death following a long gap from the 
previous adequate assessment (eg, 2 or more consecutive missed 
scheduled disease status assessments). The long gap is defined 
as ≥95 days (ie, 12 weeks + 10 days per the protocol defined 
visit window). If no adequate assessment prior to minimum of 
(PD, death), the long gap is calculated from the randomization 
date. 
Date of last adequate assessment prior 
to the first occurrence of 2 or more 
consecutive missing scheduled 
assessments 
1 Adequate disease assessment is defined as a response assessment other than “not assessed” or “not evaluable.” If 
there is no adequate response assessment prior to the start of anticancer treatment, it will be censored at the 
randomization date. 
8.2. 
Objective Response Rate (ORR) 
Objective response rate will be derived from BOR. Best overall response is defined as the best 
time point response that a subject achieves during the course of the study, with the response 
ranked according to the following order (from best to worst): CR>PR>SD>PD>UNK>Other 
(including Not Evaluable and Not Assessed). The number and proportion of ITT subjects with 
each category of BOR will be presented by treatment arms. 
Per RECIST v1.1, SD that occurred within <38 days from the randomization date is assigned as 
UNK (6 weeks minus 5 days per protocol allowed visit window). In addition, the BOR of CR or 
PR requires a confirmation scan. The specific confirmation rule can be found in Appendix A: 
Best Overall Response Confirmation Rule. 
The estimated ORR (percent of subjects with a BOR of CR or PR) and a 2-sided 95% CI (via 
exact binomial) will be provided by treatment arms. All subjects in the analysis set will be 
included in the denominator in the calculation of the percentage for each response category or 
ORR. If the subject has no response assessment, it will be treated as a non-responder in the 
analyses. 


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Objective response rate will be analyzed using one-sided Cochran-Mantel-Haenszel (CMH) test 
(see Appendix B: One-Sided Cochran–Mantel–Haenszel (CMH) Test) to compare the two 
treatment arms. The odds ratio and its 95% CI will be estimated. The strata will be those used for 
stratified randomization. If the number of responders in each arm is low (n<5), Fisher exact test 
will be used instead. The odds ratio (unstratified) and its 95% exact CI will be estimated. 
In addition, the ORR (and BOR) without confirmation per IRC as well as per Investigator 
assessments will be analyzed similarly. 
The waterfall plots of the maximum % reduction from baseline in target lesion measurement 
(sum of diameters) will be presented by treatment arms. The target lesions post-baseline vs. 
baseline have to be matched in order to calculate % change, except for the case where lesions 
disappeared (Absent or Too Small to Measure) or merged or split. If the lesion status is “Absent,” 
0 mm will be used as the measurement; if the lesion status is “too small to measure,” 5 mm will 
be used per RECIST v1.1 guidance. 
The swim lane plot of treatment duration per subject will be presented by treatment arms. 
Treatment ongoing status will be marked at the end of the lane. The BOR will be marked in 
colors. The swim lane plot will be based on ITT set. 
8.3. 
Overall Survival (OS) 
The OS analysis will be based on ITT set and will include all OS data, including data after 
crossover. 
Overall survival is defined as the time in months from the randomization date to the date of death 
due to any cause. Subjects without documentation of death at the time of the data cutoff for 
analysis will be censored at the date the subject was last known to be alive, or the data cutoff 
date, whichever is earlier. The last known alive date is the last record in the study database. For 
example, this date may be the maximum of the last visit date or last contact date, including 
telephone follow-up where the subject is known to be alive. 
As a primary analysis, a stratified one-sided log-rank test will be used to compare OS between 
the two treatment groups, with the one-sided significance level controlled at 0.025. The HR 
along with the 95% CI will be estimated using a stratified Cox model. For both the stratified log-
rank test and the stratified Cox model, the strata will be those at randomization. A Kaplan-Meier 
plot for OS will be presented by treatment arm. Estimates and 95% CIs for the 25th percentile, 
median, and 75th percentile for OS will be presented by treatment arm (if estimable). 
Probabilities of survival at selected time points (3 months, 6 months, 9 months, and 12 months) 
may also be presented. 
In addition, the following subgroup analyses will be performed: 
• Subgroup analysis with unstratified log-rank test and unstratified Cox regression 
model. The HR (AG-120/placebo) with its 95% CI will be displayed for all subgroups 
graphically in a forest plot. The subgroups will include: 
o The actual number of prior line of therapies in advanced setting (1 vs. ≥2) 
o Gender (female vs. male) 
o Extent of disease at screening (locally advanced vs. metastatic) 


