Clinical trial NCT04066491
Conditions: Biliary Tract Cancer Cholangiocarcinoma Gallbladder Cancer
Keywords: Metastatic Biliary Tract Cancer Cholangiocarcinoma Gallbladder Cancer Ampullary cancer M7824 Bintrafusp alfa Transforming growth factor-beta Programmed death-ligand 1
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2019-09-20; Completion date: 2022-11-10
Enrollment: 309 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study consisted of an open-label, safety run-in part and a randomized, double-blind, placebo-controlled Phase 2/3 part. In the Phase 2/3 part, the study was evaluated whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) in chemotherapy and immunotherapy-naïve participants with locally advanced or metastatic Biliary Tract Cancer (BTC) compared to placebo, gemcitabine and cisplatin.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: M7824 intervention 2: Placebo intervention 3: Gemcitabine intervention 4: Cisplatin
Intervention descriptions: intervention 1: Participants received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-sepcified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m\^2) and 25 mg/m\^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. intervention 2: Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified in protocol for discontinuation is met. intervention 3: Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m\^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W). intervention 4: Cisplatin was received intravenously at a dose of 25 mg/m\^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W).

Protocol documents:
Prot_000.pdf: 
Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1/ 2 1 3
Cli nic al St u d y Pr ot oc ol
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A 
P hase 
II/III, 
M u ltice nter, 
Ra n d o mize d, 
Place b o -co ntr olle d St u d y  of Ge mcita bi ne 
P l us 
Cis plati n W it h or W it h o ut B i ntraf us p alfa ( M 7 8 2 4)
as First-li ne Treat me nt of Biliar y Tract Ca ncer
St u d y N u m ber:
M S 2 0 0 6 4 7 _ 0 0 5 5
Pr ot oc ol Versi o n :
1 4 J ul y 2 0 2 1 / Versi o n 5. 0
Merc k C o m p o u n d:
M 7 8 2 4
Merc k Re gistere d C o m p o u n d N a me i n 
J a p a n:
N ot A p plica ble
St u d y P h ase:
P hase II/III
S h ort Title:
1 L  BT C P hase II/III Ge mcita bi ne P l us Cis plati n 
W it h or
W it h o ut Bi ntraf us p alfa ( M 7 8 2 4 )
C o or di n ati n g I n vesti g at or:
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
S p o ns or:
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y 
F or all c o u ntries, e xce pt t he U S , Ca na da, a n d 
Ja pa n:
Merc k Healt hcare K Ga A , Dar msta dt, Ger ma ny
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
Fra n kf urter Str. 2 5 0
6 4 2 9 3, Dar msta dt, Ger ma n y
I n t he U S a n d Ca na da:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, 
I nc.
a n affiliate of Merc k K Ga A, D ar msta dt, Ger ma n y
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A, 0 1 8 2 1, U S A
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2/ 2 1 3
I n Ja pa n:
Merc k Bi o p har ma C o., Lt d.
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
Arc o T o wer, 1 - 8-1 S hi m o me g ur o , Me g ur o - k u, 
T o k y o 1 5 3- 8 9 2 6, Ja pa n
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
I ND: 
E u dra C T: 2 0 1 9- 0 0 1 9 9 2- 3 5
Cli nical Trials. g o v: N C T 0 4 0 6 6 4 9 1
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
1. 0
Ori gi n al Pr ot o c ol
1 5 M a y 2 0 1 9
1. 1
R e gi o n -s p e cifi c a m e n d m e nt ( E U c o u ntri e s p arti ci p ati n g i n t h e 
V ol u nt ar y H ar m o ni s ati o n Pr o c e d ur e)
1 9 S e pt e m b er 2 0 1 9
2. 0
Gl o b al A m e n d m e nt
1 1 O ct o b er 2 0 1 9
2. 1
R e gi o n -s p e cifi c a m e n d m e nt ( T ai w a n a n d K or e a) 
3 D e c e m b er 2 0 1 9
3. 0
Gl o b al A m e n d m e nt
2 7 J ul y 2 0 2 0
4. 0
Gl o b al A m e n d m e nt
2 0 A pril 2 0 2 1
5. 0
Gl o b al A m e n d m e nt
1 4 J ul y 2 0 2 1
Pr ot oc ol Versi o n 5. 0 ( 1 4 J ul y 2 0 2 1) 
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  dri ver f or t his n o ns u bsta ntial a me n d me nt is t o i ncl u de a d diti o nal i nf or mati o n t o be 
ta ke n i nt o c o nsi derati o n b y  the I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) f or e x pa nsi o n 
i nt o P hase III.
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e
R e m o v e d r o w s f or M e di c al M o nit or 
a n d A p pr o v al D at e.
T e xt h a s b e e n u p d at e d f or 
c o n si st e n c y wit h M er c k pr ot o c ol 
st a n d ar d s .
S y n o p si s, O v er all D e si g n
S y n o p si s, N u m b er of P arti ci p a nt s
S y n o p si s, I n v ol v e m e nt of S p e ci al 
C o m mitt e e( s)
4. 1 O v er all D e si g n
4. 1. 2 R a n d o mi z e d, D o u bl e -bli n d 
P art
Fi g ur e 2 O utli n e of R a n d o mi z e d, 
D o u bl e -bli n d St u d y D e si g n
T e xt h a s b e e n r e vi s e d t o i n cl u d e a 
s u m m ar y of t h e a d diti o n al crit eri o n
f or e x p a n si o n i nt o P h a s e III.
A n e x p a n si o n crit eri o n w a s a d d e d t o 
i n cr e a s e c o nfi d e n c e i n a s uffi ci e ntl y 
l ar g e b e n efi ci al eff e ct of bi ntr af u s p 
alf a u n d er t h e e v ol vi n g tr e at m e nt 
l a n d s c a p e b ef or e e x p a n di n g 
tr e at m e nt t o a d diti o n al p arti ci p a nt s.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
3/ 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
2. 3 Ri s k/ B e n efit A s s e s s m e nt
T e xt h a s b e e n r e vi s e d t o i n cl u d e t h e 
m o st u p -t o- d at e a s s e s s m e nt.
R e vi si o n s ar e m a d e f or c o n si st e n c y 
wit h ot h er pr o gr a m d o c u m e nt s.
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
T e xt h a s b e e n r e vi s e d t o i n cl u d e 
a d diti o n al r ati o n al e f or t h e st u d y 
e x p a n si o n crit eri a .
A n e x p a n si o n crit eri o n w a s a d d e d t o 
i n cr e a s e c o nfi d e n c e i n a s uffi ci e ntl y 
l ar g e b e n efi ci al eff e ct of bi ntr af u s p 
alf a u n d er t h e e v ol vi n g tr e at m e nt 
l a n d sc a p e b ef or e e x p a n di n g 
tr e at m e nt t o a d diti o n al p arti ci p a nt s.
5. 2 E x cl u si o n Crit eri a
E x cl u si o n crit eri o n 1 0 h a s b e e n s plit 
i nt o 2 s e p ar at e b ull et s wit h o ut 
c h a n g e i n c o nt e nt .
T h e crit eri o n w a s s plit at t h e r e q u e st 
of t h e V H P. 
6. 6. 1 D o si n g I n str u cti o n s
T e xt r el at e d t o l o c al r e q uir e m e nt s 
f or d o si n g of g e m cit a bi n e a n d 
ci s pl ati n h a s b e e n r e vi s e d. 
Li n k s t o S e cti o n s 6. 6. 3 a n d 6. 6. 4 
r ef erri n g t o d o s e m o difi c ati o n 
i n str u cti o n s f or g e m cit a bi n e a n d 
ci s pl ati n w er e a d d e d .
R e vi si o n s w er e m a d e t o i m pr o v e 
cl arit y .
6 . 6. 4 D o s e M o difi c ati o n of 
G e m cit a bi n e, Ci s pl ati n, a n d 
Bi ntr af u s p alf a/ Pl a c e b o f or R e n al 
I m p air m e nt
T e xt w a s a d d e d t o cl arif y n o ot h er 
Cr Cl f or m ul a s h o ul d b e u s e d.
T h e t e xt w a s a d d e d t o cl arif y a 
st u d y pr o c e d ur e.
6. 9. 5 Bl e e di n g E v e nt s
T e xt w a s r e str u ct ur e d ( wit h o ut 
c h a n gi n g c o nt e nt) .
T h e t e xt w a s r e vi s e d f or cl arit y a n d 
c o n si st e n c y wit h ot h er pr o gr a m 
d o c u m e nt s.
N ot e: Mi n or c h a n g e s h a v e b e e n p erf or m e d t hr o u g h o ut t h e pr ot o c ol t o a d dr e s s c o n si st e n c y p ert ai ni n g t o m aj or 
c h a n g e s m a d e i n t h e pr ot o c ol or t o a d d f urt h er cl arit y a n d pr e ci si o n.
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 1 b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4/ 2 1 3
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Ta ble of C o nte nts
.............................................................................................................. 4
Ta ble of Ta bles
.............................................................................................................. 8
Ta ble of Fi g ures
.............................................................................................................. 9
1
Pr ot oc ol S u m mar y .............................................................................. 1 0
1. 1
S y n o psis ..............................................................................................1 0
1. 2
Sc he ma ................................................................................................ 1 5
1. 3
Sc he d ule of Acti vities ......................................................................... 1 5
2
I ntr o d ucti o n......................................................................................... 4 0
2. 1
St u d y  Rati o nale................................................................................... 4 0
2. 2
Bac k gr o u n d ......................................................................................... 4 1
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 4 2
3
O bjecti ves a n d E n d p oi nts ................................................................... 4 3
4
St u d y  Desi g n....................................................................................... 4 5
4. 1
O verall Desi g n .................................................................................... 4 5
4. 1. 1
O pe n -la bel, Safety R u n -i n Part........................................................... 4 6
4. 1. 2
Ra n d o mize d, D o u ble -bli n d Part ......................................................... 4 7
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 4 8
4. 3
J ustificati o n f or D ose .......................................................................... 5 3
4. 3. 1
C he m ot hera p y ..................................................................................... 5 3
4. 3. 2
Bi ntraf u s p alfa wit h C he m ot hera p y .................................................... 5 3
4. 4
E n d of St u d y  Defi niti o n...................................................................... 5 4
5
St u d y  P o p ulati o n................................................................................. 5 4
5. 1
I ncl usi o n Criteria ................................................................................5 4
5. 2
E xcl usi o n Criteria ...............................................................................5 7
5. 3
Lifest yl e C o nsi derati o ns .....................................................................6 0
5. 4
Scree n Fail ures .................................................................................... 6 0
6
St u d y  Inter ve nti o n(s) .......................................................................... 6 0
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 6 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5/ 2 1 3
6. 2
St u d y  Inter ve nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y ..................................................................................... 6 1
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g ..............................................................................................6 3
6. 3. 1
St u d y  I nter ve nti o n Assi g n me nt .......................................................... 6 3
6. 3. 2
Bli n di n g ..............................................................................................6 3
6. 3. 3
E mer ge nc y  U n bli n di n g....................................................................... 6 4
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 6 4
6. 5
C o nc o mita nt T hera p y ......................................................................... 6 5
6. 5. 1
Resc ue Me dici nes ............................................................................... 6 5
6. 5. 2
Per mitte d Me dici nes ........................................................................... 6 5
6. 5. 3
Pr o hi bite d Me dici nes .......................................................................... 6 5
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 6 6
6. 5. 4. 1
Pre me dicati o n ..................................................................................... 6 7
6. 6
D ose Sel ecti o n a n d M o dificati o n ........................................................ 6 7
6. 6. 1
D osi n g I nstr ucti o ns ............................................................................. 6 7
6. 6. 2
Defi niti o n of D ose -li miti n g T o xicit y.................................................. 6 9
6. 6. 3
Treat me nt M o dificati o n ...................................................................... 6 9
6. 6. 3. 1
Bi ntraf us p alfa/ Place b o -relate d A d verse Dr u g Reacti o ns .................. 7 0
6. 6. 3. 2
Ge mcita bi ne a n d/ or Cis plati n -relate d A d verse Dr u g Reacti o ns......... 7 2
6. 6. 4
D ose M o dificati o n of Ge mcita bi ne, Cis plati n, a n d Bi ntraf us p 
alfa/ Place b o f or Re nal I m pair me nt ..................................................... 7 4
6. 6. 5
Disease S pecific Ris k: He p atic I m pair me nt ....................................... 7 4
6. 7
St u d y  Inter ve nti o n After t he E n d of t he St u d y ................................... 7 5
6. 8
S pecial Preca uti o ns ............................................................................. 7 6
6. 9
Ma na ge me nt of A d verse E ve nts of S pecial I nterest a n d ot her 
P ote ntial Ris ks .................................................................................... 7 6
6. 9. 1
I nf usi o n-relate d Reacti o ns Incl u di n g I m me diate H y perse nsiti vit y .... 7 6
6. 9. 2
I m m u ne-relate d A d verse E ve nts.........................................................8 0
6. 9. 3
T G F β I n hi biti o n Me diate d S ki n Reacti o ns................................ .........8 2
6. 9. 4
A ne mia ................................................................................................8 3
6. 9. 5
Blee di n g E ve nts ..................................................................................8 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6/ 2 1 3
6. 9. 5. 1
M uc o sal/ N o n-T u m or Blee di n g ...........................................................8 5
6. 9. 5. 2
T u m or Blee di n g .................................................................................. 8 6
6. 9. 6
Ot her P ote ntial Ris ks .......................................................................... 8 6
6. 9. 6. 1
I m paire d W o u n d Heali n g ................................................................... 8 6
6. 9. 6. 2
E m br y ofetal T o xicit y ..........................................................................8 6
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ...............................................................8 7
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 8 7
7. 1. 1
Per ma ne nt Treat me nt Disc o nti n uati o n ............................................... 8 7
7. 1. 2
Treat me nt Be y o n d I nitial Pr o gressi o n ................................................ 8 7
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................... 8 9
7. 3
L ost t o F oll o w -u p ............................................................................... 9 0
8
St u d y  Assess me nts a n d Pr oce d ures.................................................... 9 1
8. 1
Effi cac y Assess me nts a n d Pr oce d ures................................................ 9 1
8. 2
Safet y  Assess me nts a n d Pr oce d ures...................................................9 6
8. 2. 1
P h y sical E xa mi nati o ns a n d Vital Si g ns.............................................. 9 6
8. 2. 2
Electr ocar di o gra ms ............................................................................. 9 7
8. 2. 3
Cli nical Safet y  La b orat or y Assess me nts ............................................ 9 7
8. 2. 4
Re vie w C o m mittees ............................................................................ 9 8
8. 2. 4. 1
Safet y  M o nit ori n g C o m mittee............................................................ 9 8
8. 2. 4. 2
I n de pe n de nt Data M o nit ori n g C o m mittee .......................................... 9 8
8. 2. 4. 3
I n de pe n de nt Re vie w C o m mittee......................................................... 9 8
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................9 8
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n.................................................... 9 9
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts ...9 9
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ............... 9 9
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ... 1 0 0
8. 3. 5
Pre g na nc y ......................................................................................... 1 0 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7/ 2 1 3
8. 4
Treat me nt of O ver d ose .....................................................................1 0 1
8. 5
P har mac o ki netics .............................................................................. 1 0 1
8. 9
Healt h Ec o n o mics ............................................................................. 1 0 5
9. 1
Statistical H y p ot heses ....................................................................... 1 0 5
9. 2
Hierarc hical Testi n g Pr oce d ure ........................................................ 1 0 6
9. 3. 1
A nal y sis f or t he A da ptati o n Decisi o n ............................................... 1 0 7
9. 3. 2
P o wer a n d T y pe I Err or .................................................................... 1 0 8
9. 3. 3
S u b gr o u p A nal y ses f or Biliar y Tract Ca ncer S u bty pes .................... 1 0 9
9. 4
P o p ulati o ns f or A nal y ses .................................................................. 1 1 0
9. 5
Statistical A nal y ses ........................................................................... 1 1 1
9. 5. 1
Efficac y  A nalys es ............................................................................. 1 1 1
9. 5. 2
Safet y  A nalys es ................................................................................ 1 1 3
9. 5. 3
Ot he r A nalys es .................................................................................. 1 1 4
9. 5. 4
Se q ue nce of A nal ys es ....................................................................... 1 1 5
1 0
Refere nces ......................................................................................... 1 1 6
1 1
A p pe n dices ....................................................................................... 1 2 0
A p pe n di x 1
A b bre viati o ns .................................................................................... 1 2 1
A p pe n di x 2
St u d y  G o ver na nce.............................................................................1 2 4
A p pe n di x 3
C o ntrace pti o n ....................................................................................1 3 2
A p pe n di x 4
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w u p, a n d Re p orti n g................................ ..............1 3 4
A p pe n di x 5
Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w u p Assess me nts.........1 3 9
A p pe n di x 6
Cli nical L a b orat or y Tests .................................................................1 4 0
A p pe n di x 7
Me dical De vice I nci de nts: Defi niti o n a n d Pr oce d ures f or 
Rec or di n g, E val uati n g, F oll o w u p, a n d Re p orti n g ........................... 1 4 4
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8/ 2 1 3
A p pe n di x 8
Ma na ge me nt of I mm u ne -relate d A d verse E ve nts ............................1 4 5
A p pe n di x 1 0
C o u ntr y -s pecific Re q uire me nts ........................................................ 1 8 4
A p pe n di x 1 1
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) Versi o n 
1. 1 ..................................................................................................... 1 8 6
A p pe n di x 1 2
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 9 5
A p pe n di x 1 3
S p o ns or Si g nat ure Pa ge .................................................................... 2 1 1
A p pe n di x 1 4
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 2 1 2
A p pe n di x 1 5
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 2 1 3
T a ble of T a bles
Ta ble 1
Sc he d ule of Acti vities – Da y  1 t o Da y 1 6 8 ( Bi ntraf us p 
alfa/ Place b o Pl us C he m ot hera p y) ....................................................... 1 6
Ta ble 2
Sc he d ule of Acti vities – Da y  1 6 9 O n war ds ( Bi ntraf us p 
alfa/ Place b o M o n ot hera p y) a n d Acti vities F oll o wi n g St u d y  
I nter ve nti o n Disc o nti n uati o n ..............................................................2 7
Ta ble 5
St u d y  O bjecti ves a n d E n d p oi nts......................................................... 4 3
Ta ble 6
St u d y  Inter ve nti o n A d mi nistrati o n ..................................................... 6 1
Ta ble 7
Treat me nt M o dificati o n f or Bi ntraf us p alfa/ Place b o, Ge mcita bi ne, 
a n d Cis plati n ....................................................................................... 7 0
Ta ble 8
D ose M o dificati o n f or Ge mcita bi ne a n d Cis plati n ............................. 7 2
Ta ble 9
N o n he mat ol o g ical T o xicit y................................................................ 7 3
Ta ble 1 0
D ose M o dificati o n f or Ne utr o pe nia a n d T hr o m b oc y t o pe nia..............7 3
Ta ble 1 1
D ose M o dificati o n f or Re nal I m pair me nt ........................................... 7 4
Ta ble 1 2
Dia g n ostic Criteria f or Ac ute C h ola n gitis .......................................... 7 5
Ta ble 1 3
Treat me nt M o dificati o n of Bi ntraf us p alfa/ Place b o f or S y m pt o ms 
of I nf usi o n -Relate d Reacti o ns I ncl u di n g I m me diate 
H y perse nsiti vit y .................................................................................. 7 8
Ta ble 1 4
M o dificati o n of C o m bi nati o n Treat me nt f or I nf usi o n -relate d 
Reacti o ns/ H y perse nsiti vit y ................................................................. 8 0
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9/ 2 1 3
Ta ble 1 5
E val uati o n G ui da nce f or S us pecte d A ne mia ...................................... 8 4
Ta ble 1 6
Defi niti o ns of Pr o gressi ve Disease ..................................................... 8 8
Ta ble 1 7
P har mac o ki netic Para meters .............................................................1 0 2
Ta bl e 1 9
St o p pi n g B o u n daries U n der t he Pla n ne d Sc he d ule of A nal ys es ...... 1 0 8
Ta ble 2 0
O verall a n d L ocal P o wer f or A nal ys is Wit hi n Biliar y Tract Ca ncer 
S u bt y pe(s) ......................................................................................... 1 0 9
Ta ble 2 1
P o wer of Biliar y  Tract Ca ncer S u bty pe I nteracti o n Test.................. 1 1 0
Ta ble 2 2
Pr o ba bilit y  of O bser vi n g Efficac y f or a Biliar y Tract Ca ncer 
S u bt y p e B y  C ha nce........................................................................... 1 1 0
Ta ble 2 3
A nal y sis Sets..................................................................................... 1 1 1
Ta ble 2 4
E fficac y E n d p oi nts a n d Statistical A nal ysis Met h o ds ...................... 1 1 2
Ta ble 2 5
Safet y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ......................... 1 1 4
Ta ble 2 6
Se q ue nce of Pla n ne d A nal y ses ......................................................... 1 1 5
T a ble of Fi g ures
Fi g ure 1
O verall St u d y  Desi g n Sc he ma............................................................ 1 5
Fi g ure 2
O utli ne of Ra n d o mize d , D o u ble-bli n d St u d y  Desi g n......................... 4 7
Fi g ure 3
Decisi o n Tree f or C o nti n uati o n of Treat me nt Be y o n d Pr o gressi ve 
Disease ................................................................................................8 9
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 / 2 1 3
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol 
Title: 
A 
P hase II/III, M ultice nter, 
Ra n d o mize d, 
Place b o -c o ntr olle d St u d y  of 
Ge mcita bi ne P l us Cis plati n W it h or W it h o ut Bi ntraf us p alfa (M 7 8 2 4 ) as First -li ne Treat me nt of 
Biliar y  Tract Ca ncer
S h ort Title: 1 L  BT C P hase II/III Ge mcita bi ne P l us Cis plati n W it h or W it h o ut Bi ntraf us p alfa
(M 7 8 2 4 )
R ati o n ale: T he gl o bal sta n dar d of care ( S o C) f or first-li ne ( 1 L) c he m ot hera p y for l ocally a d va nce d 
or metastati c biliar y  tract ca ncer (B T C ) is a c o m bi nati o n of ge mcita bi ne a n d cis plati n ( Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k [ N C C N] a n d E ur o pea n S ociet y f or Me dical O nc ol o g y  [ E S M O] 
g ui deli nes ), h o we ver, t he pr o g n osis of patie nts wit h a d va nce d B T C re mai ns li mite d. Bi ntraf us p 
alfa (M 7 8 2 4 ), a first-i n-class, bif u ncti o nal f usi o n pr otei n, tar gets t he pr o gra m me d deat h -li ga n d 1 
( P D-L 1) a n d h u ma n tra nsf or mi n g gr o wt h fact or beta ( T G F β), b ot h maj or 
mec ha nis ms 
of 
i m m u n os u p pressi o n i n t he t u m or micr oe n vir o n me nt. 
M ore o ver, 
co m b i nati o n c he m ot hera p y
re gi me ns t hat i ncl u de a P D-L 1 i n hi bit or ma y ma xi mize t he c ha nce of t u m or res p o nse t o c yt ot o xic 
c he m ot hera p y, lea di n g t o pr ol o n ge d s ur vi val. Cli nicall y , bi ntraf us p alfa m o n ot hera p y  has s h o w n 
pr o misi n g cli nical efficac y si g nals i n sec o n d-li ne ( 2 L) treat me nt of B T C , s u g gesti n g t hat 
bi ntraf us p alfa i m m u n ot hera py i n c om bi nati o n wit h c he m ot hera p y c o ul d be a reas o na ble a p pr oac h 
t o i m pr o ve sta n dar d 1 L treat me nt. T he c urre nt st u d y ai ms t o e val uate w het her bi ntraf us p alfa i n 
c o m bi nati o n wit h ge mc ita bi ne pl us cis plati n i m pr o ves o verall s ur vi val ( O S) i n a d va nce d B T C 
c o m pare d wit h S o C ( ge mcita bi ne pl us cis plati n) al o ne. T his a p pr oac h is s u p p orte d b y  scie ntific 
e vi de nce a n d pr o misi n g cli nical efficac y data wit h t he g oal of f ulfilli n g a n u n met me dical nee d 
a n d bri n gi n g cli nical be nefit t o patie nts.
O bjecti ves a n d E n d p oi nts:
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
O p e n -l a b el, S af et y  R u n-i n
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a 2 4 0 0 m g o n c e e v er y 3 w e e k s i n c o m bi n ati o n wit h g e m cit a bi n e 
a n d ci s pl ati n i n l o c all y a d v a n c e d or m et a st ati c bili ar y tr a ct c a n c er ( B T C )
Pri m ar y
T o a s s e s s if bi ntr af u s p alf a 2 4 0 0 m g
o n c e e v er y 
3 w e e k s i s s af e a n d t ol er a bl e a n d t o c o nfir m t hi s 
d o s e a s t h e r e c o m m e n d e d P h a s e II d o s e f or t h e 
r a n d o mi z e d, d o u bl e-bli n d p art of t h e st u d y
O c c urr e n c e of d o s e -li miti n g t o xi citi e s ( D L T s) d uri n g t h e D L T 
e v al u ati o n p eri o d
S e c o n d ar y
T o a s s e s s t h e s af et y pr ofil e of bi ntr af u s p alf a i n 
c o m bi n ati o n wit h g e m cit a bi n e a n d ci s pl ati n

O c c urr e n c e 
of 
tr e at m e nt-e m er g e nt 
a d v er s e 
e v e nt s 
( T E A E s) a n d tr e at m e nt-r el at e d a d v er s e e v e nt s ( A E s)

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥3) i n l a b or at or y 
t e st s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 / 2 1 3
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
R a n d o mi z e d, D o u bl e -bli n d P art 
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a i n c o m bi n ati o n wit h g e m cit a bi n e pl u s ci s pl ati n v er s u s pl a c e b o 
wit h g e m cit a bi n e pl u s ci s pl ati n i n p arti ci p a nt s wit h a d v a n c e d or m et a st ati c B T C w h o h a v e n ot r e c ei v e d 
c h e m ot h er a p y/i m m u n ot h er a p y i n t h e a d v a n c e d/ m et a st ati c s etti n g
Pri m ar y
T o a s s e s s o v er all s ur vi v al ( O S )
O S
S e c o n d ar y
T o a s s e s s pr o gr e s si o n -fr e e s ur vi v al (P F S )
P F S a c c or di n g t o R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s V er si o n 1. 1 ( R E CI S T 1. 1) a s a s s e s s e d b y t h e 
I n v e sti g at ora
T o a s s e s s o bj e cti v e r e s p o n s e r at e ( O R R) 
C o nfir m e d o bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 a s 
a s s e s s e d b y t h e In v e sti g at or a
T o a s s e s s d ur ati o n of r e s p o n s e ( D O R) 
D O R a s s e s s e d b y c o nfir m e d c o m pl et e r e s p o n s e or p arti al 
r e s p o n s e u ntil d e at h or pr o gr e s si o n of di s e a s e a c c or di n g t o 
R E CI S T 1. 1 a s a s s e s s e d b y t h e In v e sti g at or a
T o a s s e s s d ur a bl e r e s p o n s e r at e ( D R R)
D ur a bl e c o nfir m e d r e s p o n s e of at l e a st 6 m o nt h s a c c or di n g 
t o R E CI S T 1. 1 a s a s s e s s e d b y t h e I n v e sti g at ora
T o a s s e s s t h e s af et y pr ofil e of bi ntr af u s p alf a or 
pl a c e b o i n c o m bi n ati o n wit h g e m cit a bi n e pl u s 
ci s pl ati n
O c c urr e n c e of T E A E s a n d tr e at m e nt- r el at e d A E s , i n cl u di n g 
a d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI)
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c ( P K) pr ofil e of 
bi ntr af u s p alf a 

P K pr ofil e of bi ntr af u s p alf a i n t er m s of Ce oi a n d C tro u g h f or 
p arti ci p a nt s i n t h e bi ntr af u s p alf a ar m

P K pr ofil e of bi ntr af u s p alf a i n t er m s of A U C 0-t , A U C0- ∞, 
C m a x, tm a x, a n d t½ f or p arti ci p a nt s i n t h e s af et y r u n-i n p art 
of t h e st u d y o nl y
T o e v al u at e t h e i m m u n o g e ni cit y of bi ntr af u s p alf a 
a n d t o c orr el at e it t o e x p o s ur e
I m m u n o g e ni cit y a s m e a s ur e d b y a nti dr u g a nti b o d y a s s a y s at 
b a s eli n e a n d o n -tr e at m e nt f or p arti ci p a nt s i n t h e bi ntr af u s p 
alf a ar m
A U C 0-t = ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o t o t h e l a st s a m pli n g ti m e at w hi c h t h e 
c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n, A U C 0- ∞= A U C fr o m ti m e z er o e xtr a p ol at e d t o i nfi nit y, 
b a s e d o n t h e pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at t h e l a st s a m pli n g ti m e, C e oi = c o n c e ntr ati o n o b s er v e d 
i m m e di at el y at t h e e n d of i nf u si o n, Cm a x = m a x i m u m o b s er v e d c o n c e ntr ati o n, Ctr o u g h= c o n c e ntr ati o n o b s er v e d 
i m m e di at el y b ef or e n e xt d o si n g, I R C =I n d e p e n d e nt R e vi e w C o m mitt e e, t½ = a p p ar e nt t er mi n al h alf -lif e, tm a x =ti m e t o 
r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al.
a
If t h e st u d y i s n ot e x p a n d e d t o P h a s e III, t u m or- b a s e d effi c a c y e n d p oi nt s will al s o b e a s s e s s e d a s p er t h e 
I R C. 
O ver all Desi g n: T his is a m ultice nter st u d y co nsisti n g of a n o pe n -la bel, safet y ru n -i n part f oll o we d 
b y  a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d P hase II/III part. 

T he o pe n -la bel, safety r u n-i n part will c o nfir m t he safet y an d t olera bilit y  of 1 L bi ntraf us p alfa 
i n c o m bi nati o n wit h ge mcita bi ne a n d cis plati n i n c he m ot hera p y a n d i m m u n ot hera py- nai ve
partici pa nts wit h l ocally a d va nce d or metastatic B T C . D ose -li miti n g t o xicit y ( D L T) will be 
e val uate d i n 2 se parate re gi o nal c o h orts ( Asia n sites a n d n o n- Asia n sites) i n t he first 2 1 da y s 
f oll o wi n g t he first d ose of bi ntraf us p alfa. Si x D L T -e val ua ble partici pa nts will be recr uite d 
se q ue ntiall y i n eac h c o h ort, wit h a n a d diti o nal 6 partici pa nts recr uite d if D L T is o bser ve d i n 2 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 / 2 1 3
or 3 partici pa nts. If D L T is o bser ve d i n ≤1 ( of 6) or ≤3 ( of 1 2) p artici pa nts, t he re gi o n ma y 
start t o e nr oll partici pa nts i nt o t he ra n d o mize d, d o u ble-bli n d part of t he st u d y .

T he ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d P hase II/III part will e val uate w het her 
b i ntraf us p alfa i n c o m bi nati o n wit h t he c urre nt S o C ( ge mcita bi ne pl us cis plati n) i m pr o ves O S 
i n c he m ot hera p y a n d i m m u n ot hera p y-nai ve partici pa nts wit h l ocall y ad va nce d or metastatic 
B T C c o m pare d wit h place b o, ge mcita bi ne , a n d cis plati n. I nitial 1 5 0 partici pa nts recr uite d i n 
P hase II w h o ha ve n o d oc u me ntati o n (electr o nic case re p ort f or m (eC R F )) of a n y s yste mic 
a nti bi otic treat me nt wit hi n 3 0 d a y s pri or t o ra n d o mizati o n (a nti bi otics- naive) will be a nal y ze d 
f or efficac y f or a n e x pa nsi o n decisi o n f or f ull P hase III sa m ple size. If t he pres pecifie d criteria
are met , t he st u d y will be e x pa n de d i nt o P hase III. If t he st u d y is n ot e x pa n de d t o P hase III, it 
will be c o m plete d as a P hase II st u dy .
U nless ot her wise s pecifie d, all st u d y assess me nts a p pl y to b ot h t he o pe n -la bel, safety r u n-i n a n d 
t he ra n d o mized, d o u ble -bli n d parts of t he st u d y . 
N u m ber of P artici p a nts: T he pla n ne d n u m ber of partici pa nts i n t he st u d y  is a ma xi m u m of 5 2 4:

1 2 t o 2 4 partici pa nts i n t he o pe n -la bel, safety r u n-i n part of t he st u d y

U p t o 3 0 0 partici pa nts or 5 0 0 partici pa nts i n P hase II/III, if e x pa n de d.
T he ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d part has a n a da pti ve desi g n t hat all o ws f or 
e x pa nsi o n of P hase II i nt o P hase III t hr o u g h t he e nr oll me nt of a d diti o nal partici pa nts. T he a nal ysis 
f or t he a da ptati o n decisi o n will be c o n d ucte d i n t he first 1 5 0 a nti bi otics - naive partici pa nts , w he n 
8 0 P F S
e ve nts ha ve occ urre d
a n d o nce at least 1 9 wee ks 
of f oll o w- u p f or t he first 
1 5 0 a nti bi otics - naive partici pa nt s ra n d o mize d is reac he d. 
E x pa nsi o n i nt o P hase III will ta ke place if:
If t he st u d y will n ot be e x pa n de d t o f ull P hase III sa m ple size, t he I nde pe n de nt Data M o nit ori n g 
C o m mittee (I DM C ) will c o nsi der t o ma ke a rec o m me n dati o n t o st o p t he st u d y earl y f or f utilit y if 
t he o bs er ve d P F S H R is > 1 a n d ta ki n g i nt o acc o u nt t he t otalit y of a vaila ble data i ncl u di n g a vaila ble 
O S data at t his p oi nt.
T he sa m ple size calc ulati o n f or t he ra n d o mize d, d o u ble -bli n d part is base d o n t he f oll o wi n g 
ass u m pti o ns:

1: 1 ra n d o mizati o n 

Al p ha of 0. 0 2 5 ( 1-si de d)

E x p o ne ntial distri b uti o n of O S
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 / 2 1 3

O S H R of 0. 7 0 c orres p o n di n g t o a n i ncrease i n me dia n O S fr o m 1 1. 7 m o nt hs i n t he c o ntr ol ar m 
t o 1 6. 7 m o nt hs i n t he b i ntraf us p alfa ar m, e x pecte d dr o p o ut rate of 5 % at 4 0 m o nt hs

Ass u m pti o ns f or t he a da ptati o n decisi o n a nal ys is:

O R R o d ds rati o of 2. 0 c orres p o n di n g t o 2 5 % O R R i n t he c o ntr ol ar m a n d 4 0 % O R R i n t he 
b i ntraf us p alfa ar m

P F S H R of 0. 6 5 c orres p o n di n g t o a n i ncrease i n me dia n P F S fr o m 5. 8 m o nt hs i n t he c o ntr ol 
ar m t o 8. 9 m o nt hs i n t he b i ntraf us p alfa ar m; e x pecte d dr o p o ut rate of 1 5 % .

E x p o ne ntial distri b uti o n of P F S.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 
I n t he o pe n -la bel, safety r u n-i n part , partici pa nts will recei ve b i ntraf us p alfa (2 4 0 0 m g
e ver y 
3 wee ks ) i n c o m bi nati o n wit h ge mcita bi ne ( 1 0 0 0 m g/ m 2) a n d cis plati n ( 2 5 m g/ m 2) a d mi nistere d 
o n Da y 1 a n d D a y 8 f or 8 c ycles e ver y 3 wee ks , f oll o we d b y  b i ntraf us p alfa ( 2 4 0 0 m g e ver y 
3 wee ks ) u ntil 1 of t he criteria f or disc o nti n uati o n is met.
I n the ra n d o mize d, d o u ble -bli n d part, partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve eit her 
b i ntraf us p alfa ( 2 4 0 0 m g ) or matc hi n g place b o o nce e ver y 3 wee ks . Partici pa nts i n b ot h t he 
b i ntraf us p alfa a n d place b o ar ms will als o recei ve ge mcita bi ne ( 1 0 0 0 m g/ m 2) a n d cis plati n 
( 2 5 m g/ m 2) o n D a y 1 a n d D a y 8 f or 8 c ycles e ver y 3 wee ks . Treat me nt wit h b i ntraf us p alfa or 
place b o will c o nti n ue u ntil 1 of t he criteria f or disc o nti n uati o n is met (see bel o w). Ra n d o mizati o n 
will be stratifie d acc or di n g t o t he f oll o wi n g fact ors:

T y pe of B T C
(base d o n 3 a nat o mical l ocati o ns, i.e., i ntra he patic c h ola n gi ocarci n o ma, 
e xtra he patic c h ola n gi ocarci n o ma i ncl u di n g a m p ulla of Vater’s ca ncer, a n d gall bla d der ca ncer )

M etastatic at dia g n osis v ers us ot hers, w here “ ot hers” i ncl u des partici pa nts wit h u nresect a ble, 
l ocall y a d va nce d disease at dia g n osis a n d partici pa nts wit h resecta ble disease at dia g n osis w h o 
ha ve u n der g o ne pri or s ur gical resecti o n wit h c urati ve i nte nt

Asia sites vers us n o n -Asia sites 
I n partici pa nts wit h c o m plete res p o nse ( C R), bi ntraf us p alfa/ place b o s h o ul d c o nti n ue f or 2 ye ars 
after t he first o nset of C R or u ntil 1 of t he criteria f or disc o nti n uati o n is met , w hic he ver occ urs 
first. I n all ot her cases, bi ntraf us p alfa/ place b o s h o ul d c o nti n ue u ntil 1 of t he criteria f or 
disc o nti n uati o n is met. All partici pa nts s h o ul d recei ve 8 c ycles of ge mcita bi ne a n d cis plati n. A n y  
misse d d ose(s) of c he m ot hera p y m a y  be ma de u p at t he e n d of t he sc he d ule d 8 c ycles ( u p t o 
1 6 a d mi nistrati o ns of ge mcita b i ne a n d cis plati n c o m bi nati o n) pr o vi de d t he partici pa nt d oes n ot 
meet a n y of t he criteria f or disc o nti n uati o n.
T w o Safet y F oll o w - u p Visits will be perf or me d: at 2 8 da y s (± 7 d a y s) a n d 1 2 wee ks ( ± 2 wee ks) 
after t he last d ose of treat me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 / 2 1 3
L o n g -ter m f oll o w- u p, i ncl u di n g s ur vi val f oll o w- u p, will be perf or me d e ver y 3 m o nt hs ( ± 2 wee ks) 
( or e ver y 6 wee ks [ ± 1 wee k] if t he partici pa nt has i nitiate d a n d c o nti n ui n g 2 L  treat me nt) after t he 
1 2- wee k Safet y  Foll o w -u p V isit, u nless t he partici pa nt is re p orte d as l ost t o f oll o w- u p, dea d, or 
after st u d y ter mi nati o n.
I n v ol ve me nt of S peci al C o m mittee(s): Yes

A S afet y M o nit ori n g C o m mittee ( S M C) will assess safety of partici pa nts i n t he o pe n -la bel,
safety r u n-i n part

A n 
I D M C will 
u n derta ke peri o dic re vie w of safety data t hr ou g h o ut t he ra n d o mize d, 
d o u ble -bli n d part of t he st u d y . I n or der t o ma ke a rec o m me n dati o n re gar di n g t he e x pa nsi o n of 
t he st u d y int o P hase III, t he I D M C will re vie w efficac y data fr o m t he first 1 5 0 a nti bi otics- naive 
partici pa nts e nr olle d i n P hase II a n d safet y data f or all partici pa nts treate d i n t he st u d y u ntil t he 
data c ut off of t his a nal ys is. I n t he e ve nt t hat t he st u d y is e x pa n de d t o 5 0 0 partici pa nts as a P hase 
III (f urt her t o t he a nal ys is f or a da ptati o n decisi o n), t he I DM C will be re q ueste d t o re vie w 
partici pa nts’ efficac y an d safety d ata a n d c o ul d rec o m me n d t hat t he st u d y be st o p pe d earlier f or 
efficac y or f utilit y .

A n I nde pe n de nt Re vie w C o m mittee (I R C) will re vie w ra di o gra p hic i ma ge fi n di n gs f or t he 
deter mi nati o n of o bjecti ve res p o nse a n d date of dis ease pr o gressi o n f or t he P hase II part of t he 
st u d y, a n d ma y be re q ueste d t o d o t his als o f or t he P hase III part of t he st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or W it h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 / 2 1 3
1. 2
Sc he m a
Fi g ure 1
O ver all St u d y D esi g n Sc he m a
e C R F = el e ctr o ni c c a s e r e p ort f or m, C R = c o m pl et e r e s p o n s e, D = d a y, e C C A = e xtr a h e p ati c c h ol a n gi o c ar ci n o m a , 
G C = g all bl a d d er c a n c er , i C C A =i ntr a h e p ati c c h ol an gi o c ar ci n o m a, N = n u m b er of p arti ci p a nt s, q 3 w = e v er y 3 w e e k s, 
R =r a n d o mi z ati o n.
a 
“ O t h er s” i n cl u d e s p arti ci p a nt s wit h u nr e s e ct e d, l o c all y a d v a n c e d di s e a s e at di a g n o si s a n d p arti ci p a nt s wit h 
r e s e ct a bl e di s e a s e at di a g n o si s w h o h a v e u n d er g o n e pri or s ur gi c al r e s e cti o n wit h c ur ati v e i nt e nt.
1. 3
Sc he d ule of Acti vities
T he Sc he d ule of Acti vities , as descri be d i n Ta ble 1 a n d Ta ble 2,  is t he sa me f or b ot h parts of t he 
st u d y, i.e., f or partici pa nts i n t he o pe n -la bel, safet y r u n-i n part a n d t h ose i n t he ra n d o mize d, 
d o u ble -bli n d part , e xce pt w here i n dicate d. See Ta ble 3 a n d Ta ble 4 f or t he Sc he d ule of Acti vities 
wit h res pect t o sa m pli n g f or 
 p har mac o ki netics ( P K ), a n d 
 f or t he 
o pe n -la bel, safety r u n -i n part a n d t he ra n d o mize d, d o u ble-bli n d part, res pecti vel y .
N ote: a ll acti vities/ pr oce d ures s h o ul d be sc he d ule d fr o m Wee k 1, Da y  1 (W 1 D 1 ).
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
1 6 / 2 1 3
T a ble 1
Sc he d ule of Acti vities – D a y 1 t o D a y 1 6 8 ( Bi ntr af us p alf a / Pl ace b o Pl us C he m ot her a p y)
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
A d mi ni str ati v e Pr o c e d ur e s
Wr itt e n i nf or m e d 
c o n s e nt
X
I n cl u si o n/ e x cl u si o n 
crit eri a
X 
X
D a y 1, s p e cifi e d it e m s o nl y i n S e cti o n s  5. 1
a n d  5. 2
D e m o gr a p hi c d at a
X
M e di c al hi st or y
X
I n cl u d e: hi st or y of B T C wit h st a g e at 
di a g n o si s, e n vir o n m e nt al/ o c c u p ati o n al 
e x p o s ur e t o c h e mi c al s, b a s eli n e m e di c al 
c o n diti o n s
Pri or a nti c a n c er 
dr u g/r a di ot h er a p y/
pr o c e d ur e s
X
D o c u m e nt ati o n of 
c o n c o mit a nt 
m e di c ati o n s a n d 
pr o c e d ur e s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit
E nr oll m e nt/
ra n d o mi z ati o n
X 
X
E nr oll m e nt r e q uir e s pri or c o nfir m ati o n t h at 
p arti ci p a nt f ulfill s all i n cl u si o n crit eri a a n d n o 
e x cl u si o n crit eri a .
R a n d o mi z ati o n o n D a y 1 vi a I X R S . 
A d mi ni str ati o n of t h e fir st d o s e of st u d y 
i nt er v e nti o n s h o ul d b e i niti at e d wit hi n 3 d a y s 
aft er r a n d o mi z ati o n .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
1 7 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
D o c u m e nt ati o n of 
n o n - pr ot o c ol r el at e d 
h o s pit ali z ati o n s, 
e m er g e n c y r o o m vi sit s, 
a n d o ut p ati e nt h o s pit al 
vi sit s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
1 8 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
St u d y  I nt er v e nti o n A d mi ni str ati o n
D oc u me nt N o.
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
1 9 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
Pr e m e di c ati o n a n d 
bi ntr af u s p alf a /pl a c e b o 
a d mi ni str ati o n
X c
X c
X 
X 
X 
X 
X 
X
Bi ntr af u s p alf a / pl a c e b o: W 1 D 1 , Q 3 W .
cPr e m e di c ati o n wit h a n a nti hi st a mi n e a n d 
p ar a c et a m ol ( a c et a mi n o p h e n) a p pr o xi m at el y 
3 0 -6 0 mi n ut e s pri or t o e a c h d o s e i s 
m a n d at or y f or t h e fir st 2 i nf u si o n s o nl y ( e. g., 
2 5 -5 0 m g di p h e n h y dr a mi n e a n d 5 0 0 -6 5 0 m g 
p ar a c et a m ol I V or or al e q ui v al e nt) .
All pr e m e di c ati o n m u st b e r e p ort e d i n t h e 
e C R F .
If bi ntr af u s p alf a/ pl a c e b o c a n n ot b e 
a d mi ni st er e d o n D 1 ± 3 d a y s of a gi v e n c y cl e 
(f or s af et y, t ol er a bilit y or ot h er u n a v oi d a bl e 
r e a s o n s), t h e d o si n g c a n b e p o st p o n e d f or u p 
t o + 1 8 d a y s ( e x c e pt f or W1 D 1) , aft er whi c h 
t h e d o s e will b e c o n si d er e d o mitt e d. If 
bi ntr af u s p alf a/ pl a c e b o d o si n g s c h e d ul e i s 
s hift e d, ot h er a cti viti e s s c h e d ul e d o n D 1 w hi c h 
h a v e n ot b e e n d o n e b ef or e t h e d e ci si o n will 
b e s hift e d a c c or di n gl y. T h e s af et y a s s e s s m e nt 
m u st b e d o n e o n t h e d a y of d o s i n g a n d t h e 
bl o o d s a m pl e s f or f ull c h e mi str y a n d 
h e m at ol o g y m u st b e dr a w n a d a y b ef or e or o n 
t h e d a y pri or t o d o si n g. T h e n e xt c y cl e of 
bi ntr af u s p alf a/ pl a c e b o will g et b a c k t o t h e 
ori gi n al s c h e d ul e b ut s h o ul d b e a d mi ni st er e d 
at l e a st 1 5 d a y s ( = mi ni m al i n t er v al c al c ul at e d 
wit h Q 3 W  ± 3 d a y s wi n d o w) a p art fr o m t h e 
pr e vi o u s c y cl e. If t h e mi ni m al i nt er v al i s n ot 
m ai nt ai n e d, t h e n e xt c y cl e s h o ul d b e s ki p p e d. 
C o nt a ct M e di c al M o nit or f or a n y q u e sti o n s o n 
d o si n g s c h e d ul e. If f urt h er s c h e d ul e c h a n g e i s 
n e e d e d, a n a p pr o v al fr o m t h e M e di c al M o nit or 
i s r e q uir e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 0 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
Pr e m e di c ati o n/
h y dr ati o n a n d 
g e m cit a bi n e/ ci s pl ati n
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
X d
D 1 a n d D 8, Q 3 W  f or 8 c y cl e s.
d A d mi ni st er ci s pl ati n pr e m e di c ati o n, 
a nti - e m eti c dr u g s ( e x cl u di n g st er oi d s, s e e 
S e cti o n 6. 6. 1 ), a n d I V h y dr ati o n ( d uri n g 
ci s pl ati n i nf u si o n t o pr e v e nt n e p hr ot o xi cit y) a s 
p er st a n d ar d pr a cti c e.
All pr e m e di c ati o n, i n cl u di n g h y dr ati o n ( dr u g s 
a n d fl ui d s) m u st b e r e p ort e d i n t h e e C R F .
If c h e m ot h er a p y c a n n ot b e a d mi ni st er e d o n D 1 or D 8 of a gi v e n c y cl e (f or 
s af et y , t ol er a bilit y or ot h er u n a v oi d a bl e r e a s o n s), it m a y b e a d mi ni st er e d o n 
D 1 5 of t h at c y cl e.
I n a d diti o n, an y mi s s e d d o s e( s) of c h e m ot h er a p y m a y b e m a d e u p at t h e e n d 
of t h e s c h e d ul e d 8 c y cl e s ( u p t o 1 6 a d mi ni str ati o n s of g e m cit a bi n e a n d 
ci s pl ati n c o m bi n ati o n) pr o vi d e d t h e p arti ci p a nt d o e s n ot m e et a n y of t h e 
crit eri a f or di s c o nti n u ati o n fr o m st u d y i nt er v e nti o n or st u d y p arti ci p ati o n 
(S e cti o n 7 ). T h e a d mi ni str at i o n of t h e mi s s e d d o s e o n D a y 1 5 or at t h e e n d of 
8 c y cl e s i s I n v e sti g at or’ s cli ni c al d e ci si o n. S e e  T a bl e 2 f or f urt h er i nf or m ati o n.
If a mi s s e d d o s e of c h e m ot h er a p y i s a d mi ni st er e d at a n a d diti o n al vi sit, t h e 
s af et y a s s e s s m e nt s d et ail e d i n T a bl e 1 f or W 1 D 8 s h o ul d b e c o m pl et e d , i. e., 
d o c u m e nt ati o n of c o n c o mit a nt m e di c ati o n s
a n d pr o c e d ur e s ; d o c u m e nt ati o n 
of 
n o n -pr ot o c ol 
r el at e d h o s pit ali z ati o n s, 
e m er g e n c y 
r o o m vi sit s, a n d 
o ut p ati e nt h o s pit al vi sit s ; d o c u m e nt ati o n of A E s, p h y si c al e x a mi n ati o n, vit al 
si g n s, S p O 2 , a n d c or e c h e mi str y a n d h e m at ol o g y.
P h y s i c al A s s e s s m e nt
D o c u m e nt ati o n of A E s
a n d S A E s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit
P h y si c al e x a mi n ati o n
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit. C o m pl et e P E at S cr e e ni n g a n d 
bri ef P E at all ot h er vi sit s .
Vit al si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit , in cl u di n g h ei g ht ( at S cr e e ni n g 
o nl y), w ei g ht, t e m p er at ur e, p ul s e r at e, 
r e s pir at or y r at e, a n d bl o o d pr e s s ur e.
D oc u me nt N o. 
O bject N o.
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 1 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
E C O G P S
X 
X 
X 
X 
X 
X 
X 
X 
X
E C O G P S of 0 or 1 r e q uir e d at W 1 D 1 pri or t o 
d o si n g
S ki n a s s e s s m e nt
X 
X
X
X
X
Q 6 W
1 2 -l e a d E C G
X
S p O 2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E v er y vi sit, u si n g p ul s e o xi m et er
L a b or at or y  As s e s s m e nt s
F ull c h e mi str y a n d 
h e m at ol o g y
X 
X 
X 
X 
X 
X 
X 
X 
X
S e e A p p e n di x 6 ( T a bl e - A) f or f ull c h e mi str y 
a n d h e m at ol o g y / c o a g ul ati o n p ar a m et er s. 
Bl o o d s a m pl e s m u st b e dr a w n a d a y b ef or e or 
o n t h e d a y pri or t o d o s i n g. Re s ult s of 
a st eri s k e d p ar a m et er s (*) m u st b e r e vi e w e d 
b y I n v e sti g at or b ef or e d o si n g. R e vi e w r e s ult s 
of ot h er p ar a m et er s wit hi n 5 w or ki n g d a y s of 
vi sit .
C or e c h e mi str y a n d 
h e m at ol o g y
X 
X 
X 
X 
X 
X 
X 
X
S e e  A p p e n di x 6 ( T a bl e - B) f or cor e c h e mi str y 
a n d h e m at ol o g y p ar a m et er s t o b e ev al u at e d 
at vi sit s w h er e f ull p a n el i s n ot r e q uir e d . Bl o o d 
s a m pl e s m u st b e dr a w n a d a y b ef or e or o n 
t h e d a y pri or t o d o s i n g. Re s ult s of a st eri s k e d 
p ar a m et er s (*) m u st b e r e vi e w e d b y 
I n v e sti g at or b ef or e d o si n g. R e vi e w r e s ult s of 
ot h er p ar a m et er s wit hi n 5 w or ki n g d a y s of 
vi sit .
A n e mi a
A s cli ni c all y i n di c at e d
S e e  A p p e n di x 6 ( T a bl e - C) f or p ar a m et er s t o 
b e a s s e s s e d
C A 1 9 - 9
X
X
X
X
Q 6 W . S e e  A p p e n di x 6 ( T a bl e - F)
D oc u me nt N o. 
O bject N o. 0
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 2 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
Uri n al y si s
X 
X
X
X
X
Q 6 W . F ull uri n al y si s ( di p sti c k pl u s 
mi cr o s c o p y ) at S cr e e ni n g a n d Eo T V i sit s; 
b a si c uri n al y si s ( o nl y di p sti c k i s r e q uir e d b ut 
n ot mi cr o s c o p y ) at ot h er i n di c at e d vi sit s pri or 
t o d o si n g . R e s ult s of b a si c uri n al y si s m u st b e 
r e vi e w e d b ef or e d o si n g. If b a si c uri n al y si s i s 
a b n or m al, a f ull uri n al y si s pl u s c ult ur e s h o ul d 
b e p erf or m e d. S e e  A p p e n di x 6 ( T a bl e - D) f or 
p ar a m et er s t o b e a s s e s s e d .
Pr e g n a n c y t e st
X 
X 
X 
X 
X 
X 
X 
X 
X
Q 3 W . S er u m or hi g hl y s e n siti v e uri n e h C G
pr e g n a n c y t e st (f or w o m e n of c hil d b e ari n g 
p ot e nti al ). N ot e: L o c al uri n e t e sti n g i s
st a n d ar d f or t h e pr ot o c ol u nl e s s s er u m t e sti n g 
i s r e q uir e d b y l o c al r e g ul ati o n or I R B/I E C.
A C T H, A N A, A N C A, 
a n d R F
A s cli ni c all y i n di c at e d
S e e  A p p e n di x 6 ( T a bl e - F)
H e p atiti s
X
X
X
X
H B V a n d H C V s er ol o g y at b a s eli n e.
If o n e or m or e of t h e f oll o wi n g , H B -s urf a c e 
a nti g e n, H B -c or e a nti b o d y / or H B-s urf a c e
a nti b o d y ar e p o siti v e at b a s eli n e , e x a mi n e 
H B V D N A at s cr e e ni n g a n d Q 6 W d uri n g t h e 
st u d y.
If b a s eli n e H C V a nti b o d y i s p o siti v e, e x a mi n e 
H C V R N A . If H C V R N A i s p o siti v e, m o nit or 
H C V R N A Q 6 W .
S e e  A p p e n di x 6 ( T a bl e - E). R e vi e w r e s ult s 
wit hi n 5 w or ki n g d a y s of vi sit .
Fr e e T 4 a n d T S H
X
X
X
X
Q 6 W . S e e  A p p e n di x 6 ( T a bl e - F). R e vi e w 
re s ult s wit hi n 5 w or ki n g d a y s of vi sit .
K L -6, S P -A, a n d S P - D 
X
X 
X 
X 
X 
X 
X 
X
J a p a n e s e sit e s o nl y . Q 3 W. S e e  A p p e n di x 6
(T a bl e - F). R e vi e w r e s ult s wit hi n 5 w or ki n g
d a y s of vi sit .
D oc u me nt N o.
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 3 / 2 1 3
A cti viti e s
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
N ot e s
W e e k
a If a p arti ci p a nt di s c o nti n u e s tr e at m e nt, 
s e e  T a bl e 2 f or n e xt st e p s
D a y -2 8 
u p t o 
D a y 1
1 
2 
4 
5 
7 
8
1 0 
1 1 
1 3 
1 4 
1 6 
1 7 
1 9 
2 0 
2 2 
2 3
D a y
1 
8
2 2 2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2
1 0 6 1 1 3 1 2 7 1 3 4 1 4 8 1 5 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 4 / 2 1 3
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 5 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
2 6 / 2 1 3
A C T H = a dr e n o c orti c otr o pi c h or m o n e , 
, A E s = a d v er s e e v e nt s, 
, 
B T C = bili ar y tr a ct c a n c er, C A 1 9 -9 = c ar b o h y dr at e a nti g e n 1 9 - 9, C T =c o m p ut e d t o m o gr a p h y , D = d a y, D N A = d e o x yri b o n u cl ei c a ci d, E C G = el e ctr o c ar di o gr a m, E C O G 
P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s, e C R F = el e ctr o ni c C a s e R e p ort F or m, 
 
 E o T = E n d of T r e atm e nt, 
, E U = E ur o p e a n U ni o n , 
H B = h e p atiti s B, H B V = h e p atiti s B vir u s, h C G = h u m a n c h ori o ni c g o n a d otr o pi n, H C V = h e p atiti s C vir u s, I L =It e m Li br ar y, I R B/I E C =In stit uti o n al R e vi e w 
B o ar d/ In d e p e n d e nt E t hi c s C o m mitt e e, I V =i ntr a v e n o u s, I X R S =i nt er a cti v e r e s p o n s e s y st e m, K L -6 = Kr e b s v o n d e n L u n g e n- 6 , M RI = m a g n eti c r e s o n a n c e i m a gi n g, 
P D = pr o gr e s si v e di s e a s e, P E = p h y si c al e x a mi n ati o n, 
, 
, 
P K = p h ar m a c o ki n eti c s, 
, Q 3 W= e v er y 3 w e e k s, Q 6 W = e v er y 6 w e e k s, Q 1 2 W = e v er y 1 2 w e e k s, 
 