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 If subject had both locally advanced and metastatic, it would be 
considered as metastatic 
o Intrahepatic vs. extrahepatic 
 Perihilar will be lumped into extrahepatic category 
o ECOG at baseline (0 vs. >=1) 
o Regions (North America vs. Europe vs. Asia) 
Per the protocol, placebo subjects are allowed to cross over to AG-120 upon the radiographic 
disease progression provided the eligibility criteria continue being met. To adjust for the 
crossover effect from placebo to AG-120 on OS, advanced modeling methods, such as rank 
preserving structural failure time (RPSFT) method, will be explored. More details of this method 
will be in the Appendix C: Overall Survival Analyses using Rank Preserving Structural Failure 
Time Model (RPSFT). 
8.4. 
Multiple Comparisons/Multiplicity Adjustment 
Of the secondary endpoints, OS and ORR are designated as key secondary efficacy endpoints. 
The primary and key secondary endpoints will be tested at an overall one-sided Type I error rate 
at 2.5% level based on the fixed sequence testing procedure at the time of primary analysis. 
These endpoints will be tested in the following order: 
• PFS based on IRC 
• OS 
• ORR based on IRC 
In addition, a hierarchical testing procedure will be adopted for OS analyses only if the primary 
efficacy endpoint PFS is statistically significant. Two analyses are planned for OS: 1) an interim 
analysis at the projected time of the final analysis for PFS (provided PFS is significant); 2) a 
final analysis for OS when 150 deaths are observed. Overall survival at the interim will be tested 
with the alpha being determined using the gamma spending function (gamma=-8), and the 
overall Type I error rate will be controlled at the 1-sided 0.025 level. The log-rank test stratified 
by randomization stratification factor will be used to compare OS between the two treatment 
arms. 
8.5. 
Time To Response (TTR) 
Time to response is defined as the time (in months) from the randomization date to the date of 
first occurrence of confirmed/unconfirmed response per RECIST v1.1.  
8.6. 
Duration of Response (DOR) 
Among responders (subjects who have a best response of confirmed PR or CR), DOR in months 
will be calculated as the date of the first confirmed PR or CR to the date of the first PD or death, 
whichever is earlier. Duration of response = (Earliest Date of Death/Progression – Date of First 
Confirmed PR/CR + 1)/30.4375. The censoring rule will be the same as that for the PFS analysis 


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in Table 1: Handling of Missing Response Assessment and Censoring for the Primary Analysis 
of PFS.  
For both TTR and DOR, a listing will be provided for responders only. 
8.7. 
Health-Related Quality of Life (HRQOL) 
In general, descriptive statistics will be used to summarize the individual items and sub-scale 
scores of HRQOL (ie, QLQ-C30 and QLQ-BIL21), anchor-based questions (ie, PGI-S, PGI-C) 
and the EQ-5D-5L data at each scheduled assessment time point. Data listings will also be 
provided by each endpoint and visit for each subject. 
Upon receipt of FDA’s feedback in May 2017, anchor questions (PGI-S and PGI-C) were added 
and HRQOL assessment frequency was increased from every 6 weeks prior to 1 year/every 8 
weeks thereafter (to tie with scan schedule) to every cycle (every 4 weeks). The changes were 
implemented in Protocol Amendment 3.0, Version 4, published in September 2017. 
8.7.1. 
Brief Descriptions of Questionnaires 
QLQ-C30 Questionnaire 
The QLQ-C30 contains 30 items in total and each item is a 4-point or 7-point Likert scale. These 
30 items can be categorized into a global health status/HRQOL scale, 5 functional scales, 
3 symptom scales, and 6 single-item scales. Each of the multi-item scales includes a different set 
of items. No item occurs in more than one scale: 
• 1 global health status scale (2 items) 
• 5 functional scales: physical function (5 items), role function (2 items), emotional 
function (4 items), cognitive function (2 items), social function (2 items) 
• 3 symptom scales: fatigue (3 items), nausea and vomiting (2 items), pain (2 items) 
• 6 single-item assessments relating to dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties. 
QLQ-BIL21 Questionnaire  
The QLQ-BIL21 contains 21 items in total and each item is a 4-point Likert scale. These 
21 items can be grouped into 5 scales and 3 single items: 
• 5 scales (18 items): eating symptoms (4 items), jaundice symptoms (3 items), 
tiredness (3 items), pain symptoms (4 items), anxiety symptoms (4 items) 
• 3 single-item assessments related to treatment side-effects, difficulties with drainage 
bag/tubes, concerns regarding weight loss 
PGI-S 
The anchor-based questionnaire PGI-S contains the following 3 items: 
• The severity of the physical functioning decline over the past week 
• The severity of the appetite decrease over the past week 
• The severity of the pain over the past week 