 
 R F = r h e u m at oi d f a ct or, R N A =ri b o n u cl ei c a ci d, S A E s = s eri o u s a d v er s e e v e nt s, 
S P - A/ D= s urf a ct a nt pr ot ei n A / D, S p O 2 = bl o o d o x y g e n s at ur ati o n , T 4 =t h yr o xi n e, T S H =t h yr oi d-sti m ul ati n g h or m o n e , W= w e e k , U S = U nit e d St at e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 7 / 2 1 3
T a ble 2
Sc he d ule of Acti vities – D a y 1 6 9 O n w ar ds ( Bi ntr af us p alf a / Pl ace b o M o n ot her a p y) a n d Acti vities F oll o wi n g 
St u d y I nter ve nti o n Disc o nti n u ati o n
A cti viti e s
Tr e at m e nt P h a s e
( ± 3 d a y s) a
E n d -of -
Tr e at m e nt
Vi sit
S af et y F oll o w -u p 
Vi sit
L o n g -
t er m 
F oll o w -
u p
N ot e s
W e e k
U ntil
E o T
O n D a y of 
or Wit hi n 
7 D a y s of 
D e ci si o n b
2 8 ( ± 7 ) 
D a y s  
Aft er 
L a st 
Tr e at m e
nt
1 2 ( ± 2) 
W e e k s 
Aft er 
L a st 
Tr e at m e
nt
E v er y  
3 M o nt h s
( ± 2 W e e
k s)
a If tr e at m e nt c o nti n u e s b e yo n d W e e k 4 3/ D a y  2 9 5, 
c o nti n u e a s s e s s m e nt s u ntil E o T, a s i n di c at e d i n 
t h e t a bl e
b D e ci si o n t o st o p st u d y  i nt er v e nti o n
2 5
2 8
3 1
3 4
3 7
4 0
4 3 a
D a y
1 6 9
1 9 0
2 1 1
2 3 2
2 5 3
2 7 4 2 9 5 a
A d mi ni str ati v e Pr o c e d ur e s – D o c u m e nt ati o n of:
S u b s e q u e nt 
a nti c a n c er 
t h er a p y
X 
X 
X
C o n c o mit a nt 
m e di c ati o n s a n d 
pr o c e d ur e s
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
N o n -
pr ot o c ol -r el at e d 
h o s pit ali z ati o n, 
e m er g e n c y r o o m 
vi sit s, o ut p ati e nt 
h o s pit al vi sit s
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
St u d y  I nt er v e nti o n A d mi ni str ati o n
Pr e m e di c ati o n 
a n d bi ntr af u s p 
alf a /
pl a c e b o 
a d mi ni str ati o n
X 
X 
X 
X 
X 
X 
X
Q 3 W
Bi ntr af u s p alf a/ pl a c e b o: W 1 D 1 , Q 3 W
Pr e m e di c ati o n i s m a n d at or y f or fir st 2 i nf u si o n s o nl y 
( s e e T a bl e 1)
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 8 / 2 1 3
A cti viti e s
Tr e at m e nt P h a s e
( ± 3 d a y s) a
E n d -of -
Tr e at m e nt
Vi sit
S af et y F oll o w -u p 
Vi sit
L o n g -
t er m 
F oll o w -
u p
N ot e s
W e e k
U ntil
E o T
O n D a y of 
or Wit hi n 
7 D a y s of 
D e ci si o n b
2 8 ( ± 7 ) 
D a y s  
Aft er 
L a st 
Tr e at m e
nt
1 2 ( ± 2) 
W e e k s 
Aft er 
L a st 
Tr e at m e
nt
E v er y  
3 M o nt h s
( ± 2 W e e
k s)
a If tr e at m e nt c o nti n u e s b e yo n d W e e k 4 3/ D a y  2 9 5, 
c o nti n u e a s s e s s m e nt s u ntil E o T, a s i n di c at e d i n 
t h e t a bl e
b D e ci si o n t o st o p st u d y  i nt er v e nti o n
2 5
2 8
3 1
3 4
3 7
4 0
4 3 a
D a y
1 6 9
1 9 0
2 1 1
2 3 2
2 5 3
2 7 4 2 9 5 a
Pr e m e di c ati o n
/ h y dr ati o n, 
a n d 
g e m cit a bi n e/
ci s pl ati n
If c h e m ot h er a p y c a n n ot b e a d mi ni st er e d o n D 1 or D 8 of a gi v e n c y cl e (f or s af et y , 
t ol er a bilit y or ot h er u n a v oi d a bl e r e a s o n s), it m a y b e a d mi ni st er e d o n D 1 5 of t h at c y cl e. 
I n a d diti o n, a n y mi s s e d d o s e( s) of c h e m ot h er a p y m a y b e m a d e u p at t h e e n d of t h e 
s c h e d ul e d 8 c y cl e s ( u p t o 1 6 a d mi ni str ati o n s of g e m cit a bi n e a n d ci s pl ati n c o m bi n ati o n) 
pr o vi d e d t h e p arti ci p a nt d o e s n ot m e et a n y of t h e crit eri a f or di s c o nti n u ati o n fr o m st u d y 
i nt er v e nti o n or st u d y p arti ci p ati o n ( S e cti o n 7) . T h e a d mi ni str ati o n of t h e mi s s e d d o s e o n 
D a y 1 5 or at t h e e n d of 8 c y cl e s i s I n v e sti g at or’ s cli ni c al d e ci si o n. R e s u mi n g 
c h e m ot h er a p y aft er a n i nt err u pti o n of m or e t h a n 1 2 w e e k s s h o ul d b e di s c u s s e d wit h t h e 
M e di c al M o nit or ( s e e S e cti o n 6. 6. 3 )
Mi s s e d d o s e s of c h e m ot h er a p y s h o ul d b e m a d e u p a s f oll o w s:

A d mi ni st er D a y 1 of a n a n y mi s s e d d o s e of c h e m ot h er a p y o n D 1 W 1  of t h e n e xt 
a p pr o pri at e s c h e d ul e d d o si n g wit h bi ntr af u s p alf a / pl a c e b o, i. e., We e k 2 5, 2 8, 3 1, 3 4, 
3 7, 4 0, 4 3, et c

T o e n a bl e a d mi ni str ati o n of c h e m ot h er a p y o n D a y 8, s c h e d ul e a n a d diti o n al vi si t 
7 d a y s l at er, i . e., at W e e k s 2 6, 2 9, 3 2, 3 5, 3 8, 4 1, a n d/ or 4 4, et c, a s a p pr o pri at e
If a mi s s e d d o s e of c h e m ot h er a p y i s a d mi ni st er e d at a n a d diti o n al vi sit, t h e s af et y 
a s s e s s m e nt s d et ail e d i n T a bl e 1 f or W 1 D 8 s h o ul d b e c o m pl et e d, i. e., d o c u m e nt ati o n of 
c o n c o mit a nt m e di c ati o n s 
a n d pr o c e d ur e s, d o c u m e nt ati o n of n o n -pr ot o c ol r el at e d 
h o s pit ali z ati o n s, e m er g e n c y r o o m vi sit s, a n d o ut p ati e nt h o s pit al vi sit s, d o c u m e nt ati o n of 
A E s, p h y si c al e x a mi n ati o n, vit al si g n s, S p O 2 , a n d c or e c h e mi str y a n d h e m at ol o g y
D 1 a n d D 8, Q 3 W  f or 8 c y cl e s.
A d mi ni st er ci s pl ati n pr e m e di c ati o n, a nti -e m eti c dr u g s 
( e x cl u di n g st er oi d s, s e e S e cti o n 6. 6. 1 ), a n d I V 
h y dr ati o n ( d uri n g ci s pl ati n i nf u si o n t o pr e v e nt 
n e p hr ot o xi cit y) a s p er st a n d ar d pr a cti c e .
All pr e m e di c ati o n, i n cl u di n g h y dr ati o n ( dr u g s a n d 
fl ui d s) m u st b e r e p ort e d i n t h e e C R F.
P h y s i c al A s s e s s m e nt s
D o c u m e nt ati o n 
of A E s a n d 
S A E s
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
X c
X
At e v er y vi sit .
c A c c or di n g t o t h e d efi niti o n of A E re p orti n g p eri o d a n d 
foll o w - u p of A E s/ S A E s.
C o n d u ct 1 2 -w e e k S af et y F oll o w -u p V i sit a n d L o n g-
t er m F oll o w-u p Vi sit vi a t el e p h o n e c all s or p ati e nt 
c h art r e vi e w s u nl e s s t h er e i s m e di c al n e c e s sit y f or a 
cli ni c al vi sit .
P h y si c al 
e x a mi n ati o n
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
Bri ef p h y si c al e x a mi n ati o n
Vit al si g n s
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
I n cl u di n g w ei g ht, t e m p er at ur e, p ul s e r at e, r e s pir at or y 
r at e, a n d bl o o d pr e s s ur e
E C O G P S
X 
X 
X 
X
Q 6 W
X 
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
2 9 / 2 1 3
A cti viti e s
Tr e at m e nt P h a s e
( ± 3 d a y s) a
E n d -of -
Tr e at m e nt
Vi sit
S af et y F oll o w -u p 
Vi sit
L o n g -
t er m 
F oll o w -
u p
N ot e s
W e e k
U ntil
E o T
O n D a y of 
or Wit hi n 
7 D a y s of 
D e ci si o n b
2 8 ( ± 7 ) 
D a y s  
Aft er 
L a st 
Tr e at m e
nt
1 2 ( ± 2) 
W e e k s 
Aft er 
L a st 
Tr e at m e
nt
E v er y  
3 M o nt h s
( ± 2 W e e
k s)
a If tr e at m e nt c o nti n u e s b e yo n d W e e k 4 3/ D a y  2 9 5, 
c o nti n u e a s s e s s m e nt s u ntil E o T, a s i n di c at e d i n 
t h e t a bl e
b D e ci si o n t o st o p st u d y  i nt er v e nti o n
2 5
2 8
3 1
3 4
3 7
4 0
4 3 a
D a y
1 6 9
1 9 0
2 1 1
2 3 2
2 5 3
2 7 4 2 9 5 a
S ki n 
a s s e s s m e nt
X 
X 
X 
X
Q 6 W
X 
X 
X
C o n d u ct 1 2 -w e e k S af et y F oll o w -u p V i sit vi a t el e p h o n e 
c all s or p ati e nt c h art r e vi e w s u nl e s s t h er e i s m e di c al 
n e c e s sit y f or a cli ni c al vi sit
1 2 -l e a d E C G
X
S p O 2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
U si n g p ul s e o xi m et er
L a b or at or y  As s e s s m e nt s
F ull c h e mi str y 
a n d h e m at ol o g y
X 
X 
X 
X 
X 
X 
X
Q 3 W
X 
X
S e e  A p p e n di x 6 ( T a bl e - A) f or full c h e mi str y a n d 
h e m at ol o g y / c o a g ul ati o n. Bl o o d s a m pl e s m u st b e 
dr a w n a d a y b ef or e or o n t h e d a y pri or t o d o s i n g. 
R e s ult s of a st eri s k e d p ar a m et er s (*) m u st b e 
r e vi e w e d b y I n v e sti g at or bef or e d o si n g. R e vi e w 
r e s ult s of ot h er p ar a m et er s wit hi n 5 w or ki n g d a y s of 
vi sit .
A n e mi a 
A s cli ni c all y i n di c at e d
S e e  A p p e n di x 6 ( T a bl e - C) f or p ar a m et er s t o b e 
a s s e s s e d .
C A 1 9 - 9
X 
X 
X 
X
Q 6 W
X
Q 6 W . S e e  A p p e n di x 6 ( T a bl e - F)
Uri n al y si s
X 
X 
X 
X
Q 6 W
X 
X
F ull uri n al y si s ( di p sti c k pl u s mi cr o s c o p y) at E o T vi sit . 
B a si c uri n al y si s ( o nl y di p sti c k i s r e q uir e d b ut n ot 
mi cr o s c o p y ) at e a c h vi sit i n di c at e d pri or t o d o si n g . 
R e vi e w r e s ult s of b a si c uri n al y si s b ef or e d o si n g. If 
b a si c uri n al y si s i s a b n or m al, p erf or m a f ull uri n al y si s 
pl u s c ult ur e . S e e  A p p e n di x 6 ( T a bl e - D) f or 
p ar a m et er s t o b e a s s e s s e d .
Pr e g n a n c y t e st
X 
X 
X 
X 
X 
X 
X
Q 3 W
X
S er u m or hi g hl y s e n siti v e uri n e h C G pr e g n a n c y t e st 
(f or w o m e n of c hil d b e ari n g p ot e nti al). N ot e: L o c al 
uri n e t e sti n g i s st a n d ar d f or t h e pr ot o c ol u nl e s s s er u m
t e sti n g i s r e q uir e d b y l o c al r e g ul ati o n or t h e I R B/I E C.
A C T H, A N A, 
A N C A, a n d R F
A s cli ni c all y i n di c at e d
S e e  A p p e n di x 6 ( T a bl e - F)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 0 / 2 1 3
A cti viti e s
Tr e at m e nt P h a s e
( ± 3 d a y s) a
E n d -of -
Tr e at m e nt
Vi sit
S af et y F oll o w -u p 
Vi sit
L o n g -
t er m 
F oll o w -
u p
N ot e s
W e e k
U ntil
E o T
O n D a y of 
or Wit hi n 
7 D a y s of 
D e ci si o n b
2 8 ( ± 7 ) 
D a y s  
Aft er 
L a st 
Tr e at m e
nt
1 2 ( ± 2) 
W e e k s 
Aft er 
L a st 
Tr e at m e
nt
E v er y  
3 M o nt h s
( ± 2 W e e
k s)
a If tr e at m e nt c o nti n u e s b e yo n d W e e k 4 3/ D a y  2 9 5, 
c o nti n u e a s s e s s m e nt s u ntil E o T, a s i n di c at e d i n 
t h e t a bl e
b D e ci si o n t o st o p st u d y  i nt er v e nti o n
2 5
2 8
3 1
3 4
3 7
4 0
4 3 a
D a y
1 6 9
1 9 0
2 1 1
2 3 2
2 5 3
2 7 4 2 9 5 a
H e p atiti s
X 
X 
X 
X
Q 6 W
If o n e or m or e of t h e f oll o wi n g, H B -s urf a c e a nti g e n, 
H B -c or e a nti b o d y , or H B-s urf a c e a nti b o d y ar e p o siti v e
at b a s eli n e , e x a mi n e H B V D N A at s cr e e ni n g a n d 
Q 6 W d uri n g t h e st u d y . 
If H C V a nti b o d y a n d H C V R N A w er e p o siti v e at 
b a s eli n e , e x a mi n e H C V R N A Q 6 W . S e e A p p e n di x 6
(T a bl e - E). R e vi e w re s ult s wit hi n 5 w or ki n g d a y s of 
vi sit .
Fr e e T 4 a n d 
T S H
X 
X 
X 
X
Q 6 W
X
S e e  A p p e n di x 6 ( T a bl e - F). R e vi e w r e s ult s wit hi n 5 
w or ki n g d a y s of vi sit .
K L -6, S P -A, a n d 
S P - D
X 
X 
X 
X
Q 6 W
J a p a n e s e sit e s o nl y . S e e  A p p e n di x 6 ( T a bl e - F). 
R e vi e w r e s ult s wit hi n 5 w or ki n g d a y s of vi sit.
D oc u me nt N o.
O bject N o.
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 1 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 2 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 3 / 2 1 3
2 L = s e c o n d -li n e, 3 L =t hir d-li n e, A C T H = a dr e n o c orti c otr o pi c h or m o n e, 
, A E s = a d v er s e e v e nt s, A N A = a nti n u cl e ar a nti b o d y, 
A N C A = a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s, C A 1 9 -9 = c ar b o h y dr at e a nti g e n 1 9 -9, C R = c o m pl et e r e s p o n s e, C T = c o m p ut e d t o m o gr a p h y, D = d a y, 
D N A = d e o x yri b o n u cl ei c a ci d, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s, e C R F = el e ctr o ni c C a s e R e p ort F or m, 
, E o T =E n d of T r e at m e nt, 
 E U = E ur o p e a n U ni o n , H B = h e p atiti s B, H B V = h e p atiti s B vir u s, h C G = h u m a n c h ori o ni c g o n a d otr o pi n, H C V = h e p atiti s C 
vir u s, I L =It e m Li brar y, I R B/I E C =In stit uti o n al R e vi e w B o ar d/ In d e p e n d e nt E t hi c s C o m mitt e e, I V =i ntr a v e n o u s, K L -6 = Kr e b s v o n d e n L u n g e n -6, M RI = m a g n eti c 
r e s o n a n c e i m a gi n g, P D = pr o gr e s si v e di s e a s e, 
 P K = p h ar m a c o ki n eti c s, 
 P R = p arti al 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 4 / 2 1 3
r e s p o n s e, Q 3 W = e v er y 3 w e e k s, Q 6 W = e v er y 6 w e e k s, Q 1 2 W = e v er y 1 2 w e e k s,
, 
 
 
 R F =r h e u m at oi d f a ct or, R N A =ri b o n u cl ei c a ci d, S A E s = s eri o u s a d v er s e e v e nt s, S D = st a bl e di s e a s e, S P -A/ D = s urf a ct a nt pr ot ei n -A/ D, S p O 2 = bl o o d o x y g e n 
s at ur ati o n, T 4 =t h yr o xi n e, T S H =t h yr oi d - sti m ul ati n g h or m o n e, W= w e e k , U S = U nit e d St at e s
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 5 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 6 / 2 1 3
S cr e e ni n g/
B a s eli n e
Tr e at m e nt P h a s e ( ± 3 D a y s) a
E o T Vi sit
S af et y  
F oll o w -u p 
Vi sit
N ot e s
a If tr e at m e nt c o nti n u e s b e yo n d 
W e e k
2 5/ D a y 1 6 9, c o nti n u e 
a s s e s s m e nt s u ntil E o T, a s i n di c at e d 
i n t h e t a bl e.
b D e ci si o n t o st o p st u d y  i nt er v e nti o n
D a y -2 8 u p 
t o D a y 1
W 1  
W 2  
W 3  
W 4  
W 5  
W 7
W 1 3  
W 1 9  
W 2 5
a
U ntil 
E o T
O n D a y of or 
wit hi n 7 D a y s 
of D e ci si o n b
2 8 ( ± 7 ) D a ys 
Aft er L a st 
Tr e at m e nt
D 1  
D 2  
D 8
D 1 5  
D 2 2  
D 2 9  
D 4 3  
D 8 5
D 1 2 7
D 1 6 9 a
P K s a m pli n g ( pr e -i nf u si o n/ p o st-i nf u si o n)
X/ X e
X f
X 
X
X/ -
X/ X
X/ -
X/ - 
Xg /-
X/ -
Q 1 2 W  
fr o m 
W 2 5
X
X
D uri n g tr e at m e nt, c oll e ct P K s a m pl e s 
b ef or e ( pr e -i nf u si o n: a s cl o s e t o t h e st art 
of i nf u si o n a s p o s si bl e) a n d i m m e di at el y 
aft er c o m pl eti o n of i nf u si o n 
( p o st-i nf u si o n: a s cl o s e t o c o m pl eti o n a s 
p o s si bl e a n d n o l at er t h a n 3 0 mi n ut e s 
p o st -e n d of i nf u si o n) .
Pr e d o s e s a m pl e s s h o ul d b e dr a w n e v e n 
if d o si n g i s ulti m at el y d ef err e d at t h e 
vi sit. 
If p arti ci p a nt mi s s e d a vi sit alt o g et h er, 
n o P K s a m pl e w ill b e c oll e ct e d.
R e c or d e x a ct ti m e of e a c h dr a w. A 
pr ot o c ol d e vi ati o n will b e d efi n e d if a 
s a m pl e i s n ot dr a w n, or ti m e of dr a w i s 
n ot r e c or d e d .
e O n W 1 D 1 o nl y, c oll e ct a d diti o n al P K 
s a m pl e 4 h o ur s aft er st art of bi ntr af u s p 
alf a / pl a c e b o i nf u si o n.
fO n W 1 D 2 o nl y , c oll e ct a P K s a m pl e 
2 4 h o ur s aft er st art of D 1 bi ntr af u s p 
alf a / pl a c e b o i nf u si o n.
g C oll e ct P K s a m pl e s pr e -i nf u si o n W2 5, 
t h e n Q 1 2W.
D oc u me nt N o. 
O bject N o.
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 7 / 2 1 3
, D = d a y, E o T = En d of T r e at m e nt, P K = p h ar m a c o ki n eti c s, P D = pr o gr e s si v e di s e a s e, Q 1 2 W = e v er y 1 2 w e e k s , 
, 
W = w e e k.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 8 / 2 1 3
T a ble 4
Sc he d ule of Acti vities f or 
, P K, a n d 
 S a m pli n g: R a n d o mize d, D o u ble-bli n d P art
P K s a m pli n g ( pr e -i nf u si o n/ p o st-i nf u si o n)
X/ X
X/ -
X/ X
X/ -
X/ - 
Xe /-
X/ -
Q 1 2 W  
fr o m W 2 5
X
X
D uri n g tr e at m e nt, c oll e ct P K s a m pl e s b ef or e 
( pr e-i nf u si o n: a s cl o s e t o t h e st art of i nf u si o n 
a s p o s si bl e) a n d i m m e di at el y aft er c o m pl eti o n 
of i nf u si o n ( p o st -i nf u si o n: a s cl o s e t o 
c o m pl eti o n a s p o s si bl e a n d n o l at er t h a n 
3 0 mi n ut e s p o st -e n d of i nf u si o n) .
Pr e d o s e s a m pl e s s h o ul d b e dr a w n e v e n if 
d o si n g i s ulti m at el y d ef err e d at t h e vi sit. 
R e c or d e x a ct ti m e of e a c h dr a w. If p arti ci p a nt 
mi s s e d a vi sit alt o g et h er, n o P K s a m pl e will 
b e c oll e ct e d.
A pr ot o c ol d e vi ati o n will b e d efi n e d if a 
s a m pl e i s n ot dr a w n or ti m e of dr a w i s n ot 
r e c or d e d.
e C oll e ct P K s a m pl e s pr e -i nf u si o n W2 5, t h e n 
Q 1 2 W .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


B i ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n W it h or W it h o ut Bi ntr af us p alf a
M S 2 0 0 6 4 7 _ 0 0 5 5
3 9 / 2 1 3
, D = d a y, E o T = En d of T r e at m e nt, P K = p h ar m a c o ki n eti c s, Q 1 2 W= e v er y 1 2 w e e k s, 
, W= w e e k.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 0 / 2 1 3
2
I ntr o d ucti o n
Bi ntraf us p alfa (M 7 8 2 4 , M S B 0 0 1 1 3 5 9 C) 
is a first-i n-class, bif u ncti o nal f usi o n pr otei n t hat
c o m bi nes a n a nti -pr o gra m me d deat h -li ga n d 1 (a nti-P D -L 1 ) a nti b o d y a n d t he s ol u ble e xtracell ular 
d o mai n of t he h u ma n tra nsf or mi n g gr o wt h fact or beta (T G F β) rece pt or as a T G F β ne utralizi n g 
“tra p”, i nt o a si n gle m olec ule . Bi ntraf us p alfa is bei n g de vel o pe d f or t he treat me nt of patie nts wit h 
biliar y  tract ca ncer ( B T C), i ncl u di n g i ntra he patic a n d e xtra he patic c h ola n gi ocarci n o ma ( C C A), 
gall bla d der ca ncer ( G C), a n d a m p ullar y ca ncer. B i ntraf us p alfa is t he rec o m me n de d i nter nati o nal 
n o n pr o prietar y  na me f or M 7 8 2 4.
T he c urre nt st u d y will e val uate w het her bi ntraf us p alfa i n c o m bi nati o n wit h t he c urre nt sta n dar d 
of care ( S o C), ge mcita bi ne pl us cis plati n, i m pr o ves o verall s ur vi val ( O S) i n a d va nce d B T C 
c o mpare d wit h S o C al o ne.
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y, a n d safet y of bi ntraf us p alfa is 
i n t he I nvesti gat or’s Br oc h ure (I B).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 1 / 2 1 3
2. 2
B ac k gr o u n d
Biliar y  tract ca ncer is a c ollecti ve ter m use d t o descri be a heter o ge ne o us gr o u p of t u m ors t hat 
i ncl u des i ntra he patic a n d e xtra he patic C C A a n d G C, a n d us uall y i ncl u des a m p ulla of Vater’s 
ca ncer de pe n di n g o n t he g ui deli nes or st u d y desi g n (Valle 2 0 1 6,  Valle 2 0 1 0,  Mi y aza ki 2 0 1 5) .
M ore t ha n 9 0 % of B T Cs are a de n ocarci n o mas
(Hezel 2 0 0 8 ). M ost patie nts ha ve a d va nce d disease 
at prese ntati o n a n d rela pse des pite s ur ger y. B T C patie nts ha ve a p o or pr o g n osis, wit h a n esti mate d 
5- ye ar O S of a b o ut 1 7. 5 % (Le pa ge 2 0 1 5 ). T he rec urre nce rate is a b o ut 6 7 % at 2 4 m o nt hs a m o n g 
patie nts w h o u n der g o c urati ve resecti o n (Jar na gi n 2 0 0 3 ). U nresecta ble B T C is treate d wit h 
c he m ot hera p y, b ut t he me dia n s ur vi val ti me is < 1 ye ar (Valle 2 0 1 0 ).
I n t he last fe w ye ars, t he cli nical de vel o p me nt of i m m u ne c hec k p oi nt i n hi bit ors re prese nts t he mai n 
ste p f or war d i n t he treat me nt of vari o us ca ncers. B i ntraf us p alfa is a first-i n-class bif u ncti o nal 
f usi o n pr otei n desi g ne d t o tar get P D -L 1 a n d T G F β, 2 mec ha nis ms of i m m u n os u p pressi o n i n t he 
t u m or micr oe n vir o n me nt.
B i ntraf us p alfa has s h o w n pr o misi n g cli nical efficac y si g nal i n a c o h ort of Asia n partici pa nts 
w h ose B T C ha d pr o gresse d after plati n u m -base d 1 L  treat me nt ( St u d y MS 2 0 0 6 4 7 _ 0 0 0 8). T hirt y  
Asia n partici pa nts wit h a d va nce d/ metastatic B T C w h o ha d pr o gresse d after recei vi n g plati n u m -
base d 1 L  thera p y were treate d wit h bi ntraf us p alfa 1 2 0 0 m g  ever y  2 wee ks. As of 2 3 J ul y 2 0 1 8, 
3 0 partici pa nts wit h pretreate d B T C ha d recei ve d bi ntraf us p alfa f or a me dia n d urati o n of 
8. 9 wee ks (ra n ge: 2. 0- 7 5. 6 wee ks), wit h 4 partici pa nts re mai ni n g o n treat me nt. Si x partici pa nts 
ha d a c o nfir me d o bjecti ve res p o nse b y I n de pe n de nt Re vie w C o m mittee (I R C) ( o bjecti ve res p o nse 
rate [ O R R]: 2 0. 0 %). Per a nat o mical l ocati o n, t he O R R was 0 % ( 0/ 7) f or e xtra he patic a n d 3 0 % 
( 3/ 1 0) f or i ntra he patic C C A, 2 5. 0 % ( 3/ 1 2) f or G C, a n d 0 % ( 0/ 1) f or a m p ulla of Vater’s ca ncer. 
T he O R R as assesse d b y  the I n vesti gator was 2 3. 3 % ( 9 5 % CI : 9. 9 , 4 2. 3); wit h 1 a d diti o nal 
partici pa nt wit h i nitial pse u d o pr o gressi o n a n d s u bse q ue nt l o n g-lasti n g res p o nse, t he o verall 
cli nical res p o nse rate was 2 6. 7 %. Wit h a mi ni m u m f oll o w- u p of 8 m o nt hs, t he d urati o n of res p o nse 
( D O R) ra n ge d fr o m 8. 3 t o 1 3. 9 m o nt hs, a n d me dia n O S was 1 2. 7 m o nt hs, wit h 4/ 6 res p o nses 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 2 / 2 1 3
o n g oi n g at t he data c ut off. Besi des t he c o nfir me d 2 0. 0 % O R R, 1 partici pa nt wit h a m p ulla of 
Vater’s ca ncer ha d s hri n ka ge of l u n g a n d li ver tar get a n d n o ntar get lesi o ns after ha vi n g sto p pe d 
bi ntraf us p alfa treat me nt a n d recei vi n g ra di ot hera p y (Ga m ma K nife ® ra di os ur ger y) f or a brai n 
lesi o n. T he efficac y res ults o btai ne d i n t he B T C c o h ort are better t ha n t he hist orical data re p orte d 
b y  La marca et al (La marca 2 0 1 4 ), i n a s yste matic re vie w of 2 L  st u dies, i ncl u di n g 7 6 1 patie nts 
w hic h s h o we d a mea n O S of 7. 2 m o nt hs a n d a wei g hte d mea n O R R of 7. 7 %, as well as a 
pe m br oliz u ma b st u d y in 2 L  BT C w hic h ha d a me dia n O S of 9. 1 m o nt hs a n d a n O R R of 5. 8 % 
( K E Y N O T E- 1 5 8 st u d y, Ue n o 2 0 1 8 ). Rece ntl y , a ni v ol u ma b st u d y ex hi bite d a n O R R of 3. 3 % 
( n = 3 0) a n d a me dia n O S of 5. 2 m o nt hs i n 2 L treat me nt of Ja pa nese patie nts (I ke da 2 0 1 9 ).
H o we ver, t here was n o c orrelati o n bet wee n res p o nse a n d P D -L 1  ex pressi o n o bser ve d i n t his c o h ort 
of 3 0 partici pa nts wit h B T C, of w h o m 5 3. 3 % were P D- L 1 p ositi ve ( St u d y M S 2 0 0 6 4 7 _ 0 0 0 8).
T he S o C f or t he 1 L  treat me nt of l ocally a d va nce d or metastatic B T C is a c o m bi nati o n of 
ge mcita bi ne a n d cis plati n, as esta blis he d i n t he A B C -0 2 st u d y (Valle 2 0 1 6 ), w hic h ac hie ve d a 
res p o nse rate of 2 6. 1 % ( n = 1 6 1) ( 9 5 % c o nfi de nce i nter val [ CI]: 1 9. 3- 3 2. 8), a me dia n P F S of 
8. 0 m o nt hs ( 9 5 % CI : 6. 6 , 8. 6), a n d a me dia n O S of 1 1. 8 m o nt hs ( 9 5 % CI : 9. 5, 1 4. 3). Treat me nt 
wit h ni v ol u ma b i n c o nj u ncti o n wit h ge mcita bi ne pl us cis plati n de m o nstrate d a me dia n O S of 
1 5. 4 m o nt hs, a me dia n P F S of 4. 2 m o nt hs a n d a n O R R of 3 6. 7 % ( n = 3 0) i n treat me nt -nai ve B T C 
patie nts (I ke da 2 0 1 9).
2. 3
Be nefit/ Ris k  Assess me nt
At t he ti me of st u d y  i nitiati o n, i n St u d y M S 2 0 0 6 4 7 -0 0 0 8, a P hase I b st u d y  of 2 L B T C, bi ntraf us p 
alfa ( M 7 8 2 4) has de m o nstrate d pr o misi n g cli nical efficac y  wit h a c o nfir me d O R R of 2 3. 3 % ( 7 of 
3 0 partici pa nts) b y I n vesti gat or rea d a n d 2 0 % b y I R C, s u g gesti n g t hat t he cli nical be nefit c o ul d be 
s u bsta ntiall y better t ha n t he hist orical be nc h mar k.
T he 
f oll o wi n g ha ve bee n i de ntifie d as i m p orta nt i de ntifie d ris ks f or bi ntraf us p alfa: 
i m m u ne-relate d a d verse e ve nts (i m m u ne-relate d p ne u m o nitis, 
i m m u ne-relate d he patitis, 
i m m u ne-relate d c olitis, i m m u ne-relate d ne p hritis a n d re nal d y sf u ncti o n, i m m u ne-relate d 
e n d ocri n o pat hies [t h yr oi d dis or ders, a dre nal i ns ufficie nc y, T y pe 1 dia betes mellit us, pit uitar y 
dis or ders ], i m m u ne-relate d ras h a n d ot her i m m u ne-relate d a d verse e ve nts (ir A Es) [ m yositis, 
m y ocar ditis, e nce p halitis]), T G F -β i n hi biti o n me diate d s ki n reacti o ns, a ne mia, a n d blee di n g 
a d verse e ve nts. I nf usi o n-relate d reacti o ns are classifie d as i de ntifie d ris k f or the treat me nt wit h 
bi ntraf us p alfa.
T he i de ntifie d a n d p ote ntial ris ks wit h bi ntraf us p alfa m o n ot hera p y acr oss t u m or t ypes were o verall 
ma na gea ble a n d n o ne w safety si g nals e mer ge d i n t he E M R 2 0 0 6 4 7-0 0 1/ M S 2 0 0 6 4 7 -0 0 0 8 st u dies 
c o m pare d wit h t hera pies tar geti n g P D -( L) 1 or T G F -β. M 7 8 2 4 i nf usi o n-relate d reacti o ns (IR Rs) 
were si milar t o t h ose see n wit h m o n ocl o nal a nti b o dies. T he o verall bi ntraf us p alfa relate d I R Rs 
were o bser ve d t o be 5 % wit h se verit y  of l o w gra de, well ma na ge d, a n d di d n ot lea d t o per ma ne nt 
treat me nt disc o nti n uati o n. T he o verall safety pr ofile f or ir A Es is f o u n d t o be c o nsiste nt acr oss 
bi ntraf us p alfa st u dies a n d ali g ne d wit h t he k n o w n safet y pr ofile of a p pr o ve d a nti -P D -( L) 1 a ge nts.
Der mat ol o gic a d verse e ve nts ( A Es) relate d t o T G F β -i n hi biti o n (i nclu di n g kerat oaca nt h o mas [ K A] 
a n d c uta ne o us s q ua m o us cell ca ncers) are a n i m p orta nt i de ntifie d ris k wit h bi ntraf us p alfa. T hese 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 3 / 2 1 3
lesi o ns were pre vi o usly o bser ve d i n i n di vi d uals wit h ge netic m utati o ns i n t he T G F β rece pt or (i .e., 
Fer g us o n -S mit h s yn dr o me), a n d patie nts treate d wit h t he T G F β -tar geti n g a ge nt, fres oli m u ma b 
(G o u die 
2 0 1 1 , M orris 
2 0 1 4 ). O verall, 
in t he E M R 2 0 0 6 4 7 _ 0 0 1/ M S 2 0 0 6 4 7 _ 0 0 0 8 st u dies, 
treat me nt-e mer ge nt T G F β i n hi biti on me diate d s ki n reacti o ns were re p orte d i n 6 9/ 6 3 0 ( 1 1. 0 %)
partici pa nts . T hey were well ma na ge d wit h si m ple e xcisi o n or res ol ve d s p o nta ne o usl y a n d di d n ot 
re q uire a ny partici pa nt t o disc o nti n ue treat me nt. T he ris k of t hese lesi o ns wit h bi ntraf us p alfa was 
c o nsi dere d ma na gea ble i n t hese st u dies, partic ularl y i n t he c o nte xt of e nc o ura gi n g cli nical acti vit y 
a gai nst a n a d va nce d ca ncer. N ote: fres oli m u ma b is n ot a p pr o ve d i n Ja pa n.
A n a nal ysis of o bser ve d treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) of bi ntraf us p alfa a n d t he 
k n o w n safety pr ofile of ge mcita bi ne/cis plati n di d n ot re veal pr o mi ne nt o verla p pi n g t o xicit y for 
s pecial c o nsi derati o n i n t he st u d y desi g n; h o we ver, as ge nerall y  see n wit h c he m ot hera p y, l o w 
bl o o d c o u nts, fati g ue, na usea, v o miti n g, a n d i nf usi on reacti o n ( mai nly d ue t o cis plati n) are 
c o m m o n si de effects, a n d i nterstitial l u n g disease (I L D), diarr hea, a n d oral s ores are less c o m m o n 
b ut re q uire dili ge nt m o nit ori n g 
w hile 
i n vesti gati n g bi ntraf us p alfa i n c o m bi nati o n wit h 
c he m ot hera p y.  Co nsi deri n g bi ntraf us p alfa’s o bser ve d efficac y in B T C, a n d ma na gea ble safety 
pr ofile, as o bser ve d i n 2 P hase I st u dies (E M R 2 0 0 6 4 7 _ 0 0 1 a n d M S 2 0 0 6 4 7 _ 0 0 0 8 ), t he be nefit/ris k 
assess me nt a p pears fa v ora ble t o c o n d uct t his P hase II/III gl o bal st u d y .
M ore 
detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bly 
e x pecte d A Es of bi ntraf us p alfa m a y  be f o u n d i n Secti o n 4. 2 a n d t he I B.
Base d o n t he a vai la ble n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.
3
O bjecti ves a n d E n d p oi nts
T he st u d y c o m prises a n o pe n -la bel, safety r u n -i n part, a n d a ra n d o mize d, d o u ble-bli n d part f or t he 
e val uati o n of efficac y an d safety. Pri mar y  objecti ves a n d e n d p oi nts are prese nte d se parately f or 
t he 2 parts i n Ta ble 5.
T a ble 5
St u d y O bjecti ves a n d E n d p oi nts
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
O p e n -l a b el, S af et y  R u n-i n
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a 2 4 0 0 m g Q 3 W  in c o m bi n ati o n wit h g e m cit a bi n e a n d ci s pl ati n i n 
l o c all y a d v a n c e d or m et a st ati c B T C
Pri m ar y
T o a s s e s s if bi ntr af u s p alf a 2 4 0 0 m g
Q 3 W is s af e 
a n d t ol er a bl e a n d t o c o nfir m t hi s d o s e a s t h e 
r e c o m m e n d e d P h a s e II d o s e f or t h e r a n d o mi z e d, 
d o u bl e -bli n d p art of t h e st u d y
O c c urr e n c e of D L T s d uri n g t h e D L T e v al u ati o n p eri o d
S e c o n d ar y
T o a s s e s s t h e s af et y pr ofil e of bi ntr af u s p alf a i n 
c o m bi n ati o n wit h g e m cit a bi n e a n d ci s pl ati n

O c c urr e n c e of T E A E s a n d tr e at m e nt-r el at e d A E s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥3) i n l a b or at or y 
t e st s
R a n d o mi z e d, D o u bl e -bli n d P art 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 4 / 2 1 3
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a i n c o m bi n ati o n wit h g e m cit a bi n e pl u s ci s pl ati n v er s u s pl a c e b o wit h 
g e m cit a bi n e 
pl u s 
ci s pl ati n i n p arti ci p a nt s 
wit h 
a d v a n c e d 
or 
m et a st ati c 
B T C 
w h o 
h a v e 
n ot 
r e c ei v e d 
c h e m ot h er a p y/i m m u n ot h er a p y i n t h e a d v a n c e d/ m et a st ati c s etti n g
Pri m ar y
T o a s s e s s O S
O S
S e c o n d ar y
T o a s s e s s P F S
P F S 
a c c or di n g 
t o R E CI S T 1. 1 
a s 
a s s e s s e d 
b y 
t h e 
I n v e sti g at ora
T o a s s e s s O R R
C o nfir m e d o bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 a s 
a s s e s s e d b y t h e I n v e sti g at ora
T o a s s e s s D O R
D O R a s s e s s e d b y c o nfir m e d c o m pl et e r e s p o n s e or p arti al 
r e s p o n s e u ntil d e at h or pr o gr e s si o n of di s e a s e a c c or di n g t o 
R E CI S T 1. 1 a s a s s e s s e d b y t h e I n v e sti g at ora
T o a s s e s s D R R
D ur a bl e c o nfir m e d r e s p o n s e of at l e a st 6 m o nt h s a c c or di n g 
t o R E CI S T 1. 1 a s a s s e s s e d b y t h e I n v e sti g at ora
T o a s s e s s t h e s af et y pr ofil e of bi ntr af u s p alf a or 
pl a c e b o i n c o m bi n ati o n wit h g e m cit a bi n e pl u s 
ci s pl ati n
O c c urr e n c e of T E A E s a n d tr e at m e nt-r el at e d A E s , i n cl u di n g 
a d v er s e e v e nt s of s p e ci al i nt er e st
T o c h ar a ct eri z e t h e P K pr ofil e of bi ntr af u s p alf a

P K pr ofil e of bi ntr af u s p alf a i n t er m s of C e oi a n d C tr o u g h f or 
p arti ci p a nt s i n t h e bi ntr af u s p alf a ar m

P K pr ofil e of bi ntr af u s p alf a i n t er m s of A U C 0-t , A U C0- ∞, 
C m a x, tm a x, a n d t½ f or p arti ci p a nt s i n t h e s af et y ru n -i n p art 
of t h e st u d y o nl y
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 5 / 2 1 3
0-t
ti m e at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n, A U C 0- ∞= A U C fr o m ti m e z er o 
e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at t h e l a st s a m pli n g ti m e, B T C = bili ar y 
tr a ct c a n c er, Ce oi = c o n c e ntr ati o n o b s er v e d i m m e di at el y at t h e e n d of i nf u si o n, C m a x = m a x i m u m o b s er v e d 
c o n c e ntr ati o n, C tr o u g h= c o n c e ntr ati o n o b s er v e d i m m e di at el y b ef or e n e xt d o si n g, D L T = d o s e -li miti n g t o xi cit y, 
D O R = d ur ati o n of r e s p o n s e, D R R = d ur a bl e r e s p o n s e r at e, 
 
, I L =It e m Li br ar y, I R C =I n d e p e n d e nt R e vi e w 
C o m mitt e e, 
O R R = o bj e cti v e r e s p o n s e r at e, O S = o v er all s ur vi v al, 
P F S = pr o gr e s si o n -fr e e s ur vi v al, P K = p h ar m a c o ki n eti c s, 
, Q 3 W= o n c e e v er y 3 
w e e k s, 
, R E CI S T 1. 1 = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 1. 1, 
t½ = a p p ar e nt t er mi n al h alf- lif e, T E A E s =tr e at m e nt-e m er g e nt a d v er s e e v e nt s, t m a x=ti m e t o r e a c h t h e m a xi m u m 
o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al.
a
If t h e st u d y i s n ot e x p a n d e d t o P h a s e III, t u m or- b a s e d effi c a c y e n d p oi nt s will al s o b e a s s e s s e d a s per t h e 
I R C.
4
St u d y Desi g n
4. 1
O ver all Desi g n
T his m ultice nter , i nter nati o nal st u d y co nsists of a n o pe n -la bel, safet y ru n- i n part a n d a ra n d o mize d,
d o u ble -bli n d, place b o -c o ntr olle d P hase II/III part. I n Phase II/III part, t he st u d y will e val uate 
w het her bi ntraf us p alfa i n c o m bi nati o n wit h t he c urre nt S o C ( ge mcita bi ne pl us cis plati n) i m pr o ves 
O S i n c he m ot hera p y a n d i m m u n ot hera p y-nai ve partici pa nts wit h l ocall y ad va nce d or metastatic 
B T C c o m pare d t o place b o, ge mcita bi ne a n d cis plati n (see Fi g ure 1 ):

A m ultice nter, o pe n -la bel, safet y r u n-i n t o c o nfir m t he safet y an d t olera bilit y of 1 L bi ntraf us p 
alfa i n c o m bi nati o n wit h ge mcita bi ne a n d cis plati n. Safet y  will be assesse d b y  a Safet y 
M o nit ori n g C o m mittee ( S M C). T he safety r u n-i n part of t he st u d y will e nr oll 6 t o 1 2 d ose d 
partici pa nts i n Asia a n d i n n o n- Asia, wit h c o m petiti ve e nr o ll me nt wit hi n eac h re gi o n

A 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 t o e val uate t he efficac y a n d 
safety of bi ntraf us p alfa wit h ge mcita bi ne pl us cis plati n as 1 L  treat me nt. A t otal of ma xi m u m 
3 0 0 partici pa nts will be recr uite d i n P hase II a n d t he a nal ys is f or t he a da ptati o n decisi o n will 
be c o n d ucte d i n t he first 1 5 0 partici pa nts i n P hase II w h o ha ve n o d oc u me ntati o n (e C R F) of 
a n y sys te mic a nti bi otic treat me nt wit hi n 3 0 da ys pri or t o ra n d o mizati o n (referre d t o as 
a nti bi otics - naive fr o m here o n f or si m plicit y ). 
E x pa nsi o n i nt o P hase III will ta ke place if:

T h e o d ds rati o of a c o nfir me d O R R is ≥ 1. 6 or P F S H R is < 0. 7 5 , a n d

t he pr o ba bilit y  of s uccess e xcee ds a pres pecifie d t hres h ol d (s uccess is defi ne d as pr ojecte d 
O S H R bel o w a pres pecifie d t hres h ol d at t he pri mar y  anal y sis). Details will be s pecifie d i n 
a n a p pe n di x t o t he ID M C c harter a n d I D M C statistical a nal ys is pla n. 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 6 / 2 1 3
If t he pres pecifie d criteria are met, t he st u d y will e x pa n d i nt o P hase III a d di n g u p t o 
5 0 0 partici pa nts i n t otal. If t he st u d y is n ot e x pa n de d i nt o P hase III, it will be c o m plete d as a 
P hase II st u dy.
T he st u d y  pla ns t o e nr oll a ma xi m u m of 5 2 4 eli gi ble partici pa nts fr o m c o u ntries i n Asia, E ur o pe, 
S o ut h A merica, a n d t he U S. E nr oll me nt i n t he ra n d o mize d, d o u ble-bli n d part will be c o m petiti ve.
T he S p o ns or will m o nit or e nr oll me nt i n t he st u dy a n d ma y  ma ke deter mi nati o ns t o li mit e nr oll me nt 
i n certai n c o u ntries a n d/ or re gi o ns i n or der t o o btai n a st u d y po p ulati o n re prese ntati ve acr oss t he 
partici pati n g gl o bal re gi o ns (f or e . g., Asia n vers us n o n-Asia n c o u ntries) .
U nless ot her wise s pecifie d, all st u d y assess me nts a p pl y to b ot h t he o pe n -la bel, safety r u n-i n a n d 
t he ra n d o mize d, d o u ble-bli n d parts of t he st u d y .
St u d y  i nter ve nti o n i n t his pr ot oc ol refers t o bi ntraf us p alfa/ p lace b o, ge mcita bi ne, a n d/ or cis plati n.
4. 1. 1
O pe n -la bel , Safet y R u n -i n P art
Pri or t o t he ra n d o mizati o n p hase, t he safety of bi ntraf us p alfa i n c o m bi nati o n wit h ge mcita bi ne 
a n d cis plati n will be c o nfir me d i n a n o pe n -la bel,safet y r u n-i n. I n t he safety r u n-i n part , partici pa nts 
will be treate d wit h bi ntraf us p alfa at a d ose of 2 4 0 0 m g o nce e ver y  3 wee ks i n c o m bi nati o n wit h 
ge mcita bi ne at 1 0 0 0 m g/ m 2 a n d cis plati n at 2 5 m g/ m 2 d ose d o n Da y 1 a n d Da y 8 f or 8 c ycles e ver y 
3 wee ks .
D ose -li miti n g t o xicit y (D L T) will be e val uate d i n t he first 2 1 d a y s f oll o wi n g t he first d ose of 
bi ntraf us p alfa (see Secti o n 6. 6. 2
f or t he defi niti o n
of 
D L T ). Safet y  
will be e val uate d 
i n de pe n de ntly i n 2 se parate c o h orts:

I n t he Asia n sites’ c o hort

I n t he n o n -Asia n sites’ c o h ort.
Si x D L T -e val ua ble partici pa nts will be recr uite d se q ue ntiall y i n eac h c o h ort (as detaile d i n t he 
S M C C harter) . If D L T is o bser ve d i n 2 or 3 of t he 6 partici pa nts, a n a d diti o nal 6 e val ua ble 
partici pa nts will be a d de d t o the c o h ort. De pe n di n g o n t he decisi o n of t he S M C, t he n u m ber of 
partici pa nts i n t he safet y r u n-i n part ma y be e x pa n d e d f urt her. If D L T is o bser ve d i n ≤1 ( of 6) or
≤3 ( of 1 2) partici pa nts, t he re gi o n m a y  start t o e nr oll partici pa nts i nt o t he ra n d o mize d, 
d o u ble -bli n d part of t he st u d y . If D L T is o bser ve d i n ≥4 o ut of 6 or 1 2 partici pa nts i n t he re gi o nal 
c o h ort, recr uit me nt i n t hat re gi o n will be te m p oraril y halte d. T he S M C will re vie w t he safet y 
fi n di n gs wit h et h nicit y an d a n a p pr o priate meas ure will be a d de d t o t his st u d y pr ot oc ol, if 
a p plica ble.
Treat me nt d urati o n a n d criteria f or d ose a n d sc he d ule m o dificati o ns 
are descri be d i n 
Secti o ns 4. 1. 2 , 6. 6. 1 , a n d 7.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 7 /2 1 3
4. 1. 2
R a n d o mize d, D o u ble -bli n d P art
T he ra n d o mize d, d o u ble -bli n d part is c o m prise d of P hase II a n d P hase III. A t otal of ma xi m u m 
3 0 0 partici pa nts will be recr uite d i n P hase II a n d t he a nal ys is f or t he a da ptati o n decisi o n will be 
c o n d ucte d i n t he first 1 5 0 a nti bi otics-na ive partici pa nts f or efficac y data a n d f or safet y data fr o m 
all treate d partici pa nt s. St u d y e nr oll me nt will be e x pa n de d i nt o P hase III t o reac h 5 0 0 partici pa nts 
if t he pres pecifie d criteria are met (see Secti o n  4. 1 ). T he 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 P F S , O R R , O S,
a n d safet y data i n P hase II re gar dless of w het her t he 
e x pa nsi o n criteria are met, i n or der t o c o nsi der t he o verall be nefit-ris k, a n d will rec o m me n d t o t he 
st u d y tea m w het her t o c o nti n ue t he st u d y as P hase II or P hase III.
T he pri mar y  anal ys is ( P A) of t he st u d y will be c o n d ucte d o n data fr o m all partici pa nts i n t he 
ra n d o mize d, d o u ble -bli n d part of t he st u d y b ut will n ot i ncl u de data fr o m partici pa nts i n t he safety 
r u n-i n part. If n eit her of t he criteria f or st u d y e x pa nsi o n i nt o P hase III are met, n o f urt her 
partici pa nts will be e nr ol le d, a n d t he st u d y will be c o m plete d as a P hase II st u d y. T he desi g n of 
t he ra n d o mize d, d o u ble-bli n d part of t he st u d y  is o utli ne d i n Fi g ure 2.
Fi g ure 2
O utli ne of R a n d o mize d, D o u ble -bli n d St u d y Desi g n
P F S = pr o gr e s si o n -fr e e s ur vi v al.
Partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve eit her bi ntraf us p alfa ( 2 4 0 0 m g ) or 
matc hi n g place b o o nce e ver y 3 wee ks . I n b ot h t he bi ntraf us p alfa a n d place b o ar ms, partici pa nts 
will be d ose d wit h ge mcita bi ne ( 1 0 0 0 m g / m2) a n d cis plati n ( 2 5 m g / m2) o n D a y 1 a n d D a y 8 f or 
8 c ycles e ver y 3 wee ks . Treat me nt all ocati o n/ra n d o mizati o n will be stratifie d acc or di n g t o t he 
f oll o wi n g fact ors:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 8 / 2 1 3
1.
T y pe of B T C ( o n t he basis t hat a nat o mical l ocati o n ma y  reflect a differe nt t u m or ori gi n as well 
as a differe nt eti ol o g y): 

i ntra he patic C C A

e xtra he patic C C A i ncl u di n g a m p ulla of Vater ’s ca ncer

gall bla d der ca ncer ( G C).
2.
M etastatic at dia g n osis v ers us ot hers, w here “ ot hers” i ncl u des partici pa nts wit h u nresect a ble, 
l ocall y a d va nce d disease at dia g n osis a n d partici pa nts wit h resecta ble disease at dia g n osis w h o 
ha ve u n der g o ne pri or s ur gical resecti o n wit h c urati ve i nte nt
3.
Asia sites vers us n o n -Asia sites 
I n partici pa nts wit h c o m plete res p o nse ( C R ), treat me nt wit h bi ntraf us p alfa / place b o will c o nti n ue 
f or 2 ye ars after t he first o nset of C R or u ntil 1 of t he criteria f or disc o nti n uati o n i n Secti o n 7 is
met , w hic he ver occ urs first. Partici pa nts wit h C R ma y  be a ble t o c o nti n ue treat me nt b e y o n d 
2 ye ars, s u bject t o disc u ssi o n bet wee n t he I n vesti gat or a n d t he Me dical M o nit or. I n all ot her cases, 
treat me nt wit h bi ntraf us p alfa / place b o will c o nti n ue u ntil 1 of t he criteria f or disc o nti n uati o n i n 
Secti o n 7 is met. All partici pa nts will recei ve 8 c ycles of ge mcita bi ne a n d cis plati n. A n y  misse d 
d ose(s) of c he m ot hera p y 
ma y be ma de 
u p at t he e n d of t he sc he d ule d 8 c ycles ( u p t o 
1 6 a d mi nistrati o ns of ge mcita bi ne a n d cis plati n c o m bi nati o n) pr o vi de d t he partici pa nt d oes n ot 
meet a n y of t he criteria f or disc o nti n uati o n. Refer t o t he Sc he d ule of Acti vities f or details of 
assess me nts t o be perf or me d (see Secti o n 1. 3 ).
T w o Safet y F oll o w - u p Visits will be perf or me d : at 2 8 da y s (± 7 d a y s) a n d 1 2 wee ks ( ± 2 wee ks) 
after t he last d ose of treat me nt.
L o n g -ter m f oll o w- u p, i ncl u di n g s ur vi val f oll o w- u p, will be perf or me d e ver y 3 m o nt hs ( ± 2 wee ks) 
( or e ver y 6 wee ks [ ± 1 wee k] if t he partici pa nt has i nitiate d a n d c o nti n ui n g 2 L  treat me nt) after t he 
1 2- wee k Safet y  Foll o w -u p V isit, u nless t he partici pa nt is re p orte d as l ost t o f oll o w- u p, dea d, or 
after st u d y ter mi nat i o n. 
L o n g -ter m f oll o w-u p ca n be perf or me d usi n g c hart re vie ws or tele p h o ne calls.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
O ver all St u d y Desi g n
I n ge neral, f oll o wi n g t he o bser vati o n of bi ntraf us p alfa a ntit u m or acti vit y in t he P hase I e xpa nsi o n 
st u d y M S 2 0 0 6 4 7 _ 0 0 0 8, base d o n a s mall sa m ple size, ra n d o mize d f oll o w- u p st u dies w o ul d be 
c o n d ucte d eit her as a P hase II-li ke pr o of of c o nce pt st u d y or a c o nfir mat or y Phase III st u d y. 
M o vi n g directl y  fr o m P hase I t o a f ull P hase III st u d y has t he p ote ntial t o re duce de vel o p me nt 
ti me, b ut s uc h a n a g gressi ve a p pr oac h m a y  be ver y  ris k y wit h o ut pr o of of c o nce pt data. T o miti gate 
t his ris k, w hile als o o pti mizi n g de vel o p me nt ti me, a n a da pti ve P hase II/III desi g n will be e m pl o ye d 
i n t his st u d y. A si milar a p pr oac h has bee n descri be d pre vi o usl y t o e x pe dite o nc ol o g y  dr u g 
de vel o p me nt, s uc h t hat if a n i nteri m a nal ys is (I A) has a defi niti vel y  positi ve o utc o me, t he st u d y 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
4 9 / 2 1 3
e x pa n ds i nt o a pla n ne d P hase III p o p ulati o n (C he n 2 0 1 8 ). I n t his st u d y, ex pa nsi o n of P hase II i nt o 
P hase III re q uires eit her a P F S H R < 0. 7 5 or a c o nfir me d O R R o d ds rati o ≥1. 6 bet wee n t he 
treat me nt a n d c o ntr ol ar ms. T he O R R o d ds rati o is i ncl u de d i n t he e x pa nsi o n criteria t o 
c o m ple me nt t he li mitati o n of pre dicta bilit y  of t he O S H R wit h t he P F S H R t o c orrectl y e xpa n d the 
st u d y, si nce t he c orrelati o n bet wee n P F S H R a n d O S H R is i nfl ue nce d by ma n y fact ors, i ncl u di n g 
t he s yner gistic effect of c o m bi nati o ns a n d later li nes of treat me nt. T h us, a n a d diti o nal criteri o n, 
i.e., assess me nt of p r o ba bilit y of s uccess t o reac h t he pr ojecte d O S H R at t he pri mar y  anal y sis, 
will be pr o vi de d t o t he I D M C t o be ta ke n i nt o c o nsi derati o n f or t heir rec o m me n dati o n. H o we ver, 
t he act ual t hres h ol d f or t he pr o ba bilit y  of s uccess criteri o n is n ot d oc u me nte d i n t h e pr ot oc ol a n d,
t heref ore, n ot a p pare nt t o t he I n vesti gat ors a n d partici pa nts t o mi ni mize bias i n ter ms of recr uiti n g 
a differe nt patie nt p o p ulati o n f or after t he decisi o n t o e x pa n d .
F or e xa m ple, i n t he case of N S C L C, t he o nl y i n dicati o n w here c he m ot hera p y a n d i m m u n ot hera p y 
c o m bi nati o n data are a vaila ble, t here is a g o o d c orrelati o n bet wee n O S H R a n d P F S H R i n t he 
s u bset a nalys is of differe nt P D-L 1  e x pressi o n gr o u ps, s uc h as P D-L 1 hi g h, p ositi ve, a n d ne gati ve 
i n t he 1 L n o ns q ua m o us N S C L C st u d y ( K E Y N O T E- 1 8 9, Ga n d hi 2 0 1 8 ). H o we ver, less c orrelati o n 
was o bser ve d i n t he 1 L s q ua m o us N S C L C st u d y ( K E Y N O T E - 4 0 7, Paz- Ares 2 0 1 8 ). T he res p o nse 
rate of ge mcita bi ne a n d cis plati n c o m bi nati o n i n t he a vaila ble P hase III st u dies is varia ble, ra n gi n g 
fr o m 1 5 % ( K H B O 1 4 0 1-MI T S U B A st u d y, Sa kai 2 0 1 8) t o 3 2 % (J C O G 1 1 1 3 F U G A -B T st u d y, 
M oriza ne
2 0 1 8) . A n o d ds rati o of 1. 6 c orres p o n ds t o a 1 0 % i ncrease i n O R R, ass u mi n g O R R i n 
t he ge mcita bi ne a n d cis plati n ar m is 2 5 %.
C h oice of C o m p ar at or
T he 1 L  So C treat me nt f or patie nts wit h a d va nce d -sta ge or u nresecta ble B T C is a c o m bi nati o n of 
ge mcita bi ne a n d cis plat i n (Valle 2 0 1 6 , Mi y aza ki 2 0 1 5 , refer t o N C C N 2 0 1 8) base d o n t he res ults 
of t he P hase III A B C -0 2 st u d y co n d ucte d i n t he U K
(Valle 2 0 1 0 ), w here t he c o m bi nati o n of 
ge mcita bi ne/cis plati n e x hi bite d a res p o nse rate of 2 6. 1 % ( 4 2 o ut of 1 6 1 pa rtici pa nts; 9 5 % CI : 1 9. 3 , 
3 2. 8 ), m e dia n P F S of 8. 0 m o nt hs
( 9 5 % CI : 6. 6, 8. 6) wit h e ver y 3 m o nt hs of ra di ol o gical 
assess me nt ,a n d m e dia n O S of 1 1. 7 m o nt hs ( 9 5% CI : 9. 5 , 1 4. 3) i n 1 L treat me nt of l ocall y ad va nce d 
or metastatic B T C . A si milar be nefit was see n i n t he ra n d o mize d, P hase II B T-2 2 Ja pa nese st u d y ,
wit h a me dia n O S of 1 1. 2 m o nt hs ( 9 5 % CI : 9. 1 , 1 2. 5) , P F S of 5. 8 m o nt hs wit h e ver y 6 wee ks of 
ra di ol o gical assess me nt, a n d 1 9. 5 % O R R ( 9 5 % CI : 8. 8, 3 4. 9) i n t he cis plati n pl us ge mcita bi ne 
c o m bi nati o n gr o u p (O k usa ka 2 0 1 0 ).
Si nce t he N C C N g ui deli nes rec o m me n d ge mcita bi ne wit h cis plati n f or 1 L treat me nt as cat e g or y 1 
e vi de nce le vel a n d ge mcita bi ne/cis plati n is t he S o C i n 1 L  BT C, t he c o ntr ol ar m of t he ra n d o mize d, 
d o u ble -bli n d part of t his st u d y  is j ustifie d.
Rece ntl y , i n t he K H B O 1 4 0 1 -MI T S U B A st u d y, t he tri plet re gi me n of ge mcita bi ne, cis plati n, a n d 
S 1 ( G C S), de m o nstrate d a n O S be nefit c o m pare d t o ge mcita bi ne a n d cis plati n ( Ge m-Cis ) i n 
Ja pa nese patie nts (Sa kai 2 0 1 8 ). T he me dia n O S was 1 3. 5 m o nt hs i n t he G C S ar m a n d 1 2. 6 m o nt hs 
i n t he G e m-C is ar m, wit h a H R of 0. 7 9 1 ( CI : 0. 6 2 8 , 0. 9 9 6) ( p = 0. 0 4 6). Alt h o u g h t he O S be nefit 
was statisticall y si g nifica nt, t he be nefit i n me dia n O S was o nl y  0. 9 m o nt hs. D uri n g b ot h t he 1 L 
st u d y peri o d a n d t he s u bse q ue nt 2 L treat me nt, o nl y 2 5 % of patie nts i n t he Ge m-C is ar m recei ve d 
S 1 c o m pare d t o 1 0 0 % of patie nts i n t he G C S ar m. I n ad diti o n, t he d ose i nte nsit y of ge mcita bi ne 
a n d cis plati n i n t he G C S ar m was 2 5 % l o wer t ha n i n t he G e m-Cis ar m. T hese fi n di n gs ma y  in dicate 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 0 / 2 1 3
t he cli nical be nefit of se q ue ntial treat me nt wit h ge mcita bi ne a n d cis plati n as 1 L f oll owe d b y  S1 as 
2 L  rat her t ha n t he tri plet of G C S re gi me n. Ta ke n t o get her, t he ge mcita bi ne pl us cis plati n re gi me n 
re mai ns a S o C i n 1 L e ve n i n c o u ntries w here S 1 is a vaila ble.
T ar get Dise ase
Gall bla d der ca ncer, i ntra he patic C C A a n d e xtra he patic C C A , i ncl u di n g a m p ullar y ca ncer were 
i ncl u de d as tar get i n dicati o ns i n t he A B C - 0 2 st u d y (Valle 2 0 1 0 ). I n t his pr ot oc ol, peri hilar a n d 
distal bile d uct ca ncers are ha n dle d as a n e xtra he patic C C A si nce e xtra he patic C C A was se parate d 
tra diti o nall y int o peri hilar, mi d -d uct, a n d distal C C A , alt h o u g h it m a y  be diffic ult t o disti n g uis h 
cli nicall y ce ntral i ntra he patic C C A fr o m hilar C C A , partic ularl y i n t he prese nce of a peri d uctal 
i nfiltrati n g gr o wt h patter n (A mi n 2 0 1 7 ).
A nti bi otics -n a ive p atie nts f or t he e x p a nsi o n decisi o n
Acc u m ulati n g e vi de nce s h o ws t hat a nti bi otics use d bef ore c hec k p oi nt i n hi bit ors are ass ociate d 
wit h p o or pr o g n osis (Pi nat o 2 0 1 9 , C hala bi 2 0 2 0). S o me of t he st u dies e x hi bite d e ve n deteri orate d 
efficac y of c hec k p oi nt i n hi bit or treat me nt i n c o nj u ncti o n wit h a nti bi otics c o m pare d t o t he 
c o m parat or ar m. I n St u d y  Pr ot oc ol Versi o n 3. 0 ( date d 2 7 J ul y 20 2 0) , partici pa nts w h o use d 
s yste mic a nti bi otics d uri n g t he scree ni n g peri o d are n ot eli gi ble f or t he st u d y; t heref ore, t he f ull 
P hase III sa m ple size is e x pecte d t o be lar gel y a nti bi otics -nai ve partici pa nts. T he a nti bi otics -nai ve 
p o p ulati o n will be t he basis of t he a nal ys is f or t he e x pa nsi o n decisi o n fro m P hase II t o P hase III 
i n or der t o ha ve a p o p ulati o n m ore re prese ntati ve of t he a ntici pate d p o p ulati o n i n t he f ull P hase III 
sa m ple size.
Effic ac y E n d p oi nts
I n t his st u dy, t he pri mar y e n d p oi nt is O S . 
T he ass u me d me dia n O S of t he c o ntr ol ar m of t his st u d y is bei n g set as 1 1.7 m o nt hs base d o n t he 
A B C -0 2 st u d y (Valle 2 0 1 0 ).
Cr oss o ver bet wee n treat me nt ar ms (i.e., fr o m place b o t o bi ntraf us p alfa after c o nfir mati o n of 
pr o gressi ve disease [P D ]) is n ot all o we d, t o a v oi d a ny i m pact o n O S o utc o mes.
T here ha ve bee n re p orts t hat t he res p o nse rate of a sal va ge li ne of c he m ot hera p y after 
i m m u n ot hera p y is better t ha n t he res p o nse rate of t he last c he m ot hera p y bef ore i m m u n ot hera py 
(Par k 2 0 1 8 ). I n vi e w of t he s u g gesti o n t hat i m m u n ot hera py m a y  increase a t u m or’s se nsiti vit y to 
c he m ot hera p y,  t he ass ociati o n of bi ntraf us p alfa treat me nt a n d o bjecti ve res p o nse of 2 L treat me nt 
will be assesse d i n t his st u d y  t o descri be t he i nfl ue nce of bi ntraf us p alfa o n s u bse q ue nt t hera p y.
D ur ati o n of Tre at me nt
T he n u m ber of c y cles a n d d urati o n of ge mcita bi ne a n d cis plati n treat me nt t o be use d i n t his st u d y 
was deter mi ne d base d o n t he A B C -0 2 st u d y (Valle 2 0 1 0 ) a n d is defi ne d as 8 c ycles, gi ve n e ver y 
3 wee ks . T his treat me nt sc he d ule is c o nsiste nt wit h c urre nt S o C a n d reflects b ot h t he t o xicit y of 
c he m ot hera p y a n d t he o bser vati o n t hat t here is c urre ntl y n o pr os pecti ve st u d y t hat de m o nstrates a 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 1 / 2 1 3
cli nical be nefit of c o nti n ue d ge mcita bi ne a n d cis plati n c o m bi nati o n treat me nt b e y o n d 8 c ycles. T o 
e ns ure partici pa nts are a ble t o recei ve 8 c ycles of c he m ot hera p y, a n y misse d d oses m a y  be ma de 
u p after t he 8 sc he d ule d c ycles ( u p t o 1 6 a d mi nistrati o ns of ge mcita bi ne a n d cis plati n c o m bi nati o n) 
pr o vi de d t he partici pa nt d oes n ot meet a n y of t he criteria f or disc o nti n uati o n.
D ue t o t he lac k of pr os pecti ve st u dies, t he o pti mal d urati o n of i m m u n ot hera py is n ot yet clear, 
partic ularl y w het her it s h o ul d c o nti n ue u ntil disease pr o gressi o n or be ter mi nate d after a fi xe d 
n u m ber of a d mi nistrati o ns. T o date, C hec k M ate - 1 5 3 is t he o nl y  st u d y of a P D - 1 i n hi bit or t hat 
pr os pecti vel y e xa mi ne d t he be nefit of ni v ol u ma b treat me nt d urati o n, wit h 1 ar m c o nti n ui n g
treat me nt u ntil P D
a n d t he ot her ar m disc o nti n ui n g treat me nt at 1 ye ar (re-treat me nt was 
per missi ble i n t he e ve nt of disease pr o gress i o n). B ot h P F S a n d O S were s u peri or i n t he c o nti n u o us 
treat me nt ar m c o m pare d t o t he 1- ye ar treat me nt ar m (S pi gel 2 0 1 7 ). I n this st u d y, bi ntraf us p 
alfa/ place b o treat me nt will c o nti n ue f or 2 years i n partici pa nts wit h C R or u ntil 1 of t he criteri a f or 
disc o nti n uati o n is met (Secti o n 7) ; c o nti n uati o n of treat me nt wit h bi ntraf us p alfa / place b o b e y o n d 
2 ye ars after t he first o nset of C R ma y  be p ossi ble s u bject t o disc ussi o n bet wee n t he I n vesti gat or 
a n d t he Me dical M o nit or.
I n all ot her cases, treat me nt wit h bi ntraf us p alfa / place b o will c o nti n ue 
u ntil 1 of t he crit eria f or disc o nti n uati o n i n Secti o n 7 is met. 
I m m u ne-relate d res p o nse patter ns, s uc h as a n i nitial i ncrease i n t u m or b ur de n or t he a p peara nce of 
ne w lesi o ns, ter me d ‘ pse u d o pr o gressi o n’, m a y  lea d t o misi nter pretati o n of patie nt stat us, a n d , as a 
res ult, lea d t o s u b o pti mal cli nical decisi o ns. C o n ve nti o nal Res p o nse E val uati o n Criteria i n S oli d 
T u m ors Versi o n 1. 1 ( R E CI S T 1. 1) (Eise n ha uer 2 0 0 9 ) e val uati o n is re p orte d t o u n deresti mate t he 
be nefit of i m m u ne c hec k p oi nt i n hi bit ors i n 1 1 % of pr o gressi ve patie nts wit h 
N S C L C 
( Taz dait 2 0 1 8). I n t he case of N S C L C, a retr os pecti ve a nalys is of a s u bset of patie nts i n t he O A K 
st u d y de m o nstrate d pr ol o n ge d cli nical be nefit be y o n d P D treat me nt wit h t he P D -L 1  anti b o d y 
atez oliz u ma b i n t he 2 L  setti n g (Ritt me y er 2 0 1 7 ). I n t he B T C c o h ort of t he bi ntraf us p alfa P hase I 
st u d y, 2 at ypical res p o nses ( 1 pse u d o pr o gressi o n a n d 1 dela y e d res p o nse or a bsc o pal effect case, 
o ut of 3 0 partici pa nts) were o bser ve d b y  In vesti gat or assess me nt after P D acc or di n g t o R E CI S T 
1. 1. Alt h o u g h t he e vi de nce t o c o nti n ue P D -1/ P D -L 1 treat ment b e y o n d P D is li mite d, t his st u dy 
will e nc o ura ge I n vesti gat ors t o c o nti n ue bi ntraf us p alfa / place b o treat me nt u ntil c o nfir me d P D.
Pr o g n ostic F act ors
Se veral pre dicti ve/ pr o g n ostic fact ors i nfl ue nce O S. 
Acc or di n g t o 
a u ni variate a nal ys is 
(S uz u ki 2 0 1 9 ), t he f oll o wi n g fact ors i nfl ue nce O S f or ge mcita bi ne pl us cis plati n treat me nt:

Easter n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us ( E C O G P S) 0 vers us 1- 2 ( H R: 2. 3 8 
[ 1.7 0- 3. 3 3 ])

L ocall y  a d va nce d disease vers us metastatic diseas e ( H R: 1. 5 1 [ 1. 0 2- 2. 3 0])

A bse nce vers us prese nce of p erit o neal disse mi nati o n ( H R: 1. 5 6 [ 1. 0 7- 2. 2 2])

Prese nce vers us a bse nce of pri or s ur gical resecti o n ( H R: 1. 7 2 [ 1. 1 5-2. 6 6]) .
A K orea n gr o u p (Ki m 2 0 1 7 ) re p orte d fact ors as:

L ocall y  a d va nce d disease vers us i nitiall y  metastatic disease ( H R: 1. 9 2 [ 1. 3 8-2. 6 7])

N or mal vers us ele vate d b aseli ne car b o h y drate a nti ge n 1 9- 9 ( H R: 1. 3 1 [ 1. 0 -1. 5 8])
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 2 / 2 1 3

M eas ura ble disease b y R E CI S T 1. 1 : n o vers us yes  ( H R: 1. 4 0 [ 1. 1 5-1. 7 0]). 
T o date, n o pre dicti ve fact ors ha ve bee n i de ntifie d f or t he efficac y  of bi ntraf us p alfa i n B T C fr o m 
t he P hase I st u d y. Mis matc h re pair– deficie nt t u m ors are m ore res p o nsi ve t o P D -1/ P D -L 1  bl oc ka de 
t ha n mis matc h re pair– pr oficie nt t u m ors (Le 2 0 1 5 ). H o we ver, micr osatellite i nsta bilit y ( M SI)-hi g h 
was re p orte d i n o nl y 1 % of 1 0 2 C C A patie nts (Wi n kel ma n n 2 0 1 8 ). Gi ve n t he desi g n, eli gi bilit y 
criteria, a n d practical c o nsi derati o ns of t he c urre nt st u d y , a n d t he fact t hat t he rele va nce of P D-L 1  
e x pressi o n i n t he t u m or or t u m or micr oe n vir o n me nt i n B T C t o pre dict treat me nt res p o nse t o 
P D -1/ P D -L 1  a nti b o dies is n ot y et u n derst o o d (i n St u d y M S 2 0 0 6 4 7 _ 0 0 0 8 , n o c orrelati o n bet wee n 
res p o nse a n d P D-L 1 e x pressi o n was o bser ve d i n 3 0 pa rtici pa nts wit h B T C, of w h o m 5 3. 3 % were 
P D -L 1  positi ve), t he 3 fact ors o utli ne d i n Secti o n 4. 1. 2
were
selecte d as ra n d o mizati o n 
stratificati o n fact ors i n t his st u d y.
St u d y Bli n di n g
A ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d desi g n was selecte d f or t his st u d y t o re d uce bias 
i n t he e val uati o n of t he efficac y, safety, a n d patie nt -re p orte d o utc o mes ( P R Os). Bli n di n g is 
i m p orta nt si nce k n o wle d ge of treat me nt assi g n me nt c o ul d p ote ntiall y bias t he partici pa nt’s relate d 
o utc o mes or I nvesti gat or assess me nt of t u m or i ma gi n g. T he use of place b o i n c o m bi nati o n wit h 
c he m ot hera p y will e ns ure t he o bjecti vit y  of I n vesti gat or-assesse d pr o gressi o n as well as a n y 
decisi o ns t o i nterr u pt/ disc o nti n ue t hera py. T he d o u ble -bli n d , place b o -c o ntr olle d nat ure of t he 
st u dy als o all o ws o bjecti ve assess me nt of t he relate d ness of A Es , w hile P R Os ca n be i nter prete d 
m ore relia bl y i n d o u ble -bli n d st u dies.
T he safet y assess me nts t o be perf or me d are sta n dar d f or o nc ol o g y  st u dies a n d will be use d t o assess 
t he be nefit -ris k bala nce of c o m bi nati o n t hera p y wit h bi ntraf us p alfa a n d ge mcita bi ne pl us cis plati n.
It is ac k n o wle d ge d t hat e ve n i n a d o u ble -bli n d setti n g, A Es t hat are u ni q ue t o acti ve treat me nt, 
e. g., s ki n-relate d t o xicit y, ma y  re veal assi g n me nt t o bi ntraf us p alfa treat me nt. H o we ver, as m ost 
partici pa nts will n ot e x perie nce t hese t o xicities, t he ris k of re p orte d A Es lea di n g t o u n bli n di n g is 
li mite d. M ore o ver, t he bli n de d desi g n will all o w a better c haracterizati o n of t he safety pr ofile of 
bi ntraf us p alfa b y  clarif yi n g t he relati ve perce nta ge of relate d A E s re p orte d f or t he 2 treat me nt 
ar ms.
Detecti o n of I nterstiti al L u n g Dise ase ( J a p a nese Sites) 
F or pr o per a n d earl y d etecti o n of e ve nts of I L D/ p ne u m o nitis i n Ja pa nese partici pa nts, ser u m Kre bs 
v o n de n L u n ge n - 6 (K L - 6), s urfacta nt pr otei n ( S P)-A a n d S P -D le vels will be meas ure d i n st u d y 
sites i n Ja pa n. I ncl usi o n of t hese mar kers will p ote ntiall y hel p t o i de ntif y treat me nt-e mer ge nt l u n g 
t o xicit y at t he earliest o p p ort u nit y  an d all o w f or f urt her i n vesti gati o ns t o be i nitiate d pr o m ptl y , 
e. g., c hest c o m p ute d t o m o gra p hy ( C T) f or c o nfir mat or y dia g n osis (K u b o 2 0 1 3 ). I n a P hase I st u d y 
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 3 / 2 1 3
of bi ntraf us p alfa i n Asia, treat me nt-relate d Gra de 5 I L D e ve nts were
re p orte d i n 2 Ja pa nese 
partici pa nts p ost -c he m ot hera p y i n a 2 L + B T C c o h ort of 3 0 partici pa nts . O ne 
partici pa nt 
e x perie nce d I L D o n treat me nt after 3 d oses of bi ntraf us p alfa . T he sec o n d ha d Gra de 3 I L D after 
3 d oses . T he patie nt i nitiall y rec o vere d b ut s u bse q ue ntl y w orse ne d wit h fatal o utc o me 6 m o nt hs 
after t he i nitial dia g n osis of I L D a n d last bi ntraf us p alfa d ose. T hese 2 cases of treat me nt-relate d 
Gra de 5 i nterstitial p ne u m o nitis re prese nt a n i nci de nce of a p pr o xi matel y 3% 
i n Ja pa nese 
partici pa nts ( o ut of 6 6 J apa nese pa rtici pa nts) a n d of 0. 3 % o verall i n bi ntraf us p alfa st u dies (i.e., 
2 A Es i n m ore t ha n 6 7 0 treate d partici pa nts). Acc or di n g t o t he literat ure, a hi g her i nci de nce of I L D 
is o bser ve d i n t he Ja pa nese p o p ulati o n (Ta ka da 2 0 1 4,  Az u ma 2 0 0 7 ). T heref ore, c o nsiste nt wit h 
g ui deli nes f or dr u g -i n d uce d l u n g i nj ur y in Ja pa n, ser u m K L -6, S P -A, a n d S P -D le vels will be 
meas ure d i n Ja pa nese partici pa nts.
4. 3
J ustific ati o n f or D ose
4. 3. 1
C he m ot her a p y
T he d oses of ge mcita bi ne ( 1 0 0 0 m g / m2) a n d cis plati n ( 25 m g/ m 2) selecte d f or t his st u d y are t he 
d oses r o uti nel y use d as S o C i n t he 1 L  treat me nt of B T C. C he m ot hera p y will be a d mi nistere d o n 
D a y s 1 a n d 8 of eac h 3 -wee k c y cle.
4. 3. 2
B i ntr af us p alf a wit h C he m ot her a p y
Si nce ge mcita bi ne a n d cis plati n are a d mi nistere d e ver y 3 wee ks, t he sa me d osi n g i nter val f or 
bi ntraf us p alfa is preferre d f or c o n ve nie nce a n d c o m plia nce. T he rec o m me n de d P hase II d ose 
( R P 2 D) f or bi ntraf us p alfa i n c o m bi nati o n wit h c he m ot hera pies is 2 4 0 0 m g , a d mi nistere d as a n 
i ntra ve n o us i nf usi o n o nce e v er y 3 wee ks , a n d was selecte d as f oll o ws:

T he R P 2 D f or d osi n g e ver y 2 wee ks wit h bi ntraf us p alfa i n m o n ot hera p y st u dies ( 1 2 0 0 m g) 
was selecte d base d o n P hase I data, P K -p har mac o d y na mic a nal ys is, a n d p o p ulati o n P K 
( p o p P K) a n d e x p os ure -res p o nse m o deli n g a n d si m ulati o ns. T hese data were als o use d t o 
esti mate t he tar get stea d y- state Ctr o u g h ( Ctr o u g h-ss); refer t o t he I B f or f urt her i nf or mati o n

F or t he selecti o n of t he o nce e ver y 3 wee ks d ose, it was ass u me d t hat t o ac hie ve efficac y, t he 
C tr o u g h-ss w o ul d nee d t o be si milar t o t hat ac hie ve d wit h 1 2 0 0 m g o nce e ver y 2 wee ks
( m o n ot hera py R P 2 D) d osi n g, a n d t hat t he maj orit y  of partici pa nts s h o ul d ac hie ve t he tar get 
C tr o u g h-ss. T he bi ntraf us p alfa 2 4 0 0 m g  e ver y 3 wee ks d osi n g re gi me n was selecte d base d o n 
t hese ass u m pti o ns a n d p o pulati o n P K -base d pre dicti o n of C tr o u g h-ss. T he safet y of 2 4 0 0 m g  o nce 
e ver y 3 wee ks i n m o n ot hera p y  setti n gs is s u p p orte d b y  preli mi nar y assess me nt of safet y an d 
e x p os ures ac hie ve d i n t he P hase I st u d y ( St u d y E M R 2 0 0 6 4 7 _ 0 0 1 ), w hic h i ncl u de d 0. 3 t o 
3 0 m g/ k g d ose escalati o n c o h orts (i ncl u di n g 3 partici pa nts w h o recei ve d at least bi ntraf us p alfa
2 4 0 0 m g e ver y 2 wee ks) a n d e x p os ure-safety m o deli n g ; refer t o t he I B f or f urt her i nf or mati o n

Base d o n t he k n o w n cleara nce mec ha nis m, t he tra nsie nt mil d c yt o ki ne pr ofile c ha n ge wit h 
bi ntraf us p alfa d osi n g, a n d t he o bser ve d safety pr ofile of bi ntraf us p alfa m o n ot hera p y, a n d 
sta n dar d d ose c he m ot hera p y re gi me ns, P K i nteracti o ns or o verla p pi n g t o xicities of bi ntraf us p 
alfa a n d c he m ot hera p y are c o nsi dere d u nli kel y, e xce pt f or blee di n g a n d a ne mia. Gi ve n t his 
h y p ot hesis, n o a dj ust me nt i n d ose selecti o n f or c he m ot hera pies is re q uire d, a n d t he bi ntraf us p 
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 4 / 2 1 3
alfa 2 4 0 0 m g  o nce e ver y 3 wee ks d ose is c o nsi dere d o pti mal f or c o m bi nati o n st u dies.H o we ver, 
i n t he cases of blee di n g e ve nts, a d ose m o dificati o n mi g ht be re q uire d. 1 2 0 0 m g Q 3 W
bi ntraf us p alfa d ose is rec o m me n de d f or t he d ose re d ucti o n i n a partici pa nt wit h a s us pecte d 
blee di n g e ve nt, si nce t his d ose is e x pecte d t o re d uce t he ris k of blee di n g ( base d o n a rece nt 
e x p os ure -safety a nal ys is f or blee di n g A Es c o n d ucte d wit h preli mi nar y  data fr o m P hase I a n d 
P hase II st u dies), w hile mai ntai ni n g p har mac ol o gicall y  rele va nt e x p os ures ass ociate d wit h 
P D -L- 1 i n hi biti o n. F or f urt her details o n d ose m o dificati o ns f or ma na ge me nt
of blee di n g s e e
Secti o n  6. 9. 5 .
I n co ncl usi o n, t he p o p ulati o n P K -base d esti mati o n of efficaci o us tar get tr o u g h c o nce ntrati o n f or 
d osi n g o nce e ver y 3 wee ks, e val uati o n of p ote ntial o verla p pi n g t o xicities, P K i nteracti o ns of t he 
c o m bi nati o n, a n d pla n ne d miti gati o n meas ures (i ncl u di n g d ose i nterr u pti o ns a n d re d ucti o ns) i n t he 
st u d y su p p ort t he safet y eval uati o n of bi ntraf us p alfa at 2 4 0 0 m g  o nce e ver y 3 wee ks
i n 
c o m bi nati o n wit h c he m ot hera p y i n t his st u d y.
4. 4
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he last 
sc he d ule d pr oce d ure as s h o w n i n Secti o n 1. 3.
T he e n d of t he st u d y is defi ne d as t he date of t he data c ut off f or t he pri mar y  OS a nal ys is w he n 
3 3 4 partici pa nts ha ve die d. H o we ver, if t he st u d y d oes n ot e x pa n d i nt o P hase III b ut c o nti n ues as 
a P hase II st u d y, t he e n d of st u d y is defi ne d acc or di n gl y, as t he data c ut off date f or t he pri mar y  O S 
a nal ys is w he n 6 0 % of partici pa nts ha ve die d. 
T he S p o ns or ma y  ter mi nate t he st u d y at a n y ti me o nce access t o t he st u d y inter ve nt i o n f or 
partici pa nts still be nefiti n g is pr o vi de d via a r oll o ver st u d y, e x pa n de d access, mar kete d pr o d uct, 
or a n ot her mec ha nis m of access, as a p pr o priate.
5
St u d y P o p ul ati o n
T he criteria i n Secti o ns 5. 1 a n d 5. 2 are desi g ne d t o e nr oll o nl y  partici pa nts, w h o are a p pr o priate 
f or t he st u d y; t here by,  ens uri n g t he st u d y fulfills its o bjecti ves. All rele va nt me dical a n d 
n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o c o nsi derati o n w he n deci di n g w het her a partici pa nt is 
s uita ble f or t his st u d y.
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi on a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical care, 
t he I nvesti gat or will c o nfir m t hat t he partici pa nt or t he partici pa nt’s le gal re prese ntati ve (w here 
all o we d b y  local la ws a n d re g ulati o ns) has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n 
A p pe n di x 2 .
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 5 / 2 1 3
A ge
1.
Are ≥1 8 ( or ≥2 0 i n Ja pa n a n d Tai wa n or a ge le gall y c o nsi dere d t o be a n a d ult) ye ars of a ge at 
t he ti me of si g ni n g t he i nf or me d c o nse nt. I n Ja pa n, a partici pa nt a ge d < 2 0 ye ars of a ge b ut 
≥1 8 ye ars of a ge m a y  p artici pate if writte n i nf or me d c o nse nt fr o m his/ her pare nt or g uar dia n 
is pr o vi de d i n a d diti o n t o t he partici pa nt’s writte n i nf or me d c o nse nt.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
Are partici pa nts wit h hist ol o gicall y or c y t ol o gicall y co nfir me d l ocal l y ad va nce d or metastatic 
B T C, i ncl u di n g i ntra he patic C C A , e xtrahe patic C C A , gall bla d der ca ncer, a n d a m p ulla of 
V ater’s ca ncer. T he hist ol o gical ori gi n of a m p ullar y carci n o mas (i ntesti nal, pa ncreatic o biliar y , 
or ot her ) will be c ollecte d . Hist ol o gical s u bt ypes s uc h as a sarc o mat oi d t u m or or H C C mi xe d 
s u bt ype, f or w hic h - ge mcita bi ne a n d cis plati n treat me nt are n ot c o nsi dere d as t he sta n dar d of 
care s h o ul d be e xcl u de d. C o ntact Me dical M o nit or f or rare s u bt y pes.
3.
Nai ve
t o c he m ot hera p y , i m m u n ot hera py, 
a n d i nter ve nti o nal ra di ol o gical treat me nt 
(tra nsarterial c he m o-e m b olizati o n, tra nsarterial e m b olizati o n, tra nsarterial i nf usi o n) f or l ocall y 
a d va nce d or metastatic B T C. Partici pa nts w h ose disease has rec urre d ≥6 m o nt hs after 
c o m pleti o n of ne oa dj u va nt or a dj u va n t treat me nts will be c o nsi dere d eli gi ble.
4.
A vaila bilit y  of t u m or tiss ue ( pri mar y or metastatic) (fres h or archi val bi o psies ) bef ore t he first 
a d mi nistrati o n of st u d y i nter ve nti o n. A vaila bilit y  of t u m or tiss ue is ma n dat or y e xce pt f or t he 
safety r u n-i n part . Br us h c yt ol o g y an d cell bl oc ks are n ot acce pta ble. T u m or tiss ue (fres h or 
arc hi val) m ust be s uita ble f or bi o mar ker assess me nt as descri be d i n t he La b orat or y  Ma n ual.
5.
At least 1 meas ura ble lesi o n acc or di n g t o R E CI S T 1. 1. Partici pa nts i n t he safet y r u n -i n par t d o 
n ot re q uire a meas ura ble lesi o n at baseli ne.
6.
E C O G P S of 0 or 1 at st u d y  e ntr y a n d at Wee k 1, Da y  1 pri or t o d osi n g .
7.
Life e x pecta nc y  of ≥1 2 wee ks, as j u d ge d b y t he I n vesti gat or.
8.
A de q uate he mat ol o gical f u ncti o n defi ne d b y  white bl o o d cell c o u nt ≥2. 0 × 1 0 9/ L wit h a bs ol ute 
ne utr o p hil c o u nt ≥1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥0. 5 × 1 0 9/ L, platelet c o u nt ≥1 0 0 × 1 0 9/ L, 
a n d he m o gl o bi n ( H g b) ≥9 g/ d L ( partici pa nts ma y  ha ve bee n tra nsf use d) at st u d y e ntr y an d at 
W ee k 1 Da y 1 pri or t o d osi n g . 

Pre vi o usl y  tra nsf use d partici pa nts are all o we d i n t he st u d y wit h a sta ble H g b of ≥9 g/ d L  at 
t he ti me of st u d y e ntr y.
9.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤1. 5 × u p per li mit of n or mal 
( U L N), a n as partate a mi n otra nsferase le vel ≤3. 0 × U L N, a n d a n ala ni ne a mi n otra n sferase 
le vel ≤3. 0 × U L N. F or partici pa nts wit h li ver i n v ol ve me nt, as partate a mi n otra nsferase 
≤5. 0 × U L N a n d ala ni ne a mi n otra nsferase ≤5. 0 × U L N are acce pta ble.
1 0. A de q uate re nal f u ncti o n defi ne d b y  an esti mate d creati ni ne cleara nce ( Cr Cl) > 5 0 m L / mi n 
acc or di n g t o t he C oc kcr oft -Ga ult f or m ula or b y meas ure of Cr Cl fr o m 2 4- h o ur uri ne c ollecti o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 6 / 2 1 3

Cr Cl ( m L / mi n) = ( 1 4 0-a ge) × wei g ht ( k g) / ( 7 2 × ser u m creati ni ne [ Cr jaffe])

If fe male, × 0. 8 5

If creati ni ne
is meas ure d 
b y  t he e nz ymatic 
met h o d, 
a d d 
0. 2 
a n d 
use 
as 
Cr jaffe = 0. 2 + Cr e nz yme .
1 1 Al b u mi n ≥2. 8 g/ d L .
1 2 A de q uate c oa g ulati o n f u ncti o n defi ne d as pr ot hr o m bi n ti me or i nter nati o nal n or malize d rati o
≤1. 5 × U L N u nless t he partici pa nt is recei vi n g a ntic oa g ula nt t hera p y.
1 3
He patitis B vir us ( H B V) de o x yri b o n ucleic aci d (D N A ) p ositi ve partici pa nts m ust be treate d 
a n d o n a sta ble d ose of a nti virals (e. g., e nteca vir, te n of o vir, or la mi v u di ne; a def o vir or 
i nterfer o n is n ot all o we d) at st u d y entr y  an d wit h pla n ne d m o nit ori n g a n d ma na ge me nt 
i ncl u di n g baseli ne H B V
D N A 
q ua ntit y  acc or di n g t o a p pr o priate la beli n g g ui da nce. 
Partici pa nts recei vi n g acti ve he patitis C vir us ( H C V) t hera p y m ust be o n a sta ble d ose at st u d y 
e ntr y an d wit h pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o a p pr o priate la beli n g 
g ui da nce of a p pr o ve d a nti viral.
Se x
1 4 Are male or fe male: 

M ale P artici pa nt s
A gree t o t he f oll o wi n g d uri n g t he i nter ve nti o n peri o d a n d f or at least 4 m o nt hs
after t he last 
d ose of st u d y inter ve nti o n ( 3 5 d a y s c orres p o n di n g t o t he ti me nee de d t o eli mi nate a n y st u d y 
i nter ve nti o ns, e. g., 5 ter mi nal half-li ves pl us 9 0 da y s f or s per mat o ge nic c ycle):

Refrai n fr o m d o nati n g s per m
P L U S, eit her:

A bstai n fr o m a n y acti vit y t hat all o ws f or e x p os ure t o ejac ulate
O R

Use a male c o n d o m : 

W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial w h o is n ot c urre ntl y
pre g na nt, a n d a d vise her t o use a hi g hl y effecti ve c o ntrace pti ve met h o d wit h a fail ure rate 
of < 1 % per y ear, as descri be d i n  A p pe n di x 3 , si nce a c o n d o m ma y brea k or lea k

W he n e n ga gi n g i n a n y acti vit y  t hat all o ws f or e x p os ure t o ejac ulate.

F e male P artici pa nts
Are n ot pre g na nt or breastfee di n g, a n d at least 1 of t he f oll o wi n g c o n diti o ns a p plies:

N ot a w o ma n of c hil d beari n g p ote ntial
O R
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 7 / 2 1 3

If a w o ma n of c hil d beari n g p ote ntial , a gree t o use a hi g hl y effecti ve c o ntrace pti ve met h o d (i .e., 
wit h a fail ure rate of < 1 % per ye ar), prefera bl y wit h l o w user de pe n de nc y , as descri be d i n 
A p pe n di x 3 , f or t he f oll o wi n g ti me peri o ds:

Bef ore t he firs t d ose of st u d y i nter ve nti o n(s), if usi n g h or m o nal c o ntrace pti o n:

Has c o m plete d at least o ne 4- wee k c ycle of a n oral c o ntrace pti ve pill a n d has eit her ha d or 
has be g u n her me nses
O R

Has use d a de p ot c o ntrace pti ve or e xte n de d -c ycle c o ntrace pti ve f or at least 2 8 da ys a n d has 
a d oc u me nte d ne gati ve pre g na nc y  test usi n g a hi g hl y se nsiti ve assa y

D uri n g t he i nter ve nti o n peri o d

After t he st u d y inter ve nti o n peri o d (i.e., after t he last d ose of st u d y inter ve nti o n is a d mi nistere d) 
f or at least 6 5 d a y s (ti me nee de d t o eli mi nate a n y st u d y inter ve nti o ns , e. g., 5 ter mi nal half-li ves 
pl us 3 0 da y s f or a me nstr ual c ycle), a n d as i n dicate d i n t he res pecti ve la bel ( S u m mar y of 
Pr o d uct C haracteristics [ S m P C]) f or ge mcita bi ne a n d cis plati n. Partici pa nts ha ve t o agree t o t he 
f oll o wi n gs: 

W o me n of c hil d beari n g p ote ntial s h o ul d refrai n fr o m d o nati n g e g gs fr o m t he start of d osi n g 
u ntil 2 m o nt hs after disc o nti n ui n g st u d y  i nter ve nti o n.

T he I n vesti gat or e val uates t he effecti ve ness of t he c o ntrace pti ve met h o d i n relati o ns hi p t o 
t he first d ose of st u d y i nter ve nti o n.

Ha ve a ne gati ve ser u m or hi g hl y  se nsiti ve uri ne pre g na nc y  test, as re q uire d b y  local re g ulati o ns, 
wit hi n 2 4 h o urs bef ore t he first d ose of st u d y inter ve nti o n. If a uri ne test ca n n ot be c o nfir me d 
as ne gati ve ( e. g., a n a m bi g u o us res ult), a ser u m pre g na nc y  test is re q uire d.

A d diti o nal re q uire me nts f or pre g na nc y testi n g d uri n g a n d after st u d y i nter ve nti o n are pr o vi de d 
i n Secti o n 8. 2. 3.

T he I n vesti gat or re vie ws t he me dical hist or y , me nstr ual hist or y , a n d rece nt se x ual acti vit y 
t o decrease t he ris k f or i ncl usi o n of a fe male wit h a n early, u n detecte d pre g na nc y .
I nf or me d C o nse nt
1 5. Ca pa ble of gi v i n g si g ne d i nf or me d c o nsent , as i n dicate d i n A p pe n di x 2,  w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he Inf or me d C o nse nt F or m (IC F) 
a n d t his pr ot oc ol.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Pre vi o us a n d/ or i nterc urre nt ca ncers. Wit h t he e xce pti o n of: c urati vel y -treate d ca ncers wit h n o 
rec urre nce i n > 3 years or e arl y  ca ncers treate d wit h c urati ve i nte nt, i ncl u di n g b ut n ot li mite d 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 8 / 2 1 3
t o cer vical carci n o ma i n sit u, s u perficial, n o ni n vasi ve bla d der ca ncer, basal cell carci n o ma,
s q ua m o us cell carci n o ma i n sit u, or en d osc o picall y resecte d gastr oi ntesti nal ca ncers li mite d i n 
m uc osal la y er. 
2.
Ra pi d cli nical deteri orati o n n ot relate d t o mali g na nc y w hic h, i n t he o pi ni o n of t he I nvesti gat or, 
ma y  pre dis p ose t o i na bilit y to t olerate treat me nt or st u d y pr oce d ures at st u d y entr y  an d at 
Wee k
1 Da y  1 pri or t o d osi n g.
3.
Partici pa nts wit h s ym pt o matic 
ce ntral ner v o us s yste m ( C N S) metastases 
are e xcl u de d. 
Partic i pa nts wit h a hist or y of treate d C N S metastases ( b y s ur ger y or ra diati o n t hera py) are n ot 
eli gi ble u nless t he y are j u d ge d t o ha ve f ull y rec o vere d fr o m treat me nt.
4.
Recei pt of a n y or ga n tra ns pla ntati o n, i ncl u di n g all o ge neic ste m-cell tra ns pla ntati o n, b ut wit h
t he e xce pti o n of tra ns pla nts t hat d o n ot re q uire i m m u n os u p pressi o n (e. g., c or neal tra ns pla nt, 
hair tra ns pla nt).
5.
Si g nifica nt ac ute or c hr o nic i nfecti o ns i ncl u di n g:

K n o w n hist or y  of p ositi ve test f or h u ma n i m m u n o deficie nc y vir us ( HI V) or k n o w n ac q uire d 
i m m u n o deficie nc y sy n dr o me (testi n g at S cree ni n g is n ot re q uire d). If a n I nvesti gat or has a 
str o n g s us pici o n of HI V i nfecti o n wit h o ut k n o w n hist or y for a partici pa nt i n scree ni n g, b ut t he 
partici pa nt ref uses testi n g, disc uss wit h Me dical M o nit or t o assess eli gi bilit y. ( N ote: HI V 
testi n g is n ot ma n date d f or st u d y incl usi o n; h o we ver, if it is perf or me d at a n y p oi nt i n scree ni n g 
or w hile o n st u d y, a site m ust c o nse nt t he par tici pa nt f or HI V testi n g as per l ocal sta n dar d 
g ui da nce) .

Acti ve t u berc ul osis ( prese nce of cli nical s y m pt o ms, p h y sical or ra di o gra p hic fi n di n gs of acti ve 
t u berc ul osis).

U nc o ntr olle d biliar y  infecti o n. Biliar y  tract o bstr ucti o n s h o ul d be release d b y  ste nti ng or 
perc uta ne o us tra ns he patic biliar y  drai na ge ( P T B D). Partici pa nts wit h biliar y  obstr ucti o n s h ou l d 
ha ve a de q uate biliar y  drai na ge wit h n o e vi de nce of o n g oi n g i nfecti o n wit h o ut a nti bi otics 
treat me nt d uri n g t he scree ni n g peri o d.

Acti ve bacterial , f u n gal, or viral i nfecti o n ( wit h t he e xce pti o n of he patitis B a n d he patitis C) 
re q uiri n g sys te mic t hera p y d uri n g t he scree ni n g peri o d .
6.
Acti ve a ut oi m m u ne disease t hat mi g ht deteri orate w he n recei vi n g a n i m m u n osti m ulat or y 
a ge nt:

P artici pa nts wit h t ype 1 dia betes , vitili g o, al o pecia, ps oriasis, h y p o- or h y pert h y r oi d disease n ot 
re q uiri n g i m m u n os u p pressi ve treat me nt are eli gi ble.

Partici pa nts re q uiri n g h or m o ne re place me nt wit h c ortic oster oi ds are eli gi ble if t he ster oi ds are 
a d mi nistere d o nl y  for t he p ur p ose of h or m o nal re place me nt a n d at d oses ≤1 0 m g of pre d nis o ne 
or e q ui vale nt per da y .

A d mi nistrati o n of ster oi ds f or ot her c o n diti o ns t hr o u g h a r o ute k n o w n t o res ult i n a mi ni mal 
s yste mic e x p os ure (t o pical, i ntra nasal, i ntra-oc ular, or i n halati o n) is acce pta ble .
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
5 9 / 2 1 3
7.
Hist o r y of, or c o nc urre nt, interstitial l u n g disease.
8.
K n o w n hist or y  of h yperse nsiti vit y  reacti o ns t o bi ntraf us p alfa or its pr o d ucts or k n o w n se vere 
h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies ( Gra de ≥3 Nati o nal Ca ncer I nstit ute 
[N CI ]-C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts [ C T C A E ] Versi o n 5. 0 ), a ny hist or y 
of a na p h yl a xis, or rece nt ( wit hi n 5 m o nt hs) hist or y of u nc o ntr olle d ast h ma.
9.
Cli nicall y  si gnifica nt car di o vasc ular/cere br o vasc ular disease as f oll o ws: cere bral vasc ular 
acci de nt/str o ke ( < 6 m o n t hs pri or t o e nr oll me nt), m y ocar dial i nfarcti o n ( < 6 m o nt hs pri or t o 
e nr oll me nt), u nsta ble a n gi na, c o n gesti ve heart fail ure ( Ne w Y or k 
Heart 
Ass ociati o n 
Classificati o n ≥Class II), or seri o us car diac arr hyt h mia.  
1 0.
a.
Ot her 
se vere, ac ute , or c hr o nic me dical 
c o n diti o n s, i ncl u di n g i m m u ne c olitis, 
i nfla m mat or y bo wel disease, i m m u ne p ne u m o nitis, or ps y c hiatric c o n diti o ns, i ncl u di n g 
rece nt ( wit hi n t he past year) or acti ve s uici dal i deati o n or be ha vi or. 
b. Partici pa nts wit h hist or y  of blee di n g diat hesis or rece nt maj or blee di n g e ve nts c o nsi dere d 
b y  t he I n vesti gat or as hi g h ris k f or st u d y i nter ve nti o n are als o e xcl u de d .
1 1. C hr o nic o bstr ucti ve p ul m o nar y  disease e xacer bati o n or ot her res pirat or y ill ness re q uiri n g 
h os pitalizati o n or precl u di n g st u d y t hera p y wit hi n 3 0 da y s bef ore ra n d o mizati o n. 
1 2. Partici pa nts w h o 
are ca n di dates f or li ver tra ns pla ntati o n a n d w h o 
ca n recei ve t he 
tra ns pla ntati o n wit hi n a me dicall y acce pta ble peri o d.
Pri or/ C o nc o mit a nt T her a p y
1 3. C o nc urre nt treat me nt wit h n o n per mitte d dr u gs. Par tici pa nts w h o ha ve c o m plete d pri or 
a dj u va nt t hera p y ≥6 m o nt hs pri or t o ra n d o mizati o n are eli gi ble.
1 4. Pri or t hera py wit h 
a n y a nti b o d y/ dr u g tar geti n g T- cell c ore g ulat or y pr otei ns (i m m u ne 
c hec k p oi nts) ,
i ncl u di n g b ut 
n ot 
li mite d t o
a nti-P D - 1, a nti-P D -L 1, 
a nti-c yt ot o xic 
T- l ym p h oc y t e-ass ociate d a nti ge n 4 ( C T L A - 4) a nti b o d y, or a nti-4- 1 B B a nti b o d y is n ot 
all o we d, i ncl usi ve of l ocalize d a d mi nistrati o n of s uc h a ge nts. 
1 5. Pri or t hera p y wit h a n y a nti b o d y / dr u g tar geti n g T G F β/ T G F β rece pt or. 
1 6. Ra diati o n wit hi n 2 8 da y s ot her t ha n f ocal palliati ve b o ne-directe d ra di ot hera p y . 
1 7. S y ste mic t hera p y wit h i m m u n os u p pressi ve a ge nts wit hi n 7 da y s bef ore t he start of st u d y 
i nter ve nti o n; or use of a n y in vesti gati o nal dr u g wit hi n 2 8 da y s bef ore t he start of st u d y 
i nter ve nti o n. 
1 8. Li ve v acci ne a d mi nistrati o n wit hi n 4 wee ks of st u d y i nter ve nti o n a d mi nistrati o n.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 9. Partici pati o n i n a n y  c o nc urre nt i nter ve nti o nal cli nical st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 0 / 2 1 3
Di a g n ostic Assess me nts
2 0. U na ble t o t olerate C T or ma g netic res o na nce i ma gi n g ( M RI) i n t he o pi ni o n of t he I n vesti gat or 
a n d/ or aller g y t o c o ntrast material.
Ot her E xcl usi o ns
2 1. Maj or s ur ger y wit hi n 2 8 da ys bef ore t he start of st u d y inter ve nti o n (e xcl u di n g pri or dia g n ostic 
bi o ps y a n d ste nti n g/ P T B D f or t he p ur p ose of releasi n g biliar y tract o bstr ucti o n). 
2 2. Pre g na nc y  or breastfee di n g. 
2 3. K n o w n alc o h ol or dr u g a b use. 
2 4. Le gal i nca pacit y or li mite d le gal ca pacit y. 
5. 3
Lifest yle C o nsi der ati o ns
N o s pecific lifest yl e or dietar y restricti o ns are re q uire d d uri n g t he st u d y.
5. 4
Scree n F ail ures
I n di vi d uals w h o d o n o t meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) m a y  be 
rescree ne d. Rescree ne d partici pa nts will be assi g ne d a ne w partici pa nt n u m ber.
Partici pa nts w h o ha ve a n a b n or mal li ver f u ncti o n test at S cree ni n g, t hat ma y n or malize wit h biliar y 
drai na ge or ste nti n g, ca n be rescree ne d. It is rec o m me n de d t hat partici pa nts wit h ot her la b orat or y 
a b n or malities t hat ma y res ol ve, c o nc o mita nt me dicati o n t hat will be disc o nti n ue d, re q uire me nt of 
re-bi o ps y, or u n de r g oi n g a pr o hi bite d pr oce d ure t hat will be c o m plete d, are disc uss e d wit h t he 
Me dical M o nit or wit h re gar d t o w het her t he scree ni n g wi n d o w ca n b e e xte n de d, rat her t ha n 
scree n-faili n g t he partici pa nt. 
I n ot her sit uati o ns, w he n a partici pa nt is a scree n fail ure, t he site s h o ul d c o ntact t he M e dical 
M o nit or t o disc uss w het her t he partici pa nt ca n be rescree ne d.
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n de d t o be a d mi nis tere d t o a st u d y partici pa nt per t he st u d y pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
Details of t he st u d y  i nter ve nti o ns a d mi nistere d are pr o vi de d i n  Ta ble 6.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 1 / 2 1 3
T a ble 6
St u d y I nter ve nti o n A d mi nistr ati o n
St u d y  I nt er v e nti o n N a m e
B i ntr af u s p alf a
(M 7 8 2 4 )
Pl a c e b o
G e m cit a bi n e a
Ci s pl ati n a
D o s e F or m ul ati o n
St eril e c o n c e ntr at e 
s ol uti o n f or 
i nf u si o n
St eril e c o n c e ntr at e 
s ol uti o n f or 
i nf u si o n. T h e 
c o m p o siti o n of t h e 
pl a c e b o i s i d e nti c al 
t o t h e c o m p o siti o n 
of bi ntr af u s p alf a
dr u g pr o d u ct, 
e x c e pt f or t h e 
pr e s e n c e of 
bi ntr af u s p alf a
C o n c e ntr at e f or 
S ol uti o n f or 
I nf u si o n or P o w d er
C o n c e ntr at e f or 
S ol uti o n f or 
I nf u si o n or P o w d er
U nit D o s e 
Str e n gt h/ D o s a g e L e v el
N ot a p pli c a bl e
D e p e n d s o n 
c o m m er ci al 
pr o d u ct
D e p e n d s o n 
c o m m er ci al 
pr o d u ct
R o ut e of A d mi ni str ati o n
I ntr a v e n o u s 
I ntr a v e n o u s 
I ntr a v e n o u s 
I ntr a v e n o u s
D o s e F r e q u e n c y
Q 3 W
Q 3 W
O n D a y 1 a n d 
D a y 8, Q 3 W a
O n D a y 1 a n d 
D a y 8, Q 3 W a
D o si n g I n str u cti o n s (s e e 
S e cti o n 6. 6. 1 )
Fl a t d o s e of 
2 4 0 0 m g 
a d mi ni st er e d o v er 
a mi ni m u m of 
1 h o ur a n d u p t o 
2 h o ur s 
A d mi ni st er e d o v er 
a mi ni m u m of 
1 h o ur a n d u p t o 
2 h o ur s 
1 0 0 0 m g/ m 2
2 5 m g/ m 2
S u p pli er/ M a n uf a ct ur er
M er c k H e alt h c a r e 
K G a A/ 
M er c k
H e alt h c ar e
K G a A/ 
M er c k H e alt h c ar e 
K G a A / c o m m er ci al 
m a n uf a ct ur er
M er c k H e alt h c ar e 
K G a A / c o m m er ci al 
m a n uf a ct ur er
P a c k a gi n g a n d L a b eli n g
St u d y i nt er v e nti o n : E a c h vi al will b e p a c k a g e d a n d l a b el e d p er all a p pli c a bl e 
r e g ul at or y r e q uir e m e nt s a n d G o o d M a n uf a ct uri n g Pr a cti c e G ui d eli n e s.
P a c k a gi n g a n d 
l a b eli n g will b e 
pr e p ar e d t o pr ot e ct 
t h e bli n d e d n at ur e 
of st u d y.
P a c k a gi n g a n d 
l a b eli n g will b e 
pr e p ar e d t o pr ot e ct 
t h e bli n d e d n at ur e 
of st u d y.
If pr o vi d e d a s 
c o m m er ci al 
pr o d u ct, pr ef er t o 
S m P C f or 
g e m cit a bi n e or 
p a c k a g e i n s ert f or 
m or e i nf or m ati o n
If pr o vi d e d a s 
c o m m er ci al 
pr o d u ct, pr ef er t o 
S m P C f or ci s pl ati n 
or p a c k a g e i n s ert 
f or m or e 
i nf or m ati o n
Q 3 W = e v er y 3 w e e k s , S m P C = S u m m ar y of Pr o d u ct C h ar a ct eri sti c s.
a.
C h e m ot h er a p y s h o ul d b e a d mi ni st er e d o v er 8 c y cl e s. If c h e m ot h er a p y c a n n ot b e a d mi ni st er e d o n D a y 1 or 
D a y 8 of a gi v e n c y cl e (f or s af et y, t ol er a bilit y or ot h er u n a v oi d a bl e r e a s o n s), t h e mi s s e d d o s e m a y b e 
a d mi ni st er e d o n D a y 1 5 of t h at c y cl e or m a y b e m a d e u p at t h e e n d of t h e s c h e d ul e d 8 c y cl e s ( u p t o 1 6 
a d mi ni str ati o n s of g e m cit a bi n e a n d ci s pl ati n c o m bi n ati o n) . T h e a d mi ni str ati o n of t h e mi s s e d d o s e o n D a y 1 5 or at 
t h e e n d of 8 c y cl e s i s I n v e sti g at or’ s cli ni c al d e ci si o n.
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he I nvesti gat or, i nstit uti o n, or t he Hea d of t he me dical 
i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 2 / 2 1 3

U p o n recei pt of t he st u d y inter ve nti o n(s), t he I nvesti gat or or desi g nee m ust c o nfir m a p pr o priate 
te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g tra nsit a n d a ny discre pa ncies are re p orte d 
a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y . F urt her 
g ui da nce a n d i nf or mati o n f or st u d y inter ve nti o n acc o u nta bilit y are pr o vi de d i n t he P har mac y 
Ma n ual .

O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter ve nti o n(s) a n d o nl y  aut h orize d 
site staff m a y  su p pl y it. All 
st u d y inter ve nti o n(s) m ust 
be st ore d i n a sec ure, 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns, a n d wit h access li mite d t o t he I n vesti gat or an d a ut h orize d site staff.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y for ms s o t hat acc urate rec or ds 
will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:

C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.

T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.

T he dis p ositi o n (i ncl u di n g ret ur n, i f a p plica ble) of a n y u n use d st u d y i nter ve nti o n(s).

Dates, q ua ntities, batc h n u m bers, vial n u m bers, e x pir y dates, a n d t he partici pa nt n u m bers.

T he I nvesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d oc u me nt t hat partici pa nts were 
pr o vi de d t he d oses specifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d were f ully 
rec o ncile d.

U n use d st u d y inter ve nti o n(s) m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y b e re-dis pe nse d t o a 
differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nta bilit y f or ms.
Destr ucti o n of use d a n d u n use d st u d y inter ve nti o n(s) s h o ul d be perf or me d at site if all o we d b y  
l ocal la w o nl y after S p o ns or a ut h orizati o n. If t hat is n ot p ossi ble, t he S p o ns or/ desi g nee will b e 
res p o nsi ble.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y inter ve nti o n(s) are 
pr o vi de d i n t he P har mac y  Ma n ual.
B i ntraf us p alfa/ place b o s h o ul d be st ore d 
 
 u ntil use. B i ntraf us p 
alfa/ place b o 
 a n d s h o ul d be st ore d i n t he ori gi nal pac ka gi n g.
A d diti o nal i nstr ucti o ns 
f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of bi ntraf us p 
alfa/ place b o will be pr o vi de d i n t he P har mac y  Ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 3 / 2 1 3
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
F or b ot h parts of t he st u d y, t h e i nteracti ve res p o nse s yste m (I X R S) will be use d t o assi g n u ni q ue 
partici pa nt n u m bers a n d t o assi g n st u d y i nter ve nti o n t o partici pa nts at eac h st u d y inter ve nti o n visit.
D uri n g t he ra n d o mize d, d o u ble -bli n d pa rt, f oll o wi n g c o nfir mati o n of a partici pa nt’s eli gi bilit y a n d 
at t he last practical m o me nt pri or t o a d mi nistrati o n of t he st u d y i nter ve nti o n, eac h partici p a nt will 
be ce ntrall y all ocate d t o eit her bi ntraf us p alfa or place b o i n a 1: 1 rati o usi n g t he I XR S , as per a 
c o m p uter-ge nerate d ra n d o mizati o n list.
Bef ore t he st u d y is i nitiate d, t he tele p h o ne n u m ber a n d call-i n directi o ns a n d/ or t he l o g-i n 
i nf or mati o n a nd directi o ns f or usi n g t he I XR S will be pr o vi de d t o eac h site. T he site will c o ntact 
t he IX R S pri or t o starti n g t he a d mi nistrati o n of st u d y i nter ve nti o n f or eac h partici pa nt. 
Treat me nt all ocati o n/ra n d o mizati o n will be stratifie d acc or di n g t o t he f oll o wi n g 3 fact ors:

T y pe of B T C: i ntra he patic C C A vers us e xtra he patic C C A i ncl u di n g a m p ulla of Vater’s ca ncer 
vers us G C

M etastatic at dia g n osis v ers us ot hers, w here “ ot hers” i ncl u des partici pa nts wit h u nresecta ble , 
l ocall y a d va nce d disease at dia g n osis a n d partici pa nts wit h resecta ble disease at dia g n osis w h o 
ha ve u n der g o ne pri or s ur gical resecti o n wit h c urati ve i nte nt

Asia sites vers us n o n- Asia sites
6. 3. 2
Bli n di n g
Bli n di n g Met h o d
F oll o wi n g t he o pe n -la bel, safet y r u n-i n part , t he sec o n d part of t his st u d y will be d o u ble -bli n d. 
T heref ore, t he partici pa nt , In vesti gat or , c o ntract researc h or ga nizati o n (C R O ), a n d S p o ns or 
pers o n nel i n v ol ve d i n t he treat me nt a d mi nistrati o n or cli nical e val uati o n of partici pa nts, will be 
u na ware of t he gr o u p assi g n me nts a n d will n ot k n o w w het her t he st u d y i nter ve nti o n a d mi nistere d 
c o ntai ns bi ntraf us p alfa or place b o. T he c he m ot hera p y a ge nts, ge mcita bi ne a n d cis plati n, will be 
o pe n -la bel.
T he st u d y  tea m will re mai n bli n de d t hr o u g h o ut t he st u d y, i.e., bli n di n g will be mai ntai ne d d uri n g 
t he e ntire st u d y peri o d, e xce pt i n t he e ve nt t hat e mer ge nc y un bli n di n g b y  the S p o ns or’s dr u g safety 
de part me nt is necessar y  for partici pa nt safety as descri be d i n Secti o n  6. 3. 3 . I DM C is n ot part of 
t he st u d y tea m a n d will be u n bli n de d (see Secti o n 8. 2. 4. 2)
Assi g n me nt Met h o d Rete nti o n
T he Bi oa nal ys t will ha ve access t o t he ra n d o mizati o n list t o facilitate a nal ysis of t he P K/
 
sa m ples (i.e., t o a v oi d t he u n necessar y  a nalys is of place b o sa m ples). T he Bi oa nal ys t will n ot s hare 
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 4 / 2 1 3
t he ra n d o mizati o n details or res ults of t he a nal ysis t o pre ve nt the st u d y  tea m fr o m bei n g u n bli n de d 
pre mat urel y. Details will be s pecifie d i n a Fire wall C harter, as a p pr o priate.
U n bli n di n g Cli nic al St u dies f or S a m ple A n al ysis of S peci al D at a
T he bi oa nal yt ical m o nit ors 
a n d a nal yt ical la b orat or y for meas ure me nt 
of bi ntraf us p alfa
c o nce ntrati o ns will be u n bli n de d si nce o btai ni n g t he res ult re veals t he st u d y inter ve nti o n ar m f or 
t he partici pa nt. B i ntraf us p alfa c o nce ntrati o n i nf or mati o n t hat m a y u n bli n d t he st u d y will n ot be 
re p orte d wit h p artici pa nt i de ntifiers t o i n vesti gati ve sites or bli n de d pers o n nel u ntil t he st u d y has 
bee n u n bli n de d.
6. 3. 3
E mer ge nc y U n bli n di n g
I n a n e mer ge nc y, t he In vesti gat or is s olely res p o nsi ble f or deter mi ni n g if u n bli n di n g of a 
partici pa nt’s st u d y inter ve nti o n assi g n me nt is warra nte d. Partic i pa nt safety m ust al wa ys be t he first 
c o nsi derati o n i n t his decisi o n. If t he In vesti gat or deci des t hat u n bli n di n g is warra nte d, t he 
In vesti gat or s h o ul d ma ke e ver y eff ort t o c o ntact t he S p o ns or pri or t o t he u n bli n di n g, u nless t his 
c o ul d dela y e mer ge nc y treat me nt. T he S p o ns or m ust be n otifie d wit hi n 2 4 h o urs after u n bli n di n g.
T he I n vesti gat or m ust pr o vi de t he S p o ns or t he reas o n f or u n bli n di n g wit h o ut re veali n g t he st u d y 
i nter ve nti o n, e xce pt t o t he desi g nate d dr u g safet y re prese ntati ve via t he E mer ge nc y  Un bli n di n g 
N otificati o n F or m. T he date of a n d reas o n f or u n bli n di n g m ust be rec or de d i n t he s o urce d oc u me nts 
a n d electr o nic Case Re p ort F or m ( eC R F ). C o ntact i nf or mati o n f or u n bli n di n g i n a n e mer ge nc y is 
gi ve n o n t he partici pa nt e mer ge nc y  car d pr o vi de d t o eac h partici pa nt, as n ote d i n A p pe n di x 2.
T he S p o ns or’s dr u g safet y de part me nt will s u b mit a n y S us pecte d U ne x pecte d Seri o us A d verse 
Reacti o n
(S U S A R ) re p orts t o re g ulat or y aut h orities a n d et hics c o m mittees wit h u n bli n de d 
i nf or mati o n, per a p plica ble re g ulati o ns. O nl y bli n de d i nf or mati o n will be pr o vi de d t o t he st u d y 
tea m.
6. 4
St u d y I nter ve nti o n C o m pli a nce
All st u d y partici pa nt s will recei ve st u d y inter ve nti o n at t he i n vesti gati o nal site. Well -trai ne d 
me dical staff will m o nit or a n d perf or m t he st u d y i nter ve nti o n a d mi nistrati o n. T he i nf or mati o n of 
eac h st u d y inter ve nti o n a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d ose (c he m ot hera py 
o nl y )/t otal v ol u me i nf use d (bi ntraf us p alfa/ place b o) will be re c or de d o n t he e C R F. I n case of d ose 
re d ucti o n of bi ntraf us p alfa/ place b o, t he date, ti me, a d mi nistere d d ose, t otal v ol u me i nf use d, a n d 
reas o n f or d ose re d ucti o n will be rec or de d o n t he e C R F. T he I n vesti gat or will ma ke s ure t hat t he 
i nf or mati o n e ntere d i nt o t he e C R F re gar di n g st u d y inter ve nti o n a d mi nistrati o n is acc urate f or eac h 
partici pa nt; a n y  reas o n f or n o nc o m plia nce s h o ul d be d oc u me nte d.
N o nc o m plia nce is defi ne d as a partici pa nt missi n g > 1 c ycle of st u d y i nter ve nti o n (i.e., bi ntraf us p 
alfa/ place b o, ge m cita bi ne, a n d/ or cis plati n) f or n o n me dical reas o ns a n d barri n g a n y e xte n uati n g 
circ u msta nces i n t he o pi ni o n of t he I n vesti gat or. E xte n uati n g circ u msta nces s h o ul d be d oc u me nte d 
a n d disc usse d wit h t he S p o ns or i n a d va nce . 
C o nse q ue nces of n o nc o m plia nce m a y  l ea d t o disc o nti n uati o n of st u d y inter ve nti o ns as descri be d 
i n Secti o n 7. 1. I n case of o ver d ose, see Secti o n 8. 4. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 5 / 2 1 3
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he eC R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d fr o m 
t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g a n y 
c ha n ges. F or prescri pti o n a n d o ver-t he-c o u nter me dici nes, 
vacci nes, vita mi ns, a n d her bal 
s u p ple me nts, rec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
6. 5. 1
Resc ue Me dici nes
N ot a p plica ble.
6. 5. 2
Per mitte d Me dici nes
T he o nl y  per mitte d me dicati o ns are t he f oll o wi n g: t he st u d y me dicati o ns, i.e., bi ntraf us p alfa, 
place b o, ge mcita bi ne, a n d cis plati n.
A n y  me dici nes t hat are c o nsi dere d necessar y  to pr otect t he partici pa nt’s welfare i n e mer ge ncies 
ma y  be gi ve n at t he I n vesti gat or’s discreti o n, re gar dless if it res ults i n a pr ot oc ol de viati o n.
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y t he cli nical st u d y pr ot oc ol; see Secti o n 6. 5. 3 ) t hat 
are c o nsi dere d necessar y  for t he partici pa nts’ welfare a n d will n ot i nterfere wit h t he st u d y 
i nter ve nti o n ma y  be gi ve n at t he I n vesti gat or’s discreti o n.
Me dicati o ns 
ma y  be a d mi nistere d f or t he ma na ge me nt 
of s ym pt o ms 
ass ociate d wit h t he 
a d mi nistrati o n of bi ntraf us p alfa / place b o, as re q uire d. T hese mi g ht i ncl u de a nal gesics, a nti na usea 
me dicati o ns, 
a nti hista mi nes, di uretics, a ntia n xiet y 
me dicati o ns, a n d me dicati o n 
f or pai n 
ma na ge me nt, i ncl u di n g narc otic a ge nts.
6. 5. 3
Pr o hi bite d Me dici nes
As state d i n t he e xcl usi o n criteria (see Secti o n 5. 2 ), partici pa nts m ust n ot ha ve ha d a n y pri or 
t hera py w it h a n y anti b o d y /dr u g tar geti n g T -cell c ore g ulat or y pr otei ns (i m m u ne c hec k p oi nts), s uc h 
as a nti-P D - 1, a nti-P D -L 1, a nti-C T L A - 4 a nti b o d y, or a nti- 4-1 B B a nti b o d y, or c o nc urre nt 
a ntica ncer treat me nt ( e. g., c yt ore d ucti ve t hera p y, i m m u ne t hera py,  or cyt o ki ne t hera p y, e xce pt f or 
er yt hr o p oieti n a n d gra n ul oc y te-c ol o n y sti m ulati n g fact or), c o nc urre nt s yste mic t hera p y wit h 
ster oi ds or ot her i m m u n os u p pressi ve a ge nts, or use of a n y in vesti gati o nal dr u g wit hi n 2 8 d a y s 
bef ore t he start of st u d y i nter ve nti o n. Ster oi ds as pre me dicati o n (see Secti o n 6. 5. 4. 1 ) are n ot 
acce pta ble.
I n a d diti o n, t he f oll o wi n g treat me nts m ust n ot be a d mi nistere d d uri n g t he st u d y:

I m m u n ot hera py, 
i m m u n os u p pressi ve dr u gs 
(i.e.,
s yste mic c ortic oster oi ds), or 
ot her 
e x peri me ntal p har mace utical pr o d ucts 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 6 / 2 1 3
o
S h ort -ter m a d mi nistrati o n of s yste mic ster oi d (i.e., f or aller gic reacti o ns or t he ma na ge me nt 
of ir A Es a n d ot her A Es) is all o we d. Pr o p h y lactic use of ster oi d f or c o ntrast a ge nts s h oul d 
f oll o w t he l ocal g ui da nce.
o
Ster oi ds wit h n o or mi ni mal s yste mic effect (t o pical, i ntra nasal, i ntra-oc ular, i n halati o n) are 
all o we d 
o
H or m o ne re place me nt wit h c ortic oster oi ds f or a dre nal i ns ufficie nc y is all o we d if t he ster oi ds 
are a d mi nistere d o nl y  for t he p ur p ose of h or m o nal re place me nt a n d at d oses ≤1 0 m g 
pre d nis o ne or e q ui vale nt per da y .