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The possible outcomes include: 
• None 
• Mild 
• Moderate 
• Severe 
• Very Severe  
PGI-C 
The anchor-based questionnaire PGI-C contains the following 3 items: 
• The overall change in the physical functioning since the start of taking the study 
medication 
• The overall change in the appetite since the start of taking the study medication 
• The overall change in the pain since the start of taking the study medication 
The possible outcome includes: 
• Very much better 
• Moderately better 
• A little better 
• No change  
• A little worse 
• Moderately worse 
• Very much worse 
EQ-5D-5L Questionnaires  
The EQ-5D-5L contains 5 dimensions (Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
and Anxiety/Depression) as well as the EQ visual analogue scale (VAS). Five dimensions return 
categorical outcomes, and the VAS is a 0-100 number. 
8.7.2. 
Statistical Analyses 
8.7.2.1. 
QLQ-C30 and QLQ-BIL21 Analyses 
Each scale will be transformed into a 0-100 score following EORTC guidelines: 
• Estimate the average of the items that contribute to the scale; this is the raw scale 
score 
• Use a linear transformation to standardize the raw scale score, so that it ranges from 
0 to 100. Scale score = (raw score – 1)/range *100. The only exception is Physical 
Function in QLQ-C30, where the scale score per EORTC QLQ-C30 manual is [1-  
(raw score – 1)/range]*100. Here, range is the difference between the possible 


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maximum and minimum response to each individual item. For instance, if the item is 
scored from 1 to 4, then range=3. 
Transformed scores for each scale and the absolute change from baseline will be summarized by 
treatment and scheduled visit. A mixed-effect model with repeated measurements on the change 
from baseline across visits for key scale scores (such as pain, appetite loss, and physical 
function) over the course of before crossover period may be explored with baseline score, 
treatment, visit, treatment-by-visit as fixed effects, and subject as random effects. 
8.7.2.2. 
Anchor Based Approach to Find Clinically Meaningful Change 
Estimation of meaningful change is achieved by computing the change scores for the EORTC-
QLQ-C30 and EORTC-QLQ-BIL21 scores between baseline and follow-up associated with 
minimal improvement groups defined on PGI-C and change from baseline to post-baseline 
PGI-S (ΔPGI-S) ratings as anchors. This approach will be taken for only before-crossover data. 
Minimally sufficient improvement is directly defined from the PGI-C by analyzing those 
subjects who report a minimal level of improvement on the anchors. Minimally sufficient 
improvement for the PGI-S is operationalized by taking the difference in PGI-S between baseline 
and follow-up and selecting participants with a one-point improvement. Average EORTC-QLQ-
C30 and EORTC-QLQ-BIL21 scores will be computed for each of the anchor-based minimally 
sufficient improvement group definitions. 
Relevant subscales of the EORTC-QLQ-C30 and EORTC-QLQ-BIL21 will be paired with their 
most-appropriate PGI-C/PGI-S rating (eg, the physical functioning PGI-C/S will be employed 
for the EORTC-QLQ-C30 physical function subscale). Similarly, the EORTC-QLQ-C30 appetite 
item and EORTC-QLQ-BIL21 eating symptoms subscale will be paired with the appetite 
PGI-C/S. Finally, the EORTC-QLQ-C30 and EORTC-QLQ-BIL21 pain subscales will each be 
paired with the PGI-C/S as anchors. 
EORTC-QLQ-C30 and EORTC-QLQ-BIL21 change scores will be plotted as cumulative 
distribution functions (CDFs) for change. Cumulative distribution functions will be stratified on 
their respective anchor variables (PGI-C and ΔPGI-S). In addition, after unblinding, the CDFs 
will be stratified by treatment-arm. 
8.7.2.3. 
EQ-5D-5L Analysis 
The EQ-5D contains a descriptive system with one response for each of 5 dimensions (Mobility, 
Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression). The first response is 
coded as 1 (indicating no problems), the second response is coded as a 2 (indicating slight 
problems), the third response is coded as a 3 (indicating moderate problems), the forth response 
is coded as a 4 (indicating severe problems), and the fifth response is coded as a 5 (indicating 
unable to function). Ambiguous responses (eg, more than one response in a dimension) are 
treated as missing values. For each dimension, the number and percentage of subjects in each 
category will be summarized by treatment and visits. 
The EQ-5D-5L also contains a utility scale of health state (VAS) ranging between 0 (worst 
health) and 100 (best health). Summary statistics for VAS scores and the absolute change from 
baseline will be reported by treatment and visits. 
 