Vacci nati o n wit h li ve vacci nes w hile o n st u d y is pr o hi bite d. A d mi nistrati o n of i nacti vate d 
vacci nes (i.e. , i nacti vate d i nfl ue nza vacci nes) or a p pr o ve d S A R S -C O V -2 vac ci nes is all o we d.
If t he a d mi nistrati o n of a n o n- per mitte d c o nc o mita nt dr u g bec o mes necessar y  duri n g t he st u d y, t he 
partici pa nt s h o ul d be wit h dra w n fr o m st u d y i nter ve nti o n (t he S p o ns or m a y  be c o ntacte d t o disc uss 
w het her t he st u d y i nter ve nti o n m ust be disc o nti n ue d) ; see Secti o n 7. 1 .
T he f oll o wi n g treat me nts are per mitte d, b ut s h o ul d be use d wit h ca uti o n d uri n g t he st u d y :

T h ose wit h p ote n tial t o ca use dr u g i nteracti o ns wit h cis plati n:
o
All o p uri n ol, 
c olc hici ne, pr o be neci d, s ulfi n p yraz o ne* : i ncrease i n ser u m uric aci d 
c o nce ntrati o n
o
Ce p hal os p ori ns, a mi n o gl yc osi des, a m p h oterici n B: i ncrease ne p hr ot o xic a n d ot ot o xic effects 
of cis plati n i n t hese or ga ns 
o
C y cl os p ori ne: e xcessi ve i m m u n os u p pressi o n, wit h ris k of l y m p h o pr oliferati o n 
o
C y clizi ne* , p he n ot hiazi nes: ma y mas k ot ot o xicit y s ym pt o ms 
o
F ur ose mi de ( hi g h d oses), h y dralazi ne, diaz o xi de , a n d pr o pra n ol ol: i nte nsif y ne p hr ot o xicit y 
o
Oral a ntic oa g ula nts: re q uire a n i ncrease d fre q ue nc y of i nter nati o nal n or malize d rati o 
m o nit ori n g 
o
Pe nicilla mi ne: ma y  di mi nis h t he effecti ve ness of cis plati n 
o
P he n y t oi n: re d uce d e pile ps y c o ntr ol.

Ot her a ntic o n v ulsa nts ( p ossi ble i nteracti o ns t hat ha ve bee n d escri be d wit h cis plati n)

Ne p hr ot o xic dr u gs (c o nc o mita nt use s h o ul d be a v oi de d i n parti ci pa nts treate d wit h cis plati n) .
* N ot a p pr o ve d i n Ja pa n.
6. 5. 4
Ot her I nter ve nti o ns
T he f oll o wi n g n o n dr u g i nter ve nti o ns m ust n ot b e a d mi nistere d d uri n g t he st u d y (wit h i n 2 8 d a y s 
bef ore ra n d o mizati o n ):

Maj or 
s ur ger y, e xce pt f or ur ge nt palliati ve s ur ger y, pri or dia g n ostic bi o psies
a n d 
ste nti n g/P T B D f or t he p ur p ose of releasi n g biliar y tract o bstr ucti o n. Disc uss wit h t he Me dical 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 7 / 2 1 3
M o nit or 
if u n pla n ne d maj or s ur ger y is re q uire d d uri n g t he st u d y to pla n f or ti mi n g of 
re-treat me nt

Ra di ot hera p y, e xce pt f or palliati ve b o ne- directe d ra di ot hera p y.
T he f oll o wi n g n o n dr u g i nter ve nti o ns m ust n ot be a d mi nistere d d uri n g t he st u d y (a n d wit hi n 
2 8 da y s bef ore ra n d o mizati o n):

Her bal re me dies wit h i m m une-sti m ulati n g pr o perties (e. g., mistlet oe e xtract) or k n o w n t o 
p ote ntiall y  i nterfere wit h maj or or ga n f u ncti o n (e. g., h y perici n) .

A n y  tra diti o nal C hi nese me dicati o n wit h a p pr o val f or use as a ntica ncer treat me nt (re gar dless of 
t he t ype of ca ncer) will n ot be per mitte d. Tra diti o nal C hi nese me dicati o n f or i n dicati o ns ot her 
t ha n a ntica ncer treat me nt, s uc h as s u p p orti ve care, ma y be a d mi nistere d at t he discreti o n of t he 
I n vesti gat or. A 
n o ne x ha usti ve list of pr o hi bite d C hi nese me dicati o ns 
are pr o vi de d i n
A p pe n di x 1 0 .
6. 5. 4. 1
Pre me dic ati o n
T o miti gate p ote ntial I RRs, pre me dicati o n wit h a n a nti hista mi ne a n d wit h paraceta m ol (e. g.,
2 5- 5 0 m g di p he n h y dra mi ne a n d 5 0 0 - 6 5 0 m g paraceta m ol [aceta mi n o p he n] i ntra ve n o us or ora l 
e q ui vale nt) a p pr o xi matel y 30 t o 6 0 mi n utes pri or t o eac h d ose of bi ntraf us p alfa (i n t he o pe n -la bel,
safety r u n-i n part) or bi ntraf us p alfa/ place b o (i n t he ra n d o mize d, d o u ble-bli n d p art) is ma n dat or y 
f or t he first 2 i nf usi o ns. 
Pre me dicati o n is o pti o nal a n d at t he discreti o n of t he I n vesti gat or after t he sec o n d i nf usi o n. 
H o we ver, if Gra de 2 i nf usi o n reacti o ns are see n d uri n g t he first 2 i nf usi o ns, pre me dicati o n s h o ul d 
n ot be st o p pe d (see Secti o n 6. 9. 1) . Ster oi ds as pre me dicati o n are n ot per mitte d , e xce pt f or 
a nti-e mesis .See als o Secti o n 6. 6. 1 f or g ui da nce o n t he pr o p h yl actic use of ster oi ds f or a nti-e mesis.
6. 6
D ose Selecti o n a n d M o dific ati o n
6. 6. 1
D osi n g Instr ucti o ns
Bi ntraf us p alfa or place b o s h o ul d be a d mi nistere d pri or t o ge mcita bi ne a n d cis plati n d osi n g w he n 
gi ve n o n t he sa me da y . Pre me dicatio n is ma n dat or y pri or t o t he first 2 i nf usi o ns of bi ntraf us p alfa
( o pe n-la bel, safety r u n-i n part) or bi ntraf us p alfa / place b o (ra n d o mize d, d o u ble -bli n d part) b ut is 
o pti o nal t hereafter (see Secti o n 6. 5. 4. 1 ).
Partici pa nts assi g ne d t o t he o pe n -la bel, safety r u n-i n part or t o t he bi ntraf us p alfa ar m i n t he 
ra n d o mize d, d o u ble-bli n d part will recei ve a n i ntra ve n o us i nf usi o n of bi ntraf us p alfa as a fl at d ose 
of 2 4 0 0 m g o ver a mi ni m u m of 1 h o ur 
a n d u p t o 2 h o urs
o nce e ver y 3 wee ks u ntil c o nfir me d disease pr o gressi o n, 
u nacce pta ble t o xicit y, or u ntil a n y criteri o n f or disc o nti n uati o n of t he st u d y inter ve nti o n 
( Secti o n 7. 1 ) or disc o nti n uati o n/ wit h dra wal fr o m t he st u d y (Secti o n 7. 2 ) is met . I n or der t o ma na ge 
s pecific A Es (as s pecifie d i n S ecti o n 6. 9. 5 ), a bi ntraf us p alfa d ose of 1 2 0 0 m g ma y  be a d mi nistere d 
wit hi n 1 h o ur 
P artici pa nts wit h C R s h o ul d c o nti n ue st u d y 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 8 / 2 1 3
i nter ve nti o n f or 2 years after t he first o nset of C R or u ntil 1 of t he criteria f or disc o nti n uati o n is 
met, w hic he ver occ urs first .
Partici pa nts assi g ne d t o t he place b o ar m of t he ra n d o mize d, d o u ble -bli n d part will recei ve a n 
i ntra ve n o us i nf usi o n of place b o o ver a mi ni m u m of 1 h o ur 
 
a n d u p t o 2 h o urs 
) e ver y 3 wee ks u ntil c o nfir me d disease 
pr o gressi o n, u nacce pta ble t o xicit y, or u ntil a n y criteri o n f or disc o nti n uati o n of t he st ud y  
i nter ve nti o n ( Secti o n 7. 1 ) or disc o nti n uati o n/ wit h dra wal fr o m t he st u d y (Secti o n 7. 2 ) is met . I n 
or der t o ma na ge s pecific A Es (as s pecifie d i n S ecti o n 6. 9. 5 ), a n i ntra ve n o us i nf usi o n of place b o 
c orres p o n di n g t o a bi ntraf us p alfa d ose of 1 2 0 0 m g m a y  be a d mi nistere d wit hi n 1 h o ur 
P artici pa nts wit h C R s h o ul d c o nti n ue st u d y i nter ve nti o n f or 
2 ye ars after t he first o nset of C R or u ntil 1 of t he criteria f or disc o nti n uati o n is met, w hic he ver 
occ urs first .
T o kee p t he d ose i nte nsit y of bi ntraf us p alfa/ place b o, f oll o w t he d osi n g sc he d ule i nstr ucti o n i n 
Ta ble 1.  M o dificati o n of t he i nf usi o n rate d ue t o I R Rs is descri be d i n Secti o n
6. 9. 1. M o difi cati o n 
of t he d ose of bi ntraf us p alfa/ place b o d ue t o blee di n g e ve nts is descri be d i n Secti o n  6. 9. 5.
Partici pa nts w h o e x perie nce a C R s h o ul d be treate d wit h bi ntraf us p alfa/ place b o f or 2 ye ars after 
t he first o nset of C R . H o we ver, the I n vesti gat or ma y  te m p oraril y wit h h ol d t he treat me nt after t he 
C R f or 1 2 m o nt hs i n t he a bse nce of pr o gressi o n after e nteri n g C R de pe n di n g o n t he cli nical 
decisi o n. T he I n vesti gat or m a y  res u me bi ntraf us p alfa/ place b o after t he i nterr u pti o n if it is 
c o nsi dere d cli nicall y be neficial, after c o ns ultati o n wit h t he Me dical M o nit or.
I n cases of C R, c o nti n uati o n of bi ntraf us p alfa/ place b o m a y  be all o we d b e y o n d 2 ye ars after t he 
first o nset of C R, s u bject t o disc ussi o n bet wee n t he I n vesti gat or a n d Me dical M o nit or ta ki n g b ot h 
cli nical be nefit a n d safet y i nt o c o nsi derati o n.
F or b ot h t he bi ntraf us p alfa ar m a n d t he place b o ar m i n t he ra n d o mize d, d o u ble -bli n d part or f or 
t he bi ntr af us p alfa ar m i n t he o pe n -la bel, safet y ru n- i n part , ge mcita bi ne ( 1 0 0 0 m g / m2) a n d 
cis plati n ( 2 5 m g/ m 2) will be a d mi nistere d i ntra ve n o usl y o n Da y s 1 a n d 8 of e ver y 2 1- d a y  cycl e f or 
8 c ycles i n acc or da nce wit h t he l ocal la bel ( S m P C), pac ka ge i nsert , or N H S -a p pr o ve d practice (i n 
t he U K o nl y ) f or ge mcita bi ne a n d cis plati n. If c he m ot hera p y ca n n ot be a d mi nistere d o n Da y 1 or 
D a y 8 of a gi ve n c ycle (f or safet y , t olera bilit y or ot her u na v oi da ble reas o ns), t he misse d d ose ma y 
be a d mi nistere d o n Da y 1 5 of t hat c ycle . I n a d diti o n, an y  misse d d ose(s) of c he m ot hera p y ma y be 
ma de u p at t he e n d of t he sc he d ule d 8 c ycles ( u p t o 1 6 a d mi nistrati o ns of ge mcita bi ne a n d cis plati n 
c o m bi nati o n) pr o vi de d t he partici pa nt d oes n ot meet a n y of t he criteria f or disc o nti n uati o n of st u dy 
i nter ve nti o n or disc o nti n uati o n of st u d y ( Secti o n 7) . T he a d mi nistrati o n of t he misse d d ose o n Da y 
1 5 or at t he e n d of 8 c y cles is I n vesti gat or’s cli nical decisi o n. T he I n vesti gat or s h o ul d tr y t o kee p 
t he d ose i nte nsit y of ge mcita bi ne a n d cis plati n as hi g h as p ossi ble, wit h d osi n g sc he d ule d o n 
D a y s 1 a n d 8 d uri n g t he 8 treat me nt c y cles, a n d d ose of ge mcita bi ne a n d/ or cis plati n m o difie d, as 
a p pr o priate. F or d ose m o difi cati o ns, see Secti o n 6. 6. 3 Secti o n 6. 6. 4 , a n d Ta ble 1 3.
Intra ve n o us h y drati o n ( gi ve n d uri n g cis plati n i nf usi o n t o pre ve nt ne p hr ot o xicit y ) s h o ul d be 
a d mi nistere d as per sta n dar d practice.
A 
c ortic oster oi d -s pari n g a p pr oac h f or a nti-e metic 
pr o p h y la xis s h o ul d be c o nsi dere d si nce c o nc urre nt use of c ortic oster oi d ma y ne gati vel y i m pact t he 
efficac y of i m m u ne c hec k p oi nt i n hi bit or t hera p y. T h us, i n t his st u d y, a 5-H T 3 a nta g o nist a n d/ or a 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
6 9 / 2 1 3
ne ur o ki ni n - 1 ( N K 1) i n hi bit or s h o ul d be use d f or a nti-e mesis. If na usea a n d/ or v o miti n g are n ot 
cli nicall y ma na gea ble b y  5-H T 3 a nta g o nist a n d/ or ne ur o ki ni n - 1 i n hi bit or, pr o p h yl actic use of 
ster oi d is all o we d.
T u m or meas ure me nts t o deter mi ne res p o nse will be perf or me d as i n dicate d i n t he Sc he d ule of 
Acti vities (see Secti o n  1. 3 ). 
6. 6. 2
Defi niti o n of D ose -li miti n g T o xicit y
A D L T is a t o xicit y  relate d t o t he st u d y i nter ve nti o n t hat meets t he f oll o wi n g criteria as e val uate d 
i n t he o pe n-la bel, safety r u n -i n:
1.
Gra de 3 or 4 ir A E t hat nee ds per ma ne nt disc o nti n uati o n of bi ntraf us p alfa treat me nt. A 
mali g na nt s ki n lesi o n i n d uce d b y  bi ntraf us p alfa t hat is l ocal a n d ca n be resecte d wit h a 
ne gati ve resecti o n mar gi n is n ot a D LT.
2.
Gra de 3 or 4 n o n he mat ol o gic t o xicit y  ot her t ha n ir A E, e xce pt f or t he f oll o wi n g:

Gra de 3 I R Rs res ol vi n g wit hi n 6 h o urs fr o m t he e n d of i nf usi o n a n d c o ntr olle d wit h me dical 
ma na ge me nt

Tra nsie nt ( ≤6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver t hat are c o ntr olle d wit h me dical 
ma na ge me nt

Tra nsie nt ( ≤4 8 h o urs ) Gra de 3 na usea or v o miti n g des pite o pti mal s u p p orti ve care

Tra nsie nt ( ≤7 2 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, or hea dac he

T o xi cities t hat d o n ot re q uire me dical i nter ve nti o n as treat me nt.
3.
A life-t hreate ni n g he mat ol o gical t o xicit y (u nless clearl y attri b uta ble t o c he m ot hera p y al o ne), 
w hic h is har dl y me dicall y  ma na gea ble, i ncl u di n g a blee di n g e ve nt res ulti n g i n ur ge nt 
i nter ve nti o n a n d a d missi o n t o a n i nte nsi ve care u nit.
4.
Gra de 5 t o xicit y .
T he D L T criteria are selecte d base d o n t o xicit y  t hat necessitates per ma ne nt disc o nti n uati o n of t he 
st u d y i nter ve nti o n. 
T he D L T e val uati o n peri o d is t he first 2 1 da y s f oll o wi n g t he first d ose of bi ntraf us p alfa .
6. 6. 3
Tre at me nt M o dific ati o n
A n I nvesti gat or m a y  attri b ute eac h t o xicit y eve nt t o bi ntraf us p alfa/ place b o, ge mcita bi ne a n d/ or 
cis plati n al o ne, or t o t he c o m bi nati o n , a n d use t he a p pr o priate treat me nt m o dificati o n as per t he 
matri x s h o w n i n Ta ble 7.  
T o xicit y  nee ds t o res ol ve t o Gra de ≤1 or baseli ne pri or t o res u mi n g t he st u d y i nter ve nti o n t o w hic h 
t he t o xicit y was attri b ute d. H o we ver, t he st u d y inter ve nti o n ca n be res u me d e ve n if t he t o xicit y 
d oes n ot res ol ve t o Gra de ≤1 or baseli ne if t he t o xicit y is ma na gea ble a n d/ or as ym pt o matic. If a 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 0 / 2 1 3
partici pa nt e x perie nces se veral t o xicities a n d t here are c o nflicti n g rec o m me n dati o ns, t he m ost 
c o nser vati ve d ose a n d/ or treat me nt m o dificati o n rec o m me n de d s h o ul d be f oll o we d (c he m ot hera py 
d ose re d ucti o n a p pr o priate t o t he m ost se vere t o xicit y). Ot her A Es (e. g., i nfecti o ns) s h o ul d be 
ha n dle d i n a si milar ma n ner, if cli nicall y i n dicate d.
B i ntraf us p alfa/ place b o treat me nt m a y  be i nterr u pte d, m o difie d, or disc o nti n ue d d ue t o t o xicit y
(Ta ble 7) .
C he m ot hera p y a n d bi ntraf us p alfa/ place b o m a y  be i nterr u pte d f or a ma xi m u m of 1 2 wee ks.
Be y o n d 1 2 wee ks, disc uss f urt her treat me nt pla ns wit h t he Me dical M o nit or. If a t o xicit y is 
i nc orrectly a ttri b ute d t o t he st u d y inter ve nti o n a n d t he treat me nt is m o difie d, t he dr u g m a y  g o bac k 
t o t he pre m o difie d c o n diti o n. 
A n y  q uesti o ns or c o ncer ns s h o ul d be disc usse d wit h t he Me dical M o nit or.
T a ble 7
Tre at me nt M o dific ati o n f or B i ntr af us p alf a / Pl ace b o, Ge mcit a bi ne, a n d 
Cis pl ati n
Attri b ut e d Dr u g 
a s a C a u s e of 
A d v er s e Dr u g 
R e a cti o n
Tr e at m e nt M o difi c ati o n
B i ntr af u s p alf a/ Pl a c e b o
C h e m ot h er a p y
B i ntr af u s p 
alf a / Pl a c e b o

F or ir A E s, f oll o w A S C O g ui d eli n e i n
A p p e n di x 8

A d v er s e e v e nt s r el at e d t o bi ntr af u s p 
alf a / pl a c e b o w hi c h ar e n ot c o v er e d i n 
t h e A S C O g ui d eli n e, s e e t h e g ui d a n c e 
i n t hi s s e cti o n.

F or bl e e di n g a n d r a pi d pr o gr e s si n g 
a n e mi a , f oll o w t h e m o difi c ati o n 
g ui d a n c e i n S e cti o n s 6. 9. 4 a n d  6. 9. 5 .

C o n si d er t o d o s e if t h e t o xi cit y d o e s 
n ot m e et t h e D L T crit eri a i n 
S e cti o n 6. 6. 2 o n t h e d a y of d o si n g

Wi t h h ol d t h e d o s e if m e di c all y 
i n di c at e d. 

I n t h e c a s e of h e m at ol o gi c al a n d r e n al 
i m p air m e nt, f oll o w t h e m o difi c ati o n s i n 
T a bl e 1 0 a n d  T a bl e 1 1 , r e s p e cti v el y.
C h e m ot h er a p y

C o n si d er t o d o s e if t h e t o xi cit y d o e s 
n ot m e et t h e D L T crit eri a i n 
S e cti o n 6. 6. 2 o n t h e d a y of d o si n g

Wi t h h ol d t h e d o s e if m e di c all y 
i n di c at e d.

F or bl e e di n g a n d r a pi d pr o gr e s si n g 
a n e mi a, f oll o w t h e m o difi c ati o n 
g ui d a n c e i n S e cti o n s 6. 9. 4 a n d  6. 9. 5 .

F oll o w  T a bl e 8 , T a bl e 9 , T a bl e 1 0 , 
a n d  T a bl e 1 1 , a s a p pr o pri at e t o t h e 
r e a cti o n

R e s u m e g e m cit a bi n e a n d/ or ci s pl ati n 
aft er i m pr o vi n g t o Gr a d e 1 or l o w er
A S C O = A m eri c a n S o ci et y of Cli ni c al O n c ol o g y , D L T = d o s e -li miti n g t o xi cit y, ir A Es =i m m u n e -r el at e d a d v er s e 
e v e nt s.
6. 6. 3. 1
B i ntr af us p alf a/ Pl ace b o-rel ate d A d verse Dr u g Re acti o ns
A n y  ad verse dr u g reacti o n ( A D R) assesse d as relate d t o bi ntraf us p alfa or place b o m a y  re q uire 
per ma ne nt or tra nsie nt disc o nti n uati o n of bi ntraf us p alfa/ place b o treat me nt. F or t he ma na ge me nt 
of certai n A D Rs assesse d t o be ir A Es, f oll o w t he A merica n S ociet y of Cli nical O nc ol o g y ( A S C O )
g ui deli ne wit h m o dificati o n i n A p pe n di x 8.  T he A S C O g ui da nce d o es n ot necessaril y s u perse de 
t he cli nical decisi o n of t he I nvesti gat or . If t he I nvesti gat or c o nsi ders t hat it is me dicall y  more 
a p pr o priate f or t he partici pa nt t o c o nti n ue i n t he st u d y or t o ter mi nat e t he st u d y, e ve n if de viati n g 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 1 / 2 1 3
fr o m t he g ui da nce , t he I nvesti gat or s h o ul d c o ns ult t he Me dical M o nit or. Si n gle la b orat or y val ues 
o ut of t he n or mal ra n ge t hat d o n ot ha ve a n y cli nical c orrelate d o n ot necessaril y  nee d treat me nt 
i nterr u pti o n. Q uesti o ns or c o ncer ns re gar di n g t he ma na ge me nt a n d/ or f oll o w-u p of A D Rs s h o ul d 
als o be disc usse d wit h t he Me dical M o nit or.
I nf usi o n-relate d reacti o ns, ir A Es, T G F β i n hi biti o n me diate d s ki n reacti o ns, a ne mia, a n d blee di n g 
e ve nts s h o ul d be ma na ge d a n d f oll o we d- u p as descri be d i n t he s u bse q ue nt pr ot oc ol secti o ns. 
Per ma ne nt disc o nti n uati o n of st u d y inter ve nti o n ma y  be rec o m me n de d, s o t he rele va nt pr ot oc ol 
secti o n m ust be re vie we d:

G ui da nce o n I R Rs a n d h y perse nsiti vit y  is prese nte d i n Secti o n 6. 9. 1

Ma na ge me nt a n d g ui da nce of s us pecte d ir A Es is pr o vi de d i n Secti o n
6. 9. 2 a n d A p pe n di x 8

G ui da nce a n d ma na ge me nt of T G F β
i n hi biti o n me diate d s ki n reacti o ns is disc usse d i n 
Secti o n 6. 9. 3

G ui da nce o n a ne mia is prese nte d i n Secti o n 6. 9. 4.

G ui da nce a n d ma na ge me nt of blee di n g e ve nts are disc usse d i n Secti o n 6. 9. 5
I n ge neral, t he f oll o wi n g a p plies f or A D Rs relate d t o bi ntraf us p alfa/ place b o n ot c o vere d b y  th e 
A S C O g ui deli ne:
A n y Gr a de 4 A D Rs re q uire per m a ne nt tre at me nt disc o nti n u ati o n, e xce pt e n d ocri n o p at hies 
t h at h a ve bee n c o ntr olle d b y h or m o ne re pl ace me nt, or si n gle l a b or at or y v al ues o ut of n or m al 
r a n ge t h at d o n ot h a ve cli nic al rele v a nce .
A n y Gr a de 3 A D Rs re q uire tre at me nt disc o nti n u ati o n, e xce pt f or a n y of t he f oll o wi n g:

Tra nsie nt ( ≤6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver t hat is c o ntr olle d wit h me dical 
ma na ge me nt

Tra nsie nt ( ≤2 4 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, e mesis t hat res ol ves 
t o ≤Gra de 1

T u m or flare p he n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites of k n o w n or 
s us pecte d t u m ors

A n y  Gra de ≥3 dr u g -relate d a m yl ase or li pase a b n or malit y that is n ot ass ociate d wit h s ym pt o ms 
or cli nical ma nifestati o ns of pa ncreatitis

Gr a de 3 H g b decrease ( < 8. 0 g/ d L) t hat is cli nicall y ma na gea ble wit h bl o o d tra nsf usi o ns or 
er yt hr oi d gr o wt h fact or use (see Secti o n s 6. 9. 4 a n d 6. 9. 5 f or f urt her details)

K A
a n d c uta ne o us s q ua m o us cell carci n o ma (c S C C). A n y  sus pici o us s ki n lesi o n s h o ul d be 
bi o psie d a n d s ur gicall y re m o ve d

I ncre ases i n E C O G P S t o ≥3 t hat res ol ve t o ≤2 b y  Da y 1 of t he ne xt i nf usi o n (i.e., i nf usi o n 
s h o ul d n ot be gi ve n if t he E C O G P S is ≥3 o n t he da y of treat me nt, a n d s h o ul d be dela ye d u ntil 
E C O G P S is ≤2)

E n d ocri n o pat hies c o ntr olle d wit h h or m o ne re place me nt t hera py
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 2 / 2 1 3
A n y Gr a de 2 A D Rs s h o ul d be m a n a ge d as f oll o ws:

If a Gra de 2 A D R res ol ves t o Gra de ≤1 b y  the last da y  of t he c urre nt c ycle, treat me nt m a y  
c o nti n ue

If a Gra de 2 A D R d oes n ot res ol ve t o Gra de ≤1 b y  the last d a y  of t he c urre nt c ycle b ut is 
ma na gea ble a n d/ or n ot cli nicall y rele va nt, t he Me dical M o nit or s h o ul d be c o ns ulte d t o assess if 
it is cli nicall y reas o na ble t o a d mi nister t he f oll o wi n g i nf usi o n.
N ote t hat treat me nt rec o m me n dati o ns re gar di n g c o nti n uati o n, h ol d, or disc o nti n uati o n b y  gra de 
are differe nt de pe n di n g o n t he s pecific t o xicit y (see A p pe n di x 8 ). T o xicit y  gra di n g is assi g ne d 
base d o n N CI -C T C A E Versi o n 5. 0. T he A S C O g ui d eli ne s h o ul d be use d o nl y  for t he ma na ge me nt 
of i m m u ne -relate d t o xicit y d ue t o bi ntraf us p alfa / place b o. 
6. 6. 3. 2
Ge mcit a bi ne 
a n d / or 
Cis pl ati n -rel ate d 
A d verse 
Dr u g 
Re acti o ns
If a d ose re d ucti o n f or c he m ot hera p y-relate d t o xicit y ot her t ha n ne utr o pe nia a n d t hr o m b oc yt o pe nia 
occ urs wit h ge mcita bi ne or cis plati n, t he d ose m a y  not be re-escalate d. Partici pa nts ca n ha ve a 
ma xi m u m of 2 d ose re d ucti o ns (if a p plica ble) t o eac h of t he c o m p o ne nts t hr o u g h o ut t he c o urse of 
t he st u d y for t o xicities. If partici pa nts re q uire a t hir d d ose m o dificati o n, t hat a ge nt will be 
disc o nti n ue d.
Re d ucti o n of 1 c he m ot hera p y a ge nt a n d n ot t he ot her a ge nt is a p pr o priate if t he t o xicit y  is relate d 
t o 1 of t he treat me nts b ut n ot t o t he ot her. If t he t o xicit y is relate d t o t he c o mbi nati o n of b ot h 
c he m ot hera p y a ge nts,
eit her ge mcita bi ne or cis plati n, or
b ot h dr u gs de pe n di n g o n t he 
I n vesti gat or’s cli nical decisi o n sh o ul d be re d uce d acc or di n g t o t he rec o m me n de d d ose 
m o dificati o ns i n Ta ble 8 ( ge mcita bi ne a n d cis plati n), Ta ble 9 ( n o n he mat ol o gical t o xicit y), Ta ble 
1 0 ( ne utr o pe nia a n d t hr o m b oc yt o pe nia), a n d Ta ble 1 1 (re nal i m pair me nt).
T a ble 8
D ose M o dific ati o n f or Ge mcit a bi ne a n d Cis pl ati n
T o xi cit y
G e m cit a bi n e
Ci s pl ati n
-1 l e v el
Fir st o c c urr e n c e
Gi v e 7 5 %
Gi v e 7 5 %
-2 l e v el
S e c o n d o c c urr e n c e
Gi v e 5 0 %
Gi v e 5 0 %
-3 l e v el
T hir d o c c urr e n c e
P er m a n e nt c e s s ati o n
P er m a n e nt c e s s ati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 3 / 2 1 3
N o n he m at ol o gic al T o xicit y Rel ate d t o Ge mcit a bi ne a n d/ or Cis pl ati n
T a ble 9
N o n he m at ol o gic al T o xicit y
T o xi cit y  Gr a d e
G e m cit a bi n e D o s e
Ci s pl ati n D o s e
N a u s e a / vo miti n g
N o r e d u cti o n
N o r e d u cti o n
Ot h er n o n h e m at ol o gi c al t o xi cit y 
Gr a d e 3 a
1 l e v el r e d u cti o n
1 l e v el r e d u cti o n
Ot h er n o n h e m at ol o gi c al t o xi cit y 
Gr a d e 4 a
1 l e v el r e d u cti o n or p er m a n e nt 
di s c o nti n u ati o n b
1 l e v el r e d u cti o n or p er m a n e nt 
di s c o nti n u ati o n b
a
Ot h er t h a n h y p er s e n siti vit y, i nf u si o n -r elat e d r e a cti o n, a n d n o n h e m at ol o gi c al t o xi cit y t h at d o e s n ot r e q uir e 
m e di c al i nt er v e nti o n i n cl u di n g, b ut n ot li mit e d t o, al o p e ci a
a n d f ati g u e.
b
Cli ni c al j u d g m e nt.
Res u me ge mcita bi ne a n d/ or cis plati n after i m pr o ve me nt t o Gra de ≤1 wit h d ose m o dificati o n f or 
c he m ot hera p y- relate d t o xicit y. F or Gra de 4 t o xicit y , t he I n vesti gat or will ma ke a cli nical decisi o n 
w het her t o disc o nti n ue treat me nt or t o res u me wit h d ose m o dificati o n. T he use of a nti-e metics
ot her t ha n pr o p h yl actic ster oi ds s h o ul d f oll o w t he g ui da nce pr o vi de d i n Secti o n 6. 6. 1 .
He m at ol o gic al T o xicit y Rel ate d t o Ge mcit a bi ne a n d/ or Cis pl ati n 
T a ble 1 0
D o se M o dific ati o n f or Ne utr o pe ni a a n d T hr o m b oc yt o pe ni a
T o xi cit y  Gr a d e o n t h e D a y  of D o si n g
G e m cit a bi n e D o s e
Ci s pl ati n D o s e
N e utr o p hil s 0. 5 × 1 0 9 / L t o < 1. 0 × 1 0 9 / L
1 l e v el r e d u cti o n
N o r e d u cti o n
N e utr o p hil s < 0. 5 × 1 0 9 / L
S ki p d o s e
S ki p d o s e
Pl at el et s 5 0 × 1 0 9 / L t o < 1 0 0 × 1 0 9 / L
1 l e v el r e d u cti o n
N o r e d u cti o n
Pl at el et s < 5 0 × 1 0 9 / L 
S ki p d o s e
S ki p d o s e
I n the case of c he m ot hera p y-relate d a ne mia (H g b
< 8 g/ d L), fe brile ne utr o pe nia, ne utr o p hils 
< 0. 5 × 1 0 9/ L, or platelets < 5 0 × 1 0 9/ L f or l o n ger t ha n 7 da y s, res u me ge mcita bi ne a n d cis plati n 
wit h 1 le vel re d ucti o n after i m pr o vi n g t o Gra de 1 or less. Ot her t ha n t hese re d ucti o ns, t he d ose ca n
be re-escalate d t o baseli ne. T he I n vesti gat or m a y  re d uce t he d ose of ge mcita bi ne a n d/ or cis plati n 
f urt her t o t hat i n dicate d i n Ta ble 1 0 (i.e., d ose re d ucti o n u p t o -2 le vel eit her/ b ot h ge mcita bi ne 
or/a n d cis plati n, or ge mcita bi ne m o n ot hera p y) t o kee p d ose i nte nsit y as hi g h as p ossi ble o n Da y s 1 
a n d 8 of e ver y 21- d a y  cyc le d osi n g if t he partici pa nt nee ds or a ntici pates t o s ki p d osi n g m ore 
fre q ue ntly d ue t o c he m ot hera p y -relate d he mat ol o gical t o xicities.
If a Gra de 2 a ne mia d oes n ot res ol ve t o Gra de ≤ 1 b y  the last d a y  of t he c urre nt c ycle b ut is 
ma na gea ble a n d/ or n ot cli nicall y  rele va nt, t he Me dical M o nit or s h o ul d be c o ns ulte d t o assess if it 
is cli nicall y reas o na ble t o a d mi nister t he f oll o wi n g i nf usi o n.
Ot her wise, adj ust ge mcita bi ne a n d cis plati n d ose acc or di n g t o  Ta ble 1 0 base d o n t he bl o o d c o u nt 
o n t he d a y  of or a d a y  bef ore d osi n g . A d mi nistrati o n of gra n ul oc y t e-c ol o n y sti m ulati n g fact or
s h o ul d f oll o w l ocal g ui deli nes or N C C N g ui deli ne s. T he use of er yt hr o p oieti n s h o ul d f oll o w l ocal 
g ui deli ne s. 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 4 / 2 1 3
6. 6. 4
D ose M o dific ati o n of Ge mcit a bi ne, Cis pl ati n , a n d B i ntr af us p 
alf a / Pl ace b o f or Re n al I m p air me nt
I n t he case of re nal t o xicit y, d ose m o dificati o n of ge mcita bi ne a n d cis plati n will be a p plie d as per 
Ta ble 1 1 , re gar dless of t he ca use. If baseli ne Cr Cl is < 6 0 m L / mi n, m o dif y  the starti n g d ose of 
cis plati n acc or di n gly.
Cis plati n -i nd uce d re nal i m pair me nt m ust be rec o vere d t o Gra de 1 or baseli ne val ue i n or der t o 
res u me cis plati n treat me nt.
T a ble 1 1
D ose M o dific ati o n f or Re n al I m p air me nt
Cr e ati ni n e Cl e ar a n c e ( m L/ mi n)
G e m cit a bi n e
Ci s pl ati n
≥6 0 ( Gr a d e 1 or b ett er)
Gi v e 1 0 0 %
Gi v e 1 0 0 %
5 0 -5 9 
Gi v e 1 0 0 %
-1 r e d u cti o n a
4 0 -4 9
Gi v e 1 0 0 %
-2 r e d u cti o n s
3 0 -3 9
Gi v e 1 0 0 %
P er m a n e nt di s c o nti n u ati o n
< 3 0 ( Gr a d e 3)
P er m a n e nt di s c o nti n u ati o n 
P er m a n e nt di s c o nti n u ati o n
Cr C L = cr e ati ni n e cl e ar a n c e.
a
Eli gi bilit y crit eri a r e q uir e a Cr C L > 5 0 m L/ mi n; if b a s eli n e Cr C L i s < 6 0 m L/ mi n, m o dif y t h e st arti n g 
d o s e of ci s pl ati n a c c or di n gl y.
T he Cr Cl will be esti mate d b y  the C oc kcr oft -Ga ult f or m ula or calc ulate d fr o m 2 4- h o ur uri ne 
c ollecti o n. N o ot her f or m ula s h o ul d be use d f or t he Cr Cl calc ulati o n. If a n e nz ymatic met h o d is 
use d f or ser u m creati ni ne meas ure me nt, a d d 0. 2 ( Crjaffe = 0. 2 + Cr e nz y me) t o calc ulate. 
Treat me nt of bi ntraf us p alfa/ place b o s h o ul d be m o difie d acc or di n g t o t he A S C O g ui deli ne 
(A p pe n di x 8 ) if t he ca use of re nal i m pair me nt is attri b ute d t o a n ir A E. If re nal i m pair me nt is relate d 
t o c he m ot hera p y, f oll o w Ta ble 8 . If re nal i m pair me nt is relate d t o bi ntraf us p alfa / place b o, f oll o w 
Ta ble 7.
6. 6. 5
Dise ase S pecific Ris k: He p atic I m p air me nt
B T C ca n ca use c h olestasis t hat c o ul d i n d uce ac ute c h ola n gitis. Ac ute c h ola n gitis is a cli nical 
s yn dr o me c haracterize d b y  fe ver, ja u n dice, a n d a b d o minal pai n t hat de vel o ps as a res ult of stasis 
a n d i nfecti o n i n t he biliar y tract. Partici pa nts wit h ac ute c h ola n gitis ma y de vel o p se ptic s h oc k a n d 
t h us re q uire fre q ue nt m o nit ori n g f or si g ns of s h oc k. 
Dia g n ostic criteria f or ac ute c h ola n gitis are s u m marize d i n Ta ble 1 2 (Kiri ya ma 2 0 1 3 ). If biliar y 
i nfecti o n is s us pecte d, t he st u d y inter ve nti o n m ust be wit h hel d. T he In vesti gat or s h o ul d c o nsi der 
biliar y  drai na ge as well as treat me nt wit h a nti bi otics. Biliar y  tract o bstr ucti o n s h o ul d be relie ve d 
b y  PT B D, perc uta ne o us tra ns he patic gall bla d der drai na ge, e n d osc o pic ste nti n g, ste nti n g via P T B D 
t u be, or b y pass s ur ger y, a n d m u st be free of i nfecti o n pri or t o d osi n g. F or ste nti n g, a c o vere d, 
e x pa n da ble metallic ste nt s h o ul d be use d if a nat o micall y an d tec h nically a p plica ble rat her t ha n a 
s mall dia meter plastic t u be ste nt. Ne utr o pe nia ca use d b y  ge mcita bi ne a n d cis plati n, as well as 
i m m u n o m o d ulati o n wit h bi ntraf us p alfa, c o ul d w orse n wit h biliar y  tract i nfecti o n. If biliar y  tract 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 5 / 2 1 3
i nfecti o n is cli nicall y de nia ble or i m pr o ve d, t he st u d y inter ve nti o n ca n be res u me d.
I m m u ne-relate d c h ola n gitis s h o ul d be differe ntiate d if me dicall y i n dicate d.
He patitis B vir us ( H B V) D N A p ositi ve partici pa nts m ust be treate d a n d o n a sta ble d ose of 
a nti virals (e. g., e nteca vir, te n of o vir, or la mi v u di ne; a def o vir or i nterfer o n is n ot all o we d) at st u d y 
e ntr y an d f or t he d urati o n of t he st u d y, i n a d diti on t o pla n ne d m o nit ori n g a n d ma na ge me nt 
i ncl u di n g H B V -D N A q ua ntit y  acc or di n g t o a p pr o priate la beli n g g ui da nce. H C V ri b o n ucleic aci d 
(R N A ) s h o ul d be m o nit ore d d uri n g t he st u d y if H C V R N A is p ositi ve at baseli ne. If a li ver f u ncti o n 
test is ele vate d i n an H B V - or H C V -p ositi ve partici pa nt, H B V D N A or H C V R N A m ust be 
m o nit ore d t o e xcl u de t he p ossi bilit y  of reacti vati o n of viral he patitis. In case of viral reacti vati o n, 
f oll o w t he l ocal H B V a n d H C V ma na ge me nt g ui deli ne.
If a n I n vesti gat or ca n attri b ute t he ca use of he patic i m pair me nt t o bi ntraf us p alfa a n d/ or 
c he m ot hera p y, f oll o w t he ir A E g ui deli ne i n A p pe n di x 
8
or t he n o n he mat ol o gical d ose 
m o dificati o n i n  Ta ble 8 a n d Ta ble 9.
T a ble 1 2  
Di a g n ostic Criteri a f or Ac ute C h ol a n gi tis
6. 7
St u d y I nter ve nti o n A fter t he E n d of t he St u d y
Partici pa nts will be f oll o we d f or s ur vi val a n d A Es as s pecifie d i n t he Sc he d ule of Acti vities
(see Secti o n  1. 3).
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t he y lea ve t he st u d y b eca use 
s uc h care w o ul d n ot differ fr o m w hat is n or mally e x pecte d f or patie nts wit h B T C.
A. S y st e mi c 
In ﬂa m m ati o n
A- 1. F e v er a n d/ or s h a ki n g c hill s
B o d y t e m p er at ur e > 3 8° C
A- 2. L a b or at or y d at a: e vi d e n c e of i n ﬂa m m at or y 
r e s p o n s e
W B C < 4 × 1 0 9 / L, or > 1 0 × 1 0 9 / L
C R P ≥1 m g/ d L ( 1 9 0 n m ol/ L)
B. C h ol e st a si s
B- 1. J a u n di c e
T- Bil ≥2 m g/ d L
B- 2. L a b or at or y d at a: a b n or m al li v er f u n cti o n 
t e st s
A L P > 1. 5 × U L N
γ G T P > 1. 5 × U L N
A S T > 1. 5 × U L N
A L T > 1. 5 × U L N
C. I m a gi n g
C- 1. Bili ar y dil at ati o n
C- 2. E vi d e n c e of t h e eti ol o g y o n i m a gi n g 
( stri ct ur e, st o n e, st e nt, et c)
A L P = al k ali n e p h o s p h at a s e, A L T = al a ni n e a mi n otr a n sf er a s e, A S T = a s p art at e a mi n otr a n sf er a s e, C R P = C -r e a cti v e 
pr ot ei n, γ G T P = g a m m a -gl ut a m yl tr a n s p e pti d a s e, T -Bil =t ot al bilir u bi n, U L N = u p p er li mit of n or m al, W B C = w hit e 
bl o o d c ell.
S u s p e ct e d di a g n o si s: O n e it e m i n A a n d 1 it e m i n eit h er B or C.
D e ﬁnit e di a g n o si s: O n e it e m i n A, 1 it e m i n B, a n d 1 it e m i n C.
Ot h er f a ct or s t h at ar e h el pf ul i n t h e di a g n o si s of a c ut e c h ol a n giti s i n cl u d e a b d o mi n al p ai n (ri g ht u p p er q u a dr a nt 
or u p p er a b d o mi n al).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 6 / 2 1 3
6. 8
S peci al Prec a uti o ns
As a part of safet y-relate d preca uti o nar y  meas ures, a sta n dar dize d ris k ma na ge me nt a p pr oach is 
pla n ne d f or bi ntraf us p alfa f or IR Rs , ir A Es, T G F β i n hi biti o n me diate d s ki n reacti o ns, a ne mia, a n d 
blee di n g A Es . T h is a p pr oac h is mai nl y  base d o n t he m o n ocl o nal a nti b o d y mec ha nis m of P D -L 1  
i n hi biti o n a n d T G F β i n hi biti o n.

As a r o uti ne preca uti o n, f or t he first 2 i nf usi o ns, all partici pa nts e nr olle d i n t his st u d y  m ust be 
o bser ve d f or 2 h o urs f oll o wi n g t he e n d of i nf usi o n i n a n area wit h res uscitati o n e q ui p me nt a n d 
e mer ge nc y age nts. If n o I R Rs are o bser ve d d uri n g t he first 2 i nf usi o ns, t he ma n date d 2- h o ur 
p ost -i nf usi o n o bser vati o n ti me m a y  be re d uce d t o 6 0 mi n utes . T he s u bse q ue nt ge mcita bi ne 
a n d/ or cis plati n i nf usi o n ca n be i nitiate d d uri n g t he 1- t o 2-h o ur o bser vati o n peri o d 

At all ti mes d uri n g bi ntraf us p alfa/ place b o treat me nt, i m me diate e mer ge nc y treat me nt of a n 
I R R or a se vere hy perse nsiti vit y  reacti o n acc or di n g t o i nstit uti o nal sta n dar ds m ust be ass ure d

T o treat p ossi ble h y perse nsiti vit y  reacti o ns li ke a na p h ylactic reacti o ns, de xa met has o ne 1 0 m g 
a n d e pi ne p hri ne i n a 1: 1 0 0 0 dil uti o n (or e q ui vale nts ) s h o ul d al wa ys be a vaila ble al o n g wit h 
e q ui p me nt f or assiste d ve ntilati o n. 
See Secti o n  6. 9 f or f urt her details.
6. 9
M a n a ge me nt of A d verse E ve nts of S peci al I nterest a n d ot her 
P ote nti al Ris ks
A d verse e ve nts of s pecial i nterest ( A E SI) are seri o us or n o nseri o us A Es t hat are of cli nical i nterest 
a n d s h o ul d be cl osel y f oll o we d.
F or t his st u d y , A E SIs i ncl u de t he f oll o wi n g:

I nf usi o n-relate d reacti o ns i ncl u di n g i m me diate h y perse nsiti vit y

I m m u ne-relate d A Es

T G F β i n hi biti o n me diate d s ki n reacti o ns

A ne mia

Blee di n g A Es
6. 9. 1
I nf usi o n-rel ate d Re acti o ns I ncl u di n g I m me di ate 
H y perse nsiti vit y
I nf usi o n-relate d reacti o ns (i ncl u di n g i m me diate h y perse nsiti vit y ) are c o m m o n A D Rs
wit h 
m o n ocl o nal a nti b o dies, relate d t o dr u g a d mi nistrati o n . T he y  are A E SI  a n d i de ntifie d ris ks f or 
bi ntraf us p alfa ; I R Rs are als o li kel y ca use d by cis plati n. 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 7 / 2 1 3
I nf usi o n-rel ate d R e acti o ns
I R Rs are defi ne d as a n y si g ns or s ym pt o ms e x perie nce d b y  partici pa nts d uri n g t he i nf usi o n of 
p har mac ol o gic or bi ol o gic a ge nts or a n y e ve nt occ urri n g d uri n g or wit hi n 1 da y  of dr u g 
a d mi nistrati o n. T he y are i de ntifie d base d o n a list of Me dical Dicti o nar y f or Re g ulat or y Ac ti vities 
( Me d D R A) preferre d ter ms a n d criteria o n t he ti mel y relati o ns hi p t o a n i nf usi o n. E ve nts are
di vi de d i nt o reac ti o ns vers us si g ns a n d sy m pt o ms:

Reacti o ns are c o nsi dere d w he n o nset is o n t he da y of i nf usi o n ( d uri n g or after t he i nf usi o n) or 
t he d a y  after t he i nf usi o n (irres pecti ve of res ol uti o n date) f or I RR, dr u g h y perse nsiti vit y , 
a na p h yl actic reacti o n, h y perse nsiti vit y, a n d ty pe 1 h y perse nsiti vit y

Si g ns a n d s y m pt o ms of I R Rs a n d h yperse nsiti vit y/aller gic reacti o ns are c o nsi dere d w he n o nset 
is o n t he da y  of i nf usi o n ( d uri n g or after t he i nf usi o n) a n d res ol ve d c o m pletel y wit h t he e n d 
date wit hi n 2 d a y s after o nset of ( b ut n ot li mite d t o) p y re xia, c hills, fl us hi n g, h y p ote nsi o n, 
d y s p nea, w heezi n g, bac k pai n, a b d o mi nal pai n, a n d urticaria.
See  Ta ble 1 3 f or i nstr ucti o ns o n-treat me nt m o dificati o n of bi ntraf us p alfa / place b o f or I R Rs.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 8 / 2 1 3
T a ble 1 3
Tre at me nt M o dific ati o n 
of B i ntr af us p alf a / Pl ace b o f or S y m pt o ms of 
I nf usi o n- Relate d Re acti o ns I ncl u di n g I m me di ate H y perse nsiti vit y
N CI - C T C A E Gr a d e ( D e s cri pti o n)
Tr e at m e nt M o difi c ati o n
Gr a d e 1 – mil d

Mil d 
tr a n si e nt r e a cti o n; i nf u si o n i nt err u pti o n n ot 
i n di c at e d; i nt er v e nti o n n ot i n di c at e d
I n cr e a s e m o nit ori n g of vit al si g n s a s m e di c all y i n di c at e d 
a s p arti ci p a nt s ar e d e e m e d m e di c all y st a bl e
Gr a d e 2 – m o d er at e

T h er a p y or i nf u si o n i nt err u pti o n i n di c at e d b ut if 
r e s p o n d s pr o m ptl y t o s y m pt o m ati c tr e at m e nt ( e. g.,
a nti hi st a mi n e s, 
N S AI D s, 
n ar c oti c s,
I V
fl ui d s); 
pr o p h yl a cti c m e di c ati o n s i n di c at e d f or 2 4 h o ur s.

St o p bi ntr af u s p alf a / pl a c e b o i nf u si o n 

I n cr e a s e m o nit ori n g 
of vit al si g n s a s m e di c all y 
i n di c at e d

If s y m pt o m s r e s ol v e q ui c kl y or d e cr e a s e t o Gr a d e 1, 
r e s u m e i nf u si o n at 5 0 % of ori gi n al r at e wit h c l o s e 
m o nit ori n g of a n y w or s e ni n g , ot h er wi s e h ol d d o si n g 
u ntil 
r e s ol uti o n 
of 
s y m pt o m s 
wit h 
m a n d at e d 
pr e m e di c ati o n f or t h e n e xt s c h e d ul e d vi sit

C o n si d er tr e at m e nt wit h c orti c o st er oi d s if s y m pt o m s 
p er si st

At t h e n e xt i nf u si o n, c o n si d er H 2 -bl o c k er s ( e. g.,
f a m oti di n e or r a niti di n e) a s cli ni c all y i n di c at e d. If 
p arti ci p a nt s h a v e a s e c o n d Gr a d e ≥2 I R R o n t h e 
r e d u c e d-r at e i nf u si o n wit h t h e s u g g e st e d m e di c ati o n, 
st o p t h e i nf u si o n a n d r e m o v e t h e p arti ci p a nt fr o m 
tr e at m e nt

If w or s e n s 
t o Gr a d e 
3 or 4, f oll o w tr e atm e nt 
m o difi c ati o n g ui d eli n e s a c c or di n gl y
Gr a d e 3 or Gr a d e 4 – s e v er e or lif e- t hr e at e ni n g

Gr a d e 3: Pr ol o n g e d ( e. g., n ot r a pi dl y r e s p o n si ve t o 
s y m pt o m ati c m e di c ati o n a n d / or bri ef i nt err u pti o n of 
i nf u si o n); r e c urr e n c e of s y m pt o m s f oll o wi n g i niti al 
i m pr o v e m e nt; h o s pit ali z ati o n i n di c at e d f or cli ni c al 
s e q u el a e

Gr a d e 
4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; ur g e nt 
i nt er v e nti o n i n di c at e d

St o p bi ntr af u s p alf a / pl a c e b o i nf u si o n i m m e di at el y 
a n d di s c o n n e ct i nf u si o n t u bi n g fr o m t h e p arti ci p a nt 
wit h a d diti o n al a p pr o pri at e m e di c al m e a s ur e s a n d 
cl o s e m o nit ori n g u ntil d e e m e d m e di c all y st a bl e b y 
att e n di n g In v e sti g at or. H o s pit ali z ati o n a n d/ or cl o s e 
m o nit ori n g i s r e c o m m e n d e d

A d mi ni str ati o n of gl u c o c orti c oi d s m a y b e r e q uir e d

P er m a n e ntl y wit h dr a w 
p arti ci p a nt fr o m bi ntr af u s p 
alf a / pla c e b o tr e at m e nt a n d d o n ot a d mi ni st er a n y 
f urt h er bi ntr af u s p alf a / pl a c e b o tr e at m e nt
I R R =inf u si o n -r el at e d r e a cti o n, I V =i ntr a v e n o u s, N CI -C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt s , N S AI D s= n o n st er oi d al a nti -i nfl a m m at or y dr u g s. 
If t h e bi ntr af u s p alf a i nf u si o n i s i nt err u pt e d or t h e r at e r e d u c e d t o 5 0 % of t h e pr e vi o u s i nf u si o n r at e, it i s 
r e c o m m e n d e d t h at t h e r at e r e m ai n s r e d u c e d f or all s u b s e q u e nt i nf u si o n s. T h e s p e e d m a y b e a dj u st e d d e p e n di n g 
o n t h e pr e s e nt ati o n of I R R s d uri n g s u b s e q u e nt i nf u si o n s.
F or Gr a d e 3 or 4 i nf u si o n -r el at e d r e a cti o n s, bi ntr af u s p alf a / pl a c e b o di s c o nti n u ati o n i s m a n d at e d. 
F or Gr a d e 3 i nf u si o n-r el at e d r e a cti o n s, “ pr ol o n g e d” i s d efi n e d i n t hi s pr ot o c ol a s l a sti n g > 6 h o ur s.
F or all t y p e s a n d gr a d e s of i nf u si o n r e a cti o n s, d et ail s a b o ut dr u g p h y si c al c o n stit uti o n, m et h o d of pr e p ar ati o n, a n d 
i nf u si o n m u st b e r e c or d e d.
H y perse nsiti vit y R e acti o n
If a h y perse nsiti vit y reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical practice. A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h ylactic reacti o ns 
acc or di n g t o t he W or ki n g 
Gr o u p 
of t he Res uscitati o n 
C o u ncil ( UK ) ca n be f o u n d at 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
7 9 / 2 1 3
w w w.res us. or g. u k/ pa ges/reacti o n. p df . Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y dela y e d 
reacti o ns t o t he I n vesti gat or i m me diatel y.
S y m pt o ms ma y  i ncl u de b ut are n ot li mite d t o: 

I m paire d air wa y

Decrease d o x y ge n sat urati o n ( < 9 2 %)

C o nf usi o n

Let har g y

H y p ote nsi o n

Pale/cla m m y  s ki n

C y a n osis
Ma na ge me nt of h y p erse nsiti vit y i ncl u des: 

E pi ne p hri ne i njecti o n a n d i ntra ve n o us de xa met has o ne

Partici pa nt s h o ul d be place d o n car diac, bl o o d press ure, heart rate, a n d o x y ge n sat urati o n 
m o nit or i m me diatel y

Alert inte nsi ve care u nit f or p ossi ble tra nsfer, if re q uire d.
Pr o p h yl a xis of Fl u -li ke S y m pt o ms
F or pr o p h yl a xis of fl u-li ke s ym pt o ms, 
a n o nster oi dal a nti-i nfla m mat or y dr u g ( N S AI D), 
e. g., i b u pr ofe n 4 0 0 m g  or c o m para ble N S AI D d ose, ma y  be a d mi nistere d 2 h o urs bef ore a n d 
8 h o urs after t he start of eac h i ntra ve n o us i nf usi o n.
Cis pl ati n -rel ate d H y perse nsiti vit y
IR Rs d ue t o i ntra ve n o us c he m ot hera p y ca n be mi ni mize d wit h cl ose m o nit ori n g f or a n y earl y 
de vel o p me nt of a n y s i g ns a n d s ym pt o ms ( mai nl y h y perse nsiti vit y  in d uce d b y  plati n u m-c o ntai ni n g 
c he m ot hera p y, k n o w n t o occ ur m ore wit h s u bse q ue nt c ycles) (Ma krilia 2 0 1 0 ). T he i nci de nce of 
cis plati n-i n d uce d h y perse nsiti vit y  ra n ges fr o m 5 % t o 2 0 % a n d occ urs wit hi n mi n utes of i nf usi o n 
m ostl y  co m m o nl y  bet wee n t he 4 t h a n d 8 t h treat me nt c o urses. O nce 
cis plati n-i n d uce d 
I R R/ hy perse nsiti vit y  occ urs, cis plati n s h o ul d be per ma ne ntly wit h dra w n.
Si nce c ortic oster oi d use as pre me dicati o n is pr o hi bite d, cl ose partici pa nt vi gila nce a n d pr o m pt 
rec o g niti o n of h y perse nsiti vit y  sy m pt o ms are a d vise d. M o derate t o se vere I R R s ym pt o ms will 
re q uire i nf usi o n i nterr u pti o n a n d pr o m pt sy m pt o matic ma na ge me nt. Refe r t o t he pr o d uct la bel f or 
I R R/i m me diate hy perse nsiti vit y  ma na ge me nt g ui deli nes. 
If t he res p o nsi ble dr u g f or IR Rs/ h y perse nsiti vit y  is n ot i de ntifie d, see Ta ble 1 4 f or i nstr ucti o ns o n 
w hic h dr u g (s) t o m o dif y.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 0 / 2 1 3
T a ble 1 4
M o dific ati o n 
of 
C o m b i n ati o n 
Tre at me nt 
f or 
I nf usi o n-rel ate d 
Re acti o ns/ H y perse nsiti vit y
Ti mi n g of I R R 
O c c urr e n c e
C a u s e of 
I R R
Fir st O c c urr e n c e
O n D a y of B i ntr af u s p alf a / Pl a c e b o
/G e m cit a bi n e/ Ci s pl ati n I nf u si o n
O n D a y of G e m cit a bi n e/ Ci s pl ati n
I nf u si o n
A p pl y 
M o difi c ati o n t o :
N o 
M o difi c ati o n a
A p pl y 
M o difi c ati o n t o :
N o 
M o difi c ati o n
a
B ef or e ci s pl ati n 
i nf u si o n
B i ntr af u s p 
alf a / 
pl a c e b o
B i ntr af u s p 
alf a / pl a c e b o
G e m cit a bi n e a n d
ci s pl ati n
N A
N A
A f e w mi n ut e s aft er 
st arti n g ci s pl ati n
i nf u si o n
Li k el y 
ci s pl ati n b
Ci s pl ati n b
B i ntr af u s p 
alf a / pl a c e b o a n d 
g e m cit a bi n e
Ci s pl ati n
B i ntr af u s p 
alf a / pl a c e b o a n d 
g e m cit a bi n e
Aft er ci s pl ati n
i nf u si o n
B i ntr af u s p 
alf a / 
pl a c e b o or 
ci s pl ati n
B i ntr af u s p 
alf a / pl a c e b o
a n d/ or ci s pl ati n
G e m cit a bi n e
Ci s pl ati n
B i ntr af u s p 
alf a / pl a c e b o a n d
g e m cit a bi n e
I R R =i nf u si o n-r el at e d r e a cti o n, N A = n ot a p pli c a bl e.
F oll o w  T a bl e 1 3 f or d o s e m o difi c ati o n of bi ntr af u s p alf a / pl a c e b o.
C i s pl ati n will b e p er m a n e ntl y t er mi n at e d i n c a s e of ci s pl ati n -r el at e d h y p er s e n siti vit y.
S e q u e n c e of i nf u si o n: 1. B i ntr af u s p alf a/ pl a c e b o, 2. G e m cit a bi n e or Ci s pl ati n , 3. T h e r e st of G e m cit a bi n e or 
Ci s pl ati n .
a
W h e n r e s u m e d.
b
C ar ef ull y o b s er v e t h e n e xt d o si n g, a s t h e p o s si bilit y of I R R s r el at e d t o bi ntr af u s p alf a r e m ai n s.
6. 9. 2
I m m u ne-rel ate d A d verse E ve nts
A n ir A E is defi ne d as a n off -tar get si de effect ass ociate d wit h e x p os ure of i m m u n o ge nic dr u g a n d 
is c o nsiste nt wit h a n i m m u ne mec ha nis m. I n t he pr ocess of i de ntificati o n of ir A Es, a n y p ossi ble 
eti ol o g y of ne o plastic, i nfecti o us, meta b olic, t o xi n, or a n y ot her fact or s h o ul d be r ule d o ut. 
Ser ol o gic al, hist ol o gical ( bi o ps y), a n d i m m u n ol o gical data s h o ul d be o btai ne d t o s u p p ort i m m u ne 
me diati o n of t he occ urre nce of a n A E. 
I m m u ne-relate d A Es are A E SI s a n d s pecific t o i m m u n ot hera pies a n d var y b y or ga n sys te m. 
T he f oll o wi n g i m m u ne -relate d A Es are i m p orta nt i de ntifie d ris ks f or bi ntraf us p alfa:

I m m u ne-relate d he patitis

I m m u ne-relate d p ne u m o nitis

I m m u ne-relate d c olitis

I m m u ne-relate d ne p hritis a n d re nal dys f u ncti o n

I m m u ne-relate d e n d ocri n o pat hies (t h yr oi d dis or ders, a dre nal i ns ufficie nc y, t ype 1 dia betes
mellit us, pit uitar y  dis or ders)

I m m u ne relate d ras h
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 1 / 2 1 3

Ot her i m m u ne- relate d e ve nts ( m yositis, m y ocar ditis, e nce p halitis)
T he f oll o wi n g ir A Es are i m p orta nt p ote ntial ris ks f or bi ntraf us p alfa:

G uillai n -Barré s y n dr o me

U veitis

Pa ncreatitis

M y ast he nia gra vis/ m yas t he nic s yn dr o me
I n ge neral, t he s pectr u m of ir A Es is si milar f or bi ntraf us p alfa c o m pare d wit h ot her c hec k p oi nt 
i n hi bit ors. Effecti ve ris k ma na ge me nt of t hese t o xicities (ir A Es) pri maril y c a use d d ue t o i n hi biti o n 
of P D -L 1 a n d P D -1 pat h wa y s is base d o n k e y  rec o m me n dati o ns (C ha m piat 2 0 1 6 ). Partici pa nt 
e d ucati o n f or o n -ti me re p orti n g of sy m pt o ms of p ote ntial ir A Es a n d pr o m pt cli nical assess me nt is 
critical f or effecti ve ma na ge me nt a n d q uic ker res ol uti o n of i m m u ne-me diate d t o xicities, t h us 
pre ve nti n g pr o gressi o n i nt o se vere f or ms of t o xicit y that ot her wise m a y  bec o me life-t hreate ni n g 
a n d diffic ult t o ma na ge or warra nt per ma ne nt disc o nti n uati o n fr o m t he st u d y.
T he Me dical M o nit or ma y be i n v ol ve d as nee de d f or f oll o w -u p. Detai ls of t he dia g n ostic w or k-u p 
will be re q ueste d b y t he st u d y  tea m.
F or re p orti n g ir A E se verit y/t o xicit y gra di n g, refer t o t he C T C A E V ersi o n 5. 0 t o xicit y gra di n g 
s yste m. T he rec o m me n dati o ns f or ir A E ma na ge me nt are g ui de d b y  t he j oi nt A S C O
Cli nical 
Practice G ui deli nes a n d N C C N g ui deli nes , liste d i n A p pe n di x 8 .
Treat me nt of ir A Es is mai nl y  de pe n de nt u p o n se verit y as defi ne d b y  NCI -C T C A E v 5. 0. I n ge neral, 
ma na ge me nt b y N C I-C T C A E v 5. 0 gra di n g, as per A S C O, is liste d bel o w:

Gra de 1: st u d y i nter ve nti o n s h o ul d be c o nti n ue d wit h cl ose m o nit ori n g, wit h t he e xce pti o n of 
s o me ne ur ol o gic, he mat ol o gic, a n d car diac t o xicities. 

Gra de 2: st u d y i nter ve nti o n ma y  be s us pe n de d f or m ost Gra de 2 t o xicities, wit h c o nsi derati o n 
of res u mi n g w he n s ym pt o ms re vert t o Gra de 1 or less. C ortic oster oi ds ma y be a d mi nistere d 
(i nitial d ose of 0. 5 t o 1 m g/ k g/ da y of pre d nis o ne or e q ui vale nt). 

Gra de 3: st u d y i nter ve nti o n is ge nerall y s us pe n de d a n d hi g h -d ose c ortic oster oi ds ( pre d nis o ne 
1 t o 2 m g / k g/ da y or met h y l pre d nis ol o ne 1 t o 2 m g/ k g/ da y ) treat me nt s h o ul d be i nitiate d. 
C ortic oster oi ds s h o ul d be ta pere d o ver t he c o urse of at least 4 t o 6 wee ks. S o me refract or y 
cases ma y re q uire i nfli xi ma b or ot her i m m u n os u p pressi ve t hera p y. 

Gra de 4: i n ge neral, per ma ne nt disc o nti n uati o n of st u d y inter ve nti o n is rec o m me n de d, wit h t he 
e xce pti o n of e n d ocri n o pat hies t hat ha ve bee n c o ntr olle d b y  h or m o ne re place me nt.
Per ma ne nt 
treat me nt disc o nti n u ati o n is re q uire d i n case of 
i m m u ne-relate d Gra de 4 
ras h/i nfla m mat or y der matitis, ne p hritis, a ut oi m m u ne he m ol y tic a ne mia,
he m ol yt ic ure mic 
s yn dr o me, 
a plastic 
a ne mia, 
i m m u ne 
t hr o m b oc yt o pe nia,
a n d 
ac q uire d 
t hr o m b otic 
t hr o m b oc yt o pe nic p ur p ura ( T T P). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 2 / 2 1 3
F or Gra d e 4 i m m u ne-relate d l ym p h o pe nia, per ma ne nt disc o nti n uati o n of st u d y inter ve nti o n will 
be re q uire d, if l ym p h o pe nia 
is c o nsi dere d i m m u ne-relate d i n nat ure, n o clear alter nati ve 
e x pla nati o n e xists f or t he e ve nt, a n d Gra de 4 l y m p h o pe nia d oes n ot res ol ve wit hi n 1 4 da y s.
Per ma ne nt disc o nti n uati o n of st u d y inter ve nti o n is n ot re q uire d w he n t he A E is ma nifest b y  a 
si n gle la b orat or y val ue o ut of n or mal ra n ge wit h o ut a n y cli nical c orrelates. I n this case, st u d y 
i nter ve nti o n s h o ul d be hel d u ntil t he eti ol o g y is deter mi ne d. If t he e ve nt is n ot c o nsi dere d 
i m m u ne-relate d a n d res ol ves t o Gra de ≤1, restarti n g st u d y i nter ve nti o n ma y  be c o nsi dere d.
F or a d diti o nal or ga n/s yste m s pecific ma na ge me nt 
g ui deli nes, see t he g ui deli ne ta bles i n 
A p pe n di x 8 .
6. 9. 3
T G F β I n hi biti o n M e di ate d S ki n Re acti o ns
T G F β i n hi biti o n me diate d ski n reacti o ns, i ncl u di n g h y per kerat osis, K A a n d/ or c S C C s, are 
i m p orta nt i de ntifie d ris ks a n d A E SI f or bi ntraf us p alfa .
S ki n assess me nts are perf or me d at b aseli ne a n d e ver y 6 wee ks f or all partici pa nts as s pecifie d i n 
t he Sc he d ule of Acti vities (Secti o n 1. 3 ). Referral t o a der mat ol o gist is rec o m me n de d i n case of 
s us pici o us lesi o ns. Basel i ne s ki n assess me nts i ncl u de a detaile d me dical hist or y  of ge netic or 
iatr o ge nic s ki n c o n diti o ns, s ki n t ype, ge o gra p hical l ocati o n, si g nifica nt ultra vi olet e x p os ure/s u n 
da ma ge of s ki n, a n d occ u pati o nal or e n vir o n me ntal e x p os ure t o ra diati o n or c he micals. 
Ma na ge me nt g ui deli nes f or p ote ntial T G F β i n hi biti o n me diate d s ki n reacti o ns:

Disc o nti n uati o n or i nterr u pti o n is n ot re q uire d i n m ost cases. C o nti n uati o n of treat me nt s h o ul d 
be e val uate d b y t he I n vesti gat or

E m ollie nts ma y  c o nti n ue t o be use d

A d ia g n ostic a n d treat me nt pla n s h o ul d be de vel o pe d i n c olla b orati o n bet wee n t he I nvesti gat or 
a n d der mat ol o gist. I n ge neral, treat me nt of T G F β i n hi biti o n me diate d s ki n lesi o ns s uc h as 
h y per kerat osis, K A a n d c S C C s h o ul d be base d o n l ocal g ui deli nes/ S o C . Lesi o n e val uati o n 
s h o ul d i ncl u de e xcisi o n bi o ps y of 1 re prese ntati ve lesi o n t o c o nfir m dia g n osis

Treat me nt a n d f oll o w-u p f or K A a n d c S C C will de pe n d o n t he n u m ber a n d l ocalizati o n of 
lesi o ns:

F or si n gle lesi o ns: 
o
F ull e xcisi o n ma y  be rec o m me n de d. 

I n case of m ulti ple lesi o ns or a l ocati o n n ot s uita ble f or f ull e xcisi o n: 
o
Ot her treat me nt o pti o ns ma y  be offere d by t he der mat ol o gist, s uc h as: 

M o hs s ur gery, cr y ot hera p y , or ot her sta n dar d treat me nt o pti o ns de pe n di n g 
o n t he pat h ol o g y

Use of reti n oi ds if rec o m me n de d b y  t he der mat ol o gist, ma y  be c o nsi dere d 
after disc ussi o n wit h t he Me dical M o nit or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 3 / 2 1 3

Cl ose cli nical f oll o w- u p f or re-e val uati o n, res ol uti o n, or p ote ntial rec urre nce s h o ul d be 
i m ple me nte d

S p o nta ne o us res ol uti o n of K A lesi o ns wi t h o ut s ur gical i nter ve nti o n has bee n o bser ve d, 
t ypicall y occ urri n g wit hi n wee ks after disc o nti n ui n g bi ntraf us p alfa

T he n u m ber a n d l ocalizati o n of lesi o ns, dia g n osis (i ncl u di n g hist o pat h ol o gical dia g n osis), 
treat me nt, a n d o utc o me s h o ul d be a p pr o priatel y  d oc u me nte d i n t he e C R F.
C o ns ult wit h t he Me dical M o nit or as nee de d f or t he ma na ge me nt of T G F β i n hi biti o n me diate d 
s ki n lesi o ns.
6. 9. 4
A ne mi a
N o ncli nical testi n g of bi ntraf us p alfa le d t o t he classificati o n of a ne mia as a n A E SI a n d i m p orta nt 
i de ntifie d ris k (refer t o t he IB f or f urt her i nf or mati o n ). 
N ota bl y t here are ma n y reas o ns f or a ne mia i n a d va nce d ca ncer patie nts, i ncl u di n g a ne mia ca use d 
b y  ge mcita bi ne a n d cis plati n c he m ot hera p y. Als o, gi ve n t hat partici pa nts wit h
a H g b le vel of 
9 g/ d L m a y  enter t he stu d y , a t h or o u g h i n vesti gati o n of ne w cases of a ne mia wit h u ns pecifie d 
eti ol o g y is re q ueste d. 
Safet y  la b orat or y testi n g of rele va nt bl o o d para meters s h o ul d be c o n d ucte d per t he Sc he d ule of 
Acti vities (see Secti o n 1. 3 ).
Si nce t he st u d y inter ve nti o n
will 
be a d mi nistere d i n c o m bi nati o n wit h 
c he m ot hera p y,  
disti n g uis h i n g a ne mia i n d uce d b y bi ntraf us p alfa / place b o fr o m t h at b y che m ot hera p y  m a y not b e 
p ossi ble. H o we ver, if t he e ve nts are assesse d as bi ntraf us p alfa/ place b o-relate d, ite ms q uerie d ma y 
i ncl u de b ut are n ot li mite d t o: detaile d rele va nt past me dical a n d treat me nt hist or y , br uisi n g 
te n de nc y, hist or y  of bl o o d tra nsf usi o ns a n d/ or de pe n de nc y , a n d a re q uest f or a n u p date d e C R F
(i ncl u di n g details s uc h as c o nc o mita nt me dicati o ns, 
all la b orat or y data, u p date d d osi n g 
i nf or mati o n, a n d rece nt t u m or e val uati o n sca ns). See als o Secti o n  6. 9. 5 f or ma na ge me nt of ra pi d 
H g b decrease .
Ge neral g ui da nce f or a ne mia ma na ge me nt a n d e val uati o n i ncl u de t he f oll o wi n g:

Partici pa nts m ust e nter t he st u d y wit h a n H g b val ue of at least 9 g/ d L a n d baseli ne a ne mia 
e val uati o n as c o n ducte d per  Ta ble 1 5

All rele va nt he mat ol o gic testi n g f or a ne mia s h o ul d be perf or me d pri or t o a bl o o d tra nsf usi o n, 
if cli nicall y feasi ble

Tra nsf usi o n s h o ul d be perf or me d at t he discreti o n of t he I nvesti gat or, base d o n cli nical 
assess me nt , a n d c o nsi dere d w he n t he partici pa nt e x perie nces si g nifica nt a ne mia. A n atte m pt 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 4 / 2 1 3
s h o ul d be ma de t o i nitiate w or k - u p (as s pecifie d bel o w) f or t he ca use of a ne mia pri or t o 
tra nsf usi o n, if cli nicall y feasi ble, s o t hat t his w or k-u p is n ot c o nf o u n de d. If partici pa nt rec o vers 
t o Gra de 1 a ne mia wit h a bl o o d tra nsf usi o n, s us pe n d t he ne xt d osi n g u ntil c o nfir mi n g a ne mia 
is sta bl y co ntr olle d, a n d t he u n derl yi n g ca use of a ne mia is res ol ve d. As g ui da nce, t he 
In vesti gat or s h o ul d wait f or at least 1 wee k p ost -tra nsf usi o n t o c o nfir m sta bilizati o n. If a ne mia 
is sta bilize d a n d t he d osi n g criteria ( H gb Gra de 1 or baseli ne) are met 1 wee k after t he 
tra nsf usi o n, t he In vesti gat or ca n pr ocee d t o t he ne xt d osi n g.

G ui da nce f or t he e val uati o n of s us pecte d a ne mias is pr o vi de d i n Ta ble 1 5. Disc uss f urt her 
ma na ge me nt wit h t he Me dical M o nit or f or cli nicall y  si g nifica nt a ne mias.
T a ble 1 5
E v al u ati o n G ui d a nce f or S us pecte d A ne mi a 
A n e mi a E v al u ati o n ( Pri or t o Tr a n sf u si o n, if F e a si bl e)
H g b a n d C B C wit h diff er e nti al ( e. g., M C V, R D W , A N C, h e m at o crit, r eti c ul o c yt e s c o u nt s)
P eri p h er al bl o o d s m e ar f or c ell m or p h ol o gi c al a s s e s s m e nt
C o m pl et e m et a b oli c p a n el i n cl u di n g li v er p a n el -L F T s, bilir u bi n, L D H, r e n al f u n cti o n, s er u m f ol at e, B 1 2, a n d ot h er 
c h e mi stri e s:

C o a g ul ati o n f a ct or s ( P T, P T T, I N R)

Uri n al y si s , i n cl u di n g c ult ur e

Ir o n p a n el ( TI B Ca , f erriti n, F e)

T S H/ h or m o n al p a n el

F e c al -o c c ult bl o o d t e sti n g

Er yt hr o p oi eti n
F urt h er R e c o m m e n d ati o n B a s e d o n S u s p e ct e d Eti ol o g y  (i n A d diti o n t o B a s eli n e A n e mi a T e sti n g)
U n k n o w n eti ol o g y, s u s p e ct 
p o s si bl e h e m ol y si s

C o o m b s t e st, fi bri n o g e n, h a pt o gl o bi n, D- di m er

C o n si d er h e m at ol o g y c o n s ult ati o n

C o n si d er bl o o d tr a n sf u si o n at cli ni c al di s cr eti o n
U n k n o w n eti ol o g y, s u s p e ct 
p o s si bl e bl e e di n g

C o n si d er bl o o d tr a n sf u si o n at cli ni c al di s cr eti o n

C o n si d er s ur gi c al/i nt er v e nti o n al r a di ol o g y c o n s ult ati o n

C o n si d er i m a gi n g, a s cli ni c all y i n di c at e d ( e. g., F A S T s c a n, C T s c a n, M RI, 
a n gi o gr a p h y)

C o n si d er e n d o s c o p y ( u p p er/l o w er) 
U n k n o w n eti ol o g y d e s pit e 
a b o v e w or k- u p

H e m at ol o g y c o n s ult ati o n

C o n si d er b o n e m arr o w a s pir ati o n/ m or p h ol o gi c e v al u ati o n
, C B C = c o m pl et e bl o o d c o u nt, C T = c o m p ut e d t o m o gr a p h y, F A S T = f o c u s e d 
a s s e s s m e nt wit h s o n o gr a p h y f or tr a u m a, F e =ir o n, H g b = h e m o gl o bi n, I N R =i nt er n ati o n al n or m ali z e d r ati o, 
L D H =l a ct at e d e h y dr o g e n a s e, L F T =li v er f u n cti o n t e st, M C V = m e a n c or p u s c ul ar v ol u m e, M R I =m a g n eti c r e s o n a n c e 
i m a gi n g, P T = pr ot hr o m bi n ti m e, P T T = p arti al t hr o m b o pl a sti n ti m e, R D W = r e d c ell di stri b uti o n wi dt h, TI B C= t otal ir o n 
bi n di n g c a p a cit y, T S H = t h yr oi d-sti m ul ati n g h or m o n e.
a
If TI B C c a n n ot b e e v al u at e d l o c all y, r e pl a c e wit h tr a n sf erri n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 5 / 2 1 3
6. 9. 5
Blee di n g E ve nts
Blee di n g e ve nts are A E SIs a n d a n i m p orta nt i de ntifie d ris k f or bi ntraf us p alfa (refer t o t he I B).
6. 9. 5. 1
M uc os al/ N o n -T u m or Blee di n g
M uc osal blee di n g e ve nts of mil d t o m o derate se verit y were o bser ve d i n partici pa nts treate d wit h 
bi ntraf us p alfa i n o n g oi n g st u dies. E ve nts m a y  incl u de e pista xis, he m o pt y sis, gi n gi val blee di n g, or 
he mat uria, a m o n g ot hers. I n ge neral, t hese reacti o ns res ol ve wit h o ut disc o nti n uati o n of treat me nt .
F or all partici pa nts:
F or Gra de 2 n o n- t u m or blee di n g, see Sectio n 6. 6. 3. 1 f or ge neral ma na ge me nt of Gra de 2 A D Rs.
F or Gra de 3 n o n- t u m or blee di n g, st u d y inter ve nti o n m ust be per ma ne ntl y disc o nti n ue d u nless a n 
alter nati ve e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mi ta nt use of a ntit hr o m b otic a ge nts, 
tra u matic e ve nt, etc.). I n case of alter nati ve e x pla nati o ns f or t he Gra de 3 blee di n g e ve nt, st u d y 
i nter ve nti o n s h o ul d be hel d u ntil t he e ve nt rec o vers t o Gra de ≤1. U p o n res u m pti o n of t he st u dy 
i nter ve nti o n, bi ntraf us p alfa d ose s h o ul d be re d uce d t o 1 2 0 0 m g Q 3 W
or rele va nt v ol u me of 
matc hi n g place b o .
F or Gra de 4 n o n- t u m or blee di n g, st u d y inter ve nti o n m ust be per ma ne ntl y  disc o nti n ue d if n o 
alter nati ve e x pla nati o n is i de ntifie d.
I n case of ra pi d decrease of he m o gl o bi n ( H g b), s uc h as a decrease greater t ha n 3. 0 g/ d L acr oss a 
3 wee ks peri o d, wit h h ol d t he s u bse q ue nt c ycles of st u d y inter ve nti o n u ntil H g b is sta bilize d a n d 
d o a t h or o u g h assess me nt of blee di n g (f or e xa m ple, u p per a n d l o wer GI  e n d osc o p y, e n ha nce me nt 
C T 
etc.); if Gr a de 1 or 
greater 
blee di n g 
is o bser ve d 
or 
s us pecte d, wit h h ol d 
t he 
bi ntraf us p alfa/ place b o u ntil t he blee di n g is res ol ve d/c o ntr olle d a n d res u me t he d ose of 
bi ntraf us p alfa re d uce d t o 1 2 0 0 m g 
Q 3 W
or c orres p o n di n g v ol u me of matc hi n g 
place b o. 
Ge mcita bi ne a n d cis plati n ma y  be res u me d earlier after c o ns ultati o n wit h t he Me dical M o nit or. 
T he d ose of bi ntraf us p alfa/ place b o m a y  be re-escalate d t o f ull d ose ( bi ntraf us p alfa 2 4 0 0 m g or 
c orres p o n di n g v ol u me f or place b o) o nce H g b is sta bilize d wit h o ut f urt her nee d f or b l o o d 
tra nsf usi o n i n t he s u bse q ue nt c ycles. T he ti mi n g of re-escalati o n m a y  nee d a case-b y -case decisi o n. 
O nce H g b decrease is rec o vere d t o ≤ Gra de 1 or baseli ne a n d sta bl y c o ntr olle d, t he I n vesti gat or is 
e nc o ura ge d t o c o m m u nicate wit h Me dical M o nit or t o re-escalate t he d ose (see Secti o n 6. 9. 4
re gar di n g sta bilizati o n of a ne mia).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 6 / 2 1 3
6. 9. 5. 2
T u m or Blee di n g
F or Gra de ≥2 t u m or blee di n g, st u d y inter ve nti o n m ust be hel d u ntil t he e ve nt rec o vers t o 
Gra de ≤1. 
If Gra de 3 or se vere blee di n g e ve nt ha d bee n o bser ve d re gar dless of ca usalit y wit h t he st u d y 
i nter ve nti o n, up o n res u m pti o n of t he st u d y i nter ve nti o n, bi nt raf us p alfa d ose s h o ul d be re d uce d t o 
1 2 0 0 m g Q 3 W or rele va nt v ol u me of matc hi n g place b o . St u d y  inter ve nti o n s h o ul d be per ma ne ntl y 
disc o nti n ue d if t he I n vesti gat or c o nsi ders t he partici pa nt t o be at ris k f or a d diti o nal se vere blee di n g.
I n case of ra pi d decrease of H g b, see Secti o n 6. 9. 5. 1.
6. 9. 6
Ot her P ote nti al Ris ks
6. 9. 6. 1
I m p aire d W o u n d He ali n g 
I m paire d w o u n d heali n g is c o nsi dere d a n i m p orta nt p ote ntial ris k (a t he oretical ris k-base d o n 
literat ure fi n di n gs) f or bi ntraf us p alfa gi ve n t he r ole of T G F β i n w o u n d heali n g. Ma na ge me nt of 
w o u n d heali n g or tiss ue da ma ge re pair s h o ul d be disc usse d wit h t he Me dical 
M o nit or 
f or 
partici pa nts re q uiri n g s ur ger y on st u d y. It is rec o m me n de d t o h o l d treat me nt f or a p pr o xi matel y 
4 wee ks p ost maj or 
s ur ger y for o bser vati o n. P ost o perati ve w o u n d heali n g will be cl osel y 
m o nit ore d.
6. 9. 6. 2
E m br y ofet al T o xicit y
E m br y ofetal t o xicities are a k n o w n ris k of t he P D -1/ P D -L 1  tar geti n g class a n d are t heref ore 
c o nsi dere d a n i m p orta nt p ote ntial ris k f or bi ntraf us p alfa . Refer t o t he IB f or f urt her i nf or mati o n.
A n a p pr o priate c o ntrace pti o n war ni n g is pr o vi de d as part of t he i ncl usi o n criteria (see Secti o n 5. 1 ). 
Partici pa nts wit h pre g na ncies or breastfee di n g are pr o hi bite d fr o m bei n g e nr olle d i n cli nical 
st u dies. Pre g na nt w o me n are n ot all o we d i n t he bi ntraf us p alfa st u d y a n d a de q uate c o ntrace pti ve 
meas ures are rec o m me n de d d uri n g t he st u d y t o mi ni mize or eli mi nate t he p ote ntial ris k t o t he 
de vel o pi n g fet us.
Res pecti ve safet y meas ures c o m prise i ncl usi o n/e xcl usi o n criteria f or partici pati o n i n cli nical 
st u dies wit h bi ntraf us p alfa, g ui da nce f or pre ve nti o n, m o nit ori n g, a n d me dical ma na ge me nt of 
p ote ntial ris ks, as well as g ui da nce o n st u d y i nter ve nti o n i nterr u pti o n or disc o nti n uati o n. See als o 
A p pe n di x 3 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 7 / 2 1 3
7
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n a n d 
P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
7. 1. 1
Per m a ne nt Tre at me nt Disc o nti n u ati o n
Partici pa nts will be wit h dra w n fr o m treat me nt f or a n y of t he f oll o wi n g reas o ns:
1.
Partici pa nts wit h P D as i nitiall y deter mi ne d b y  the site base d o n R E CI S T 1. 1 w hile o n 
treat me nt, wit h t he e xce pti o ns detaile d i n Secti o n 7. 1. 2 .
2.
Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w s ym pt o ms t hat are 
dee me d b y  the I n vesti gat or t o be cli nicall y si gnifica nt or si g nifica nt w orse ni n g of e xisti n g 
s ym pt o ms.
3.
U nacce pta ble t o xicit y ; s e e Secti o ns  6. 6 a n d 6. 9.  
4.
T hera pe utic fai l ure re q uiri n g ur ge nt a d diti o nal or alter nati ve a ntica ncer treat me nt.
5.
Occ urre nce of A E s res ulti n g i n t he per ma ne nt disc o nti n uati o n of t he st u d y i nter ve nti o n bei n g 
desire d or c o nsi dere d necessar y  b y t he I n vesti gat or a n d/ or t he partici pa nt.
6.
Occ urre nce of pre g na nc y i n t he partici pa nt.
7.
Use of a pr o hi bite d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 5. 3,  w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he st u d y inter ve nti o n if c o nsi dere d necessar y  by t he 
I n vesti gat or or t he S p o ns or.
8.
N o nc o m plia nce : see Secti o n  6. 4.
After i nitiati o n of st u d y inter ve n ti o n, partici pa nts wit h o bstr ucti ve ja u n dice a n d/ or biliar y  tract 
i nfecti o n wit h o ut c o nc o mita nt ra di ol o gical P D s h o ul d u n der g o pr o m pt biliar y  drai na ge a n d be 
retai ne d i n t he st u dy.  
T he Sc he d ule of Acti vities s pecifies t he data t o c ollect at st u d y inter ve nti o n disc o nti n uati o n a n d 
f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m plete d. See Secti o n 1. 3.
7. 1. 2
Tre at me nt Be y o n d I niti al Pr o gressi o n
See Fi g ure 3 f or treat me nt c o nti n uati o n be y o n d ra di ol o gical P D .
O nce t he site de tects P D b y  RE CI S T 1. 1, P D (as defi ne d bel o w) s h o ul d be c o nfir me d b y  th e 
I n vesti gat or o n a f urt her sca n perf or me d at least 2 8 da y s after t he i nitial I nvesti gat or detecti o n of 
P D or at t he ne xt sc he d ule d sca n. T he I n vesti gat or is e nc o ura ge d t o c o nti n ue bi ntraf us p 
alfa/ place b o treat me nt d uri n g t his ti me, i.e., fr o m t he i nitial detecti o n of P D b y  the In vesti gat or
acc or di n g t o R E CIS T 1. 1, u ntil c o nfir me d P D if all f oll o wi n g criteria (criteria 1 t o 6 ) are met:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 8 / 2 1 3
1.
St u d y  i nter ve nti o n is o n g oi n g
2.
N o ne w u nacce pta ble treat me nt or disease -relate d t o xicit y is o bser ve d
3.
T olera nce of st u d y i nter ve nti o ns
4.
Sta ble or i m pr o vi n g E C O G P S
5.
Treat me nt b e y o n d pr o gressi o n will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n (e. g., C N S metastases)
6.
Partici pa nt has si g ne d a se parate i nf or me d c o nse nt t o e ns ure a n d t o d oc u me nt t hat t he y are 
a ware of bei n g treate d be yo n d i nitial disease pr o gressi o n.
T he c o nti n uati o n of ge mcita bi ne a n d cis plati n u ntil c o nfir me d P D (or u p t o 8 c ycles, w hic he ver 
occ urs first ) is at t he discreti o n of t he I n vesti gat or if all t he state d c o n diti o ns (criteria 1 - 6) are met. 
C o nfir me d P D is defi ne d as a f urt her pr o gressi o n of a n y d etecta ble i ncrease i n t u m or b ur de n, wit h 
n o l o wer li mit t o t he ma g nit u de of t he i ncrease. A n y  enlar ge me nt of e xisti n g tar get lesi o ns, or of 
n o ntar get lesi o n b ur de n, of e xisti n g ne w lesi o ns, or a p peara nce of a n y f urt her ne w lesi o n will 
c o nstit ute f urt her pr o gressi o n. F urt her defi niti o ns are pr o vi de d i n  Ta ble 1 6.
If ra di o gra p hic assess me nt d oes n ot c o nfir m P D, t he assess me nt s h o ul d c o nti n ue acc or di n g t o t he 
Sc he d ule of Acti vities (see Secti o n 1. 3 ) u ntil f urt her pr o gressi o n or a n y ot her criteri o n for 
wit h dra wal is met.
A Decisi o n Tree f or c o nti n uati o n of treat me nt u ntil c o nfir me d P D is pr o vi de d i n Fi g ure 3.  
T a ble 1 6
Defi niti o ns of Pr o gressi ve Dise ase
T er m
D efi niti o n
C o nfir m e d P D
Sit e h a s d et e ct e d di s e a s e pr o gr e s si o n a n d h a s p erf or m e d a s e c o n d s c a n at l e a st 2 8 d a y s 
l at er t h at s h o w s f urt h er pr o gr e s si o n of di s e a s e
N ot e: C o nfir m ati o n i s m a d e 2 8 + d a y s l at er b y t h e I n v e sti g at or
F urt h er pr o gr e s si o n
F urt h er pr o gr e s si o n i s d efi n e d a s a n y d et e ct a bl e i n cr e a s e i n t u m or b ur d e n a s c o m p ar e d 
t o o n s et of P D, wit h n o l o w er li mit t o t h e m a g nit u d e of t h e i n cr e a s e. A n y e nl ar g e m e nt of 
e xi sti n g t ar g et l e si o n s, or of n o nt ar g et l e si o n b ur d e n, of e xi sti n g n e w l e si o n s, or a n y 
f urt h er n e w l e si o n will c o n stit ut e f urt h er pr o gr e s si o n
P D = pr o gr e s si v e di s e a s e.
D oc u me nte d D ate of Pr o gressi ve Dise ase
T he date t hat t he site first detects P D f or a st u d y  partici pa nt will be referre d t o as t he “site date of 
pr o gressi o n f or R E CI S T 1. 1 .” 
F or t he partici pa nts i n sc o pe of t he a da ptati ve decisi o n a nal ysis, the I RC will deter mi ne t he date 
of P D u n der R E CI S T 1. 1 se parately t hr o u g h t he I R C pr ocesses, a n d will als o deter mi ne t he date 
of fi nal i m m u ne P D u n der i m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
8 9 / 2 1 3
(ir R E CIS T ) (B o h nsac k 2 0 1 4 ). T he S p o ns or or dele gate will c ollect ra di ol o gical i ma ges f or all 
partici pa nts a n d t hese will be assesse d b y t he I RC if re q uire d.
Fi g ure 3
Decisi o n 
Tree f or C o nti n u ati o n 
of Tre at me nt Be y o n d Pr o gressi ve 
Dise ase
G E M/ C D D P = g e m cit a bi n e/ ci s pl ati n, P D = pr o gr e s s i v e di s e a s e, R E CI S T 1. 1 = R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s V er si o n 1. 1 .
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al f r o m t he St u d y
Partici pa nts ca n be wit h dra w n fr o m t he st u d y  a n d/ or treat me nt f or a n y of t he f oll o wi n g reas o ns:

A partici pa nt m a y  wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or m a y  be 
wit h dra w n at a n y ti me at t he discreti o n of t he In vesti gat or f or safety, be ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns

If t he partici pa nt wit h dra ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y data c ollecte d u p 
t o t hat p oi nt ma y still be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gical sa m ples 
c ollecte d will be destr o ye d

A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr ucti o n of a n y bi ol o gical sa m ples ta ke n. 
T he I nvesti gat or m ust d oc u me nt t his i n t he site st u d y  rec or ds.
At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a disc o nti n uati o n visit (E n d - of-Treat me nt 
Visit) will be c o n d ucte d, as liste d i n t he Sc he d ule of Acti vities ( Secti o n 1. 3 ). T he Sc he d ule of 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 0 / 2 1 3
Acti vities s pecifies t he data t o c ollect at st u d y disc o nti n uati o n a n d f oll o w- u p, a n d a n y ad diti o nal 
e val uati o ns t hat nee d t o be c o m plete d.
T he I n ves ti gat or will sec ure t he safet y of t he st u d y partici pa nts a n d ma ke e ver y atte m pt t o c ollect 
data.
I n case of wit h dra wal fr o m st u d y i nter ve nti o n:

T he da y  of E n d of Treat me nt will c orres p o n d t o t he da y  of wit h dra wal ( or wit hi n 7 da y s)

T he assess me nts sc he d ule d f or t he E n d- of -T reat me nt V isit s h o ul d be perf or me d, if p ossi ble, 
wit h 
a f oc us o n t he m ost 
rele va nt assess me nts , a n d
t he a p pr o priate e C R Fs
f or t he 
E n d - of-Treat me nt V isit m ust be c o m plete d

Partici pa nts will be as ke d t o c o nti n ue safety a n d s ur vi val f oll o w- u p, w hic h i ncl u des t he 
c ollecti o n of data o n s ur vi val, P R O q uesti o n naires, a n d s u bse q ue nt a ntica ncer t hera p y. After 
c o m pleti o n of t he lo n g -ter m foll o w - u p peri o d or after t he E n d - of-Treat me nt V isit, w hic he ver is 
a p plica ble, t he a p pr o priate e C R F secti o n f or st u d y ter mi nati o n m ust be c o m plete d.

If t he partici pa nt is e nr olle d i nt o a ne w st u d y or a n y ne w t hera p y post -wit h dra wal fr o m t he
st u d y i nter ve nti o n, t he Safet y F oll o w- u p Visit s h o ul d be sc he d ule d pri or t o t he start of t he ne w 
treat me nt irres pecti ve of t he 2 8 -d a y  Safet y Foll o w -u p peri o d.
Re pl ace me nt of P artici p a nts

If a partici pa nt i n t he o pe n -la bel, safety r u n-i n part of t he st u d y is wit h dra w n fr o m st u d y 
i nter ve nti o n or fr o m t he st u d y duri n g t he D L T e val uati o n peri o d f or a n y r eas o n ot her t ha n D L T, 
he /s he will be re place d.

If a partici pa nt i n t he safet y ru n- i n part of t he st u d y d oes n ot recei ve at least 1 d ose of bi ntraf us p 
alfa a n d of b ot h ge mcita bi ne a n d cis plati n d uri n g t he D L T e val uati o n peri o d, he/s he will be 
re place d.

If a partici pa nt i n t he ra n d o mize d, d o u ble -bli n d part of t he st u d y is wit h dra w n fr o m st u d y 
i nter ve nti o n or fr o m t he st u d y f or a n y reas o n, he/s he will n ot be re place d.
7. 3
L ost t o F oll o w - u p
A partici pa nt will be c o nsi dere d l ost t o f oll o w-u p if he or s he re peate dl y fails t o retur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns will be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:

T he site will atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he mis se d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule 
a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y .

Bef ore a partici pa nt is dee me d “l ost t o f oll o w-u p”, t he I n vesti gat or or desi g nee will ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls; 2) if 
necessar y , se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last k n o w n 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 1 / 2 1 3
maili n g a d dress, a n d 3) if a partici pa nt has gi ve n t he a p pr o priate c o nse nt, c o ntact t he 
partici pa nt’s ge neral practiti o ner or careta ker ( w here all o we d b y  local re g ulati o ns) f or 
i nf or mati o n. T hese c o ntact atte m pts will be d oc u me nte d i n t he partici pa nt’s me dical rec or d.

If t he partici pant c o nti n ues t o be u nreac ha ble, he/s he will be dee me d as “l ost t o f oll o w -u p”.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ule of 
Acti vities . See Secti o n 1. 3 .

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o n cer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Acti vities , is esse ntial a n d re q uire d f or st u dy c o n d uct.

All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial partici pa nts 
meet all eli gi bilit y criteria. T he In vesti gat or will mai ntai n a scree ni n g l o g t o rec or d details of 
all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, an d if a p plica ble, rec or d reas o ns f or scree ni ng 
fail ure.

Pri or t o perf or mi n g a n y s t u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d i n  A p pe n di x 2.

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I C F m a y  be use d f or scree ni n g or baseli ne p ur p oses pr o vi de d t he 
pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me 
defi ne d i n t he Sc he d ule of Acti v ities ( Secti o n 1. 3 ).

A ma xi m u m of 1 2 7 m L of bl o o d will be c ollecte d i n a n y o ne- m o nt h peri o d fr o m eac h 
partici pa nt i n t he st u d y , i ncl u di n g a ny e xtra assess me nts t hat ma y be re q uire d.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
8. 1. 1
T u m or Res p o nse 
C o ntrast -e n ha nce d C T of t he c hest/a b d o me n a n d pel vis c o veri n g t he area fr o m t he s u peri or e xte nt 
of t he t h oracic i nlet t o t he s y m p h y sis p u bis is t he first c h oice of i ma gi n g m o dalit y. If a partici pa nt 
s h o ul d n ot recei ve i o di nate d c o ntrast me di u m or d ue t o ra diati o n pr otecti o n reas o ns, a n M RI  of 
t he a b d o me n a n d pel vis , usi n g ga d oli ni u m e n ha nce me nt acc or di n g t o l ocal pr ot oc ol as per mitte d,
i n c o nj u ncti o n wi t h u ne n ha nce d C T of t he c hest fr o m t he t h oracic i nlet t o t he i nferi or c ost o p hre nic 
recess s h o ul d be d o ne. T he sa me met h o d s h o ul d be use d per partici pa nt t hr o u g h o ut t he st u d y.
Baseli ne a n d o n- st u d y brai n C T/ M RI  sca n s h o ul d be perf or me d if cli nicall y in dicat e d b y  
de vel o p me nt of ne w s pecific s y m pt o ms.
T u m or res p o nses t o treat me nt will be assi g ne d base d o n t he e val uati o n of t he res p o nse of tar get, 
n o ntar get, a n d ne w lesi o ns acc or di n g t o R E CI S T 1. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 2 / 2 1 3
Baseli ne sca ns will be ta ke n wit hi n 2 8 da y s pri or t o treat me nt. Disease m ust be meas ura ble, wit h 
at least 1 u ni di me nsi o nall y meas ura ble lesi o n per R E CI S T 1. 1 (e xce pt f or partici pa nts i n t he o pe n -
la bel, safety r u n-i n part) . I n ge neral, lesi o ns detecte d at baseli ne nee d t o be f oll o we d usi n g t he 
sa me i ma gi n g met h o d ol o g y  an d prefera bl y  the sa me i ma gi n g e q ui p me nt at s u bse q ue nt t u m or 
e val uati o n visits. All o n -treat me nt sca ns are t o be re peate d usi n g t he sa me met h o d at t he 
s u bse q ue nt assess me nt ti me p oi nts.
Partici pa nts will be e val uat e d wit h ra di o gra p hic i ma gi n g t o assess res p o nse e ver y 6 wee ks u p t o 
Wee k
3 7 a n d t he n e ver y  1 2 wee ks u ntil P D (see Sc he d ule of Acti vities, Secti o n 1. 3 ).
Treat me nt decisi o ns will be ma de b y  the assess me nt of t he treati n g I n vesti gat or (see Fi g ure 3) .
T u m or res p o nses t o treat me nt assesse d acc or di n g t o R E CI S T 1. 1 b y  the I nvesti gat or will be 
d oc u me nte d i n t he e C R F (all meas ure me nts s h o ul d be rec or de d i n metric n otati o n) ; ir R E CIS T will 
n ot be assesse d b y  the I n vesti gat or. A n I R C , bli n de d f or treat me nt, will re vie w ra di o gra p hic i ma ge 
fi n di n gs f or t he deter mi nati o n of o bjecti ve res p o nse a n d date of P D f or eac h of t he first 
1 5 0 a nti bi otics -nai ve partici pa nt s acc or di n g t o R E CI S T 1. 1 a n d ir R E CIS T (B o h nsac k 2 0 1 4) . A ll 
ra di ol o gical i ma ges f or t he re mai ni n g partici pa nts m ust als o be s u b mitte d.
C o nfir mati o n of C R or partial res p o nse (P R ) s h o ul d be perf or me d prefera bl y  at t he re g ularly 
sc he d ule d assess me nt i nter vals, b ut n o s o o ner t ha n 4 wee ks after t he i nitial d o c u me ntati o n. 
C o nfir mati o n of P R ca n be c o nfir me d at a n assess me nt later t ha n t he ne xt assess me nt after t he 
i nitial d oc u me ntati o n of P R pr o vi de d P D has n ot occ urre d bet wee n t he 2 ti me p oi nts.
Partici pa nts w h o start 2 L treat me nt s h o ul d be m o nit ore d f or res p o nse t o t hat treat me nt. O bjecti ve 
res p o nse acc or di n g t o R E CIS T 1. 1 t o t his 2 L treat me nt f or metastatic disease s h o ul d be re p orte d. 
A partici pa nt’s pr o gressi o n ma y  in v ol ve t he f oll o wi n g: o bjecti ve ra di ol o gical, s ym pt o matic 
pr o gressi o n, or deat h d ue t o a d va nc i n g disease. Details of R E CI S T 1. 1 met h o d ol o g y  are s u p plie d 
as A p pe n di x 1 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 3 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 4 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 5 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 6 / 2 1 3
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of baseli ne me di cal c o n diti o ns, A E s, p h y sical e xa mi nati o n fi n di n gs, vital si g ns, 
electr ocar di o gra ms ( E C Gs), a n d la b orat or y tests.
P h y sical e xa mi nati o ns, assess me nt of vital si g ns, E C O G P S, a n d E C Gs, a n d sa m pli n g f or cli nical 
safety la b orat or y assess me nts s h o ul d be c o m plete d pri or t o a d mi nistrati o n of st u d y inter ve nti o n 
( w here a p plica ble).
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
In vesti gat or will re p ort a n y A E s, w het her o bser ve d b y  the I n vesti gat or o r re p orte d b y  th e 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n  8. 3. 1 .
8. 2. 1
P h ysic al E x a mi n ati o ns a n d Vit al Si g ns
P h y sical e xa mi nati o ns, vital si g ns a n d E C O G P S will be perf or me d at Scree ni n g a n d at s u bse q ue nt 
visits as i n dicate d i n t he Sc he d ule of Acti vities (see Secti o n 1. 3 ). T hese s h o ul d be d oc u me nte d i n 
t he e C R F.
A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he car di o vasc ular, 
res pirat or y, gastr oi ntesti nal , a n d ne ur ol o gical s yste ms. 
A brief p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vasc ular s ys te m, a n d a b d o me n (li ver a n d s plee n) .
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.
Ge neral stat us, s uc h as ast he nia or a p petite, s h o ul d be e val uate d at baseli ne, as t hese are us uall y 
affecte d. Pre -e xisti n g s ym pt o ms of u n derl y i n g c o n diti o ns or a n y rece nt i nfecti o n or fe ver s h o ul d 
be c hec ke d a n d i n vesti gate d as necessar y .
A b n or mal fi n di n gs are t o be reassesse d at s u bse q ue nt visits.
Hei g ht (at Scree ni n g o nl y) a n d wei g ht will be meas ure d a n d rec or de d.
B o d y te m perat ure, p ulse rate, res pirat or y rate, a n d bl o o d press ure will be assesse d.
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d wit h a c o m pletel y aut o mate d de vice. 
Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d b y  at least 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet setti n g wit h o ut distracti o ns ( e. g., tele visi o n, cell p h o nes).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 7 / 2 1 3
Vital si g ns will be meas ure d i n a se mi-s u pi ne p ositi o n after 5 mi n utes rest a n d will i ncl u de 
te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse a n d res pirat or y rate.
Bl o o d o x y ge n sat urati o n will be meas ure d usi n g a p ulse o xi mete r i n all partici pa nts f or t he 
p ote ntial earl y detecti o n of I L D. See Secti o n 8. 2. 3 f or cli nical safety la b orat or y assess me nts t o be 
perf or me d at sites i n Ja pa n o nl y  f or p ote ntial early detecti o n of p ne u m o nitis.
8. 2. 2
Ele ctr oc ar di o gr a ms
Si n gle 1 2- lea d E C G will be o btai ne d as o utli ne d i n t he Sc he d ule of Acti vities
usi n g a n E C G 
mac hi ne t hat a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc i nter vals. 
8. 2. 3
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y tests liste d i n A p pe n di x 6
Cli nical La b orat or y Tests , at t he ti me p oi nts liste d i n t he Sc he d ule of Acti vities .All sa m ples s h o ul d 
be clearl y i de ntifie d. 
A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d necessar y  by t he 
In vesti gat or or re q uire d b y  l ocal re g ulati o ns.
T he tests will be perf or me d b y l ocal la b orat ories. Rele va nt res ults m ust be a vaila ble a n d c hec ke d 
b y  the I n vesti gat or bef ore a d mi nistrati o n of t he st u d y inter ve nti o n , as i n dicate d i n A p pe n di x 6 , 
Ta ble - A, Ta ble - B, Ta ble - C, Ta ble - D, Ta ble - E , a n d Ta ble - F (refer t o t he La b orat or y Ma n ual).
T he S p o ns or m ust recei ve a list of t he l ocal la b orat or y nor mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y must be f or war de d t o t he CR O a n d t he 
S p o ns or .
T he In vesti gat or m ust re vie w eac h la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he e C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts.
If a partici pa nt has a cli nicall y si gnifica nt a b n or mal la b orat or y test val ue t hat was n ot prese nt at 
baseli ne, t he test s h o ul d be cl osel y m o nit ore d u ntil t he test val ue has ret ur ne d t o t he n or mal ra n ge 
or t he I n vesti gat or has deter mi ne d t hat t he a b n or malit y  is c hr o nic or sta ble. 
T he re p ort of t he la b orat or y res ults m ust be retai ne d as a part of t he partici pa nt’s me dical rec or d 
or s o urce d oc u me nts.
Ser u m K L - 6, S P -A, a n d S P - D le vels will be meas ure d i n partici pa nts i n Ja pa n o nl y f or p ote ntial 
earl y detecti o n of p ne u m o nitis (A p pe n di x 6 Ta ble - F). T he incl usi o n of t hese mar kers is f or t he 
i n dicati o n of p ote ntial l u n g-relate d t o xicit y o nly;  f urt her i n vesti gati o ns, s uc h as c hest C T, etc, will 
be perf or me d f or a c o nfir mat or y  dia g n osis.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 8 / 2 1 3
Pre g na nc y  testi n g (ser u m or hi g hl y  se nsiti ve uri ne, as re q uire d b y  local re g ulati o ns) will be 
c o n d ucte d at t he ti me p oi nts s pecifie d i n t he Sc he d ule of Acti vities , i ncl u di n g at t he e n d of rele va nt 
s yste mic e x p os ure of t he st u d y i nter ve nti o n. 
A d diti o nal ser u m or hi g hl y  se nsiti ve uri ne pre g na nc y  tests m a y  be c o n d ucte d, as deter mi ne d 
necessar y  by t he I n vesti gat or or re q uire d b y  local re g ulati o n, t o esta blis h t he a bse nce of pre g na nc y 
at a n y ti me d uri n g t he st u d y.
8. 2. 4
Re vie w C o m mittee s
8. 2. 4. 1
S afet y M o nit ori n g C o m mittee
T he safety o f partici pa nts i n t he o pe n -la bel, safety r u n-i n part will be assesse d b y  a SM C. R e gi o nal 
S M C meeti n gs will be hel d after c o m pleti o n of t he D L T e val uati o n peri o d , at least 1 f or eac h of 
t he res pecti ve re gi o nal c o h orts. Details will be pr o vi de d i n t he S M C c harter.
8. 2. 4. 2
I n de pe n de nt D at a M o nit ori n g C o mm ittee
After cleara nce of a re gi o n b y  S M C, t he ra n d o mize d, d o u ble - bli n de d part of t he st u d y will be 
i nitiate d (re gi o n-wise decisi o n) . T o e ns ure partici pa nts’ safet y, a n I DM C
will be esta blis he d f or 
peri o dic re vie w of safety data t hr o u g h o ut t he ra n d o mize d d o u ble -bli n d part of t he st u d y. O n t he 
basis of t hese re g ularl y s c he d ule d safet y data re vie w s a n d of a n a d diti o nal data re vie w meeti n g t o 
be c o n d ucte d u p o n e nr oll me nt of 1 5 0 partici pa nts i n t he P hase II, t he I DM C ma y  rec o m me n d 
a d diti o nal safet y meas ures, i ncl u di n g e nr oll me nt pa use.
I n or der t o ma ke a rec o m me n dati o n re gar di n g t he e x pa nsi o n of t he st u d y int o P hase III, t he I D M C 
will re vie w efficac y  data fr o m t he first 1 5 0 a nti bi otic s- naive partici pa nts e nr olle d i n P hase II a n d 
safety data f or all partici pa nts treate d i n t he st u d y u ntil t he data c ut off of t his a nal ys is. I n t he e ve nt 
t hat t he st u d y is e x pa n de d t o 5 0 0 partici pa nts as a P hase III (f urt her t o t he a da ptati o n decisi o n), 
t he I D M C will be re q ueste d t o re vie w partici pa nts’ efficac y a n d safety data a n d c o ul d rec o m me n d 
t hat t he st u d y be st o p pe d earlier f or efficac y or f utilit y .
T he f ull me m bers hi p, ma n date, a n d pr ocesses of t he I D M C will be detaile d i n a se parate I D M C 
c harter.
8. 2. 4. 3
I n de pe n de nt Re vie w C o m mittee
T he r ole of t he I R C will be t o re vie w ra di o gra p hic i ma ge fi n di n gs f or t he deter mi nati o n of t he 
o bjecti ve res p o nse a n d date of disease pr o gressi o n f or t he P hase II part of t he st u d y, a n d m a y  b e 
re q ueste d t o d o t his als o f or t he P hase III part of t he st u d y. T he f ull me m bers hi p, ma n date, a n d 
pr ocesses of t he I R C will be detaile d i n t he I R C c harter .
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A E a n d a seri o us a d verse e ve nt (S A E ) are i n A p pe n di x 4. A def i niti o n of 
A E SI is als o pr o vi de d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
9 9 / 2 1 3
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y  incl u de d i n 
t he st u d y (date of first si g nat ure of i nf or me d c o nse nt/ date of first si g nat ure of first i nf or me d 
c o nse nt) a n d c o nti n ues u ntil t he 2 8- da y  S afet y Foll o w - u p Visit, defi ne d as 2 8 da y s 
 after 
t he last st u d y inter ve nti o n a d mi nistrati o n . T hereafter, all S A Es a n d treat me nt-relate d n o nseri o us
A E s s h o ul d be d oc u me nte d u ntil t he last S afet y F oll o w - u p Visit, defi ne d as 1 2 wee ks 
 