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8.8. 
Post Crossover  
Upon the radiographic progression of disease, subjects will be unblinded. If it’s determined that 
they received placebo, subjects will be allowed to cross over to AG-120, provided they continue 
to be eligible for the study. Data after crossover will be analyzed separately, but in a similar 
fashion as outlined above. 
In particular, tumor assessments after crossover will be based on Investigator assessment. Tumor 
measurements will be re-baselined prior to the start of crossover. The corresponding endpoints 
include: 
• PFS per Investigator assessment (PFS2) 
• Objective response rate /best overall response per Investigator assessment. Note that 
SD<38 days of the first AG-120 dose date will be assigned as UNK. 
• Time To Response and DOR per Investigator assessment 


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9. 
SAFETY ANALYSIS 
Unless specified otherwise, the safety data will be summarized by treatment based on SAS. 
Specifically, it will include placebo before crossover, AG-120 as dosed, AG-120 after crossover, 
and total AG-120. The total AG-120 includes all the subjects who have ever been dosed with 
AG-120 (that is, the sum of AG-120 as dosed and AG-120 after crossover). If a subject receives 
at least one dose of AG-120, the actual arm will be AG-120 as dosed. The same rule applies to 
the after crossover. 
9.1. 
Adverse Events 
Treatment emergent adverse events (TEAEs) are defined as any AEs that begin or worsen on or 
after the start of study drug through 28 days after the last dose of study drug. All AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary, unless 
otherwise specified. The severity will be graded based on the NCI CTCAE. All AEs will be 
listed. Only TEAEs will be summarized and will be referred to as AEs hereafter. 
If a subject experiences multiple AEs under the same PT within an SOC, then the subject will be 
counted only once for that PT within that SOC. If a subject experiences the same AE more than 
once with different intensity or grade, then the event with the highest grade will be tabulated in 
“by grade” tables. 
Tables summarizing the incidence of AEs will be generated by treatment arms for each of the 
following: 
• Overall summary of AEs 
• All AEs by SOC and PT 
• Most common AEs by PT (ie, those events reported by ≥5% of subjects in any 
treatment group) 
• Most common Treatment-Related AEs by PT (ie, those events reported by ≥5% of 
subjects in any treatment group) 
• Grade 3 or higher AEs by SOC and PT 
• Most common Grade 3 or higher AEs by PT (ie, those Grade 3 or higher AEs 
reported by ≥5% of subjects in any treatment group) 
• Related AEs by SOC and PT 
• Related Grade 3 or higher AEs by SOC and PT. 
• SAEs by SOC and PT 
• Related SAEs by SOC and PT 
• AEs leading to study drug discontinuation by SOC and PT 
• AEs leading to study drug reduced by SOC and PT 
• AEs leading to study drug held by SOC and PT 
• Related AEs leading to study drug discontinuation by SOC and PT 