after t he last st u d y i nter ve nti o n a d mi nistrati o n . O n g oi n g e ve nts at t he 1 2- wee k S afet y F oll o w - u p 
V isit s h o ul d c o nti n ue t o be m o nit ore d a n d d oc u me nte d u ntil res ol uti o n or res ol uti o n wit h se q uelae.
A n y S A E assesse d as relate d t o st u d y  i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d i n 
A p pe n di x 4 , w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he last a d mi nistrati o n of 
st u d y i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A E s (i ncl u di n g S A E s) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 4 .
8. 3. 2
Met h o d 
of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his/her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as A E s, 
re gar dless if re p orte d by t he partici pa nt or o bser ve d b y t he In vesti gat or.
C o m plete, acc urate a n d c o nsiste nt data o n all A E s e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o priate re p ort for m as 
s pecifie d i n A p pe n di x 4 .
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A E s are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
a n d are assesse d f or t heir o utc o me at t he 2 8 -da y  Safety F oll o w -u p V isit. All S A Es o n g oi n g at t he
2 8- d a y  Safet y Foll o w -u p V isit m ust be m o nit ore d a n d f oll o we d u p b y  the I n vesti gat or u ntil 
sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he partici pa nt is d oc u me nte d as “l ost t o 
f oll o w-u p”. Reas o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is 
als o t he res p o nsi bilit y of t he I nvesti gat or t o e ns ure t hat a n y necessar y ad diti o nal t hera pe utic
meas ures a n d f oll o w- u p pr oce d ures are perf or me d. F urt her i nf or mati o n o n f oll o w- u p pr oce d ures 
is gi ve n i n A p pe n di x 4 .
M o nit ori n g of S pecific A d verse E ve nts
Details re gar di n g t he m o nit ori n g a n d ma na ge me nt of A Es
of s pecial i nterest ca n be f o u n d i n 
Secti o n  6. 9.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 0 / 2 1 3
8. 3. 4
Re g ul at or y 
Re p orti n g 
Re q uire me nts 
f or Seri o us A d verse 
E ve nts
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust re p ort S A Es ( partic ularly deat hs) i n acc or da nce wit h a p plica ble site-s pecific 
re q uire me nts t o t he I nstit uti o nal Re vie w B oar d (I R B)/In de pe n de nt Et h ics C o m mittee (IE C) t hat 
a p pr o ve d t he st u d y.
I n acc or da nce wit h I C H G o o d Cli nical Practice ( G C P ) a n d t he Ja pa nese mi nisterial or di na nce o n 
G C P, t he S p o ns or/ desi g nee will i m me diatel y inf or m all t he st u d y In vesti gat ors a n d t he Hea ds of 
t he st u d y sites of fi ndi n gs t hat c o ul d a d versel y a ffect t he safety of p artici pa nts, i m pact t he c o n d uct 
of t he st u d y or alter t he I R B/IE C ’s a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he st u d y. I n li ne wit h 
res pecti ve a p plica ble re g ulati o ns, t he S p o ns or/ desi g nee will i m me diatel y inf or m all t he st u d y 
I n vesti gat ors a n d t he Hea ds of t he st u d y sites of A E s t hat are b ot h seri o us a n d u ne x pecte d a n d 
c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (S U S A Rs). I n ad diti o n, per a p plica ble 
re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he stu d y  In vesti gat ors a n d t he Hea ds of t he st u d y 
sites of all S A Es w hic h were re p orte d t o t he H ealt h A ut h orities. I n acc or da nce wit h t he Ja pa nese 
re g ulat or y re q uire me nts c o ncer ni n g safet y re p orti n g, t he I n vesti gat or s h o ul d place c o pies of t he 
Safet y  Re p orts i n t he I n vesti gat or Site File. T he Hea d of t he st u d y site s h o ul d als o mai ntai n c o pies 
of S afet y R e p orts a p pr o priatel y.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p o rts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
F or st u dies c o vere d b y  the E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities 
re gar di n g t he re p orti n g of S A Es/ S U S A Rs/ Safet y  Iss ues will be carrie d o ut i n acc or da nce wit h t hat 
Directi ve a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
8. 3. 5
Pre g n a nc y
O nl y  pre g na ncies t he I n vesti gat or c o nsi ders t o be relate d t o t he st u d y i nter ve nti o n (e. g., res ulti n g 
fr o m a dr u g i nteracti o n wit h a c o ntr ace pti ve met h o d ) are A E s. H o we ver, all pre g na ncies wit h a n 
esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n  8. 3. 1 m ust be rec or de d i n t he A E 
pa ge/secti o n of t he e C R F f or b ot h pre g na ncies i n fe male partici pa nts a n d pre g na ncies i n fe male 
part ners of male partici pa nts. T he I nvesti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n e x pe dite d 
ma n ner of a n y pre g na nc y  usi n g t he Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d b y  th e 
sa me pr ocess s pecifie d f or S A E re p orti n g i n A p pe n di x 4 , secti o n o n re p orti n g S A Es a n d D L Ts .
I n vesti gat ors m ust 
acti vel y foll o w - u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he partici pa nts are wit h dra w n fr o m t he st u d y .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 1 / 2 1 3
T he I n vesti gat or m ust n otif y  t he S p o ns or/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y Re p ort 
F or m. If a n ab n or mal o utc o me occ urs, t he S A E R e p ort F or m will be use d if t he partici pa nt s ustai ns 
a n e ve nt a n d t he Pare nt -C hil d/ Fet us A d verse E ve nt Re p ort F or m if t he c hil d/fet us s ustai ns a n 
e ve nt. A n y a b n or mal o utc o me (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y ) m ust 
be re p orte d i n a n e x pe dite d ma n ner, 
as s pecifie d i n 
Secti o n 8. 3. 1 , w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y.
I n t he e ve nt of a pre g na nc y  in a partici pa nt occ urri n g d uri n g t he st u d y, t he partici pa nt m ust be 
disc o nti n ue d fr o m st u d y inter ve nti o n. T he S p o ns or/ desi g nee m ust be n otifie d wit h o ut dela y  an d 
t he partici pa nt m ust be foll o we d as i n dicate d a b o ve.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d os e of st u d y i nter ve nti o n greater t ha n 1 0 % of t he hi g hest dail y  d ose wit hi n a 
2 4- h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.
T here are n o k n o w n s ym pt o ms of bi ntraf us p alfa o ver d ose t o date. F or i nf or mati o n re gar di n g 
o ver d oses of ge mcita bi ne a n d cis plati n, refer t o t he c urre nt pr o d uct i nf or mati o n a p plica ble t o t he 
re gi o n. T he I n vesti gat or s h o ul d use his or her cli nical j u d g me nt w he n treati n g a n o ver d ose of t he 
st u d y i nter ve nti o n.
E v e n if it is n ot ass ociate d wit h a n A E or a S A E, a n y o ver d ose is rec or de d i n t he e C R F a n d re p orte d 
t o dr u g safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a S A E Re p ort F or m, f oll o wi n g 
t he pr oce d ure i n A p pe n di x 4 , secti o n o n re p orti n g S A Es a n d D L Ts .
8. 5
P h ar m ac o k i netics
P har mac o ki netics of bi ntraf us p alfa will be e val uate d f or all partici pa nts i n t he first part of t he 
st u d y (o pe n -la bel, safet y r u n-i n) a n d all t h ose i n t he bi ntraf us p alfa ar m i n t he d o u ble -bli n d, 
ra n d o mize d part ( Ce oi a n d C tr o u g h o nl y ); b li n di n g will be mai ntai ne d as descri be d i n Secti o n  6. 3. 2 . 
T he f oll o wi n g P K para meters will be calc ulate d , w he n a p pr o priate (Ta ble 1 7) :
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 2 / 2 1 3
T a ble 1 7
P h ar m ac o ki netic P ar a meters
S y m b ol
D efi niti o n
A U C 0-t
T h e ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o ( = d o si n g ti m e) t o t h e l a st 
s a m pli n g ti m e (tl a st) at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n. 
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n)
A U C 0- α
T h e A U C fr o m ti m e z er o ( d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e pr e di ct e d v al u e f or t h e 
c o n c e ntr ati o n at tl a st, as e sti m at e d u si n g t h e li n e ar r e gr e s si o n fr o m λ z d et er mi n ati o n. A U C 0- ∞= A U C 0-
t + C l a st pr e d / λz
C E OI
T h e c o n c e ntr ati o n o b s er v e d i m m e di at el y at t h e e n d of i nf u si o n
C m a x
M a xi m u m o b s er v e d c o n c e ntr ati o n,
C tr o u g h
T h e c o n c e ntr ati o n o b s er v e d i m m e di at el y b ef or e n e xt d o si n g ( c orr e s p o n di n g t o pr e d o s e or tr o u g h 
c o n c e ntr ati o n f or m ulti pl e d o si n g)
t½
A p p ar e nt t er mi n al h alf -lif e. t½ = l n ( 2)/ λz
tm a x
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al ( u nl e s s 
ot h er wi s e d efi n e d, t a k e t h e 1 st o c c urr e n c e i n c a s e of m ulti pl e/i d e nti c al C m a x v al u e s)
W h ole 
bl o o d sa m ples of a p pr o xi matel y 3. 5 m L will be c ollecte d f or meas ure me nt of ser u m
c o nce ntrati o ns of bi ntraf us p alfa . C ollecti o n ti mes are s pecifie d i n t he Sc he d ule of Acti vities (see 
Secti o n  1. 3, Ta ble 3, a n d Ta ble 4 ). T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m ple 
will be rec or de d t o calc ulate act ual ti me ela pse d si nce t he pri or d ose a d mi nistrati o n . T he sa m pli n g 
ti mi n g ma y  be altere d d uri n g t he st u d y base d o n ne wl y  availa ble data (e. g., t o o btai n data cl oser 
t o t he ti me of pea k plas ma c o nce ntrati o ns) t o e ns ure a p pr o priate m o nit ori n g.
T he q ua ntificati o n of bi ntraf us p alfa i n ser u m will be perf or me d usi n g a vali date d assa y met h o d. 
C o nce ntrati o ns will be use d t o e val uate t he P K of bi ntraf us p alfa .
W here c ollecte d at t he sa me ti me p oi nts, the P K a n d  
sa m ples ma y  be use d i nterc ha n gea bl y 
if t he de dicate d sa m ple has i ns ufficie nt q ua ntit y , as partici pa nts will ha ve c o nse nte d t o all 
c ollecti o ns a n d tests.
Re mai ni n g sa m ples c ollecte d f or a nal ys es of bi ntraf us p alfa ser u m c o nce ntrati o n ma y  als o be use d 
t o e val uate i m m u n o ge nicit y an d safety or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or 
after t he st u d y.
Details o n pr ocess es f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y  Ma n ual. 
Rete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d of st u d y are s pecifie d i n t he 
res pecti ve I CF.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CIC CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 3 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 4 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 5 / 2 1 3
9. 1
St atistic al H y p ot heses
T he f oll o wi n g h y p ot heses will be teste d.
Pri m ar y E n d p oi nt: O ver all S ur vi v al
T he f oll o wi n g n ull h y p ot hesis will be teste d :
   :   () =     (),  ≥1 vers us    :   () =     (),  < 1
w here  ⋅
  () re prese nts t he hazar d at ti me  a n d  t he u n k n o w n c o nsta nt of pr o p orti o nalit y  of 
hazar ds i n t he treat me nt gr o u ps M ( bi ntraf us p alfa) a n d C (c o ntr ol).
Sec o n d ar y E n d p oi nt: Pr o gressi o n -free S ur vi v al
T he f oll o wi n g n ull h y p ot hesis will be teste d:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 6 / 2 1 3
    :    () =      (),  ≥1 vers us     :    () =      (),  < 1
w here  ⋅
   () re prese nts t he hazar d at ti me  a n d  t he u n k n o w n c o nsta nt of pr o p orti o nalit y  of 
hazar ds i n t he treat me nt gr o u ps M ( bi ntraf us p alfa) a n d C (c o ntr ol).
Sec o n d ar y E n d p oi nt: O bjecti ve Res p o nse
Treat me nt gr o u ps will be c o m pare d i n ter ms of differe nce of O R R (Δ    =     −    ), 
bet wee n t he treat me nt gr o u ps, wit h M f or bi ntraf us p alfa a n d C f or c o ntr ol.
T he f oll o wi n g n ull h y p ot hesis will be t este d:
    : Δ   ≤0 vers us     : Δ   > 0 .
9. 2
Hier a rc hic al Testi n g Pr oce d ure
A hierarc hical testi n g pr oce d ure as prese nte d is a p plie d t o t he c o nfir mat or y tests f or t he h y p ot heses 
s pecifie d i n Secti o n 9. 1 .
T he h y p ot hesis f or t he pri mar y  en d p oi nt O S will be teste d b y  a gr o u p se q ue ntial a p pr oac h i n 
i nteri m a n d pri mar y a nal yses at a si g nifica nce le vel of 2. 5 % 1-si de d. If, t he O S n ull h yp ot hesis is
rejecte d, t he h y p ot hesis f or t he sec o n dar y en d p oi nt, P F S, will be teste d c o nfir mat or y by a gr o u p 
se q ue ntial a p pr oac h. If, t he P F S n ull h y p ot hesis is rejecte d, t he h y p ot hesis f or t he sec o n dar y 
e n d p oi nt, O R R, will be teste d li ke wise.
T he gr o u p se q ue ntial a ppr oac h f or testi n g O S, P F S a n d o bjecti ve res p o nse will use al p ha-s pe n di ng 
f u ncti o n of La n -De Mets a p pr oac h acc or di n g t o t he act ual n u m ber of o bser ve d e ve nts re gar di n g 
t he t otal e ve nt n u m ber pla n ne d f or t he P A f or O S ( 3 3 4 e ve nts), i.e., t he sa me i nf or mati o n fracti o n 
wit h O S will be use d f or P F S a n d o bjecti ve res p o nse. O’ Bria n -Fle mi n g b o u n daries are use d f or 
O S a n d P oc oc k b o u n daries are use d f or P F S a n d o bjecti ve res p o nse (Gli m m 2 0 1 0 ).
Pres pecif y i n g t he or der of t he h y p ot heses t o be teste d, t he fa mil y  wise err or rate f or t his a p pr oac h 
t o se q ue ntiall y rejecti ve m ulti ple test pr oce d ure (Ma urer 1 9 9 5 ) is c o ntr olle d at 2. 5 % o ne-si de d.
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 7 / 2 1 3
9. 3. 1
A n al ysis f or t he A d a pt ati o n Decisi o n
T he a nal ys is f or a da ptati o n decisi o n will be c o n d ucte d i n t he first 1 5 0 a nti bi otics - naive partici pa nts 
w he n 8 0 P F S e ve nts ha ve occ urre d a n d o nce at least 1 9 wee ks of f oll o w- u p f or t he first 
1 5 0 a nti bi otics - naive partici pa nt s ra n d o mize d is reac he d.
I n case m ulti ple partici pa nts are ra n d o mize d o n t he sa me da y  as t he 1 5 0 t h a nti bi otics - naive 
partici pa nt, t he a nal ysis f or a da ptati o n decisi o n will i ncl u de all a nti bi otics - naive partici pa nts 
ra n d o mize d u p t o t his da y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 8 / 2 1 3
T he decisi o n is base d o n a c o nfir me d o bjecti ve res p o nse o d ds rati o a n d P F S H R (as assesse d b y  
t he IR C) . The st u d y  will be e x pa n de d i nt o P hase III if:

O d ds rati o of a c o nfir me d o bjecti ve res p o nse (O R O R ) is ≥1. 6 or

P F S H R ( H R P F S ) is < 0. 7 5 , a n d

a f urt her crite ri o n t hat uses m ore of t he a vaila ble i nteri m i nf or mati o n a n d all o ws a q ua ntificati o n 
of t he f ut ure O S treat me nt effect base d o n a vaila ble i nter-s u bject i nf or mati o n a b o ut t he 
relati o ns hi p bet wee n differe nt efficac y en d p oi nts is met . T his criteri o n is base d o n t he 
pr o ba bilit y  of s uccess. S uccess is defi ne d as o bser vi n g a n H R f or O S less t ha n a pres pecifie d 
t hres h ol d. E x pa nsi o n is f oresee n if t he pr o ba bilit y  of s uccess is e xcee di n g a pre defi ne d 
t hres h ol d o n t o p of t he a b o ve descri be d criteria of O R R a n d P F S. T he details a b o ut t he 
met h o d ol o g y  an d t hres h ol ds will be s pecifie d i n a n a p pe n di x t o t he I DM C c harter a n d I D M C 
a nal ys is pla n.
If t he st u d y will n ot be e x pa n de d t o f ull P hase III sa m ple size, t he ID M C will c o nsi der t o ma ke a 
rec o m me n dati o n t o st o p t he st u d y earl y f or f utilit y if t he o bser ve d P F S H R is > 1 a n d ta ki n g i nt o 
acc o u nt t he t otalit y of a vaila ble data i ncl u di n g a vaila ble O S data at t his p oi nt .T his is a n o n- bi n di n g 
f utilit y a nalys is.
9. 3. 2
P o wer a n d T y pe I Err or 
Ta ble 1 9 pr o vi des t he st o p pi n g b o u n daries as well as l ocal p o wer f or t he pla n ne d a nal ys es base d 
o n se parate P hase II a n d P hase III pla n ni n g . C o m p utati o ns were d o ne usi n g E A S T. 
T a ble 1 9
St o p pi n g B o u n d aries U n der t he Pl a n ne d Sc he d ule of A n al yses
N
N u m b er of 
E v e nt s
p ( 1 - si d e d)
Z S c or e
H R at B o u n d ar y
O v er
all 
P o w
er
L o c al 
P o w er
I A
P A
I A
P A
O v er
all
I A
P A
I A
P A
I A
P A
Effi -
c a c y
F uti -
lit y
Effi -
c a c y
Effi -
c a c y
F uti -
lit y
Effi -
c a c y
3 0 0 a
-
1 8 0
-
2. 5 % 
2. 5 %
- 
- 
-1. 9 6
- 
-
0. 7 5
6 7 %
-
6 7 %
5 0 0 
2 1 0 
3 3 4
0. 5 % 
2. 4 % 
2. 5 %
-2. 5 9 7
0 . 6 9 8
-1. 9 8 6
0. 7 0 
1. 1 0 
0. 8 1
9 0 % 
5 0 % 
4 1 %
H R = h a z ar d r ati o, I A =i nt eri m a n al y si s, P A = pri m ar y a n al y si s.
H a z ar d r ati o i s a n e x p e ct e d o n e b a s e d o n t h e a s s u m pti o n of e x p o n e nti al di stri b uti o n. T h e d e ci si o n will b e b a s e d o n 
t h e p-v al u e .
a M a xi m u m s a m pl e si z e of P h a s e II.
Besi des t he se parate pla n ni n g of P hase II a n d P hase III, a si m ulati o n st u d y was perf or me d t o 
i nc or p orate all decisi o n criteria f or i nteri m a n d pri mar y a nal ys es. A m ulti-state m o del was use d t o 
m o del t he i nter-s u bject relati o ns hi p bet wee n t he differe nt e n d p oi nts. U n der t he n ull h y p ot hesis H 0, 
t he st u d y will be e x pa n de d i n 3. 5% of cases. U n der t he alter nati ve H 1, t he st u d y will be e x pa n de d 
i n 4 1 % of cases. O verall, t he p o wer of t his st u d y  is 68 % re gar dless of w het her t he st u d y ex pa n ds 
or n ot. T h ose 6 8 % are t he s u m of 2 9 % p o wer wit h n o e x pa nsi o n, 1 8 % p o wer at t he i nteri m a nal ys is 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 0 9 / 2 1 3
wit h e x pa nsi o n, a n d 2 1 % p o wer at t he pri mar y  anal ys is wit h e x pa nsi o n. H o we ver, t he P hase III 
p o wer ( p o wer gi ve n t he st u d y is e x pa n de d) is 9 5 %. Fr o m t his pers pecti ve, t he st u d y is s ufficie ntl y 
p o were d if e x pa n de d t o f ull sa m ple size .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 0 / 2 1 3
9. 4
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w (Ta ble 2 3 ). T he fi nal decisi o n t o e xcl u de partici pa nts 
fr o m a ny a nal ys is p o p ulati o n will be ma de d uri n g a bli n de d data re vie w meeti n g pri or t o data base 
l oc k a n d u n bli n di n g (e xce pt f or t he D L T a nalys is set).
A nal y sis p o p ulati o ns i ncl u de partici pa nts fr o m b ot h t he safet y ru n- i n part a n d t he ra n d o mize d 
d o u ble -bli n d part of t he st u d y  u nless ot her wise i n dicate d.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 1 / 2 1 3
T a ble 2 3
A n al ysis Sets
A n al y s i s S et
D e s cri pti o n
S cr e e ni n g
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
r a n d o mi z ati o n a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y
I nt e nt-t o-Tr e at
All p arti ci p a nt s w h o w er e r a n d o mi z e d t o st u d y i nt er v e nti o n. A n al y s e s p erf or m e d o n t h e 
I T T p o p ul ati o n will c o n si d er p arti ci p a nt s’ all o c ati o n t o st u d y i nt er v e nti o n gr o u p s a s 
r a n d o mi z e d
S af et y R u n -i n
All p arti ci p a nt s fr o m t h e s af et y r u n -i n p art w h o w er e a d mi ni st er e d a n y d o s e of a n y 
st u d y i nt er v e nti o n
D o s e -li miti n g t o xi cit y
All p arti ci p a nt s w h o c o m pl et e d t h e s af et y r u n -i n, i. e., t h e 2 1-d a y D L T e v al u ati o n 
p eri o d, wit h o ut mi s si n g a d o s e or b ei n g wit h dr a w n d uri n g t h e D L T e v al u ati o n p eri o d f or 
r e a s o n s ot h er t h a n t o xi cit y
All p arti ci p a nt s fr o m t h e s af et y r u n -i n p art w h o ar e e v al u a bl e f or D L T
S af et y ( S A F)
All p arti ci p a nt s fr o m t h e r a n d o mi z e d, d o u bl e -bli n d p art w h o w er e a d mi ni st er e d a n y 
d o s e of a n y st u d y i nt er v e nti o n. A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d
P h ar m a c o ki n eti c
All p arti ci p a nt s w h o c o m pl et e d at l e a st 1 i nf u si o n of bi ntr af u s p alf a a n d pr o vi d e d at 
l e a st 1 s a m pl e wit h a m e a s ur a bl e c o n c e ntr ati o n of bi ntr af u s p alf a
, D L T = d o s e-li miti n g t o xi cit y, I T T =i nt e nt-t o-tr e at.
9. 5
St atistic al A n al yses
T o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss st u d y ce nters. T he 
fact or ‘ce nter’ will n ot be c o nsi dere d i n statistical m o dels or s u b gr o u p a nal yses d ue t o t he hi g h 
n u m ber of partici pa ti n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of partici pa nts 
ra n d o mize d at eac h ce nter.
I n ge neral, c o nti n u o us varia bles will be s u m marize d usi n g n u m ber ( n), mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m, ma xi m u m, Q 1, a n d Q 3. Cate g orical varia bles will be s u m marize d usi n g 
fre q ue nc y co u nts a n d perce nta ges. Pr o p orti o ns will be calc ulate d base d o n t he n u m ber of 
partici pa nts i n t he a nal ysis set of i nterest, u nless ot her wise s pecifie d i n t he I A P. All safet y an d 
efficac y e n d p oi nts will be s u m marize d b y treat me nt ar m.
9. 5. 1
Effic ac y A n al yses
All efficac y anal ys es will be perf or me d o n t he i nte nt-t o-treat (IT T) p o p ulati o n. Partici pa nts fr o m 
t he safety r u n -i n part will n ot be part of t he I T T p o p ulati o n a n d will be a nal yze d se paratel y.
Efficac y  e n d p oi nts a n d statistical a nalys is met h o ds are o utli ne d i n  Ta ble 2 4.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 2 / 2 1 3
T a ble 2 4 
Effic ac y E n d p oi nts a n d St atistic al A n al ysis Met h o ds
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
O S

O S i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e d at e of d e at h d u e t o a n y c a u s e

F or p arti ci p a nt s ali v e, O S will b e c e n s or e d at t h e l a st d at e t h e p arti ci p a nt i s k n o w n t o b e ali v e

K M  e sti m at e s a n d a s s o ci at e d st ati sti c s (O S r at e s at 3, 6, 9, 1 2, 2 4, a n d 3 6 m o nt h s; m e di a n 
O S) a n d c orr e s p o n di n g 9 5 % C I s will b e pr e s e nt e d b y tr e at m e nt gr o u p

O S n ull h y p ot h e si s is t e st e d u si n g t e st st ati sti c s of str atifi e d l o g -r a n k t e st ( s a m e str at a a s 
u s e d f or r a n d o mi z ati o n)

U n str atifi e d s e n siti vit y a n al y si s

E sti m ati o n of t h e tr e at m e nt eff e ct ( H R  ) b y a C o x pr o p orti o n al h a z ar d s m o d el ( str atifi e d b y 
r a n d o mi z ati o n str at a, e a c h str at u m d efi n e s s e p ar at e b a s eli n e h a z ar d f u n cti o n); ti e s h a n dl e d 
b y r e pl a ci n g t h e pr o p orti o n al h a z ar d s m o d el b y t h e di s cr et e l o gi sti c m o d el; 9 5 % C I s f or t h e 
H R will b e c al c ul at e d

Gr a p hi c al c h e c k of t h e pr o p orti o n al h a z ar d a s s u m pti o n

S e c o n d ar y
N ot e: If t h e st u d y i s n ot e x p a n d e d t o t h e f ull s a m pl e si z e, t h e pri m ar y a n al y si s of t u m or a s s e s s m e nt -b a s e d e n d p oi nt s, 
s u c h a s P F S, O R R, a n d D O R, will b e b a s e d o n t h e I R C a s s e s s m e nt r at h er t h a n t h e I n v e sti g at or a s s e s s m e nt. T h e 
I n v e sti g at or a s s e s s m e nt will s er v e a s s e n siti vit y a n al y si s.
P F S a c c or di n g 
t o R E CI S T 1. 1 
a s s e s s e d b y 
t h e 
In v e sti g at or

P F S i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e d at e of t h e fir st d o c u m e nt ati o n of 
o bj e cti v e P D a s a s s e s s e d b y t h e I n v e sti g at or a c c or di n g t o R E CI S T 1. 1 or d e at h d u e t o a n y 
c a u s e i n t h e a b s e n c e of d o c u m e nt e d P D, w hi c h e v er o c c ur s fir st

Pr o gr e s si o n or d e at h, w hi c h o c c urr e d l at er t h a n 2 s c h e d ul e d t u m or a s s e s s m e nt i nt er v al s 
aft er t h e l a st e v al u a bl e r e s p o n s e a s s e s s m e nt will b e c e n s or e d at t h e d at e of t h e l a st 
e v al u a bl e r e s p o n s e a s s e s s m e nt f or P F S a n al y s e s

P F S ti m e will b e c e n s or e d at t h e l a st e v al u a bl e a s s e s s m e nt d at e b ef or e t h e st art of a n e w 
a nti c a n c er tr e at m e nt if n o e v e nt o c c urr e d s o f ar. I n t h e c a s e of a n o n -e v al u a bl e b a s eli n e 
a s s e s s m e nt or all p o st -b a s eli n e a s s e s s m e nt s b ei n g n o n - e v al u a bl e, t h e p arti ci p a nt will b e 
c e n s or e d at t h e r a n d o mi z ati o n d at e

K M  e sti m at e s a n d a s s o ci at e d st ati sti c s ( P F S r at e s at 3, 6, 9, 1 2, a n d 2 4 m o nt h s; m e di a n 
P F S) a n d c orr e s p o n di n g 9 5 % C Is will b e pr e s e nt e d b y tr e at m e nt gr o u p

P F S n ull h y p ot h e si s is t e st e d u si n g t e st st ati sti c s of str atifi e d l o g -r a n k t e st ( s a m e str at a a s 
u s e d f or r a n d o mi z ati o n)

E sti m ati o n of t h e tr e at m e nt eff e ct ( H R  ) b y a C o x pr o p orti o n al h a z ar d s m o d el ( str atifi e d b y 
r a n d o mi z ati o n str at a, e a c h str at u m d efi n e s s e p ar at e b a s eli n e h a z ar d f u n cti o n); ti e s h a n dl e d 
b y r e pl a ci n g t h e pr o p orti o n al h a z ar d s m o d el b y t h e di s cr et e l o gi sti c m o d el; 9 5 % C I s f or t h e 
H R will b e c al c ul at e d

Gr a p hi c al c h e c k of t h e pr o p orti o n al h a z ar d s a s s u m pti o n

S e n siti vit y a n al y s e s of P F S will b e p erf or m e d i n cl u di n g, b ut n ot li mit e d t o:
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 3 / 2 1 3
E n d p oi nt
St ati sti c al A n al y si s M et h o d s

Alt er n ati v e c e n s ori n g r ul e s, i n cl u di n g a n a n al y si s t h at c o u nt s d e at h a n d pr o gr e s si o n 
a c c or di n g t o R E CI S T 1. 1 a s a P F S e v e nt r e g ar dl e s s of t h e st art of a n e w a nti c a n c er 
t h er a p y a n d i g n ori n g t h e n u m b er of mi s si n g e v al u a bl e t u m or a s s e s s m e nt s b ef or e 
pr o gr e s si o n or d e at h

C o m p ari s o n of P F S a s a s s e s s e d b y t h e I n v e sti g at or a n d I R C , a s a p pli c a bl e
O bj e cti v e 
r e s p o n s e 
a c c or di n g t o 
R E CI S T 1. 1 
a s s e s s e d b y
t h e
In v e sti g at or

O R R, i . e., t h e r at e of p arti ci p a nt s h a vi n g a n o bj e cti v e r e s p o n s e of c o nfir m e d C R or P R will be 
c al c ul at e d al o n g wit h t h e c orr e s p o n di n g 2 - si d e d e x a ct Cl o p p er-P e ar s o n 9 5 % CI p er 
tr e at m e nt gr o u p

Diff er e n c e i n O R R i s e sti m at e d b a s e d o n t h e C o c hr a n -M a nt el -H a e n s z el m et h o d (t a ki n g i nt o 
a c c o u nt t h e r a n d o mi z ati o n str at a) a n d t e st st ati sti c s ar e u s e d f or t e sti n g n ull h y p ot h e si s of 
o bj e cti v e r e s p o n s e . O d d s r ati o i s e sti m at e d b a s e d o n l o gi sti c m o d el s f or o bj e cti v e r e s p o n s e. 
L o gi sti c m o d el s will b e fitt e d wit h t h e e n d p oi nt a s d e p e n d e nt v ari a bl e, s u b gr o u p, tr e at m e nt, 
a n d wit h a n d wit h o ut t h e tr e at m e nt b y s u b gr o u p i nt er a cti o n a s e x pl a n at or y v ari a bl e s
D O R 
a c c or di n g t o 
R E CI S T 1. 1 
a s s e s s e d b y 
t h e 
In v e sti g at or

D O R a c c or di n g t o R E CI S T 1. 1 a s a s s e s s e d b y t h e I n v e sti g at or will b e d efi n e d f or p arti ci p a nt s 
wit h c o nfir m e d r e s p o n s e a s t h e ti m e fr o m fir st r e s p o n s e u ntil t h e fir st d o c u m e nt e d di s e a s e 
pr o gr e s si o n or d e at h

K M  e sti m at e s a n d a s s o ci at e d st ati sti c s (r e s p o n s e r at e s at 3, 6, 9, 1 2, a n d 2 4 m o nt h s; m e di a n 
D O R) a n d c orr e s p o n di n g 9 5 % Ci s will b e pr e s e nt e d b y tr e at m e nt gr o u p. P arti ci p a nt s wit h o ut 
a n e v e nt at t h e a n al y si s c ut off d at e will b e c e n s or e d o n t h e d at e of t h e l a st t u m or a s s e s s m e nt
D ur a bl e 
r e s p o n s e 
a c c or di n g t o 
R E CI S T 1. 1 
a s s e s s e d b y 
t h e 
In v e sti g at or

D R R, i . e., t h e r at e of p arti ci p a nt s h a vi n g a c o nfir m e d o bj e cti v e r e s p o n s e of C R or P R l a sti n g 
> 6 m o nt h s will b e c al c ul at e d al o n g wit h t h e c orr e s p o n di n g 2 -si d e d E x a ct Cl o p p er -P e ar s o n 
9 5 % CI p er tr e at m e nt gr o u p

P arti ci p a nt s f or w h o m t h e D O R i s c e n s or e d will b e tr e at e d a s f ail ur e s ( s u c c e s s e s) i n t h e 
a n al y si s of d ur a bl e r e s p o n s e if t h e c e n s or e d D O R i s b el o w ( at l e a st) 6 m o nt h s a n d 
1 2 m o nt h s, r e s p e cti v el y

Diff er e n c e i n D R R (l a sti n g > 6 m o nt h s) i s e sti m at e d b a s e d o n t h e C o c hr a n -M a nt el -H a e n s z el 
m et h o d (t a ki n g i nt o a c c o u nt t h e r a n d o mi z ati o n str at a)
B T C = bili ar y tr a ct c a n c er, CI = c o nfi d e n c e i nt er v al, C R = c o m pl et e r e s p o n s e, D O R = d ur ati o n of r e s p o n s e, 
D R R = d ur a bl e r e s p o n s e r at e, H R = h a z ar d r ati o, I A P =i nt e gr at e d a n al y si s pl a n, I R C =I n d e p e n d e nt R e vi e w 
C o m mitt e e, K M = K a pl a n -M ei er, O R R = o bj e cti v e r e s p o n s e r at e, O S = o v er all s ur vi v al, P D = pr o gr e s si v e di s e a s e, 
 P F S = pr o gr e s si o n-fr e e s ur vi v al, P R = p arti al r e s p o n s e, R E CI S T 1. 1 = R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 1. 1.
9. 5. 2
S afet y A n al yses
All safety a nal ys es will be perf or me d o n t he Safet y a nal ys is set ( S A F) or t he Safet y  Ru n- i n a nal ys is 
set, wit h t he e xce pti o n of t he a nalys es of D L T i n t he safet y r u n -i n part of t he st u d y, w hic h will be 
perf or me d o n t he D L T a nal y sis set.
Safet y  en d p oi nts i ncl u de A E s ( T E A Es, S A Es, treat me nt-relate d A Es, A E SI , ir A Es), cli nical 
la b orat or y assess me nts, vital si g ns, p h y sical e xa mi nati o ns, E C G para meters, a n d E C O G P S as 
descri be d i n Secti o n 8. 2 . Treat me nt -e mer ge nt A E s are t h ose e ve nts wit h o nset dates occ urri n g 
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 4 / 2 1 3
d uri n g t he o n -treat me nt peri o d or if t he w orse ni n g of a n e ve nt is d uri n g t he o n -treat me nt peri o d. 
A n y  AE s wit h a n o nset or w orse ni n g date after t he o n- treat me nt peri o d will be re p orte d se parately.
All A E s will be c o de d acc or di n g t o Me d D R A. T he se verit y of AE s a n d la b orat or y res ults will be 
gra de d usi n g t he N CI -C T C A E Versi o n 5. 0 t o xicit y gra di n g scale. I mm u ne -relate d A Es will be 
i de ntifie d usi n g a 2- le vel a p pr oac h acc or di n g t o a pres pecifie d searc h list of Me d D R A Preferre d 
Ter ms, d oc u me nte d i n a versi o n-c o ntr olle d re p osit or y mai ntai ne d b y  the S p o ns or a n d fi nalize d f or 
a nal ys is prior t o data base l oc k, a n d a me dical assess me nt (case defi niti o n).
Safet y  e n d p oi nts a n d statistical a nal ysis met h o ds are o utli ne d i n  Ta ble 2 5.
T a ble 2 5
S afet y E n d p oi nts a n d St atistic al A n al ysis Met h o ds
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
D L T i n t h e s af et y 
r u n-i n
T h e i n ci d e n c e of D L T will b e t a b ul at e d f or t h e D L T A n al y si s S et
R a n d o mi z e d, 
d o u bl e -bli n d p art
N ot a p pli c a bl e
S e c o n d ar y  
A E s, cli ni c al 
l a b or at or y 
a s s e s s m e nt s, vit al 
si g n s, p h y si c al 
e x a mi n ati o n, E C G 
p ar a m et er s, a n d 
E C O G P S

P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e

T h e s af et y e n d p oi nt s will b e a n al y z e d u si n g d e s cri pti v e st ati sti c s

T h e i n ci d e n c e of T E A E s, S A E s, tr e at m e nt -r el at e d AE s, A E SI, a n d ir A E s r e g ar dl e s s of 
attri b uti o n, will b e s u m m ari z e d b y Pr ef err e d T er m a n d S y st e m Or g a n Cl a s s f or e a c h 
tr e at m e nt ar m, a n d d e s cri b e d i n t er m s of s e v erit y a n d r el ati o n s hi p t o tr e at m e nt

T h e w or st o n -tr e at m e nt gr a d e s f or c h e mi str y a n d h e m at ol o g y l a b or at or y r e s ult s will b e 
s u m m ari z e d

S hift s i n t o xi cit y gr a di n g fr o m b a s eli n e t o hi g h e st gr a d e d uri n g t h e o n -tr e at m e nt p eri o d will 
b e di s pl a y e d

F or l a b or at or y t e st s wit h o ut a n N CI- C T C A E gr a d e d efi niti o n, r e s ult s will b e pr e s e nt e d 
c at e g ori c all y ( e . g., b el o w, wit hi n, or a b o v e n or m al li mit s)

F urt h er d et ail s of s af et y a n al y s e s (i n cl u di n g A E s, cli ni c al l a b or at or y a s s e s s m e nt s, vit al 
si g n s, p h y si c al e x a mi n ati o n, E C G p ar a m et er s, a n d E C O G P S) will b e pr o vi d e d i n t h e I A P
A E = a d v er s e e v e nt, A E SI = a d v er s e e v e nt s of s p e ci al i nt er e st, D L T = d o s e -li miti n g t o xi cit y, E C G = el e ctr o c ar di o gr a m, 
E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s, I A P =i nt e gr at e d a n al y si s pl a n, 
ir A E =i m m u n e-r el at e d a d v er s e e v e nt, N CI-C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y Crit eri a f or 
A d v er s e E v e nt s, S A E = s eri o u s a d v er s e e v e nt, T E A E =tr e at m e nt- e m er g e nt a d v er s e e v e nt.
If t he st u d y ex pa n ds t o P hase III, t he s u m mar y an d a nal ys is of A E s will be perf or me d base d o n t he 
3- tier a p pr oac h (Cr o we 2 0 0 9 ), as f urt her detaile d i n t he st u d y IA P. If t he st u d y is n ot e x pa n de d, 
t he sa m ple size f or a n a nal ysis base d o n t he 3-tier a p pr oac h is re gar de d as t o o s mall.
9. 5. 3
Ot her A n al yses
Details of t he P K , 
, a n d 
 a nal ys es will be i n t he I A P t hat 
will be fi nalize d bef ore data base l oc k. I nte grate d a nal ys es acr oss st u dies, s uc h as t he P o p P K 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 5 / 2 1 3
a nal ys is wil l be prese nte d se paratel y fr o m t he mai n C S R. E x p os ure -res p o nse a nal yses f or efficacy 
a n d safet y will als o be prese nte d se paratel y fr o m t he mai n C S R. 
Ha n dli n g of missi n g data will be descri be d i n t he I A P.
9. 5. 4
Se q ue nce of A n al yses
T he se q ue nce of pla n ne d a nal ys es is as s h o w n i n  Ta ble 2 6.  
T a ble 2 6
Se q ue nce of Pl a n ne d A n al yses
A n al y s e s
O p e n -l a b el,
S af et y R u n -i n

S af et y a s s e s s m e nt i n t h e 6 p arti ci p a nt s i n t h e A si a n sit e s’ c o h ort a n d 6 p arti ci p a nt s i n t h e 
n o n -A si a n sit e s’ c o h ort, or u p t o 1 2 p arti ci p a nt s i n e a c h c o h ort; D L T will b e e v al u at e d i n 
t h e fir st 2 1 d a y s

A n al y si s of effi c a c y e n d p oi nt s w h e n t h e l a st p arti ci p a nt of t h e o p e n -l a b el p art of t h e st u d y 
h a s r e a c h e d a mi ni m u m f oll o w - u p ti m e of 1 2 m o nt h s
R a n d o mi z e d, 
a d a pt ati o n 
d e ci si o n

A n al y si s of effi c a c y w h e n t h e t ar g et n u m b er of 8 0 P F S e v e nt s h a v e o c c urr e d i n t h e fir st 
1 5 0 a nti bi oti c s -n ai v e p arti ci p a nt s a n d o n c e at l e a st 1 9 w e e k s of f oll o w- u p f or t h e fir st 1 5 0 
a nti bi oti c s -n a iv e p arti ci p a nt s r a n d o mi z e d i s r e a c h e d.
Pri m ar y a n al y si s 
if fi n al s a m pl e 
si z e i s n ot 
e x p a n d e d

P A w h e n O S e v e nt s h a v e o c c urr e d o n t h e 6 0 % of t ot al P h a s e II p arti ci p a nt s, e x p e ct e d at 
2 9 m o nt h s aft er r a n d o mi z ati o n of t h e fir st p arti ci p a nt
I nt eri m a n d 
pri m ar y a n al y s e s 
if fi n al s a m pl e 
si z e i s N = 5 0 0

I A at t h e d at a c ut off d at e of 6 3 % of O S e v e nt s f or t h e P A ( 2 1 0 /3 3 4 e v e nt s), e x p e ct e d at 
2 7 m o nt h s aft er r a n d o mi z ati o n

P A w h e n t h e t ar g et n u m b er of 3 3 4 O S e v e nt s h a v e o c c urr e d i n a t ot al of 5 0 0 p arti ci p a nt s, 
e x p e ct e d at 4 0 m o nt h s aft er r a n d o mi z ati o n of t h e fir st p arti ci p a nt
D L T = d o s e -li miti n g t o xi cit y, I A =i nt eri m a n al y si s, O S = o v er all s ur vi v al, P A = pri m ar y a n al y si s, P F S = pr o gr e s si o n-fr e e 
s ur vi v al.
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 6 / 2 1 3
1 0
Refere nces
A mi n M B, E d ge S, Gree ne F, et al, e ds. A merica n J oi nt C o m mittee o n Ca ncer ( AJ C C) Ca ncer 
Sta gi n g Ma n ual. 8 t h e d. S pri n ger; 2 0 1 7.
Az u ma A, K u d o h S. Hi g h pre vale nce of dr u g -i n d uce d p ne u m o nia i n Ja pa n. J p n Me d Ass oc J. 
2 0 0 7; 5 0: 4 0 5 - 4 1 1.
Blaze b y J M, C o nr o y  T, B ott o mle y  A, et al. Cli nical a n d ps y c h o metric vali dati o n of a q uesti o n naire 
m o d ule, t he E O R T C Q L Q -S T O 2 2, t o assess q ualit y  of life i n patie nts wit h gastric ca ncer. E ur J 
Ca ncer. 2 0 0 4; 4 0( 1 5): 2 2 6 0 - 8.
B o h nsac k O, L u dajic K, H o os A. A da ptati o n of t he i m m u ne-relate d res p o nse criteria: ir R E CI S T. 
A n n O nc ol. 2 0 1 4; 2 5(s u p pl 4):i v 3 6 1, i v 3 7 2.
C hala bi M, Car d o na A, Na gar kar D R, et al. Efficac y  of c he m ot hera p y a n d atez oliz u ma b i n patie nts 
wit h n o n -s mall-cell l u n g ca ncer recei vi n g a nti bi otics a n d pr ot o n p u m p i n hi bit ors: p o ole d p ost h oc 
a nal ys es of t he O A K a n d P O P LA R trials. A n n O nc ol. 2 0 2 0 A pr; 3 1( 4): 5 2 5- 3 1.
C ha m piat S, La m b otte O, Barrea u E, et al. Ma na ge me nt 
of i m m u ne c hec k p oi nt bl oc ka d e 
d y si m m u ne t o xicities: a c olla b orati ve p ositi o n pa per. A n n O nc ol. 2 0 1 6; 2 7: 5 5 9-7 4.
C he n C, A n ders o n K, Me hr otra D V, et al. A 2- i n-1 a da pti ve p hase 2/ 3 desi g n f or e x pe dite d 
o nc ol o g y  dr u g de vel o p me nt. C o nte m p Cli n Trials. 2 0 1 8; 6 4: 2 3 8- 4 2.
Cr o we BJ, Xia H A, Berli n J A, et al. Rec o m me n dati o ns f or safety pla n ni n g, data c ollecti o n, 
e val uati o n a n d re p orti n g d uri n g dr u g, bi ol o gic a n d vacci ne de vel o p me nt: a re p ort of t he safet y 
pla n ni n g, e val uati o n, a n d re p orti n g tea m. Cli n Trials. 2 0 0 9; 6: 4 3 0 - 4 0.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5: 2 2 8 - 4 7.
Ga n d hi L, R o drí g uez -A bre u D, Ga d geel S, et al. Pe m br oliz u ma b pl us c he m ot hera p y i n metastatic 
n o n- s mall-cell l u n g ca ncer. N E n gl J Me d. 2 0 1 8; 3 7 8( 2 2): 2 0 7 8 - 9 2.
Gli m m E, Ma urer W, Bretz F. Hierarc hical testi n g of m ulti ple e n d p oi nts i n gr o u p -se q ue ntial trials. 
Stat Me d. 2 0 1 0 Ja n 3 0; 2 9( 2): 2 1 9 - 2 8.
G o u die D R, D’ Ale ssa n dr o M, Merri ma n B, et al. M ulti ple self-heali n g s q ua m o us e pit heli o ma is 
ca use d b y a disease -s pecific s pectr u m of m utati o ns i n T G F B R 1. Nat Ge net. 2 0 1 1; 4 3( 4): 3 6 5- 9.
Hezel A F, Z h u A X. S y ste mic t hera p y f or biliar y tract ca ncers. O nc ol o gist. 2 0 0 8; 1 3( 4): 4 1 5- 2 3.
H wa n g I K, S hi h WJ, a n d D E Ca ni J S. Gr o u p se q ue ntial desi g ns usi n g a fa mil y of t ype I err or 
pr o ba bilit y  s pe n di n g f u ncti o ns. Stat Me d. 1 9 9 0 Dec; 9( 1 2): 1 4 3 9 - 4 5.
I ke da M, Ue m o M, M oriza ne C, et al. A m ultice nter, o pe n -la bel, p hase I st u d y of ni v ol u ma b al o ne
or i n c o m bi nati o n wit h ge mcita bi ne pl us cis plati n i n patie nts wit h u nresecta ble or rec urre nt biliar y 
tract ca ncer. J Cli n O nc ol. 2 0 1 9; 3 7( 4): 1. A bstract 3 0 6.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 7 / 2 1 3
Jar na gi n W R, 
R u o L,  Little S A, et al. Patter ns of i nitial disease rec urre nce after resecti o n of 
ga ll bla d der carci n o ma a n d hilar c h ola n gi ocarci n o ma: I mplicati o ns f or a dj u va nt t hera pe utic 
strate gies. Ca ncer. 2 0 0 3; 9 8( 8): 1 6 8 9- 7 0 0.
Ki m BJ, H y u n g J, Y o o C, et al. Pr o g n ostic fact ors i n patie nts wit h a d va nce d biliar y  tract ca ncer 
treate d wit h first-li ne ge mcita bi ne pl us cis plati n: retr os pecti ve a nal ys is of 7 4 0 patie nts. Ca ncer 
C he m ot her P har mac ol. 2 0 1 7; 8 0( 1): 2 0 9- 1 5.
Kiri y a ma S, Ta ka da T, S tras ber g S M, et al. T G 1 3 g ui deli nes f or dia g n osis a n d se verit y gra di n g of 
ac ute c h ola n gitis ( wit h vi de os). J He pat o biliar y  Pa ncreat Sci. 2 0 1 3; 2 0( 1): 2 4- 3 4.
K u b o K, Az u ma A, Ka naza wa M, et al. C o nse ns us state me nt f or t he dia g n osis a n d treat me nt of 
dr u g -i n d uce d l u n g i nj uries. Res pir I n vesti g. 2 0 1 3; 5 1( 4): 2 6 0 - 7 7.
La marca A, H u b ner R A, Da vi d R y der W, et al. Sec o n d -li ne c he m ot hera p y in a d va nce d biliar y 
ca ncer: a s ys te matic re vie w. A n n O nc ol. 2 0 1 4; 2 5( 1 2): 2 3 2 8- 3 8.
La n Y, Z h a n g D, X u C, et al. E n ha nce d precli nical a ntit u m or acti vit y of M 7 8 2 4, a bif u ncti o nal 
f usi o n pr otei n si m ulta ne o usl y tar geti n g P D -L 1 a n d T G F -β. Sci Tra nsl Me d. 2 0 1 8; 1 0( 4 2 4): pii 
eaa n 5 4 8 8. 
La n ger CJ, Ga d geel S M, B or g haei H, et al. Car b o plati n a n d pe metre xe d wit h or wit h o ut 
pe m br oliz u ma b f or a d va nce d, n o n- s q ua m o us n o n -s mall-cell l u n g ca ncer: a ra n d o mise d, p hase 2 
c o h ort of t he o pe n -la bel K E Y N O T E-0 2 1 st u d y . La ncet O nc ol. 2 0 1 6; 1 7( 1 1): 1 4 9 7- 1 5 0 8.
Le D T, Ura m J N, Wa n g H, et al. P D -1 b l oc ka de i n tu m ors wit h mis matc h-r e pair d eficie nc y. Ne w 
E n gl J Me d. 2 0 1 5; 3 7 2 : 2 5 0 9- 2 0.
Le pa ge C, Ca p ocaccia R, Hac kl M, et al. S ur vi val i n patie nts wit h pri mar y  li ver ca ncer, gall bla d der 
a n d e xtra he patic biliar y tract ca ncer a n d pa ncreatic ca ncer i n E ur o pe 1 9 9 9- 2 0 0 7: Res ults of 
E U R O C A R E - 5. E ur J Ca ncer. 2 0 1 5; 5 1( 1 5): 2 1 6 9 - 7 8. 
Ma kril ia N, S y ri g o u E, Ka kla ma n os I, et al. H y perse nsiti vit y  reacti o ns ass ociate d wit h plati n u m 
a nti ne o plastic a ge nts: a s yste matic re vie w. Met Base d Dr u gs. 2 0 1 0; pii 2 0 7 0 8 4. 
Ma urer W, H ot h or n L, Le h mac her W. M ulti ple c o m paris o ns i n dr u g cli nical trials a n d prec li nical 
assa ys: a pri ori or dere d h y p ot heses. I n Bi o metrie i n der C he misc h- P har maze utisc he n I nd ustrie, 
V ol. 6, V oll mar, J. (e d.), 3 -1 8. St utt gart: Fisc her Verla g, 1 9 9 5.
Mi y aza ki M, Y os hit o mi H, Mi ya ka wa S, et al. Cli nical practice g ui deli nes f or t he ma na ge m e nt of 
biliar y  tract ca ncers 2 0 1 5: t he 2n d e diti o n. J He pat o biliar y Pa ncreat Sci. 2 0 1 5; 2 2( 4): 2 4 9 - 7 3.
M oriza ne
C, O k usa ka T, Miz usa wa J, et al. Ra n d o mize d p hase III st u d y of ge mcita bi ne pl us S- 1 
c o m bi nati o n t hera p y vers us ge mcita bi ne pl us cis plati n c o m bi nati o n t hera p y in a d va nce d biliar y  
tract ca ncer: A Ja pa n Cli nical O nc ol o g y  Gr o u p st u d y (J C O G 1 1 1 3, F U G A -B T). J Cl i n O nc ol. 
2 0 1 8; 3 6(s u p pl 4): 2 0 5.
M orris J C, Ta n A R, Ole nc ki T E, et al. P hase I st u d y of G C 1 0 0 8 (fres oli m u ma b): A h u ma n a nti-
tra nsf or mi n g gr o wt h fact or-beta ( T G F β) m o n ocl o nal a nti b o d y in patie nts wit h a d va nce d mali g na nt 
mela n o ma or re nal cell carci n o ma. Pl o S O ne. 2 0 1 4; 9( 3):e 9 0 3 5 3.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 8 / 2 1 3
Ne uzillet C, Tijeras -Ra balla n d A, C o he n R, et al. Tar geti n g t he T G F β pat h wa y f or ca ncer t hera p y. 
P har mac ol T her. 2 0 1 5; 1 4 7: 2 2- 3 1.
O k usa ka T, Na kac hi K, F u k ut o mi A, et al. Ge mcita bi ne al o ne or i n c o m bi nati o n wit h cis plati n i n 
patie nts wit h biliar y tract ca ncer: a c o m parati ve m ultice ntre st u d y in Ja pa n. Br J Ca ncer. 
2 0 1 0; 1 0 3( 4): 4 6 9 - 7 4. 
Par k S E, Lee S H, A h n J S, et al. I ncrease d res p o nse rates t o sal va ge c he m ot hera p y a d mi nistere d 
after P D -1/ P D -L 1 i n hi bit ors i n patie nts wit h n o n -s mall cell l u n g ca ncer. J T h orac O nc ol. 
2 0 1 8; 1 3( 1): 1 0 6 - 1 1.
Paz- Ares L,  Luft A, Vice nte D, et al. Pe m br oliz u ma b pl us c he m ot hera p y f or s q ua m o us 
n o n- s mall-cell l u n g ca ncer. N E n gl J Me d . 2 0 1 8; 3 7 9: 2 0 4 0 - 5 1.
Pi nat o D L , H o wlett S, Otta via ni D, et al. Ass ociati o n of Pri or A nti bi otic Treat me nt Wit h S ur vi val 
a n d Res p o nse t o I m m u ne C hec k p oi nt I n hi bit or T hera p y i n Patie nts Wit h Ca ncer. J A M A O nc ol. 
2 0 1 9 Dec 1; 5( 1 2): 1 7 7 4 -1 7 7 8.
Re n W, Pe n gell y R, Farre n- Dai M, et al. Re veali n g t he mec ha nis m f or c o vale nt i n hi biti o n of 
gl yc osi de h y d r olases by car bas u gars at a n at o mic le vel. Nat C o m m u n. 2 0 1 8; 9( 1): 3 2 4 3.
Ritt me y er A, Barlesi F, Water ka m p 
D, et al. Atez oliz u ma b vers us d oceta xel i n patie nts wit h 
pre vi o usl y  treate d n o n -s mall-cell l u n g ca ncer ( O A K): a p hase 3, o pe n -la bel, m ultice ntre 
ra n d o mise d c o ntr olle d trial. La ncet. 2 0 1 7; 3 8 9( 1 0 0 6 6): 2 5 5- 6 5.
Sa kai D, Ka nai M, K o ba y as hi S, et al. Ra n d o mize d p hase III st u d y of ge mcita bi ne, cis plati n pl us 
S - 1 ( G C S) vers us 
ge mcita bi ne, 
cis plati n 
( G C) f or a d va nce d 
biliar y  tract ca ncer 
( K H B O 1 4 0 1-MI T S U B A). A n n O n c ol. 2 0 1 8; 2 9(s u p pl 8): viii 2 0 5 -viii 2 7 0.
Sat o Y, Hara da K, Itats u K, et al. E pit helial- mese nc h y mal tra nsiti o n i n d uce d b y  tra nsf or mi n g 
gr o wt h fact or-{ beta } 1/ S nail acti vati o n a g gra vates i n vasi ve gr o wt h of c h ola n gi ocarci n o ma. A m J 
Pat h ol. 2 0 1 0; 1 7 7( 1): 1 4 1 - 5 2.
S p i gel D, Sc h wartz ber g L, Water h o use D, et al. Is ni v ol u ma b safe a n d effecti ve i n el derl y a n d P S 2 
patie nts wit h n o n -small cell lu n g c a ncer ( N S C LC) ? Res ults of C hec k Mate 1 5 3. J T h orac O nc ol. 
2 0 1 7; 1 2( 1): S 1 2 8 7 - 8. 
S uz u ki Y, Ka n M ot o y as u, Ki m ura G, et al. Pre dicti ve fact ors of t he treat me nt o utc o me i n patie nts 
wit h a d va nce d biliar y tract ca ncer recei vi n g ge mcita bi ne pl us cis plati n as first -li ne c he m ot hera py.  
J Gastr oe nter ol. 2 0 1 9; 5 4( 3): 2 8 1- 9 0.
Ta ka da T. Ti me t o sta n d u p; a re Ja pa nese pr o ne t o diff use al ve olar da ma ge? A usti n J P ul m Res pir 
Me d. 2 0 1 4; 1( 2): 1 0 0 9.
Ue n o M, C h u n g H C, Na grial A, et al. Pe m br oliz u ma b f or a d va nce d biliar y  ade n ocarci n o ma: 
Res ults fr o m t he m ultic o h ort, p hase II K E Y N O T E- 1 5 8 st u d y . A n n Ca ncer. 2 0 1 8; 2 9(s u p pl 8).
Valle J, Wasa n H, Pal mer D H, et al. Cis pl ati n pl us ge mcita bi ne vers us ge mcita bi ne f or biliar 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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 1 9 / 2 1 3
Valle J W, B or bat h I, Kha n S A, et al. Biliar y  ca ncer: E S M O cli nical p ractice g ui deli nes f or 
dia g n osis, treat me nt a n d f oll o w - u p. A n n O nc ol. 2 0 1 6; 2 7: v 2 8 -v 3 7 .
Wi n kel ma n n R, Sc h nei der M, Hart ma n n S, et al. Micr osatellite insta bilit y  o cc urs rarel y i n patie nts 
wit h ch ola n gi ocarci n o ma: A retr os pecti ve st u d y fr o m a Ger ma n tertiar y care h os pital. I nt J M ol 
Sci. 2 0 1 8; 1 9: 1 4 2 1 - 3 2.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 0 / 2 1 3
1 1
A p pe n dices
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 1 / 2 1 3
A p pe n di x 1
A b bre vi ati o ns
1 L
Fir st -li n e
2 L
S e c o n d -li n e
A D R
A d v er s e dr u g r e a cti o n
A E
A d v er s e e v e nt
A E SI
A d v er s e e v e nt s of s p e ci al i nt er e st
A S C O
A m eri c a n S o ci et y of Cli ni c al O n c ol o g y
B T C
Bili ar y tr a ct c a n c er
C C A
C h ol a n gi o c ar ci n o m a
CI
C o nfi d e n c e i nt er v al
C N S
C e ntr al n er v o u s s y st e m
C R
C o m pl et e r e s p o n s e
Cr C L
Cr e ati ni n e cl e ar a n c e
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
c S C C
C ut a n e o u s s q u a m o u s c ell c ar ci n o m a
C S R
Cli ni c al St u d y R e p ort
C T
C o m p ut e d t o m o gr a p h y
C T C A E
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s
C T L A - 4
C yt ot o xi c T -l y m p h o c yt e-a s s o ci at e d a nti g e n 4
D L T
D o s e -li miti n g t o xi cit y
D N A
D e o x yri b o n u cl ei c a ci d
D O R
D ur ati o n of r e s p o n s e
D R R
D ur a bl e r e s p o n s e r at e
E C G
El e ctr o c ar di o gr a m
E C O G P S
E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s
e C R F
El e ctr o ni c C a s e R e p ort F or m
E S M O
E ur o p e a n S o ci et y f or M e di c al O n c ol o g y
F S H
F olli cl e -sti m ul ati n g h or m o n e
G C
G all bl a d d er c a n c er
G C P
G o o d Cli ni c al Pr a cti c e
G C S
G e m cit a bi n e, ci s pl ati n , a n d S 1
G e m -ci s
G e m cit a bi n e -ci s pl ati n
H B V
H e p atiti s B vir u s
H C V
H e p atiti s C vir u s
H g b
H e m o gl o bi n
HI V
H u m a n i m m u n o d efi ci e n c y vir u s
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 2 / 2 1 3
H R
H a z ar d r ati o
H R T
H or m o n e r e pl a c e m e nt t h er a p y
I A
I nt eri m a n al y si s
I A P
I nt e gr at e d a n al y si s pl a n
I B
I n v e sti g at or’ s Br o c h ur e
I C F
I nf or m e d C o n s e nt F or m
I C H
I nt er n ati o n al C o u n cil f or H ar m o ni s ati o n
I D M C
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e
I E C
I n d e p e n d e nt Et hi c s C o m mitt e e
I L
It e m Li br ar y
I L D
I nt er stiti al l u n g di s e a s e
ir A E
I m m u n e-r el at e d a d v er s e e v e nt
I R B
I n stit uti o n al R e vi e w B o ar d
I R C
I n d e p e n d e nt R e vi e w C o m mitt e e
I R R
I nf u si o n-r el at e d r e a cti o n s
I V
I ntr a v e n o u s
I X R S
I nt er a cti v e R e s p o n s e S y st e m
K A
K er at o a c a nt h o m a
K L - 6
Kr e b s v o n d e n L u n g e n - 6
M e d D R A
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s 
M RI
M a g n eti c r e s o n a n c e i m a gi n g
M SI
M i cr o s at ellit e i n st a bilit y
N C C N
N ati o n al C o m pr e h e n si v e C a n c er N et w or k
N C C N 2 0 1 8
N ati o n al C o m pr e h e n si v e C a n c er N et w or k G ui d eli n e s 2 0 1 8
N CI
N ati o n al C a n c er I n stit ut e
N S AI D
N o n st er oi d al a nti -i nfl a m m at or y dr u g
N S C L C
N o n -s m all c ell l u n g c a n c er
O R R
O bj e cti v e r e s p o n s e r at e
O S
O v er all s ur vi v al
P A
Pri m ar y a n al y si s
P D
Pr o gr e s si v e di s e a s e
P F S
Pr o gr e s si o n -fr e e s ur vi v al
P K
P h ar m a c o ki n eti c
P o p P K
P o p ul ati o n p h ar m a c o ki n eti c s
P R
P arti al r e s p o n s e
D oc u me nt N o. 
O bject N o. 
e
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 3 / 2 1 3
P T
Pr ot hr o m bi n ti m e
P T B D
P er c ut a n e o u s tr a n s h e p ati c bili ar y dr ai n a g e
Q 3 W
E v er y 3 w e e k s
Q 6 W
E v er y 6 w e e k s
Q 1 2 W
E v er y 1 2 w e e k s
R E CI S T 1. 1
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 1. 1
R N A
Ri b o n u cl ei c a ci d
R P 2 D
R e c o m m e n d e d P h a s e II d o s e
S A E
S eri o u s a d v er s e e v e nt
S D
S t a bl e di s e a s e
S M C
S af et y M o nit ori n g C o m mitt e e
S m P C
S u m m ar y of Pr o d u ct C h ar a ct eri sti c s
S o C
St a n d ar d of c ar e
S P -A/ D
S urf a ct a nt pr ot ei n -A/ D
S U S A R
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
T E A E
Tr e at m e nt -e m er g e nt a d v er s e e v e nt
T G F β
Tr a n sf or mi n g gr o wt h f a ct or b et a
T M B
T u m or m ut ati o n al b ur d e n
T T P
T hr o m b oti c t hr o m b o c yt o p e ni c p ur p ur a
U L N
U p p er li mit of n or m al
V A S
Vi s u al A n al o g S c al e
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 4 / 2 1 3
A p pe n di x 2
St u d y G o ver n a nce
Fi n a nci al Discl os ure
I n vesti gat ors a n d S u b -I nvesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial certificati o n 
or discl os ure state me nts t o t he a p pr o priate re g ulat or y aut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y.
I nf or me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y  t o t he partici pa nt 
or his/ her le gall y aut h orize d re prese ntati ve (w here all o we d b y  local la ws a n d re g ulati o ns) a n d 
a ns wer all q uesti o ns o n t he st u d y .