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• Related AEs leading to study drug reduced by SOC and PT 
• Related AEs leading to study drug held by SOC and PT 
• On-treatment death due to AE by SOC and PT, where on-treatment is defined as 
within 28 days of last dose. 
• On-treatment death due to related AE by SOC and PT, where on-treatment is defined 
as within 28 days of last dose. 
All AEs will be listed by subject. By-subject listings will be provided for AEs leading to 
on-treatment death, SAEs, and AEs leading to discontinuation of treatment. 
9.2. 
Adverse Events of Special Interest 
QT prolongation AEs will be summarized for the following: 
a) QT prolongation all grades by PT  
b) QT prolongation Grade 3 or higher by PT 
c) Treatment-related QT prolongation all grades by PT 
Time to first QT prolongation AE will be summarized continuously and by ≤15 days, 16-30, 31-
45, 46-60, and >60 days for all grade and Grade 2 or higher AEs.  
9.3. 
On-Treatment Death 
All on-treatment deaths (≤28 days of last dose) and the reason of deaths will be summarized by 
treatment based on SAS set.  
In addition, all-cause mortality will be summarized including the deaths ≤30 days of the first and 
last dose, and ≤60 days of the first and last dose. 
9.4. 
Laboratory Data 
Unless specified otherwise, lab data will be summarized by treatment and scheduled visits. Data 
after crossover will be summarized by scheduled visits in a separate table or listing. The baseline 
used in the “after crossover” outputs will be the closest assessment prior to subjects receive 
open-label AG-120. 
9.4.1. 
Hematology 
For hematologic parameters, the actual values and the change from baseline will be summarized 
by treatment and scheduled visits.  
Shift tables will be presented based on CTCAE grade by treatment, including 
• WBC (low) 
• Absolute Neutrophil Count (low) 
• Hgb (low) 
• Platelets (low) 


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9.4.2. 
Clinical Chemistry 
For chemistry parameters, the actual values and the change from baseline will be summarized by 
treatment and scheduled visits. 
Shift tables from baseline to worst value based on CTCAE grade will be presented by treatment, 
including 
• Bilirubin (high) 
• Alkaline Phosphatase (high) 
• ALT (high) 
• AST (high) 
• Sodium (low) 
• Potassium (low/high) 
• Phosphate (low) 
In addition, subjects with liver dysfunction will be presented in a listing. Liver dysfunction is 
defined as elevated ALT or AST of ≥ 3x ULN and associated with increase in total bilirubin ≥2x 
ULN (±10 days). 
9.4.3. 
CA19-9 Level 
The actual values and the change from baseline for CA19-9 level will be summarized by 
treatment arm and scheduled visits. A corresponding data listing will be provided. 
9.4.4. 
Coagulation Analysis 
The following coagulation tests will be presented in a listing: prothrombin time (PT), activated 
partial thromboplastin time (aPTT), and international normalized ratio (INR). 
9.4.5. 
Urinalysis 
Urinalysis results will be listed. 
9.4.6. 
Pregnancy Tests 
The pregnancy test results will be listed. 
9.5. 
Physical Examination 
A by-subject listing will be presented for any clinically significant findings from physical 
examination. 
9.6. 
Vital Signs 
Vital signs (except height) will be presented as both actual values and changes from baseline by 
treatment and scheduled visits. Vital sign measurements will also be listed. 


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9.7. 
Electrocardiograms (ECGs) 
Descriptive statistics for the actual values and changes from baseline over time will be 
summarized for each ECG parameter: QT (msec), RR interval (msec) and QTcF (Fridericia’s 
correction). QTcF is calculated as QTcF = QT/cube root of RR interval. 
The proportion of subjects with maximum post-baseline absolute QTcF intervals that fall into 
following categories will be presented: 
• ≤450 msec 
• >450 and ≤480 msec 
• >480 to ≤500 msec 
• >500 msec 
The proportion of subjects who have a maximum post-baseline change from baseline in QTcF 
intervals of the following categories will be presented: 
• ≤0 msec 
• >0 to ≤30 msec 
• >30 to ≤60 msec 
• >60 msec 
A listing of subject-level ECG measurement will be provided. 
9.8. 
Left Ventricular Ejection Fraction (LVEF) 
The LVEF data will be listed. 
9.9. 
ECOG Performance Status (PS) 
The ECOG PS will be summarized by treatment arms and visits, and by shift tables from 
baseline to worst values across all visits by treatment arms. 
A by-subject listing will be provided. 
9.10. 
Interim Analysis  
There will be no formal interim analyses of the data. Interim safety reviews will be conducted by 
an IDMC on a regular basis. Details are specified in the protocol and IDMC charter. 
 


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10. 
GENERAL METHODS 
Summary statistics will be presented by treatment and scheduled visit, unless stated otherwise.  
Unless otherwise specified, descriptive statistics for continuous data will include the number of 
subjects with data to be summarized (n), mean, standard deviation, median, minimum, and 
maximum. 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages. The total number of subjects in the treatment arm will be used as the denominator 
for percent calculations, unless stated otherwise. 
Descriptive statistics associated with time-to-event analyses will include the number of events, 
the number of subjects censored, 25% quartile, median, 75% quartile, and 95% CI for median. 
These statistics will be presented for all time-to-event analyses, unless stated otherwise. 
Listings will be provided for selected endpoints. Listings will be sorted by site, treatment, and 
subject IDs. 
10.1. 
General Rules 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). 
Study days are numbered relative to the day of the first dose of study medication (designated as 
Day 1) for safety related outputs, and relative to the randomization date for the efficacy related 
outputs. The preceding day is Day −1, the day before that is Day −2, etc. 
Other conventions include the following: 
• Data from all study centers will be combined in the analysis, unless specified 
otherwise. 
• Confidence intervals, if presented, will be 2-sided 95% CIs unless otherwise 
specified. 
• All analyses and summary tables will have the analysis population sample size for 
each treatment group (treatment arm, overall, etc.) in the column heading (ie, number 
of subjects). 
10.2. 
Unscheduled Visits and Visit Windows 
Unscheduled visits will not be mapped and will not be included in the summary statistics per 
visit tables. However, they will be included in the data listing as well as the shift tables. 
10.3. 
Baseline Values 
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, and prior to, the start of study drug administration. In case subjects are not dosed, the latest 
assessment will be considered as baseline. Values collected at unscheduled visits prior to the 
start of the study drug administration will be included in the calculation of baseline values. In 
majority of cases, C1D1 assessment should be treated as the baseline as the study protocol 
requires assessment to be done pre-dose at C1D1. For visits after crossover, the closest 


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assessment prior to the start of AG-120 will be considered as the baseline for crossover data 
analysis. 
10.4. 
Computing and Coding Standards 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.2 or higher 
Coding 
 
 
Adverse Events 
MedDRA Version 21.1 or higher 
 
Medical Histories 
MedDRA Version 21.1 or higher 
       Prior and Concomitant Medications 
WHODrug Version 2018 Q1 or higher 
Grading 
 
 
AEs 
CTCAE Version 4.03 
 
Labs 
CTCAE Version 4.03 
10.5. 
Missing/Partial Dates in Adverse Events and Concomitant 
Medications/Therapies 
Missing/Partial Start Dates: 


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If the stop date is non-missing and the imputed start date is greater than the stop date, the stop 
date will be used as the start date. 
1) Missing day only 
• If the month and year are the same as the month and year of the first dose date, the 
first dose date will be used 
• If the month and year are before the month and year of the first dose date, the last 
day of the month will be assigned to the missing day 
• If the month and year are after the month and year of the first dose date, the first 
day of the month will be assigned to the missing day 
2) Missing day and month 
• If the year is the same as the year of the first dose date, the first dose date will be 
used 
• If the year is prior to the year of the first dose date, December 31 will be assigned 
to the missing fields 
• If the year is after the year of the first dose date, January 1st will be assigned to the 
missing fields 
3) Missing day, month, and year 
• The first dose date will be used 
If the first dose date is missing, no imputation will be performed. 
Missing/Partial Stop Dates: 
1) Missing day only 
• The last day of the month will be assigned as the missing day 
2) Missing day and month 
• December 31 will be assigned to the missing fields 
3) Missing day, month, and year 
• The event will be regarded as ongoing 
All the imputed dates will be compared against the End of Study date, death date, and data cutoff 
date. The earliest date will be chosen. 
10.6. 
Missing/Partial Dates in On-study Anticancer Therapies 
On-study anticancer therapy with start dates that are completely or partially missing will be 
imputed as follows: 