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y .

Parti ci pa nts or t heir le gall y aut h orize d re prese ntati ve (w here all o we d b y  local la ws a n d 
re g ulati o ns) will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts 
of 2 1 C F R 5 0; t he Ja pa nese mi nisterial or di na nce o n G o o d Cli nical Practice ( G C P); l ocal 
re g ulati o ns; I nter nati o nal C o u ncil f or Har m o nisati o n (IC H) g ui deli nes; Healt h I ns ura nce 
P orta bilit y  an d Acc o u nta bilit y  Act re q uire me nts, w here a p plica ble; a n d t he I RB)/I n de pe n de nt 
Et hics C o m mittee (I E C) or st u d y  ce nter.

T he me dical rec or d will i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.

If t he I C F is u p da te d d uri n g t heir partici pati o n i n t he st u d y, partici pa nts m ust be re-c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n.

A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y  a ut h orize d 
re prese ntati ve.

T he ori gi nal si g ne d a n d d ate d c o nse nt will re mai n at t he I n vesti gat or’s site a n d will be safely 
arc hi ve d s o t hat it ca n be retrie ve d at a n y t i me f or m o nit ori n g, a u diti n g a n d i ns pecti o n p ur p oses.
Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
D at a Pr otecti o n

T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir i nf or me d 
c o nse nt. All partici pa nt rec or ds or datasets tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier 
o nl y ; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot be transferre d.

T he S p o ns or m ust i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d data will be use d per 
l ocal data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure will als o be e x plai ne d t o t he 
partici pa nt a n d pre g na nt part ners (if a p plica ble), w h o will be re q uire d t o gi ve c o nse nt f or t heir 
data t o be use d, as s pecifie d i n t he i nf or me d c o nse nt .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 5 / 2 1 3

T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y  Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y  ap pr o priate 
I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect ors. All s uc h pers o ns will strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y .
St u d y A d mi nistr ati ve
T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n vesti gat ors f or decisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G C P. T he C o or di nati n g I n vesti gat or will pr o vi de e x pert me dical 
i n p ut a n d a d vice o n t he st u d y desi g n a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off 
of t he C S R.
T he st u d y will a p pear i n t he f oll owi n g cli nical st u dies re gistries: cli nicaltrials. g o v, E u dra C T, Ja pa n 
P har mace utical I nf or mati o n Ce nter (J A PI C), a n d c hi na dr u gtrials. or g.c n.
T his st u d y re q uires a si g nifica nt l o gistic a n d a d mi nistrati ve str uct ure f or its efficie nt e xec uti o n. 
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate O perati o ns Ma n ual. 
T his will be pre pare d u n der t he s u per visi o n of t he Cli nical Trial Lea der i n cl ose c olla b orati o n wit h 
t he res p o nsi ble u nits at t he S p o ns or.
T he S p o ns or will c o or di nate t he st ud y  an d will pr o vi de s u p p ort f or t he C o ntract Researc h 
Or ga nizati o ns ( C R Os) f or s o me acti vities of t he st u d y. S p o ns or Gl o bal Cli nical O perati o ns will 
perf or m o versi g ht of t he acti vities perf or me d b y t he C R Os.
T he Cli nical Trial S u p plies De part me nt of t he S p o ns or will s u p pl y the st u d y me dicati o n of 
bi ntraf us p alfa t hat will be distri b ute d t o t he sites b y a C R O.  
Safet y  la b orat or y assess me nts will be perf or me d l ocall y by i n vesti gati o nal sites. P har mac o ki netic, 
assess me nts will be perf or me d u n der t he 
res p o nsi bilit y a n d/ or s u per visi o n of t he S p o ns or. 
T he Gl o bal Dr u g Safet y  De part me nt, Merc k 
Healt hcare K Ga A, Dar msta dt, Ger ma n y, or its 
desi g nate d re prese ntati ves will s u per vise dr u g safet y  a n d t he ti mely re p orti n g o f A Es a n d S A Es.
Q ualit y  ass ura nce of t he st u d y c o n d uct will be perf or me d b y t he De vel o p me nt Q uality Ass ura nce 
De part me nt, Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y.
T he Gl o bal Bi ostatistics De part me nt will s u per vise t he statistical a nal ys es ( wit h t he e xce pti o n of 
t he P K data a nalys es, w hic h will be o uts o urce d t o a C R O).
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate O perati o ns Ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 6 / 2 1 3
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he Declarati o n 
of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) 
I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G C P G ui deli nes

T he Ja pa nese mi nisterial or di na nce o n G C P 

A p plica ble la ws a n d re g ulati o ns.

T he I n vesti gat or m ust 
s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I CF, 
I n vesti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e . g., a d vertise me nts) t o a n I RB/I E C a n d 
t he IR B/I E C m ust re vie w a n d a p pr o ve t he m bef ore t he st u d y  is i nitiate d.

T he S p o ns or i nitiates t he st u d y at a site after o btai ni n g writte n a p pr o val fr o m t he Hea d of t he 
st u d y site, base d o n fa v ora ble o pi ni o n/a p pr o val fr o m t he c o ncer ne d I R B/I E C.

A n y  pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges necessar y  to 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica ble, a me nd me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities.
T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y to t he I RB/I E C a n n uall y or m ore 
fre q ue ntly per t he I R B’s/I E C’s re q uire me nts, p oli cies, a n d pr oce d ures.

N otif y i n g t he I RB/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as re q uire d b y  IR B/ I E C 
pr oce d ures

Pr o vi di n g o versi g ht of t he st u d y co n d uct at t he site a n d a d here nce t o re q uire me nts of 2 1 C F R, 
I C H g ui deli nes, t he IR B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), 
a n d all ot her a p plica ble l ocal re g ulati o ns
T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he Healt h 
A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or use 
d uri n g t he st u d y. T hese pr o vi de t he mea ns 
f or partici pa nts t o i de ntif y the msel ves as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y inf or mati o n 
a b o ut t his partici pati o n t hat m a y  be nee de d t o deter mi ne t he c o urse of me dical treat me nt f or t he 
partici pa nt. T he i nf or mati o n o n t he E mer ge nc y Me dical S u p p ort car d ma y incl u de t he pr ocess 
f or e mer ge nc y u n bli n di n g (if a p plica ble).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 7 / 2 1 3

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y In vesti gat or cari n g f or 
t he partici pa nt.  C o nse q ue ntl y, t he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y  c o ntact 
i nf or mati o n o n t he car d. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y  su bse q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n vesti gat ors.

W he n t he I n vesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o c o ntact a 
S p o ns or ( or desi g nee) p h y sicia n. T his i ncl u des pr o visi o n of a 2 4-h o ur c o ntact n u m ber at a call 
ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate S p o ns or ( or 
desi g nee) p h y sicia n t o assist wit h
t he me dical e mer ge nc y an d t o pr o vi de s u p p ort f or t he 
p ote ntial u n bli n di n g of t he partici pa nt c o ncer ne d.
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
T he S p o ns or is e ntirel y  res p o nsi ble f or A Es t hat are ass ociate d wit h t his st u d y an d ca use da ma ge 
t o t he healt h of t he partici pa nts, e xce pt f or A Es ca use d b y  an i nte nti o nal a n d/ or si g nifica nt 
de viati o n o n t he part of t he I n vesti gat or, t he st u d y site, a n d/ or t he partici pa nt. T he S p o ns or ta kes 
o ut i ns ura nce t o f ulfill t he res p o nsi bilit y .
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or will write a C S R i n c o ns ultati o n wit h t he C o or di nati n g 
I nvesti gat or.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore s u b missi o n. 
T his all o ws Merc k t o pr otect pr o pr ietar y i nf or mati o n a n d t o pr o vi de c o m me nts. 

T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y  in t heir e ntiret y an d n ot as i n di vi d ual site data. I n this case, a C o or di nati n g 
I n vesti gat or will be desi g nate d by a gree me nt.

A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
Disse mi n ati o n of Cli nic al St u d y D at a
After c o m pleti o n of t he st u d y, a C S R will be writte n b y  the S p o ns or i n c o ns ultati o n wit h t he 
C o or di nati n g I n vesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3, a n d will be s u b mitte d i n 
acc or da nce wit h l ocal re g ulati o ns.
A n y  an d all scie ntific, c o m mercial, a n d tec h nical i nf or mati o n discl ose d b y  the S p o ns or i n t his 
pr ot oc ol or else w here s h o ul d be c o nsi dere d t he c o nfi de ntial a n d pr o prietar y  pr o perty of t he 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 8 / 2 1 3
S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or mati o n i n c o nfi de nce a n d s hall n ot discl ose t he 
i nf or mati o n t o a n y t hir d part y  exce pt t o s uc h of t he I n vesti gat or’s e m pl o yees a n d staff w h o ha d 
bee n ma de a ware t hat t he i nf or mati o n is c o nfi de ntial a n d w h o are b o u n d t o treat it as s uc h a n d t o 
w h o m discl os ure is necessar y  to e val uate t hat i nf or mati o n. T he I n vesti gat or s hall n ot use s uc h 
i nf or mati o n f or a n y p ur p ose ot her t ha n f or deter mi ni n g m ut ual i nterest i n perf or mi n g t he st u d y 
a n d, if t he parties deci de t o pr ocee d wit h t he st u d y, f or t he p ur p ose of c o n d ucti n g t he st u d y.
T he I n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o pe d fr o m t his cli nical st u d y  will be use d 
b y  the S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y  inter ve nti o n a n d t heref ore ma y be 
discl ose d as re q uire d t o ot her cli nical I n vesti gat ors, t o t he U S F o o d a n d Dr u g A d mi nistrati o n, a n d 
t o ot her g o ver n me nt a ge ncies. T he I n vesti gat or als o u n dersta n ds t hat, t o all o w f or t he use of t he 
i nf or mati o n deri ve d fr o m t he cli nical st u d y, t he I n vesti gat or has t he o bli gati o n t o pr o vi de t he 
S p o ns or wit h c o m plete test res ults a n d all data de vel o pe d i n t he st u d y .

N o p u blicati o n or discl os ure of st u d y res ults will be per mitte d e xce pt u n der t he ter ms a n d 
c o n diti o ns of a se parate writte n a gree me nt.
D at a Q u alit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n pri nte d or e C R Fs or tra ns mitte d t o t he S p o ns or 
or desi g nee electr o nicall y (e. g., la b orat or y data). T he I n vesti gat or is res p o nsi ble f or verif y i n g 
t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y by p h y sicall y or electr o nicall y 
si g ni n g t he e C R F. Details f or mana gi n g e C R Fs are i n t he O perati o ns Ma n ual.

T he I n vesti gat or m ust 
mai ntai n 
acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he e C RF.

T he I nvesti gat or will
per mit st u d y-relate d m o nit ori n g, q ualit y  ass ura nce a u dits, I RB/I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d s o urce 
data.

M o nit ori n g details descri bi n g strate g y (e. g., ris k-base d i nitiati ves i n o perati o ns a n d q ualit y  suc h 
as Ris k Ma na ge me nt 
a n d Miti gati o n 
Strate gies a n d A nal yt ical Ris k -Base d M o nit ori n g), 
met h o ds, res p o nsi bilities a n d re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n- site m o nit ori n g) are i n t he M o nit ori n g Pla n.

T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y  
c hec ki n g of t he data a n d mai ntai ni n g a vali date d data base. Data base l oc k will occ ur o nce q ualit y 
c o ntr ol a n d q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. Details will be o utli ne d i n Data 
Ma na ge me nt d oc u me nts a n d pr oce d ures.

St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n t he e C R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y 
ot her st u d y agree me nts, I CH G C P, t he Ja pa nese mi nisterial or di na nce o n G C P, a n d all 
a p plica ble re g ulat or y re q uire me nts.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 2 9 / 2 1 3

T he I n vestigat or will retai n rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I CFs, pertai ni n g t o t he 
c o n d uct of t his st u d y f or 1 5 years after st u d y c o m pleti o n, u nless l ocal re g ulati o ns, i nstit uti o nal 
p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y  be destr o y e d d uri n g t he 
rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds ma y  be tra nsferre d t o 
a n ot her l ocati o n or part y wit h o ut t he S p o ns or’s writte n n otificati o n.
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.
T he I n vesti gat or m ust kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical rec or ds) at 
t he site f or eac h st u d y partici pa nt. T he file m ust i de ntif y eac h partici pa nt, c o ntai n t he f oll o wi n g 
de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d s h o ul d be as c o m plete as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y )

St u d y  i de ntifier (i.e., t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber.

Dates of e ntr y  i nt o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h visit t o t he 
site

A n y  me dical e xa mi nati o ns an d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All a d verse e ve nts

Date t hat t he partici pa nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he st u d y 
or st u d y  i nter ve nti o n, if a p plica ble.
All s o urce data m ust be file d (e.g. , C T or M RI sca n i ma ges, electr ocar di o gra m rec or di n gs, a n d 
la b orat or y res ults). Eac h d oc u me nt m ust ha ve t he partici pa nt n u m ber a n d t he pr oce d ure date; 
i deall y, pri nte d b y  the i nstr u me nt use d f or t he pr oce d ure. As necessar y , me dical e val uati o n of t hese 
rec or ds s h o ul d be perf or me d, d oc u me nte d, si g ne d a n d date d b y t he I n vesti gat or. 
Data rec or de d o n pri nte d or e C R Fs t hat are tra nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt 
wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he I nvesti gat or m a y  nee d t o 
re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical 
rec or ds m ust be a vaila ble.
T he st u d y mo nit ors will use pri nt o uts of electr o nic files f or s o urce data verificati o n. T hese 
pri nt o uts m ust be si g ne d a n d date d b y t he I n vesti gat or a n d ke pt i n t he st u dy file.
S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble 
re g ulati o ns, a n d/ or as per IC H G C P g ui deli nes, w hic he ver is l o n ger. T he I n vesti gat or or, i n Ja pa n, 
a rec or d retai ner desi g nate d b y  the Hea d of t he st u d y site e ns ures t hat n o destr ucti o n of me dical 
rec or ds is perf or me d wit h o ut t he S p o ns or’s writte n a p pr o val.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 0 / 2 1 3
Defi niti o n of w hat c o nstit utes s o urce data is f o u n d i n t he e C R F g ui deli nes.
St u d y a n d Site St art a n d Cl os ure
First Act of Recr uit me nt

T he st u d y  start date is t he date w he n t he cli nical st u d y will be o pe n f or recr uit me nt.

T he first act of recr uit me nt is t he first date t hat t he first I C F is si g ne d a n d will be t he st u d y s tart 
date.
St u d y  Cl os ure a n d Site Ter mi nati o n

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me a n d f or 
a n y reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d cl ose d 
w he n all re q uire d d oc u me nts a n d st u d y s u p plies ha ve bee n c ollecte d a n d a site cl os ure visit has 
bee n c o m plete d.

T he I n vesti gat or m a y  initiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use a n d 
e n o u g h n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.

Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n vesti gat or ma y  i ncl u de:
o
Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I RB/I E C or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes
o
I na de q uate recr uit me nt of partici pa nts b y  t he I n vesti gat or
o
Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d.

If t he st u d y is pre mat urel y  ter mi nate d or s us pe n de d, t he S p o ns or will
pr o m ptl y  inf or m t he 
I n vesti gat ors, t he I E Cs/IR Bs, 
t he re g ulat or y a ut h orities, a n d a n y c o ntract researc h 
or g a nizati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y 
t he a p plica ble re g ulat or y re q uire me nts. T he I n vesti gat or will pr o m ptl y  inf or m t he partici pa nts 
a n d ass ure a p pr o priate partici pa nt t hera p y a n d/ or f oll o w - u p.
T he w h ol e st u d y ma y be disc o nti n ue d pre mat urel y i n t he e ve nt of a n y of t he f oll o wi n g:

Ne w i nf or mati o n lea di n g t o u nfa v ora ble ris k be nefit j u d g me nt of t he st u d y i nter ve nti o n, f or 
e xa m ple, d ue t o:

e vi de nce of i nefficac y of t he st u d y i nter ve nti o n,

occ urre nce of si g nifica nt pre vi o usl y  un k n o w n a d verse reacti o ns or u ne x pecte dl y hi g h 
i nte nsit y or i nci de nce of k n o w n a d verse reacti o ns, or

ot her u nfa v ora ble safet y fi n di n gs.
( N ote: E vi de nce of i nefficac y m a y arise fr o m t his st u d y or fr o m ot her st u dies; u nfa v ora ble safety 
fi n di n gs ma y arise fr o m cli nical or n o ncli nical e xa mi nati o ns, f or e xa m ple, t o xic ol o g y.)

S p o ns or’s decisi o n t hat c o nti n uati o n of t he st u d y is u nj ustifia ble f or me dical or et hical reas o ns.

P o or e nr oll me nt of partici pa nts ma ki n g c o m pleti o n of t he st u d y wit hi n a n acce pta ble ti me fra me 
u nli kel y .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 1 / 2 1 3

Disc o nti n uati o n of de vel o p me nt of t he S p o ns or’s st u d y  i nter ve nti o n.
Healt h A ut h orities a n d I E Cs/IR Bs will be i nf or me d a b o ut t he disc o nti n uati o n of t he st u d y in 
acc or da nce wit h a p plica ble re g ulati o ns ( Hea d of st u d y  site will als o be i nf or me d i n Ja pa n).
T he w h ole st u d y ma y be ter mi nate d or s us pe n de d u p o n re q uest of Healt h A ut h orities.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 2 / 2 1 3
A p pe n di x 3
C o ntr ace pti o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.
A w o ma n of c hil d beari n g p ote ntial is n ot :
1.
Pre me narc hal
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y

D oc u me nte d bilateral sal pi n gect o m y

D oc u me nte d bilateral o o p h orect o m y
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he fe male’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y  i nter vie w.
F or a fe male wit h per ma ne nt i nfertilit y due t o a n alter nate me dical ca use ot her t ha n t he a b o ve, 
(e. g., M ü lleria n a ge nesis, a n dr o ge n i nse nsiti vit y), I nvesti gat or discreti o n a p plies t o dete r mi ne 
st u d y e ntr y.
1.
A p ost me n o pa usal fe male

A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use.

A hi g h f ollicle -sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y b e us e d 
t o c o nfir m a p ost me n o pa usa l state i n a fe male n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal 
re place me nt t hera p y (H R T). H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, m ore 
t ha n 1 F S H meas ure me nt is re q uire d i n t he p ost me n o pa usal ra n ge.

A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of 
t he n o n-estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o c o nti n ue 
her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 3 / 2 1 3
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y  Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y

I m pl a nt a bl e pr o g e st o g e n- o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n*

I ntr a ut eri n e d e vi c e (I U D)

I ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S)

Bil at er al t u b al o c cl u si o n

V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a w o m a n of c hil d b e ari n g p ot e nti al a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, u s e 
a n a d diti o n al hi g hl y eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt

C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n

Or al

I ntr a v a gi n al*

Tr a n s d er m al*

I nj e ct a bl e*

Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n

Or al*

I nj e ct a bl e*

S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e e v al u at e d 
i n r el ati o n t o t h e d ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e nt l y a n d c orr e ctl y.
If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p ( C T F G) g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e 
m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st - o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h e a m et h o d ( L A M) ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or t hi s 
st u d y. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n).
* N ot a p pr o v e d i n J a p a n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 4 / 2 1 3
A p pe n di x 4
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w u p, a n d Re p orti n g
Defi niti o ns
A d verse E ve nt
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a 
p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E 
ca n be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s ym pt o m, 
or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, re gar dless if it is c o nsi dere d 
relate d t o t he me dici nal pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y  of eac h A E.
I n vesti gat ors will refere nce t he Nati o nal Ca ncer I nstit ute ( N CI)- C o m m o n Ter mi n ol o g y  Criteria 
f or A Es ( C T C A E), V ersi o n 5. 0 ( p u blicati o n date: 2 7 N o ve m ber 2 0 1 7), a descri pti ve ter mi n ol o g y 
t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If t he se verit y for a n A E is n ot s pecificall y gra de d b y  NCI -C T C A E, t he I n vesti gat or is t o use t he 
ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical 
j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate nin g 

Gra de 5 or Deat h 
A n y  cli nical A E wit h se verity of Gra de 4 or 5 m ust als o be re p orte d as a S A E. H o we ver, a 
la b orat or y ab n or malit y o f Gra de 4, s uc h as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he 
c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w.
If deat h occ urs, t he pri mar y  ca use of deat h or e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be rec or de d as t he o utc o me of t his s pecific e ve nt a n d deat h will 
n ot be rec or de d as se parate e ve nt. O nl y, if n o cause of deat h ca n be re p orte d (e. g., s u d de n deat h, 
u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 5 / 2 1 3
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o st u d y inter ve nti o n 
(i ncl u di n g a n y ot her n o n -st u d y inter ve nti o ns, ra diati o n t hera p y, etc) usi n g t he f oll o wi n g 
defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o t he st u d y 
i nter ve nti o n i ncl u de, b ut ma y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d t he st u d y 
i nter ve nti o n, k n o w n si de effects of t he st u d y inter ve nti o n, me dical 
hist or y , c o nc o mita nt 
me dicati o n, c o urse of t he u n derl y i n g disease, a n d st u d y pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o t he st u d y inter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be 
a vaila ble.
Rel ate d:
Reas o na bl y 
relate d t o t he st u d y inter ve nti o n. 
A E 
c o ul d 
me dicall y  
( p har mac ol o gically/ cli nicall y) b e attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y pr ot oc ol.
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal 
la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (e. g., o n a n 
electr ocar di o gra m trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical 
si g ns a n d s ym pt o ms, lea d t o st u d y inter ve nti o n disc o nti n uati o n or are c o nsi dere d ot her wise 
me dicall y  im p orta nt b y  the I n vesti gat or. If a la b orat or y ab n or malit y  fulfills t hese criteria, t he 
i de ntifie d me dical c o n diti o n (e.g., a ne mia or i ncrease d ala ni ne a mi n otra nsferase) m ust be re p orte d 
as t he A E rat her t ha n t he a b n or mal val ue itself.
Seri o us A d verse E ve nts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. Life-t hreate ni n g refers t o a n e ve nt i n w hic h t he partici pa nt is at ris k of deat h 
at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if it was m ore 
se vere.

Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity

Is a c o n ge nital a n o maly or birt h defect

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y  not res ult 
i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es w he n, base d 
u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he partici pa nt or ma y  re q uire me dical 
or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples of s uc h 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 nc y r o o m or at h o me, 
bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 6 / 2 1 3

F or t he p ur p oses of rep orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y 
i nter ve nti o n is als o c o nsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es, A E SI , a n d 
D L Ts.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y st u d y inter ve nti o n or pr oce d ures (e. g., a n 
o ver ni g ht st a y to facilitate i ntra ve n o us t hera p y) are n ot c o nsi dere d S A Es. H o we ver, all e ve nts 
lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d pr ol o n gati o n of a n electi ve h os pitalizati o n (i.e., 
u n desira ble effects of a n y a d mi nistere d treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial st u d y visit t hat d o n ot w orse n i n se verity or fre q ue nc y 
d uri n g t he st u d y are defi ne d as Baseli ne Me dical C o n diti o ns, a n d are n ot t o be c o nsi dere d A Es.
A E/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n
Pr o gressi o n of t he disease/ dis or der bei n g st u die d assesse d b y  
meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he partic i pa nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d, as defi ne d i n Secti o n  8. 3. 2 .
A d verse E ve nts of S peci al I nterest
Cate g ories of A E SI relate d t o bi ntraf us p alfa i ncl u de:

I nf usi o n-relate d reacti o ns i ncl u di n g i m me diate h y perse nsiti vit y

I m m u ne-relate d A Es

T G F β i n hi biti o n me diate d s ki n reacti o ns

A ne mia 

Blee di n g A Es
Ot her A d verse E ve nts t o be Re p orte d F oll o wi n g a S peci alize d Pr oce d ure 
N ot a p plica ble.
Rec or di n g a n d F oll o w -u p of A d verse E ve nts a n d/ or Seri o us A d verse E ve nts
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d als o o nset a n d res ol uti o n ti mes, w he n it is i m p orta nt t o assess t he ti me of A E 
o nset relati ve t o t he rec or de d st u d y inter ve nti o n a d mi nistrati o n ti me), its se verit y, its ca usal 
relati o ns hi p wit h t he st u d y i nter ve nti o n, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or 
ot her acti o n ta ke n, i ncl u di n g d ose m o dificati o n or disc o nti n uati o n of t he st u d y inter ve nti o n, a n d 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 7 / 2 1 3
its o utc o me. I n a d diti o n, seri o us cases s h o ul d be i de ntifie d, a n d t he a p pr o priate seri o us ness criteria 
d oc u me nte d. If a n A E c o nstit utes a D L T, t his will be d oc u me nte d acc or di n gl y.
S pecific g ui da nce is i n t he Case Re p ort F or m ( C R F) C o m pleti o n a n d M o nit ori n g C o n ve nti o ns 
pr o vi de d b y t he S p o ns or.
Re p orti n g Seri o us A d verse E ve nts a n d D ose- Li miti n g T o xicities
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee usi n g t he electr o nic S A E Re p ort F or m i n t he Electr o nic Data Ca pt ure 
( E D C) sys te m.
Re p orti n g of S A Es usi n g a pa per re p ort f or m is re q uire d as a bac k -u p met h o d o nl y  for a n E D C 
s yste m fail ure. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers will be i ncl u de d o n t he pa per 
f or m. All i nf or mati o n fr o m t he pa per f or m m ust be tra nscri be d i nt o t he electr o nic f or m as s o o n as 
t he s yste m bec o mes a vaila ble.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a n electr o nic S A E Re p ort F or m m ust be c o m plete d i m me diatel y t hereafter.
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e. g., me dical hist or y , c o nc o mita nt 
dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (e.g., la b orat or y 
res ults, h os pital re p ort, a ut o ps y re p ort). 
T he I n vesti gat or m ust 
res p o n d t o a n y re q uest f or f oll o w-u p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee ma y ha ve o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociat e d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w- u p will us uall y  be ma de via t he st u d y mo nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he dr u g safety de part me nt m a y  co ntact t he I n vesti gat or directl y  to o btai n f urt her 
i nf or mati o n or t o disc uss t he e ve nt.
F or Ja pa nese sites, w here h os pitalizati o n of a partici pa nt is c o nsi dere d f or o bser vati o nal meas ures, 
e. g., d uri n g t he a d mi nistrati o n of c he m ot hera p y, a n y AE occ urri n g d uri n g t he peri o d of t he h os pital 
sta y for o bser vati o n o nl y s h o ul d n ot b e re p orte d as seri o us, u nless 1 or m ore of t he criteria f or S A E 
re p orta bilit y is met.
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 8 / 2 1 3
D ose -Li m iti n g T o xicities
Eac h e ve nt meeti n g t he criteria of a D L T, as s pecifie d i n Secti o n  6. 6. 2, m ust be rec or de d i n t he 
e C R F wit hi n 2 4 H O U R S after bec o mi n g a ware of t he e ve nt. Seri o us D L Ts m ust be re p orte d i n a n 
e x pe dite d ma n ner as S A Es, as o utli ne d a b o ve.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 3 9 / 2 1 3
A p pe n di x 5
Li ver S afet y: S u g geste d Acti o ns a n d F oll o w u p As sess me nts
D uri n g treat me nt wit h bi ntraf us p alfa/ place b o, a n d ge mcita bi ne a n d cis plati n, he patic i m pair me nt 
ma y  occ ur. See Secti o n 6. 6. 3 f or details o n necessar y  dose m o dificati o n a n d A p pe n di x 8 f or 
ma na ge me nt of he patic i m m u ne -relate d a d verse e ve nts. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 0 / 2 1 3
A p pe n di x 6
Cli nic al L a b or at or y Tests
T he re q uire d la b orat or y  safety tests f or t he f ull c he mistr y a n d he mat ol og y  an d t he c ore c he mistr y 
a n d he mat ol o g y  are s u m marize d i n Ta ble -
A a n d Ta ble - B, res pecti vely. See t he Sc he d ule of 
Acti vities i n Secti o n  1. 3 f or details of w hic h pa nel t o r u n at eac h visit.
A ne mia, uri nal ys is, a n d he patitis assess me nts are s u m marize d i n Ta ble - C, Ta ble - D a n d Ta ble - E
res pecti vely. A d diti o nal la b orat or y  assess me nts are s u m marize d i n Ta ble - F.
Ta ble - A
Pr ot oc ol -Re q uire d Cli nical La b orat or y  Assess me nts ( F ull Pa nel)... 1 4 1
Ta ble - B
Cli nical L a b orat or y Assess me nts ( C ore Pa nel)................................ 1 4 2
Ta ble - C  
A ne mia Assess me nts ........................................................................ 1 4 2
Ta ble - D
Uri nal y sis Assess me nts .................................................................... 1 4 2
Ta ble - E
He patitis Assess me nts ...................................................................... 1 4 2
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 1 / 2 1 3
T a ble - A
Pr ot oc ol -Re q uire d Cli nic al L a b or at or y Assess me nts ( F ull P a nel)
L a b or at or y  
A s s e s s m e nt s
P ar a m et er s
H e m at ol o g y / 
C o a g ul ati o n
Pl at el et c o u nt*
M e a n c or p u s c ul ar v ol u m e
W B C c o u nt* wit h 
Diff er e nti al :

N e utr o p hil s*

L y m p h o c yt e s*

M o n o c yt e s

E o si n o p hil s

B a s o p hil s
R eti c ul o c yt e s a
M C H C
H e m o gl o bi n*
M C H
H e m at o crit*
Pr ot hr o m bi n Ti m e
Er yt hr o c yt e C o u nt
A cti v at e d P T T*
Pr ot hr o m bi n I N R*
Bi o c h e mi str y
Bl o o d Ur e a 
Nitr o g e n*
P ot a s si u m*
A s p art at e a mi n otr a n sf er a s e*
Bilir u bi n (t ot al, 
i n dir e ct/ dir e ct)*
Cr e ati ni n e*
S o di u m*
Al a ni n e a mi n otr a n sf er a s e*
Pr ot ei n*
Gl u c o s e
C al ci u m*
Al k ali n e p h o s p h at a s e*
G G T
Cr e ati n e 
ki n a s e
L D H*
M a g n e si u m
C hl ori d e*
P h o s p h at e
P a n cr e ati c 
a m yl a s e
Al b u mi n*
Cr e ati ni n e cl e ar a n c e 
e sti m at e d*
Li p a s e
C- r e a cti v e 
pr ot ei n*
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s a n d f oll o w -u p a s s e s s m e nt s aft er a li v er st o p pi n g or 
m o nit ori n g e v e nt ar e gi v e n i n S e cti o n  6. 6. 5 .
* L a b or at or y r e s ult s m u st b e r e vi e w e d b y t h e I n v e sti g at or pri or t o d o si n g.
Ot h er S cr e e ni n g 
T e st s

F S H a n d e str a di ol ( a s n e e d e d if p arti ci p a nt i s n ot a w o m a n of c hil d b e ari n g p ot e nti al 
o nl y)

S er u m or hi g hl y s e n siti v e uri n e h u m a n c h ori o ni c g o n a d otr o pi n ( h C G) pr e g n a n c y t e st ( a s 
n e e d e d f or a w o m a n of c hil d b e ari n g p ot e nti al). N ot e: L o c al uri n e t e sti n g will b e st a n d ar d 
f or t h e pr ot o c ol u nl e s s s er u m t e sti n g I s r e q uir e d b y l o c al r e g ul ati o n or t h e I R B/I E C
S e e al s o  T a bl e - C, T a bl e - D, a n d T a bl e - E

All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a l o c al l a b or at or y
F S H =f olli cl e -sti m ul ati n g h or m o n e, G G T = g a m m a - gl ut a m yl tr a n sf er a s e, I N R =i nt er n ati o n al n or m ali z e d r ati o, 
I R B/I E C =In stit uti o n al R e vi e w B o ar d/ In d e p e n d e nt E t hi c s C o m mitt e e, L D H =l a ct at e d e h y dr o g e n a s e, M C H = m e a n 
c or p u s c ul ar h e m o gl o bi n, M C H C = m e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n, P T T = p arti al t hr o m b o pl a sti n ti m e, 
W B C = w hit e bl o o d c ell.
a
At s cr e e ni n g/ b a s eli n e, a n d i n c a s e of a n e mi a m o nit ori n g ( s e e  T a bl e 1 5 a n d  A p p e n di x 6 T a bl e - D). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 2 / 2 1 3
T a ble - B
Cli nic al L a b or at or y Assess me nts ( C ore P a nel)
L a b or at or y  
A s s e s s m e nt s
P ar a m et er s
H e m at ol o g y
Er yt hr o c yt e c o u nt*
W B C C o u nt* wit h Diff er e nti al:

N e utr o p hil s*

L y m p h o c yt e s*

M o n o c yt e s

E o si n o p hil s

B a s o p hil s
H e m o gl o bi n*
H e m at o crit*
Pl at el et s*
Bi o c h e mi str y
Bl o o d Ur e a Nitr o g e n*
Bilir u bi n (t ot al, i n dir e ct/ dir e ct)*
Cr e ati ni n e*
A s p art at e a mi n otr a n sf er a s e*
Cr e ati ni n e cl e ar a n c e e sti m at e d*
Al a ni n e a mi n otr a n sf er a s e*
C- r e a cti v e pr ot ei n*
Al k ali n e p h o s p h at a s e*
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s a n d f oll o w -u p a s s e s s m e nt s aft er a li v er st o p pi n g or 
m o nit ori n g e v e nt ar e gi v e n i n S e cti o n  6. 6. 5 .
* L a b or at or y r e s ult s m u st b e r e vi e w e d b y t h e I n v e sti g at or pri or t o d o si n g.
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a l o c al l a b or at or y
W B C = w hit e bl o o d c ell.
T a ble - C
A ne mi a Assess me nts
Ir o n P a n el
T ot al ir o n bi n di n g c a p a cit y a , ir o n, f erriti n, s er u m f ol at e, B 1 2, r eti c ul o c yt e s, r e d c ell 
di stri b uti o n wi dt h ( a s cli ni c all y i n di c at e d)
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a l o c al l a b or at or y
a 
If t ot al ir o n bi n di n g c a p a cit y c a n n ot b e e v al u at e d l o c all y, r e pl a c e wit h tr a n sf erri n.
T a ble - D
Uri n al ysis Assess me nts
F ull Uri n al y si s
Di p sti c k pl u s mi cr o s c o pi c e v al u ati o n. Di p sti c k, i n cl u di n g p h y si c al a p p e ar a n c e, bilir u bi n, 
bl o o d, c ol or, gl u c o s e, k et o n e s, l e u k o c yt e e st er a s e, nitrit e, p H, pr ot ei n, s p e cifi c gr a vit y, 
ur o bili n o g e n, a s l o c all y a v ail a bl e
R o uti n e Uri n al y si s

S p e cifi c gr a vit y

p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, b y di p sti c k

Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al) . 
T a ble - E
He p atitis Assess me nts
H e p atiti s
H B V, H C V s er ol o g y at b a s eli n e ( h e p atiti s B s urf a c e a nti g e n, h e p atiti s B c or e a nti b o d y, 
h e p atiti s B s urf a c e a nti b o d y, a n d h e p a titi s C a nti b o d y). T h e n: 

If o n e or m or e of t h e f oll o wi n g, h e p atiti s B s urf a c e a nti g e n, h e p atiti s B c or e a nti b o d y , or 
h e p atiti s B s urf a c e a nti b o d y a r e p o siti v e at b a s eli n e, e x a mi n e H B V D N A at s cr e e ni n g 
a n d Q 6 W  d uri n g t h e st u d y.

If h e p atiti s C a nti b o d y i s p o siti v e at b a s eli n e, e x a mi n e H C V R N A. If H C V R N A i s p o siti v e, 
e x a mi n e H C V R N A e v er y 6 w e e k s. 
R e p e at H B V D N A or H C V R N A t e st a s p er S c h e d ul e of A cti viti e s i n p arti ci p a nt s wit h 
i nf e cti o n hi st or y.
All st u d y -r e q uir e d l a b or at or y a ss e s s m e nt s will b e p erf or m e d b y a l o c al l a b or at or y
D N A = d e o x yri b o n u cl ei c a ci d, H B V = h e p atiti s B vir u s, H C V = h e p atiti s C vir u s, R N A =ri b o n u cl ei c a ci d.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 3 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 4 / 2 1 3
A p pe n di x 7
Me dic al 
De vice 
I nci de nts: Defi niti o n 
a n d Pr oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w u p, a n d Re p orti n g 
N ot a p plica bl e.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 5 / 2 1 3
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 6 / 2 1 3
T a ble A 1
M a n a ge me nt 
of S ki n I m m u ne-rel ate d A d verse 
E ve nts i n P atie nts 
Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
1. 0 S ki n T o xi citi e s
1. 1 R a s h/I n ﬂa m m at or y  D er m atiti s
D e ﬁniti o n: Er yt h e m a m ultif or m e mi n or ( a t ar g et oi d r e a cti o n i n t h e s ki n a n d m u c o u s m e m br a n e s u s u all y 
tri g g er e d b y i nf e cti o n s, s u c h a s h er p e s si m pl e x vir u s e s, b ut c a n b e a s s o ci at e d wit h a n i m m u n e-r el at e d dr u g 
er u pti o n a n d if pr o gr e s s e s t o er yt h e m a m ultif or m e m aj or, it a n d c a n b e a h ar bi n g er of S C A R, s u c h a s S J S), 
li c h e n oi d (r e s e m bli n g t h e ﬂat -t o p p e d, p ol y g o n al, a n d s o meti m e s s c al y or h y p ertr o p hi c l e si o n s of 
li c h e n-pl a n u s), e c z e m at o u s (i n ﬂa m m at or y d er m atiti s c h ar a ct eri z e d b y pr uriti c, er yt h e m at o u s, s c al y, or 
cr u st e d p a p ul e s or pl a q u e s o n t h e s ki n, w hi c h i s v ul n er a bl e t o s u p eri nf e cti o n, p s ori a sif or m [r e s e m bli n g t h e 
w ell d e m ar c at e d, er yt h e m at o u s, a n d s c al y p a p ul e s a n d pl a q u e s of p s ori a si s], m or billif or m [ a n o n p u st ul ar, 
n o n b ull o u s m e a sl e s -li k e e x a nt h e m at o u s r a s h of t h e s ki n oft e n r ef err e d t o a s “ m a c ul o p a p ul ar” a n d wit h o ut 
s y st e mi c s y m pt o m s or l a b or at or y a b n or m aliti e s, e x cl u d i n g o c c a si o n al i s ol at e d p eri p h er al e o si n o p hili a], 
p al m o pl a nt ar er yt hr o d y s e st h e si a [ h a n d-f o ot s y n dr o m e; r e d n e s s, n u m b n e s s, b ur ni n g, it c hi n g, a n d s u p er ﬁci al 
d e s q u a m ati o n of t h e p al m s a n d s ol e s], n e utr o p hili c d er m at o s e s [ e . g., S w e et s y n dr o m e], a n d ot h er s)
Di a g n o sti c w or k- u p
P erti n e nt hi st or y a n d p h y si c al e x a mi n ati o n
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e cti o n, a n eff e ct of a n ot h er dr u g, or a s ki n 
c o n diti o n li n k e d t o a n ot h er s y st e mi c di s e a s e or u nr el at e d pri m ar y s ki n di s or d er
If n e ed e d, a bi ol o gi c c h e c k u p, i n cl u di n g a bl o o d c ell c o u nt a n d li v er a n d ki d n e y t e st s
Dir e ct e d s er ol o gi c st u di e s if a n a ut oi m m u n e c o n diti o n i s s u s p e ct e d, s u c h a s l u p u s or d er m at o m y o siti s: a 
s cr e e ni n g a nti n u cl e ar a nti b o d y t e st, S S- A/ A nti -R o, S S -B/ A nti -L a if pr e d o mi n a ntl y 
p h ot o di stri b ut e d/ p h ot o s e n siti vit y, a nti hi st o n e, d o u bl e - str a n d e d D N A, a n d ot h er r el e v a nt s er ol o gi e s. C o n si d er 
e x p a n di n g s er ol o gi c st u di e s or di a g n o sti c w or k- u p if ot h er a ut oi m m u n e c o n diti o n s ar e c o n si d er e d b a s e d o n 
si g n s, s y m pt o m s s ki n bi o p s y
C o n s i d er cli ni c al m o nit ori n g wit h u s e of s eri al cli ni c al p h ot o gr a p h y
R e vi e w f ull li st of p ati e nt m e di c ati o n s t o r ul e o ut ot h er dr u g -i n d u c e d c a u s e f or p h ot o s e n siti vit y
Gr a di n g
M a n a g e m e nt
Gr a di n g a c c or di n g t o C T C A E i s a c h all e n g e f or s ki n. 
I n st e a d, s e v erit y m a y b e b a s e d o n B S A, t ol er a bilit y, 
m or bi dit y, a n d d ur ati o n
G 1: S y m pt o m s d o n ot aff e ct t h e q u alit y of lif e or 
c o ntr oll e d wit h t o pi c al r e gi m e n a n d/ or or al a nti pr uriti c
C o nti n u e I C Pi
Tr e at wit h t o pi c al e m olli e nt s a n d/ or mil d -m o d er at e 
p ot e n c y t o pi c al c orti c o st er oi d s
C o u n s el p ati e nt s t o a v oi d s ki n irrit a nt s a n d s u n 
e x p o s ur e
G 2: I n ﬂa m m at or y r e a cti o n t h at aff e ct s q u alit y of lif e 
a n d r e q uir e s i nt er v e nti o n b a s e d o n di a g n o si s
C o n si d er h ol di n g I C Pi a n d m o nit or w e e kl y f or 
i m pr o v e m e nt. If n ot r e s ol v e d, i nt err u pt tr e at m e nt u ntil 
s ki n A E h a s r e v ert e d t o Gr a d e 1
C o n si d er i niti ati n g pr e d ni s o n e ( or e q ui v al e nt) at 
d o si n g 1 m g/ k g, t a p eri n g o v er at l e a st 4 w e e k s
I n a d diti o n, tr e at wit h t o pi c al e m olli e nt s, or al 
a nti hi st a mi n e s, a n d m e di u m - t o hi g h-p ot e n c y t o pi c al 
c orti c o st er oi d s
G 3: A s G 2 b ut wit h f ail ur e t o r e s p o n d t o i n di c at e d 
i nt er v e nti o n s f or a G 2 d er m atiti s
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y t o 
d et er mi n e a p pr o pri at e n e s s of r e s u mi n g
Tr e at wit h t o pi c al e m olli e nt s, or al a nti hi st a mi n e s, a n d 
hi g h -p ot e n c y t o pi c al c orti c o st er oi d s
I niti at e ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 
1- 2 m g/ k g, t a p eri n g o v er at l e a st 4 w e e k s
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 7 / 2 1 3
1. 0 S ki n T o xi citi e s
G 4: All s e v er e r a s h e s u n m a n a g e a bl e wit h pri or 
i nt er v e nti o n s a n d i nt ol er a bl e
P er m a n e ntl y  di s c o nti n u e I C Pi
S y st e mi c c orti c o st er oi d s: I V ( m et h yl) pr e d ni s ol o n e ( or 
e q ui v al e nt) d o s e d at 1 -2 m g/ k g wit h sl o w t a p eri n g 
w h e n t h e t o xi cit y r e s ol v e s
M o nit or cl o s el y f or pr o gr e s si o n t o s e v er e c ut a n e o u s 
a d v er s e r e a cti o n
S h o ul d a d mit p ati e nt i m m e di at el y wit h dir e ct 
o n c ol o g y i n v ol v e m e nt a n d wit h a n ur g e nt c o n s ult b y 
d er m at ol o g y
1. 2 B ull o u s D er m at o s e s
D e ﬁniti o n: I n cl u di n g b ull o u s p e m p hi g oi d or ot h er a ut oi m m u n e b ull o u s d er m at o s e s, b ull o u s dr u g r e a cti o n
Di a g n o sti c w or k -u p
P h y si c al e x a mi n ati o n
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e ct i o n, a n eff e ct of a n ot h er dr u g, or a s ki n 
c o n diti o n li n k e d t o a n ot h er s y st e mi c di s e a s e
If n e e d e d, a bi ol o gi c c h e c k u p, i n cl u di n g a bl o o d c ell c o u nt, li v er, a n d ki d n e y t e st s; c o n si d er s er u m a nti b o d y 
t e st s t o r ul e o ut b ull o u s p e m p hi g oi d or, u n d er t h e g ui d a n c e of d er m at ol o g y, s e n di n g p ati e nt s er u m f or i n dir e ct 
i m m u n oﬂu or e s c e nt t e sti n g t o r ul e o ut ot h er a ut oi m m u n e bli st eri n g di s e a s e s
R ef err al t o d er m at ol o g y f or bli st er s t h at ar e n ot e x pl ai n e d b y i nf e cti o u s or tr a n si e nt ot h er c a u s e s ( e . g., h er p e s 
si m pl e x, h er p e s z o st er, b ull o u s i m p eti g o, b ull o u s i n s e ct bit e, fri cti o n or pr e s s ur e bli st er)
C o n si d er s ki n bi o p s y ( b ot h h e m at o x yli n a n d e o si n e v al u ati o n of l e si o n al s ki n a n d dir e ct i m m u n o ﬂu or e s c e n c e 
e v al u ati o n of p eril e si o n al s ki n)
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c, b li st er s c o v eri n g < 1 0 % B S A a n d 
n o a s s o ci at e d er yt h e m a
If bli st er s ar e < 1 0 % B S A, a s y m pt o m ati c, a n d 
n o ni n ﬂa m m at or y ( s u c h a s t h e c a s e wit h fri cti o n 
bli st er s or pr e s s ur e bli st er s), c e s s ati o n of I C Pi i s n ot 
n e c e s s ar y, a n d o nl y o b s er v ati o n a n d/ or l o c al w o u n d 
c a r e i s w arr a nt e d.
W h e n s y m pt o m ati c b ull a e or er o si o n s, w hi c h ar e 
d er o of e d v e si cl e s or b ull a e, ar e o b s er v e d o n t h e s ki n 
or m u c o s al s urf a c e s, t h e c ut a n e o u s ir A E i s b y 
d e ﬁniti o n c o n si d er e d at l e a st G 2
S e e G 2 m a n a g e m e nt r e c o m m e n d ati o n s
G 2: Bli st eri n g t h at aff e ct s q u alit y of lif e a n d r e q uir e s 
i nt er v e nti o n b a s e d o n di a g n o si s n ot m e eti n g crit eri a 
f or Gr a d e > 2
Bli st er s c o v eri n g 1 0 % -3 0 % B S A
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y f or 
w or k -u p a n d t o d et er mi n e a p pr o pri at e n e s s of 
r e s u mi n g
Att e nti o n gi v e n t o g e n er al l o c al w o u n d c ar e, w hi c h 
i n cl u d e s pl ai n p etr ol at u m oi nt m e nt a n d b a n d a g e s or 
pl ai n p etr ol at u m oi nt m e nt g a u z e a n d b a n d a g e o v er 
a n y o p e n er o si o n s, w hi c h ar e l eft o v er o n t h e s ki n 
aft er t h e bli st er h a s p o p p e d or if t h e r o of of t h e bli st er 
e a sil y sl o u g h s of f
C o u n s el p ati e nt s t o a v oi d s ki n irrit a nt s a n d 
o v er e x p o s ur e t o s u n, w e ar pr ot e cti v e cl ot hi n g, u s e 
s u n s cr e e n s
W o r k- u p f or a ut oi m m u n e b ull o u s di s e a s e a s a b o v e
I niti at e cl a s s 1 hi g h- p ot e n c y t o pi c al c orti c o st er oi d 
( e. g., cl o b et a s ol, b et a m et h a s o n e or e q ui v al e nt) a n d 
r e a s s e s s e v er y 3 d a y s f or pr o gr e s si o n or 
i m pr o v e m e nt
L o w t hr e s h ol d t o i niti at e tr e at m e nt wit h pr e d ni s o n e 
( or e q ui v al e nt) at 0. 5- 1 m g/ k g d o si n g a n d t a p er o v er 
at l e a st 4 w e e k s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 8 / 2 1 3
1. 0 S ki n T o xi citi e s
M o nit or p ati e nt s wit h G 2 ir A E s cl o s el y f or 
pr o gr e s si o n t o i n v ol v e m e nt of gr e at er B S A a n d/ or 
m u c o u s m e m br a n e i n v ol v e m e nt. C o n si d er f oll o wi n g 
p ati e nt s cl o s el y u si n g s eri al p h ot o gr a p h y
Pri m er o n m o nit ori n g f or c o m pli c at e d c ut a n e o u s 
a d v er s e dr u g r e a cti o n s:

R e vi e w of s y st e m s: S ki n p ai n (li k e a s u n b ur n), 
f e v er s, m al ai s e, m y al gi a s, art hr al gi a s, a b d o mi n al 
p ai n, o c ul ar di s c o mf ort or p h ot o p h o bi a, s or e s or 
di s c o mf ort i n t h e n ar e s, s or e s or di s c o mf ort i n t h e 
or o p h ar y n x, o d y n o p h a gi a, h o ar s e n e s s, d y s uri a, 
s or e s or di s c o mf ort i n t h e v a gi n al ar e a f or w o m e n 
or i n v ol vi n g t h e m e at u s of t h e p e ni s f or m e n, 
s or e s i n t h e p eri a n al ar e a, or p ai n wit h b o w el 
m o v e m e nt s