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1. If the start date has month and year but day is missing, the 15 of the month will be 
imputed. 
2. If the start date has year, but day and month are missing, July 1 will be imputed. 
On-study anticancer therapy with stop dates that are completely or partially missing will be 
imputed as follows: 
1. If the stop date has month and year but day is missing, the last day of the month will be 
assigned. 
2. If the stop date has year, but day and month are missing, December 31 will be assigned. 
3. If the stop date misses day, month and year, the event will be considered as ongoing. 
If the imputed date is before the last dosing date, the last dosing date will be used as the on-study 
anticancer therapy start date. If the imputed date is after the death date then the death date will be 
used. If the imputed stop date is before start date, the stop date will be used as the start date. 
This imputation rule will only be used in efficacy endpoints derivation (such as PFS, OS). The 
listing of post-study anticancer therapy will not apply imputation rules. 
10.7. 
Missing/Partial Dates at Screening Visits 
The following rules apply to dates recorded during the screening visits (eg, prior anticancer 
therapy). 
1) Missing day only 
• The first day of the month will be used. 
2) Missing day and month 
• If the year is the same as the year of the earliest inform consent date at screening, the 
1st of January will be used. 
• If the year is before the year of the earliest inform consent date at screening, the 15th 
of June will be used. 
3) Missing day, month and year 
• No imputation will be applied. 
If the imputed end date is before the start date, the start date will be used as the end date. If the 
imputed dates are after the inform consent date at screening, then the inform consent date will be 
chosen. 


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11. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
Below is a summary of changes to the analyses specified in the protocol: 
• Pharmacokinetic Analysis Set (PAS) as well as PK-related analyses are not described 
here and will be in a stand-alone PK/pharmacodynamic report. 


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12. 
APPENDICES 
12.1. 
Appendix A: Best Overall Response Confirmation Rule 
CR CONFIRMATION: 
To confirm a CR (the first CR), another CR (the confirming CR) at least 4 weeks after the first 
CR will be looked for. It is required that there is no other overall response, except CR or NE or 
NA, between the first CR and the confirming CR. 
• If such confirming CR exists, then the subject BOR is confirmed CR. 
• If such confirming CR is guaranteed non-existing (eg, the first CR followed by PD or 
off-study), then the confirmed BOR is SD if the first CR was assessed ≥38 days after 
the randomization date, otherwise the first CR will be replaced by UNK and the BOR 
will be derived subsequently. 
PR CONFIRMATION: 
To confirm a PR (the first PR), another CR or PR at least 4 weeks after the first PR will be 
looked for. It is required that there is no other overall response, except CR or PR or NE or NA, 
between the first PR and the confirming CR or PR. 
• If such confirming CR or PR exists, then the subject’s BOR is PR (confirmed). 
• If such confirming CR or PR is guaranteed non-existing (eg, the first PR followed by 
PD or off-study), then the confirmed BOR is SD if the first PR was assessed 
≥ 38 days after the randomization date, otherwise the first PR will be replaced by 
UNK and the BOR will be derived subsequently. 
12.2. 
Appendix B: One-Sided Cochran–Mantel–Haenszel (CMH) Test 
The Cochran–Mantel–Haenszel (CMH) test compares binary responses of two treatment groups, 
adjusting for stratification factors. In the CMH test, the data are arranged in a series of associated 


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2 × 2 contingency tables, the null hypothesis is that the observed response is independent of the 
treatment used in any 2 × 2 contingency table. 
Let 
hij
O  be the observed frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in stratum 
h and 
hij
E be the expected frequency of treatment i (i=1 or 2) with outcome j (j= 1 or 2) in 
stratum h, where 
22
21
12
11
2
1
2
1
)
(
)
(
h
h
h
h
j
h
j
h
hi
hi
hij
O
O
O
O
O
O
O
O
E
+
+
+
+
⋅
+
=
 
Also, let 
hij
P be the probability of outcome being j given treatment being i (i=1 or 2, j= 1 or 2) in 
stratum h. To test the following hypothesis, 
  
 
21
11
0 :
h
h
P
P
H
=
 for all ℎ∈{1, … , 𝐻𝐻} 
versus 
21
11
1 :
h
h
P
P
H
>
 for at least one ℎ∈{1, … , 𝐻𝐻} 
The one-sided Cochran-Mantel-Haenszel Test Statistics is constructed as: 
Z
V
E
O
Z
H
h
h
h
CMH
~
)
(
11
1
11
11
∑
=
−
=
 
Where 
 
∑
∑
=
=
−
+
+
+
•
=
−
=
H
h
h
h
h
h
h
h
H
h
h
h
O
O
O
O
E
E
E
O
Var
V
1
22
21
12
11
22
11
1
11
11
11
1
))
(
(
 
The test statistic 
CMH
Z
 will be compared with standard normal distribution to obtain p-value of 
the CMH test. 
12.3. 
Appendix C: Overall Survival Analyses using Rank Preserving 
Structural Failure Time Model (RPSFT) 
Subjects who received placebo per randomization is allowed to crossover and receive AG-120 
upon radiographic PD. To account for the potential bias introduced by crossover, the RPSFT 
model (Robins and Tsiatis, 1991; White et al, 1997 & 1999) is utilized as a sensitivity analysis. 
The RPSFT model and assumptions 
RPSFT assumes that the AG-120 after the switch is acting by multiplying survival time by a 
given factor (acceleration factor) relative to placebo, and assumes the treatment effect is the 
same for all subjects regardless of when treatment is received (common treatment effect). 
Specifically, let 𝑈𝑈𝑖𝑖 denote the latent survival time if subject 𝑖𝑖 were assigned to the placebo arm, 
adhere to it and discontinue only after the event (also called counter-factual event time), 


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𝑈𝑈𝑖𝑖= 𝑇𝑇𝑖𝑖
𝑜𝑜𝑜𝑜𝑜𝑜+ 𝑇𝑇𝑖𝑖
𝑜𝑜𝑜𝑜 exp(𝜓𝜓0) 
where 𝑇𝑇𝑖𝑖
𝑜𝑜𝑜𝑜𝑜𝑜 is the time that subject 𝑖𝑖 is off treatment, and 𝑇𝑇𝑖𝑖
𝑜𝑜𝑜𝑜 is the time that subject 𝑖𝑖 is on 
treatment; exp(𝜓𝜓0) is the acceleration factor which denotes the amount by which a subject′s 
survival time is ‘increased’ by the active treatment. A positive (negative) 𝜓𝜓0 value corresponds 
to a harmful (beneficial) treatment effect. Specifically, for 
• AG-120 subjects at randomization: 𝑈𝑈𝑖𝑖(𝜓𝜓0) = 𝑇𝑇𝑖𝑖
𝑎𝑎𝑎𝑎120 exp(𝜓𝜓0); 
• placebo subjects who crossed over to AG-120: 𝑈𝑈𝑖𝑖(𝜓𝜓0) = 𝑇𝑇𝑖𝑖
𝑝𝑝𝑝𝑝𝑝𝑝+ 𝑇𝑇𝑖𝑖
𝑎𝑎𝑎𝑎120 exp(𝜓𝜓0); 
• placebo subjects without crossover: 𝑈𝑈𝑖𝑖(𝜓𝜓0) = 𝑇𝑇𝑖𝑖
𝑝𝑝𝑝𝑝𝑝𝑝. 
In order to estimate 𝜓𝜓0, we assume that 𝑈𝑈𝑖𝑖 is independent of randomized treatment assignment 
and can be viewed as baseline characteristics. Thus, if we conduct a hypothesis test (such as log-
rank test) for the treatment difference on 𝑈𝑈𝑖𝑖(𝜓𝜓0), we shall obtain a p-value close to 1 with a 
sufficiently large sample size. RPSFT works by reconstructing the survival time of subjects, as if 
they have never received active treatment. A grid search within a reasonable range will then be 
performed in order to find the estimated 𝜓𝜓0 with the largest p-value. The corresponding point 
estimate of HR between the two arms will be reported, with the 95% CI generated from 
bootstrapping method. 
Re-censoring 
Administrative censoring refers to the censoring where the event is not observed by the time of 
data cutoff. Unfortunately its time scale cannot be adjusted in the same way as event, as potential 
bias could be introduced because censoring would be dependent on time spent on treatment and 
thus treatment arm (informative censoring). To overcome this problem, the counter-factual event 
times are re-censored by the minimum 𝑈𝑈𝑖𝑖 that could have been observed for individuals (with 
and without events) across their possible treatment changes. 
Let 𝐶𝐶𝑖𝑖 be the potential censoring time for a subject 𝑖𝑖. The subject is then re-censored at the 
minimum possible censoring time: 
𝐷𝐷𝑖𝑖
∗(𝜓𝜓0) = min(𝐶𝐶𝑖𝑖, 𝐶𝐶𝑖𝑖exp(𝜓𝜓𝑜𝑜)). 
If 𝐷𝐷𝑖𝑖
∗< 𝑈𝑈𝑖𝑖, then 𝑈𝑈𝑖𝑖 is replaced by 𝐷𝐷𝑖𝑖
∗ and the subject is censored. For treatment arm where 
switching didn’t occur, re-censoring is not applied.