P h y si c al e x a mi n ati o n: I n cl u d e vit al si g n s a n d a 
f ull s ki n e x a mi n ati o n s p e ciﬁc all y e v al u ati n g all 
s ki n s urf a c e s a n d m u c o u s m e m br a n e s ( e y e s, 
n ar e s, or o p h ar y n x, g e nit al s, a n d p eri a n al ar e a). 
A s s e s s f or l y m p h a d e n o p at h y, f a ci al or di st al 
e xtr e mit y s w elli n g ( m a y b e si g n s of 
DI H S/ D R E S S). A s s e s s f or p u st ul e s or bli st er s or 
er o si o n s i n a d diti o n t o ar e a s of “ d u s k y er yt h e m a,” 
w hi c h m a y f e el p ai nf ul t o p al p ati o n. T o a s s e s s f or 
a p o siti v e Ni k ol s k y’ s si g n, pl a c e a gl o v e d ﬁn g er 
t a n g e nti all y o v er er yt h e m at o u s s ki n a n d a p pl y 
fri cti o n p ar all el t o t h e s ki n s urf a c e. Ni k ol s k y’ s si g n 
i s p o siti v e if t hi s r e s ult s i n d et a c h e d or sl o u g hi n g 
e pi d er mi s d e m o n str ati n g p o or att a c h m e nt of t h e 
e pi d er mi s t o t h e d er mi s, w hi c h i s t h e c a s e i n 
s o m e a ut oi m m u n e di s or d er s ( e. g. , p e m p hi g u s) 
a n d S J S/ T E N
G 3: S ki n sl o u g hi n g c o v eri n g > 3 0 % B S A wit h 
a s s o ci at e d p ai n a n d li miti n g s elf -c ar e A D L
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y t o 
d et er mi n e a p pr o pri at e n e s s of r e s u mi n g
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 
1- 2 m g/ k g, t a p eri n g o v er at l e a st 4 w e e k s
If b ull o u s p e m p hi g oi d i s di a g n o s e d, it m a y b e 
p o s si bl e t o a v oi d l o n g -t er m u s e of s y st e mi c 
c orti c o st er oi d s a n d tr e at wit h rit u xi m a b, a s a n 
alt er n ati v e a p pr o a c h t o tr e ati n g t h e ir A E
S e e k i nf e cti o u s di s e a s e c o n s ult ati o n if p ati e nt mi g ht 
h a v e s e c o n d ar y c ell uliti s or if p ati e nt h a s ot h er 
i nf e cti o n ri s k f a ct or s, s u c h a s n e utr o p e ni a, et c
G 4: Bli st er s c o v eri n g > 3 0 % B S A wit h a s s o ci at e d 
ﬂui d or el e ctr ol yt e a b n or m aliti e s
P e r m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt i m m e di at el y a n d pl a c e u n d er 
s u p er vi si o n of a d er m at ol o gi st
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 
1- 2
m g/ k g wit h t a p eri n g o v er at l e a st 4 w e e k s w h e n 
t h e t o xi cit y r e s ol v e s
If b ull o u s p e m p hi g oi d i s di a g n o s e d, it m a y b e 
p o s si bl e t o a v oi d l o n g -t er m u s e of s y st e mi c 
c orti c o st er oi d s a n d tr e at wit h rit u xi m a b a s a n 
alt er n ati v e a p pr o a c h t o tr e ati n g t h e ir A E
S e e k i nf e cti o u s di s e a s e c o n s ult ati o n if p ati e nt mi g ht 
h a v e s e c o n d ar y c ell uliti s or if p ati e nt h a s ot h e r 
i nf e cti o n ri s k f a ct or s, s u c h a s n e utr o p e ni a, et c
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 4 9 / 2 1 3
1. 0 S ki n T o xi citi e s
1. 3 S C A R s, I n cl u di n g S J S, T E N, A c ut e G e n er ali z e d E x a nt h e m at o u s P u st ul o si s, a n d D R E S S/ DI H S
D e ﬁniti o n: S e v er e c h a n g e s i n eit h er str u ct ur e or f u n cti o n s of s ki n, t h e a p p e n d a g e s or t h e m u c o u s 
m e m br a n e s d u e t o
a dr u g
Di a g n o sti c w or k -u p
T ot al b o d y s ki n e x a mi n ati o n wit h att e nti o n t o e x a mi ni n g all m u c o u s m e m br a n e s a s w ell a s c o m pl et e r e vi e w 
of s y st e m s
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e cti o n, a n eff e ct of a n ot h er dr u g, or a s ki n 
c o n di ti o n li n k e d t o a n ot h er s y st e mi c di s e a s e
A bi ol o gi c c h e c k u p, i n cl u di n g a C B C wit h diff er e nti al t e st, a n d li v er a n d ki d n e y f u n cti o n t e st s, i n cl u di n g 
uri n al y si s, i n a d diti o n t o t h e bl o o d w or k; if t h e p ati e nt i s f e bril e, bl o o d c ult ur e s s h o ul d b e c o n si d er e d a s w ell
S ki n bi o p si e s t o a s s e s s f or f ull -t hi c k n e s s e pi d er m al n e cr o si s, a s i s s e e n i n S J S/ T E N, a s w ell a s ot h er 
p o s si bl e eti ol o gi e s li k e p ar a n e o pl a sti c p e m p hi g u s or ot h er a ut oi m m u n e bli st eri n g d er m at o s e s or ot h er dr u g 
r e a cti o n s, s u c h a s a c ut e g e n er ali z e d e x a nth e m at o u s p u st ul o si s
C o n si d er f oll o wi n g p ati e nt s cl o s el y u si n g s eri al cli ni c al p h ot o gr a p h y
If m u c o u s m e m br a n e i n v ol v e m e nt or bli st eri n g i s o b s er v e d o n t h e s ki n, c o n si d er e arl y a d mi s si o n t o a b ur n 
c e nt er f or f urt h er m o nit ori n g a n d m a n a g e m e nt Pri m er o n m o nit o ri n g f or c o m pli c at e d c ut a n e o u s a d v er s e dr u g 
r e a cti o n s:
R e vi e w of s y st e m s: S ki n p ai n (li k e a s u n b ur n), f e v er s, m al ai s e, m y al gi a s, art hr al gi a s, a b d o mi n al p ai n, o c ul ar 
di s c o mf ort or p h ot o p h o bi a, s or e s or di s c o mf ort i n t h e n ar e s, s or e s or di s c o mf ort i n t h e or o p h ar y n x, 
o d y n o p h a gi a, h o ar s e n e s s, d y s uri a, s or e s or di s c o mf ort i n t h e v a gi n al ar e a f or w o m e n or i n v ol vi n g t h e m e at u s 
of t h e p e ni s f or m e n, s or e s i n t h e p eri a n al ar e a, or p ai n wit h b o w el m o v e m e nt s
P h y si c al e x a mi n ati o n: I n cl u d e vit al si g n s a n d a f ull s ki n e x a mi n ati o n s p e ci ﬁc all y e v al u ati n g all s ki n s urf a c e s 
a n d m u c o u s m e m br a n e s ( e y e s, n ar e s, or o p h ar y n x, g e nit al s, a n d p eri a n al ar e a). A s s e s s f or 
l y m p h a d e n o p at h y, f a ci al or di st al e xtr e mit y s w elli n g ( m a y b e si g n s of DI H S/ D R E S S). A s s e s s f or p u st ul e s or 
bli st er s or er o si o n s i n a d diti o n t o ar e a s of “ d u s k y er yt h e m a,” w hi c h m a y f e el p ai nf ul t o p al p ati o n. T o a s s e s s 
f or a p o siti v e Ni k ol s k y’ s si g n, pl a c e a gl o v e d ﬁn g er t a n g e nti all y o v er er yt h e m at o u s s ki n a n d a p pl y fri cti o n 
p ar all el t o t h e s ki n s urf a c e. Ni k ol s k y’ s si g n i s p o siti v e if t hi s r e s ult s i n d et a c h e d or sl o u g hi n g e pi d er mi s 
d e m o n str ati n g p o or att a c h m e nt of t h e e pi d er mi s t o t h e d er mi s, w hi c h i s t h e c a s e i n s o m e a ut oi m m u n e 
di s or d er s ( e . g., p e m p hi g u s) a n d S J S/ T E N
Gr a di n g
M a n a g e m e nt
All Gr a d e s
I n c a s e s of s u s p e ct e d S J S or a n y m u c o u s 
m e m br a n e i n v ol v e m e nt, di s c o nti n u e I C Pi tr e at m e nt 
a n d m o nit or cl o s el y f or i m pr o v e m e nt, r e g ar dl e s s of 
gr a d e
G 1: N A
F or S C A R s, t h er e i s n o G 1 c at e g or y; if l o w er B S A i s 
i n v ol v e d wit h b ull a e or er o si o n s, t h er e s h o ul d r e m ai n 
a hi g h c o n c er n t h at t hi s r e a cti o n will pr o gr e s s t o G 3 
or G 4
G 2: M or billif or m (“ m a c ul o p a p ul ar”) e x a nt h e m 
c o v eri n g 1 0 % - 3 0 % B S A wit h s y st e mi c s y m pt o m s, 
l y m p h a d e n o p at h y, or f a ci al s w elli n g
H ol d I C Pi a n d m o nit or p ati e nt s cl o s el y e v er y 3 d a y s 
wit h G 2 ir A E s f or pr o gr e s si o n t o i n v ol v e m e nt of 
gr e at er B S A a n d/ or m u c o u s m e m br a n e i n v ol v e m e nt
C o n si d er f oll o wi n g p ati e nt s cl o s el y u si n g s eri al 
p h ot o gr a p h y
I niti at e t h er a p y wit h t o pi c al e m olli e nt s, or al 
a nti hi st a mi n e s, a n d m e di u m - t o hi g h-str e n gt h t o pi c al 
c orti c o st er oi d s
C o n si d er i niti ati o n of pr e d ni s o n e ( or e q ui v al e nt) 
0. 5 - 1 m g/ k g t a p er e d o v er at l e a st 4 w e e k s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 0 / 2 1 3
1. 0 S ki n T o xi citi e s
G 3: S ki n sl o u g hi n g c o v eri n g < 1 0 % B S A wit h 
m u c o s al i n v ol v e m e nt a s s o ci at e d si g n s ( e . g., 
er yt h e m a, p ur p ur a, e pi d er m al d et a c h m e nt, m u c o u s 
m e m br a n e d et a c h m e nt)
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y
Tr e at s ki n wit h t o pi c al e m olli e nt s a n d ot h er 
p etr ol at u m e m olli e nt s, or al a nti hi st a mi n e s, a n d 
hi g h -str e n gt h t o pi c al c orti c o st er oi d s; di m et hi c o n e 
m a y al s o b e off er e d a s a n alt er n ati v e t o p etr ol at u m
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 
0. 5 -1 m g/ k g a n d c o n v ert t o or al c orti c o st er oi d s o n 
r e s p o n s e, w e a n o v er at l e a st 4 w e e k s
A d mit t o B ur n U nit a n d/ or c o n s ult w o u n d s er vi c e s 
wit h att e nti o n t o s u p p orti v e c ar e, i n cl u di n g ﬂui d a n d 
el e ctr ol yt e b al a n c e, mi ni mi zi n g i n s e n si bl e w at er 
l o s s e s, a n d pr e v e nti n g i nf e cti o n
Gi v e n t h e i m m u n e m e c h a ni s m of a cti o n of t h e s e 
m e di ci n e s, u s e of i m m u n e s u p pr e s si o n i s w arr a nt e d 
a n d s h o ul d b e off er e d
F or m u c o u s m e m br a n e i n v ol v e m e nt of S J S or T E N, 
a p pr o pri at e c o n s ulti n g s er vi c e s s h o ul d b e off er e d t o 
g ui d e m a n a g e m e nt i n pr e v e nti n g s e q u el a e fr o m 
s c arri n g ( e . g., o p ht h al m ol o g y; e ar, n o s e, a n d t hr o at; 
ur ol o g y; g y n e c ol o g y; et c, a s a p pr o pri at e)
G 4: S ki n er yt h e m a a n d bli st eri n g/ sl o u g hi n g c o v eri n g 
≥1 0 % t o > 3 0 % B S A wit h a s s o ci at e d si g n s ( e . g., 
er yt h e m a, p ur p ur a, e pi d er m al d et a c h m e nt, m u c o u s 
m e m br a n e d et a c h m e nt) a n d/ or s y st e mi c s y m pt o m s 
a n d c o n c er ni n g a s s o ci at e d bl o o d w or k a b n or m aliti e s 
( e. g., li v er f u n cti o n t e st el e v ati o n s i n t h e s etti n g of 
D R E S S/ DI H S)
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt i m m e di at el y t o a b ur n u nit or I C U wit h 
c o n s ult e d d er m at ol o g y a n d w o u n d c ar e s er vi c e s
C o n si d er f urt h er c o n s ult ati o n s b a s e d o n 
m a n a g e m e nt of m u c o s al s urf a c e s
( e. g., o p ht h al m ol o g y; ur ol o g y; g y n e c ol o g y; e ar, n o s e, 
a n d t hr o at s ur g er y; et c) I niti at e I V 
( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 1-2 m g/ k g, 
t a p eri n g w h e n t o xi cit y r e s ol v e s t o n or m al
I VI G or c y cl o s p ori n e m a y al s o b e c o n si d er e d i n 
s e v er e or c orti c o st er oi d -u nr e s p o n si v e c a s e s
C o n si d er p ai n/ p alli ati v e c o n s ult ati o n a n d/ or 
a d mi s si o n i n p ati e nt s pr e s e nti n g wit h D R E S S 
m a nif e st ati o n s
A d dit i o n al c o n si d er ati o n s: T h e u s u al pr o hi biti o n of c orti c o st er oi d s f or S J S i s n ot r el e v a nt h er e, a s t h e 
u n d erl yi n g m e c h a ni s m i s a T -c ell i m m u n o dir e ct e d t o xi cit y
A d e q u at e s u p pr e s si o n i s n e c e s s ar y wit h c orti c o st er oi d s or ot h er a g e nt s a n d m a y b e pr ol o n g e d i n c a s e s of 
D R E S S/ DI H S
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A D L = a cti viti e s of d ail y li vi n g, B S A = b o d y s urf a c e ar e a, C B C = c o m pl et e bl o o d c o u nt, C T C A E = C o m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt s, DI H S = dr u g-i n d u c e d h y p er s e n siti vit y s y n dr o m e, D N A = d e o x yri b o n u cl ei c a ci d, 
D R E S S = dr u g r e a cti o n wit h e o si n o p hili a a n d s y st e mi c s y m pt o m s, G = gr a d e, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, 
I C U =i nt e n si v e c ar e u nit, ir A E =i m m u n e-r el at e d a d v er s e e v e nt, I V =i ntr a v e n o u s, I VI G = i ntr a v e n o u s i m m u n o gl o b uli n, 
N A = n ot a p pli c a bl e, S C A R = s e v er e c ut a n e o u s a d v er s e r e a cti o n s, S J S = St e v e n s -J o h n s o n s y n dr o m e, T E N =t o xi c 
e pi d er m al n e cr ol y si s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 1 / 2 1 3
T a ble A 2
M a n a ge me nt 
of G astr oi ntesti n al I m m u ne-rel ate d A d verse E ve nts i n 
P atie nts Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
2. 0 GI T o xi citi e s
2. 1 C oliti s
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y i n ﬂa m m ati o n of t h e c ol o n
Di a g n o sti c w or k -u p
G 2
W o r k-u p of bl o o d ( C B C, c o m pr e h e n si v e m et a b oli c p a n el, T S H, E S R, C R P), st o ol ( c ult ur e, Cl o stri di u m diffi cil e, 
p ar a sit e, C M V or ot h er vir al eti ol o g y, o v a a n d p ar a sit e) s h o ul d b e p erf or m e d
C o n si d er t e sti n g f or l a ct of erri n (f or p ati e nt str ati ﬁc ati o n t o d et er mi n e w h o n e e d s m or e ur g e nt e n d o s c o p y) a n d 
c al pr ot e cti n (t o f oll o w -u p o n di s e a s e a cti vit y)
S cr e e ni n g l a b or at ori e s ( HI V, h e p atiti s A a n d B, a n d bl o o d Q u a nti F E R O N f or T B) t o pr e p ar e p ati e nt s t o st art 
i nﬂi xi m a b s h o ul d b e r o uti n el y d o n e i n p ati e nt s at hi g h ri s k f or t h o s e i nf e cti o n s a n d a p pr o pri at el y s el e ct e d p ati e nt s 
b a s e d o n i nf e cti o u s di s e a s e e x p ert’ s e v al u ati o n
I m a gi n g ( e. g., C T s c a n of a b d o m e n a n d p el vi s a n d GI en d o s c o p y wit h bi o p s y) s h o ul d b e c o n si d er e d a s t h er e i s 
e vi d e n c e s h o wi n g t h at t h e pr e s e n c e of ul c er ati o n i n t h e c ol o n c a n pr e di ct a c orti c o st er oi d r efr a ct or y c o ur s e, w hi c h 
m a y r e q uir e e arl y i n ﬂi xi m a b
C o n si d er r e p e ati n g e n d o s c o p y f or p ati e nt s w h o d o n ot r e s p o n d t o i m m u n o s u p pr e s si v e a g e nt s; r e p e ati n g 
e n d o s c o p y f or di s e a s e m o nit ori n g c a n b e c o n si d er e d w h e n cli ni c all y i n di c at e d a n d w h e n pl a n ni n g t o r e s u m e 
t h er a p y
G 3 - 4
All t h e w or k -u p li st e d f or G 2 ( bl o o d, st o ol, i m a gi n g, a n d s c o p e wit h bi o p s y) s h o ul d b e c o m pl et e d i m m e di at el y
C o n si d er r e p e ati n g e n d o s c o p y f or p ati e nt s w h o d o n ot r e s p o n d t o i m m u n o s u p pr e s si v e a g e nt s; r e p e ati n g 
e n d o s c o p y f or di s e a s e m o nit ori n g s h o ul d o nl y b e c o n si d er e d w h e n cli ni c all y i n di c at e d a n d w h e n pl a n ni n g t o 
r e s u m e I C Pi
Gr a di n g ( b a s e d o n C T C A E f or di arr h e a, a s m o st oft e n 
u s e d cli ni c all y)
M a n a g e m e nt
All p ati e nt s
C o u n s el all p ati e nt s t o b e a w ar e of a n d i nf or m t h eir 
h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e:
A b d o mi n al p ai n, n a u s e a, cr a m pi n g, bl o o d or m u c u s i n 
st o ol or c h a n g e s i n b o w el h a bit s, f e v er, a b d o mi n al 
di st e nti o n, o b sti p ati o n, c o n sti p ati o n
F or G 2 or hi g h er, c o n si d er p er m a n e ntl y di s c o nti n ui n g 
C T L A -4 a g e nt s a n d m a y r e st art P D -1, P D -L 1 a g e nt s if 
p ati e nt c a n r e c o v er t o G 1 or l e s s; c o n c urr e nt 
i m m u n o s u p pr e s s a nt m ai nt e n a n c e t h er a p y s h o ul d b e 
c o n si d er e d o nl y if cli ni c all y i n di c at e d i n i n di vi d u al c a s e s
G 1: I n cr e a s e of f e w er t h a n 4 st o ol s p er d a y o v er 
b a s eli n e; mil d i n cr e a s e i n o st o m y o ut p ut c o m p ar e d wit h 
b a s eli n e
C o nti n u e I C Pi; alt er n ati v el y, I C Pi m a y b e h el d 
t e m p or aril y a n d r e s u m e d if t o xi cit y d o e s n ot e x c e e d
G 1
M o nit or f or d e h y dr ati o n a n d r e c o m m e n d di et ar y 
c h a n g e s F a cilit at e e x p e dit e d p h o n e c o nt a ct wit h 
p ati e nt/ c ar e gi v er M a y o bt ai n g a str o e nt er ol o g y c o n s ult 
f or pr ol o n g e d G 1 c a s e s
G 2: I n cr e a s e of 4 t o 6 st o ol s p er d a y o v er b a s eli n e; 
m o d er at e i n cr e a s e i n o st o m y o ut p ut c o m p ar e d wit h 
b a s eli n e
S h o ul d h ol d I C Pi t e m p or aril y u ntil p ati e nt’ s s y m pt o m s 
r e c o v er t o G 1; c a n c o n si d er p er m a n e ntl y
di s c o nti n ui n g C T L A -4 a g e nt s a n d m a y r e st art P D -1, 
P D - L 1 a g e nt s if p ati e nt c a n r e c o v er t o G 1 or l e s s
C o n c urr e nt i m m u n o s u p pr e s s a nt m ai nt e n a n c e t h er a p y 
( 1 0 m g pr e d ni s o n e e q ui v al e nt d o s e) m a y b e off er e d 
o nl y if cli ni c all y i n di c at e d i n i n di vi d u al c a s e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 2 / 2 1 3
2. 0 GI T o xi citi e s
M a y al s o i n cl u d e s u p p orti v e c ar e wit h m e di c ati o n s s u c h 
a s I m o di u m if i nf e cti o n h a s b e e n r ul e d o ut
S h o ul d c o n s ult wit h g a str o e nt er ol o g y f or G 2 or hi g h er
A d mi ni st er c orti c o st er oi d s, u nl e s s di arr h e a i s tr a n si e nt, 
st arti n g wit h i niti al d o s e of 1 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt
W h e n s y m pt o m s i m pr o v e t o G 1 or l e s s, t a p er 
c orti c o st er oi d s o v er at l e a st 4 -6 w e e k s b ef or e r e s u mi n g 
tr e at m e nt, alt h o u g h r e s u mi n g tr e at m e nt w hil e o n l o w-
d o s e c orti c o st er oi d m a y al s o b e a n o pti o n aft er a n 
e v al u ati o n of t h e ri s k s a n d b e n e ﬁt s
E G D/ c ol o n o s c o p y, e n d o s c o p y e v al u ati o n s h o ul d b e 
hi g hl y r e c o m m e n d e d f or c a s e s Gr a d e ≥2 t o str atif y 
p ati e nt s f or e arl y tr e at m e nt wit h i n ﬂi xi m a b b a s e d o n t h e 
e n d o s c o pi c ﬁn di n g s a n d t o d et er mi n e t h e s af et y of 
r e s u mi n g P D-1, P D -L 1 t h er a p y
St o ol i n ﬂa m m at or y m ar k er s c a n b e c o n si d er e d 
(l a ct of erri n a n d c al pr ot e cti n) i n c a s e s of G 2 or hi g h er t o 
diff er e nti at e f u n cti o n al v i nﬂa m m at or y di arr h e a, a n d u s e 
c al pr ot e cti n t o m o nit or tr e at m e nt r e s p o n s e if pr o vi d er 
pr ef er s
R e p e at c ol o n o s c o p y i s o pti o n al f or c a s e s of G 2 or 
hi g h er f or di s e a s e a cti vit y m o nit ori n g t o a c hi e v e 
c o m pl et e r e mi s si o n, e s p e ci all y if t h er e i s a pl a n t o 
r e s u m e I C Pi
G 3: I n cr e a s e of 7 or m or e st o ol s p er d a y o v er b a s eli n e, 
i n c o nti n e n c e, h o s pit ali z ati o n i n di c at e d, s e v er e i n cr e a s e 
i n o st o m y o ut p ut c o m p ar e d wit h b a s eli n e, li miti n g s elf-
c ar e A D L
S h o ul d c o n si d er p er m a n e ntl y di s c o nti n ui n g C T L A -4 
a g e nt s a n d m a y r e st art P D - 1, P D-L 1 a g e nt s if p ati e nt 
c a n r e c o v er t o G 1 or l e s s.
A d mi ni st er c orti c o st er oi d s (i niti al d o s e of 1 -2 m g/ k g/ d 
pr e d ni s o n e or e q ui v al e nt)
C o n si d er h o s pit ali z ati o n or o ut p ati e nt f a cilit y f or p ati e nt s 
wit h d e h y dr ati o n or el e ctr ol yt e i m b al a n c e
If s y m pt o m s p er si st ≥3- 5 d a y s or r e c ur aft er 
i m pr o v e m e nt, c o n si d er a d mi ni st eri n g I V c orti c o st er oi d 
or n o n c orti c o st er oi d ( e . g., i nﬂi xi m a b)
C o n si d er c ol o n o s c o p y i n c a s e s w h er e p ati e nt s h a v e 
b e e n o n i m m u n o s u p pr e s si o n a n d m a y b e at ri s k f or 
o p p ort u ni sti c i nf e cti o n s a s a n i n d e p e n d e nt c a u s e f or 
di arr h e a (i . e., C M V c oliti s) a n d f or t h o s e w h o ar e a nti-
T N F or c orti c o st er oi d r efr a ct or y
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; ur g e nt i nt er v e nti o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e tr e at m e nt
S h o ul d a d mit p ati e nt w h e n cli ni c all y i n di c at e d; p ati e nt s 
m a n a g e d a s o ut p ati e nt s s h o ul d b e v er y cl o s el y 
m o nit or e d
A d mi ni st er 1 - 2 m g/ k g/ d m et h yl pr e d ni s ol o n e or 
e q ui v al e nt u ntil s y m pt o m s i m pr o v e t o G 1, a n d t h e n st art 
t a p er o v er 4-6 w e e k s
C o n si d er e arl y i n ﬂi xi m a b 5 -1 0 m g/ k g if s y m pt o m s 
r efr a ct or y t o c orti c ost er oi d wit hi n 2 - 3 d a y s C o n si d er 
l o w er GI e n d o s c o p y if s y m pt o m s ar e r efr a ct or y d e s pit e 
tr e at m e nt or t h er e i s c o n c er n of n e w i nf e cti o n s
A d diti o n al c o n si d er ati o n s
T h e u s e of v e d oli z u m a b m a y b e c o n si d er e d i n p ati e nt s r efr a ct or y t o i n ﬂi xi m a b a n d/ or c o ntr ai n di c at e d t o T N F - α
bl o c k er. T h e d e ci si o n s h o ul d b e m a d e o n a n i n di vi d u al b a si s fr o m g a str o e nt er ol o g y a n d o n c ol o g y e v al u ati o n. T hi s 
i s b a s e d o n c a s e s eri e s s h o wi n g pr o mi si n g r e s ult s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 3 / 2 1 3
2. 0 GI T o xi citi e s
P ati e nt s wit h h e p atiti s a n d ir A E c oliti s ar e r ar e, a n d m a n a g e m e nt s h o ul d i n cl u d e p er m a n e ntl y di s c o nti n ui n g I C Pi 
a n d off eri n g ot h er i m m u n o s u p pr e s s a nt a g e nt s t h at w or k s y st e mi c all y f or b ot h c o n diti o n s
C urr e ntl y, e nt eriti s al o n e a s t h e c a u s e of di arr h e a i s u n c o m m o n a n d r e q uir e s s m all b o w el bi o p s y a s t h e e v al u ati o n 
t o ol. It m a y b e m a n a g ed si mil ar a s c oliti s, i n cl u di n g c orti c o st er oi d a n d/ or i n ﬂi xi m a b, et c
2. 2 H e p atiti s
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y a vir al p at h ol o gi c pr o c e s s i n v ol vi n g t h e li v er p ar e n c h y m a
Di a g n o sti c w or k -u p
M o nit or p ati e nt f or a b n or m al li v er bl o o d t e st s: A S T, A L T, a n d bilir u bi n pri or t o e a c h i nf u si o n a n d/ or w e e kl y if G 1 
li v er f u n cti o n t e st el e v ati o n s. N o tr e at m e nt i s r e c o m m e n d e d f or G 1 li v er f u n cti o n t e st a b n or m alit y
F or G 2 or hi g h er:
W o r k-u p f or ot h er c a u s e s of el e v at e d li v er e n z y m e s s h o ul d b e t e st e d, vir al h e p a titi s, al c o h ol hi st or y, ir o n st u d y, 
t hr o m b o e m b oli c e v e nt, li v er ultr a s o u n d, cr o s s- s e cti o n al i m a gi n g f or p ot e nti al li v er m et a st a si s fr o m pri m ar y 
m ali g n a n c y. If s u s pi ci o n f or pri m ar y a ut oi m m u n e h e p atiti s i s hi g h, c a n c o n si d er A N A s, a nti -s m o ot h m u s cl e 
a nti b o d i e s, a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s. If p ati e nt s wit h el e v at e d al k ali n e p h o s p h at a s e al o n e, g-gl ut a m yl 
tr a n sf er a s e s h o ul d b e t e st e d. F or i s ol at e d el e v ati o n of tr a n s a mi n a s e s, c o n si d er c h e c ki n g C K f or ot h er eti ol o gi e s
Gr a di n g
M a n a g e m e nt
All p ati e nt s
C o u n s el all p ati e nt s t o b e a w ar e of a n d i nf or m t h eir 
h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e:
Y ell o wi n g of s ki n or w hit e s of t h e e y e s S e v er e n a u s e a 
or v o miti n g
P ai n o n t h e ri g ht si d e of t h e a b d o m e n Dr o w si n e s s
D ar k uri n e (t e a c ol or e d)
Bl e e di n g o r br ui si n g m or e e a sil y t h a n n or m al F e eli n g 
l e s s h u n gr y t h a n u s u al
G 1: A s y m pt o m ati c ( A S T or A L T > U L N t o 3. 0 × U L N 
a n d/ or t ot al bilir u bi n > U L N t o 1. 5 × U L N)
C o nti n u e I C Pi wit h cl o s e m o nit ori n g; c o n si d er alt er n at e 
eti ol o gi e s
M o nit or l a b or at ori e s 1 t o 2 ti m e s w e e kl y
M a n a g e wit h s u p p orti v e c ar e f or s y m pt o m c o ntr ol
G 2: A s y m pt o m ati c ( A S T or A L T > 3. 0 t o ≤5 × U L N 
a n d/ or t ot al bilir u bi n > 1. 5 t o ≤3 × U L N)
H ol d I C Pi t e m p or aril y a n d r e s u m e if r e c o v er t o G 1 or 
l e s s o n pr e d ni s o n e ≤1 0 m g/ d
F or Gr a d e 2 h e p ati c t o xi cit y wit h s y m pt o m s, m a y 
a d mi ni st er c orti c o st er oi d 0. 5 -1 m g/ k g/ d pr e d ni s o n e or 
e q ui v al e nt if t h e a b n or m al el e v ati o n p er si st s wit h 
si g ni ﬁc a nt cli ni c al s y m pt o m s i n 3 -5 d a y s I n cr e a s e 
fr e q u e n c y of m o nit ori n g t o e v er y 3 d a y s
I nﬂi xi m a b mi g ht n ot b e t h e m o st a p pr o pri at e tr e at m e nt 
o pti o n i n t h e sit u ati o n of i m m u n e- m e di at e d h e p atiti s 
gi v e n t h e p ot e nti al ri s k of i di o s y n cr ati c li v er f ail ur e 
( N ot e: N o cl e ar e vi d e n c e s h o w s t h e li v er t o xi cit y fr o m 
i nﬂi xi m a b fr o m ot h er st u di e s)
I n f oll o w- u p, m a y r e s u m e I C Pi tr e at m e nt f oll o w e d b y 
t a p er o nl y w h e n s y m pt o m s i m pr o v e t o G 1 or l e s s a n d 
c orti c o st er oi d ≤1 0 m g/ d; t a p er o v er at l e a st 1 m o nt h
P ati e nt s s h o ul d b e a d vi s e d t o st o p u n n e c e s s ar y 
m e di c ati o n s a n d a n y k n o w n h e p at ot o xi c dr u g s
G 3: S y m pt o m ati c li v er d y sf u n cti o n, ﬁbr o si s b y bi o p s y, 
c o m p e n s at e d cirr h o si s, r e a cti v ati o n of c hr o ni c h e p atiti s 
( A S T or A L T 5-2 0 × U L N a n d/ or t ot al bilir u bi n 3 -
1 0 × U L N)
P er m a n e ntl y di s c o nti n u e I C Pi
I m m e di at el y st art c orti c o st er oi d 1-2 m g/ k g 
m et h yl pr e d ni s ol o n e or e q ui v al e nt
If c orti c o st er oi d r efr a ct or y or n o i m pr o v e m e nt aft er 
3 d a y s, c o n si d er m y c o p h e n ol at e m of etil or a z at hi o pri n e 
(if u si n g a z at hi o pri n e s h o ul d t e st f or t hi o p uri n e 
m et h yltr a n sf er a s e d e ﬁci e n c y)
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 4 / 2 1 3
2. 0 GI T o xi citi e s
L a b or at ori e s at d ail y or e v er y ot h er d a y; c o n si d er 
i n p ati e nt m o nit ori n g f or p ati e nt s wit h A S T/ A L T 
> 8 × U L N a n d/ or el e v at e d t ot al bilir u bi n 3 × U L N
I n cr e a s e fr e q u e n c y of m o nit ori n g t o e v er y 1- 2 d a y s
I nﬂi xi m a b mi g ht n ot b e t h e m o st a p pr o pri at e tr e at m e nt 
o pti o n i n t h e sit u ati o n of i m m u n e- m e di at e d h e p atiti s 
gi v e n t h e p ot e nti a l ri s k of li v er f ail ur e ( N ot e: N o cl e ar 
e vi d e n c e s h o w s t h at t h e li v er t o xi cit y fr o m i n ﬂi xi m a b 
fr o m ot h er st u di e s); alt er n ati v e s i n cl u d e n o n– T N F - α
a g e nt s a s s y st e mi c i m m u n o s u p pr e s s a nt s If n o 
i m pr o v e m e nt i s a c hi e v e d wit h c orti c o st er oi d s or f or 
p ati e nt s o n c o m bi n ati o n t h er a p y wit h a n o v el a g e nt, 
wit h st a n d ar d c h e m ot h er a p y, or wit h t ar g et e d t h er a p y, 
r ef er t o h e p at ol o gi st f or f urt h er p at h ol o gi c e v al u ati o n of 
h e p atiti s
C orti c o st er oi d t a p er c a n b e att e m pt e d ar o u n d 
4- 6 w e e k s; r e -e s c al at e if n e e d e d; o pti m al d ur ati o n
u n cl e ar
G 4: D e c o m p e n s at e d li v er f u n cti o n ( e . g., a s cit e s, 
c o a g ul o p at h y, e n c e p h al o p at h y, c o m a; A S T or A L T > 2 0 
× U L N a n d/ or t ot al bilir u bi n > 1 0 × U L N)
P er m a n e ntl y di s c o nti n u e I C Pi
A d mi ni st er 2 m g/ k g/ d m et h yl pr e d ni s ol o n e e q ui v al e nt s
If c orti c o st er oi d r efr act or y or n o i m pr o v e m e nt aft er 
3 d a y s, c o n si d er m y c o p h e n ol at e m of etil
M o nit or l a b or at ori e s d ail y; c o n si d er i n p ati e nt m o nit ori n g
A v oi d t h e u s e of i n ﬂi xi m a b i n t h e sit u ati o n of 
i m m u n e-m e di at e d h e p atiti s
H e p at ol o g y c o n s ult if n o i m pr o v e m e nt w a s a c hi e v e d 
wit h c orti c o st er oi d
C orti c o st er oi d t a p er c a n b e att e m pt e d ar o u n d 
4- 6 w e e k s w h e n s y m pt o m s i m pr o v e t o G 1 or l e s s; 
r e-e s c al at e if n e e d e d; o pti m al d ur ati o n u n cl e ar
C o n si d er tr a n sf er t o t erti ar y c ar e f a cilit y if n e c e s s ar y
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s i s m o d er at e.
A D L = a cti viti e s of d ail y li vi n g, A L T = al a ni n e a mi n otr a n sf er a s e, A N A = a nti n u cl e ar a nti b o d y, A S T = a s p art at e 
a mi n otr a n sf er a s e, C B C = c o m pl et e bl o o d c o u nt, C K = cr e ati n e ki n a s e, C M V = c yt o m e g al o vir u s, C R P = C -r e a cti v e pr ot ei n, 
C T = c o m p ut e d t o m o gr a p h y, C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s, 
 
, E G D = e s o p h a g o g a str o d u o d e n o s c o p y, E S R = er yt hr o c yt e s e di m e nt ati o n r at e, 
G = gr a d e, GI = g a str oi nt e sti n al, HI V = h u m a n i m m u n o d efi ci e n c y vir u s, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, 
 I V =i ntr a v e n o u s, 
 
 
T B =t u b er c ul o si s, T N F =t u m or n e cr o si s f a ct or, T S H =t h yr oi d -sti m ul ati n g h or m o n e, U L N = u p p er li mit of n or m al.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 5 / 2 1 3
T a ble A 3
M a n a ge me nt 
of L u n g I m m u ne-rel ate d A d verse E ve nts i n P atie nts 
Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
3. 0 L u n g T o xi citi e s
3. 1 P n e u m o niti s
D e ﬁniti o n: F o c al or diff u s e i nﬂa m m ati o n of t h e l u n g p ar e n c h y m a (t y pi c all y i d e nti ﬁe d o n C T i m a gi n g)
N o s y m pt o m ati c, p at h ol o gi c, or r a di o gr a p hi c f e at ur e s ar e p at h o g n o m o ni c f or p n e u m o niti s
Di a g n o sti c w or k -u p
S h o ul d i n cl u d e t h e f oll o wi n g: C X R, C T, p ul s e o xi m etr y
F or G 2 or hi g h er, m a y i n cl u d e t h e f oll o wi n g i nf e cti o u s w or k- u p: n a s al s w a b, s p ut u m c ult ur e a n d s e n siti vit y, bl o o d 
c ult ur e a n d s e n siti vit y, a n d uri n e c ult ur e a n d s e n siti vit y
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c, c o n ﬁn e d t o 1 l o b e of t h e l u n g or 
< 2 5 % of l u n g p ar e n c h y m a, cli ni c a l or di a g n o sti c 
o b s er v ati o n s o nl y
C o nti n u e I C Pi 
If cli ni c all y i n di c at e d,
mo nit or p arti ci p a nt s w e e kl y  
or m or e fr e q u e ntl y  a s n e e d e d wit h hi st or y , p hy s i c al 
e x a mi n ati o n , a n d p ul s e o xi m etr y . M a y al s o off er 
C X R . M a y off er 1 r e p e at C T s c a n i n 3-4 w e e k s; i n 
p ati e nt s w h o h a v e h a d b a s eli n e t e sti n g, m a y off er a 
r e p e at s pir o m etr y/ D L C O i n 3-4 w e e k s
If s y m pt o m s
a p p e ar a n d/ or c h a n g e s i n t h e p h y si c al
e x a m ar e n ot e d, tr e at a s G 2
G 2: S y m pt o m ati c, i n v ol v e s m or e t h a n 1 l o b e of t h e l u n g 
or 2 5 % - 5 0 % of l u n g p ar e n c h y m a, m e di c al i nt er v e nti o n 
i n di c at e d, li miti n g i n str u m e nt al A D L
H ol d I C Pi u ntil r e s ol uti o n t o G 1 or l e s s
Pr e d ni s o n e 1 - 2 m g/ k g/ d a n d t a p er b y 5-1 0 m g/ w k o v er 
4- 6 w e e k s C o n si d er br o n c h o s c o p y wit h B A L
C o n si d er e m piri c al a nti bi oti c s
M o nit or e v er y 3 d a y s wit h hi st or y a n d p h y si c al 
e x a mi n ati o n a n d p ul s e o xi m etr y, c o n si d er C X R; n o 
cli ni c al i m pr o v e m e nt aft er 4 8 - 7 2 h o ur s of pr e d ni s o n e, 
tr e at a s G 3
G 3: S e v er e s y m pt o m s, h o s pit ali z ati o n r e q uir e d, 
i n v ol v e s all l u n g l o b e s, or 5 0 % of l u n g p ar e n c h y m a, 
li miti n g s elf-c ar e
A D L, o x y g e n i n di c at e d
G 4: Lif e -t hr e at e ni n g r e s pir at or y c o m pr o mi s e, ur g e nt 
i nt er v e nti o n i n di c at e d (i nt u b ati o n)
P er m a n e ntl y di s c o nti n u e I C Pi
E m piri c al a nti bi oti c s; ( m et h yl) pr e d ni s ol o n e I V 
1- 2
m g/ k g/ d; n o i m pr o v e m e nt aft er 4 8 h o ur s, m a y a d d 
i nﬂi xi m a b 5 m g/ k g or m y c o p h e n ol at e m of etil I V 1 g 
t wi c e a d a y or I VI G f or 5 d a y s or c y cl o p h o s p h a mi d e; 
t a p er c orti c o st er oi d s o v er 4- 6 w e e k s
P ul m o n ar y a n d i nf e cti o u s di s e a s e c o n s ult s if n e c e s s ar y
Br o n c h o s c o p y wit h B A L ± tr a n s br o n c hi al bi o p s y
P ati e nt s s h o ul d b e h o s pit ali z e d f or f urt h er m a n a g e m e nt
A d diti o n al c o n si d er ati o n s
GI a n d P n e u m o c y sti s pr o p h yl a xi s wit h P PI a n d B a ctri m m a y b e off er e d t o p ati e nt s o n pr ol o n g e d c orti c o st er oi d u s e 
( > 1 2 w e e k s), a c c or di n g t o i n stit uti o n al g ui d eli n e s
C o n si d er c al ci u m a n d vit a mi n D s u p pl e m e nt ati o n wit h pr o l o n g e d c orti c o st er oi d u s e
T h e r ol e of pr o p h yl a cti c ﬂu c o n a z ol e wit h pr ol o n g e d c orti c o st er oi d u s e ( > 1 2 w e e k s) r e m ai n s u n cl e ar, a n d 
p h y si ci a n s s h o ul d pr o c e e d a c c or di n g t o i n stit uti o n al g ui d eli n e s
Br o n c h o s c o p y + bi o p s y; if cli ni c al pi ct ur e i s c o n si st e nt wit h p n e u m o niti s, n o n e e d f or bi o p s y
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A D L = a cti viti e s of d ail y li vi n g, B A L = br o n c h o al v e ol ar l a v a g e, C T = c o m p ut e d t o m o gr a p h y, C X R = c h e st x-r a y, 
D L C O = diff u si n g c a p a cit y of l u n g f or c ar b o n m o n o xi d e, G = gr a d e, GI = g a str oi nt e sti n al, 
 
 I V =i ntr a v e n o u s, 
 P PI = pr ot o n p u m p 
i n hi bit or.
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 6 / 2 1 3
T a ble A 4
M a n a ge me nt of E n d ocri ne I m m u ne-rel ate d A d verse E ve nts i n P atie nts 
Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
4. 0 E n d o cri n e T o xi cit y
C o u n s el p ati e nt s t o i nf or m t h eir h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e a n y c h a n g e s i n t h eir h e a lt h 
si n c e t h eir l a st vi sit, e s p e ci all y a n y of t h e f oll o wi n g:
H e a d a c h e s t h at will n ot g o a w a y or u n u s u al h e a d a c h e 
p att er n s
Vi si o n c h a n g e s
R a pi d h e art b e at
I n cr e a s e d s w e ati n g
E x tr e m e tir e d n e s s or w e a k n e s s
M u s cl e a c h e s
W e i g ht g ai n or w ei g ht l o s s
Di z zi n e s s or f ai nti n g
F e eli n g m or e h u n gr y or t hir st y t h a n u s u al
H air l o s s
C h a n g e s i n m o o d or b e h a vi or, s u c h a s d e cr e a s e d s e x 
dri v e, irrit a bilit y, or f or g etf ul n e s s 
F e eli n g c ol d
C o n sti p ati o n
V oi c e g et s d e e p er
Uri n ati n g m or e oft e n t h a n u s u al
N a u s e a or v o miti n g
A b d o mi n al p ai n
4. 1 T h y r oi d
4. 1. 1 Pri m ar y  Hy p ot h yr oi di s m
D e ﬁniti o n: El e v at e d T S H, n or m al or l o w F T 4
Di a g n o sti c w or k -u p
T S H a n d F T 4 e v er y 4 -6 w e e k s a s p art of r o uti n e cli ni c al m o nit ori n g o n t h er a p y or f or c a s e d et e cti o n i n 
s y m pt o m ati c p ati e nt s
Gr a di n g
M a n a g e m e nt
G 1: T S H < 1 0 mI U/ L a n d a s y m pt o m ati c
G 2: M o d er at e s y m pt o m s; a bl e t o p erf or m A D L; T S H 
p er si st e ntl y > 1 0 mI U/ L
S h o ul d c o nti n u e I C Pi wit h cl o s e f oll o w -u p a n d 
m o nit ori n g of T S H, F T 4 M a y h ol d I C Pi u ntil s y m pt o m s 
r e s ol v e t o b a s eli n e
C o n si d er e n d o cri n e c o n s ult ati o n
Pr e s cri b e t h yr oi d h or m o n e s u p pl e m e nt ati o n i n 
s y m pt o m ati c p ati e nt s wit h a n y d e gr e e of T S H el e v ati o n 
or i n a s y m pt o m ati c p ati e nt s wit h T S H l e v el s t h at p er si st 
> 1 0 mI U/ L ( m e a s ur e d 4 w e e k s a p art)
M o nit or T S H e v er y 6 -8 w e e k s w hil e titr ati n g h or m o n e 
r e pl a c e m ent t o n or m al T S H. F T 4 c a n b e u s e d i n t h e 
s h ort -t er m ( 2 w e e k s) t o e n s ur e a d e q u a c y of t h er a p y i n 
t h o s e wit h fr a n k h y p ot h yr oi di s m w h er e t h e F T 4 w a s 
i niti all y l o w
O n c e a d e q u at el y tr e at e d, s h o ul d m o nit or t h yr oi d 
f u n cti o n ( at l e a st T S H) e v er y 6 w e e k s w hil e o n a cti v e 
I C Pi t h er a p y or a s n e e d e d f or s y m pt o m s t o e n s ur e 
a p pr o pri at e r e pl a c e m e nt; r e p e at t e sti n g a n n u all y or a s 
i n di c at e d b y s y m pt o m s o n c e st a bl e
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 7 / 2 1 3
4. 0 E n d o cri n e T o xi cit y
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u n til s y m pt o m s r e s ol v e t o b a s eli n e wit h 
a p pr o pri at e s u p pl e m e nt ati o n
E n d o cri n e c o n s ult ati o n
M a y a d mit f or I V t h er a p y if si g n s of m y x e d e m a 
( br a d y c ar di a, h y p ot h er mi a); t h yr oi d s u p pl e m e nt ati o n 
a n d r e a s s e s s m e nt a s i n G 2
A d diti o n al c o n si d er ati o n s
F or p ati e nt s wit h o ut ri s k f a ct or s, f ull r e pl a c e m e nt c a n b e e sti m at e d wit h a n i d e al b o d y - w ei g ht-b a s e d d o s e of 
a p pr o xi m at el y 1. 6 µ g/ k g/ d
F or el d erl y or fr a gil e p ati e nt s wit h m ulti pl e c o m or bi diti e s, c o n si d er titr ati n g u p fr o m l o w -d o s e, st arti n g at 2 5 -5 0 m g
E x tr e m e el e v ati o n s of T S H c a n b e s e e n i n t h e r e c o v er y p h a s e of t h yr oi diti s a n d c a n b e w at c h e d i n a s y m pt o m ati c 
p ati e nt s t o d et er mi n e w h et h er t h er e i s r e c o v er y t o n or m al wit hi n 3 -4 w e e k s
U n d er g ui d a n c e of e n d o cri n ol o g y, c o n si d er t a p eri n g h or m o n e r e pl a c e m e nt a n d r et e sti n g i n p ati e nt s wit h a hi st or y 
of t h yr oi diti s (i niti al t h yr ot o xi c p h a s e)
A dr e n al d y sf u n cti o n, if pr e s e nt, m u st al w a y s b e r e pl a c e d b ef or e t h yr oi d h or m o n e t h er a p y i s i niti at e d 
4. 1. 2 H y p ert h yr oi di s m
D e ﬁniti o n: S u p pr e s s e d T S H a n d hi g h n or m al or el e v at e d F T 4 a n d/ or trii o d ot h yr o ni n e
Di a g n o sti c w or k -u p
M o nit or T S H, F T 4 e v er y 4 -6 w e e k s fr o m t h e st art of t h er a p y or a s n e e d e d f or c a s e d et e cti o n i n s y m pt o m ati c 
p ati e nt s
C o n si d er T S H r e c e pt or a nti b o di e s if t h er e ar e cli ni c al f e at ur e s a n d s u s pi ci o n of Gr a v e s’ di s e a s e ( e . g., 
o p ht h al m o p at h y)
Cl o s e m o nit ori n g of t h yr oi d f u n cti o n e v er y 2- 3 w e e k s aft er di a g n o si s t o c at c h tr a n siti o n t o h y p ot h yr oi di s m i n 
p ati e nt s wit h t h yr oi diti s a n d h y p ert h yr oi di s m
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C a n c o nti n u e I C Pi wit h cl o s e f oll o w -u p a n d m o nit ori n g 
of T S H, F T 4 e v er y 2 -3 w e e k s u ntil it i s cl e ar w h et h er 
t h er e will b e p er si st e nt h y p ert h yr oi di s m ( s e e b el o w) or 
h y p ot h yr oi di s m ( s e e 4. 1. 1)
C o n si d er h ol di n g I C Pi u ntil s y m pt o m s r et ur n t o b a s eli n e
C o n si d er e n d o cri n e c o n s ult ati o n
β- Bl o c k er ( e . g., at e n ol ol, pr o pr a n ol ol) f or s y m pt o m ati c 
r eli ef
H y dr ati o n a n d s u p p orti v e c ar e
C orti c o st er oi d s ar e n ot u s u all y r e q uir e d t o s h ort e n 
d ur ati o n
F or p er si st e nt h y p ert h yr oi di s m ( > 6 w e e k s) or cli ni c al 
s u s pi ci o n, w or k -u p f or Gr a v e’ s di s e a s e ( T SI or T R A b) 
a n d c o n si d er t hi o n a mi d e ( m et hi m a z ol e or P T U). R ef er 
t o e n d o cri n ol o g y f or Gr a v e’ s di s e a s e
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil s y m pt o m s r e s ol v e t o b a s eli n e wit h 
a p pr o pri at e t h er a p y
E n d o cri n e c o n s ult ati o n
β- Bl o c k er ( e . g., at e n ol ol, pr o pr a n ol ol) f or s y m pt o m ati c 
r eli ef
F or s e v er e s y m pt o m s or c o n c er n f or t h yr oi d st or m, 
h o s pit ali z e p ati e nt a n d i niti at e pr e d ni s o n e 1 - 2 m g/ k g/ d 
or e q ui v al e nt t a p er e d o v er 1 -2 w e e k s; c o n si d er al s o 
u s e of S S KI or t hi o n a mi d e ( m et hi m a z ol e or P T U)
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 8 / 2 1 3
4. 0 E n d o cri n e T o xi cit y
A d diti o n al c o n si d er ati o n s
T h yr oi diti s i s tr a n si e nt a n d r e s ol v e s i n a c o u pl e of w e e k s t o pri m ar y h y p ot h yr oi di s m or n or m al. H y p ot h yr oi di s m c a n 
b e tr e at e d a s a b o v e. Gr a v e’ s di s e a s e i s g e n er all y p er si st e nt a n d i s d u e t o i n cr e a s e d t h yr oi d h or m o n e pr o d u cti o n 
t h at c a n b e tr e at e d wit h a ntit h yr oi d m e di c al t h er a p y. P h y si c al e x a mi n ati o n ﬁn di n g s of o p ht h al m o p at h y or t h yr oi d 
br uit ar e di a g n o sti c of Gr a v e s’ di s e a s e a n d s h o ul d pr o m pt e arl y e n d o cri n e r ef err al
4. 2 A dr e n al – Pri m ar y  Adr e n al I n s uf ﬁci e n c y
D e ﬁniti o n: A dr e n al gl a n d f ail ur e l e a di n g t o l o w m or ni n g c orti s ol, hi g h m or ni n g A C T H, a s w ell a s h y p o n atr e mi a a n d 
h y p er k al e mi a wit h ort h o st a si s a n d v ol u m e d e pl eti o n d u e t o l o s s of al d o st er o n e
Di a g n o sti c w or k -u p f or p ati e nt s i n w h o m a dr e n al 
i n s ufﬁci e n c y i s s u s p e ct e d:
E v al u at e A C T H ( A M), c orti s ol l e v el ( A M)
B a si c m et a b oli c p a n el ( N a, K, C O 2 , gl u c o s e)
C o n si d er A C T H sti m ul ati o n t e st f or i n d et er mi n at e 
r e s ult s
If pri m ar y a dr e n al i n s ufﬁci e n c y ( hi g h A C T H, l o w 
c orti s ol) i s f o u n d bi o c h e mi c all y:
E v al u at e f or pr e ci pit ati n g c a u s e of cri si s s u c h a s 
i nf e cti o n 
P erf or m a n a dr e n al C T f or m et a st a si s/ h e m orr h a g e
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e
E n d o cri n e c o n s ult ati o n
R e pl a c e m e nt t h er a p y wit h pr e d ni s o n e ( 5- 1 0 m g d ail y) 
or h y dr o c orti s o n e ( 1 0 -2 0 m g or all y e v er y m or ni n g, 5 -1 0 
m g or all y i n e arl y aft er n o o n)
M a y r e q uir e ﬂu dr o c orti s o n e ( 0. 1 m g/ d) f or 
mi n er al o c orti c oi d r e pl a c e m e nt i n pri m ar y a dr e n al 
i n s ufﬁci e n c y
Ti tr at e d o s e u p or d o w n a s s y m pt o m s di ct at e
G 2: M o d er at e s y m pt o m s, a bl e t o p erf or m A D L
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e
E n d o cri n e c o n s ult ati o n
I niti at e o ut p ati e nt tr e at m e nt at 2 t o 3 ti m e s m ai nt e n a n c e 
(if pr e d ni s o n e, 2 0 m g d ail y; if h y dr o c orti s o n e, 2 0 -3 0 m g 
i n t h e m or ni n g, a n d 1 0-2 0 m g i n t h e aft er n o o n) t o 
m a n a g e a c ut e s y m pt o m s
T a p er str e s s - d o s e c orti c o st er oi d s d o w n t o m ai nt e n a n c e 
d o s e s o v er 5 -1 0 d a y s
M ai nt e n a n c e t h er a p y a s i n G 1
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil p ati e nt i s st a bili z e d o n r e pl a c e m e nt 
h or m o n e
E n d o cri n e c o n s ult ati o n
S e e i n cli ni c or, f or aft er h o ur s, m a k e a n e m er g e n c y 
d e p art m e nt r ef err al f or n or m al s ali n e ( at l e a st 2 L) a n d 
I V str e s s-d o s e c orti c o st er oi d s o n pr e s e nt ati o n 
h y dr o c orti s o n e 1 0 0 m g or d e x a m et h a s o n e 4 m g (if t h e 
di a g n o si s i s n ot cl e ar a n d sti m ul ati o n t e sti n g will b e 
n e e d e d)
T a p er str e s s - d o s e c orti c o st er oi d s d o w n t o m ai nt e n a n c e 
d o s e s o v er 7 -1 4 d a y s aft er di s c h ar g e
M ai nt e n a n c e t h er a p y a s i n G 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 5 9 / 2 1 3
4. 0 E n d o cri n e T o xi cit y
A d diti o n al c o n si d er ati o n s
Pri m ar y a n d s e c o n d ar y a dr e n al i n s uf ﬁci e n c y c a n b e di sti n g ui s h e d b y t h e r el ati o n s hi p b et w e e n A C T H a n d c orti s ol. 
If t h e A C T H i s l o w wit h l o w c orti s ol, t h e n m a n a g e m e nt i s a s p er 4. 3
P ati e nt s o n c orti c o st er oi d s f or m a n a g e m e nt of ot h er c o n diti o n s will h a v e l o w m or ni n g c orti s ol a s a r e s ult of 
i atr o g e ni c, s e c o n d ar y a dr e n al i n s ufﬁci e n c y. A C T H will al s o b e l o w i n t h e s e p ati e nt s. A di a g n o si s of a dr e n al 
i n s ufﬁci e n c y i s c h all e n gi n g t o m a k e i n t h e s e sit u ati o n s ( s e e n e xt s e cti o n o n h y p o p h y siti s)
E m er g e nt t h er a p y f or s o m e o n e wit h s u s p e ct e d a dr e n al i n s uf ﬁci e n c y i s b e st d o n e wit h d e x a m et h a s o n e a s a 
sti m ul ati o n t e st c a n still b e p erf or m e d. If t h e di a g n o si s i s alr e a d y c o n ﬁr m e d, c a n u s e h y dr o c orti s o n e 1 0 0 m g.
All p ati e nt s n e e d e d u c ati o n o n str e s s d o si n g a n d a m e di c al al ert br a c el et f or a dr e n al i n s uf ﬁci e n c y t o tri g g er str e s s -
d o s e c orti c o st er oi d s b y E M S
E n d o cri n e c o n s ult ati o n pri or t o s ur g er y or a n y pr o c e d ur e f or str e s s -d o s e pl a n ni n g
4. 3 Pit uit ar y  - H y p o p h y siti s
D e ﬁniti o n: I n ﬂa m m ati o n of t h e pit uit ar y wit h v ar yi n g eff e ct s o n h or m o n e f u n cti o n. M o st c o m m o nl y pr e s e nti n g wit h 
c e ntr al a dr e n al i n s uf ﬁci e n c y. M a y al s o h a v e c e ntr al h y p ot h yr oi di s m, di a b et e s i n si pi d u s, a n d h y p o g o n a di s m
Di a g n o sti c w or k -u p
Di a g n o si s: L o w A C T H wi t h a l o w c orti s ol. L o w or n or m al T S H wit h a l o w F T 4. H y p er n atr e mi a a n d v ol u m e d e pl eti o n 
wit h di a b et e s i n si pi d u s. L o w t e st o st er o n e or e str a di ol wit h l o w L H a n d F S H
T e sti n g: 
E v al u at e A C T H, c orti s ol ( A M), T S H, F T 4, el e ctr ol yt e s
C o n si d er e v al u ati n g L H, F S H, a n d t e st o st er o n e l e v el s i n m al e s or e str o g e n i n pr e m e n o p a u s al f e m al e s wit h f ati g u e, 
l o s s of li bi d o, a n d m o o d c h a n g e s. C o n si d er M RI of t h e br ai n wit h or wit h o ut c o ntr a st wit h pit uit ar y/ s ell ar c ut s i n 
p ati e nt s wit h m ulti pl e e n d o cri n e a b n or m aliti e s ± n e w s e v er e h e a d a c h e s, or c o m pl ai nt s of vi si o n c h a n g e s
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e s
E n d o cri n e c o n s ult ati o n
H or m o n al s u p pl e m e nt ati o n a s i n G 1
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or 
lif e-t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil p ati e nt i s st a bili z e d o n r e pl a c e m e nt 
h or m o n e s
E n d o cri n e c o n s ult ati o n
H or m o n al s u p pl e m e nt ati o n a s i n G 1
C o n si d er i niti al p ul s e d o s e t h er a p y wit h pr e d ni s o n e 1 -2 
m g/ k g or al d ail y ( or e q ui v al e nt) t a p er e d o v er at l e a st 1 -
2 w e e k s
A d diti o n al c o n si d er ati o n s
B e a w ar e of t h e n e e d t o st art c orti c o st er oi d s ﬁr st w h e n pl a n ni n g h or m o n e r e pl a c e m e nt t h er a p y f or m ulti pl e 
d e ﬁci e n ci e s
All p ati e nt s n e e d i n str u cti o n o n d o u bli n g d o s e s f o r ill n e s s ( str e s s d o si n g) a n d a m e di c al al ert br a c el et f or a dr e n al 
i n s ufﬁci e n c y t o tri g g er str e s s -d o s e c orti c o st er oi d s b y E M S
C orti c o st er oi d u s e c a n c a u s e i s ol at e d c e ntr al a dr e n al i n s uf ﬁci e n c y
W o r k-u p c a n n ot b e d o n e wit h a si m pl e A M c orti s ol i n a p ati e nt o n c orti c o st er oi d s f or ot h er c o n diti o n s
L a b or at or y c o n ﬁr m ati o n of a dr e n al i n s uf ﬁci e n c y s h o ul d n ot b e att e m pt e d u ntil tr e at m e nt wit h c orti c o st er oi d s f or 
ot h er di s e a s e i s r e a d y t o b e di s c o nti n u e d. F or l o n g -t er m e x p o s ur e, c o n s ult e n d o cri n ol o g y f or r e c o v er y a n d
w e a ni n g pr ot o c ol u si n g h y dr o c orti s o n e
4. 4 Di a b et e s
D e ﬁniti o n: T 2 D M i s a c o m bi n ati o n of i n s uli n r e si st a n c e a n d i n s uf ﬁci e n c y t h at m a y r e q uir e or al or i n s uli n t h er a p y. It 
m a y b e n e w -o n s et or e x a c er b at e d d uri n g t h er a p y f or n o ni m m u n ol o gi c r e a s o n s, s u c h a s c orti c o st er oi d e x p o s ur e
A ut oi m m u n e T 1 D M r e s ult s fr o m i sl et c ell d e str u cti o n a n d i s oft e n a c ut e o n s et, wit h k et o si s a n d a n i n s uli n 
r e q uir e m e nt
Di a g n o sti c w or k -u p
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 0 / 2 1 3
4. 0 E n d o cri n e T o xi cit y
M o nit or p ati e nt s f or h y p er gl y c e mi a or ot h er si g n s a n d s y m pt o m s of n e w or w or s e ni n g D M, i n cl u di n g m e a s uri n g 
gl u c o s e at b a s eli n e a n d wit h e a c h tr e at m e nt c y cl e d uri n g i n d u cti o n f or 1 2 w e e k s, t h e n e v er y 3 - 6 w e e k s t h er e aft er. 
T o g ui d e t h e w or k -u p i n n e w -o n s et h y p er gl y c e mi a, cli ni ci a n s s h o ul d c o n si d er a p ati e nt’ s m e di c al b a c k gr o u n d, 
e x p o s ur e hi st o r y, a n d ri s k f a ct or s f or e a c h s u bt y p e of D M
L a b or at or y e v al u ati o n i n s u s p e ct e d T 1 D M s h o ul d i n cl u d e t e sti n g f or k et o si s i n uri n e a n d a n a s s e s s m e nt of t h e 
a ni o n g a p o n a m et a b oli c p a n el. A nti gl ut a mi c a ci d d e c ar b o x yl a s e, a nti -i sl et c ell, or a nti-i n s uli n a nti bo di e s ar e hi g hl y 
s p e ci ﬁc f or a ut oi m m u n e di a b et e s. I n s uli n a n d C -p e pti d e l e v el s c a n al s o a s si st i n t h e di a g n o si s
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s; f a sti n g gl u c o s e 
v al u e > U L N ( 1 6 0 m g/ d L); f a sti n g gl u c o s e v al u e > U L N 
( 8. 9 m m ol/ L); n o e vi d e n c e of k et o si s or l a b or at or y 
e vi d e n c e of T 1 D M
C a n c o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -u p a n d 
l a b or at or y e v al u ati o n
M a y i niti at e or al t h er a p y f or t h o s e wit h n e w -o n s et T 2 D M
S cr e e n f or T 1 D M if a p pr o pri at e, f or e x a m pl e, a c ut e 
o n s et wit h pri or n or m al v al u e s or cli ni c al c o n c er n f or 
k et o si s
G 2: M o d er at e s y m pt o m s, a bl e t o p erf or m A D L, f a sti n g 
gl u c o s e v al u e > 1 6 0 -2 5 0 m g/ d L; f a sti n g gl u c o s e v al u e 
> 8. 9 -1 3. 9 m m ol/ L, k et o si s or e vi d e n c e of T 1 D M at a n y 
gl u c o s e l e v el
M a y h ol d I C Pi u ntil gl u c o s e c o ntr ol i s o bt ai n e d
Titr at e or al t h er a p y or a d d i n s uli n f or w or s e ni n g c o ntr ol 
i n T 2 D M. S h o ul d a d mi ni st er i n s uli n f or T 1 D M ( or a s 
d ef a ult t h er a p y if t h er e i s c o nf u si o n a b o ut t y p e)
Ur g e nt e n d o cri n e c o n s ult ati o n f or a n y p ati e nt wit h 
T 1 D M; i n t h e a b s e n c e of e n d o cri n ol o g y , i nt er n al 
m e di ci n e m a y s uf ﬁc e
C o n si d er a d mi s si o n f or T 1 D M if e arl y o ut p ati e nt 
e v al u ati o n i s n ot a v ail a bl e or si g n s of k et o a ci d o si s ar e 
pr e s e nt
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or 
lif e-t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
G 3: > 2 5 0 - 50 0 m g/ d L ( > 1 3. 9 -2 7. 8 m m ol/ L)
G 4: > 5 0 0 m g/ d L ( > 2 7. 8 m m ol/ L)
H ol d I C Pi u ntil gl u c o s e c o ntr ol i s o bt ai n e d o n t h er a p y 
wit h r e d u cti o n of t o xi cit y t o G 1 or l e s s
Ur g e nt e n d o cri n e c o n s ult ati o n f or all p ati e nt s
I niti at e i n s uli n t h er a p y f or all p ati e nt s
A d mit f or i n p ati e nt m a n a g e m e nt: C o n c er n s f or 
d e v el o pi n g D K A, s y m pt o m ati c p ati e nt s r e g ar dl e s s of 
di a b et e s t y p e, n e w -o n s et T 1 D M u n a bl e t o s e e 
e n d o cri n ol o g y
A d diti o n al c o n si d er ati o n s
I n s uli n t h er a p y c a n b e u s e d a s t h e d ef a ult i n a n y c a s e wit h h y p er gl y c e mi a
L o n g -a cti n g t h er a p y al o n e i s n ot u s u all y s uf ﬁci e nt f or T 1 D M, w h er e h alf of d ail y r e q uir e m e nt s ar e u s u all y gi v e n i n 
di vi d e d d o s e s a s pr a n di al c o v er a g e a n d h alf a s l o n g -a cti n g
I n s uli n d o s e s will b e l o w er i n T 1 D M b e c a u s e of pr e s er v e d s e n siti vit y (t ot al d ail y r e q uir e m e nt c a n b e e sti m at e d at 
0. 3 - 0. 4 u nit s/ k g/ d)
I n T 2 D M, sli di n g-s c al e c o v er a g e wit h m e al s o v er a f e w d a y s pr o vi d e s d at a t o e sti m at e a p ati e nt’ s d ail y 
r e q uir e m e nt s a n d c a n b e u s e d t o m or e r a pi dl y titr at e b a s al n e e d s
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A C T H = a dr e n o c orti c otr o pi c h or m o n e, A D L = a cti viti e s of d ail y li vi n g, C T = c o m p ut e d t o m o gr a p h y, 
 
 D M = di a b et e s m ellit u s, E M S = e m er g e n c y m e di c al s er vi c e s, F S H =f olli cl e -sti m ul ati n g h or m o n e, F T 4 =fr e e 
t h yr o xi n e, G = gr a d e, 
 L H =l ut ei ni zi n g h or m o n e, 
M RI = m a g n eti c r e s o n a n c e i m a gi n g, P T U = pr o p ylt hi o ur a cil, S S KI = p ot a s si u m i o di d e, T 1 D M =t y p e 1 di a b et e s m e llit u s, 
T 2 D M =t y p e 2 di a b et e s m ellit u s, T R A b =t h yr oi d -sti m ul ati n g h or m o n e r e c e pt or a nti b o d y, T S H =t h yr oi d -sti m ul ati n g 
h or m o n e, T SI =t h yr oi d -sti m ul ati n g i m m u n o gl o b uli n, U L N = u p p er li mit of n or m al.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 1 / 2 1 3
T a ble A 5
M a n a ge me nt 
of M usc ul os kelet al
I m m u ne-rel ate d A d verse E ve nts i n 
P atie nts Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
5. 0 M u s c ul o s k el et al T o xi citi e s
5. 1 I n ﬂa m m at or y  Art hriti s
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y i n ﬂa m m ati o n of t h e j oi nt s
Cli ni c al s y m pt o m s: J oi nt p ai n a c c o m p a ni e d b y j o i nt s w elli n g; i nﬂa m m at or y s y m pt o m s, s u c h a s stiff n e s s aft er 
i n a cti vit y or i n t h e m or ni n g, l a sti n g > 3 0 mi n ut e s t o 1 h o ur; i m pr o v e m e nt of s y m pt o m s wit h N S AI D s or 
c orti c o st er oi d s b ut n ot wit h o pi oi d s or ot h er p ai n m e di c ati o n s m a y al s o b e s u g g e sti v e of i n ﬂa m m at or y art hriti s
Di a g n o sti c w or k -u p
G 1
C o m pl et e r h e u m at ol o gi c hi st or y a n d e x a mi n ati o n of all p eri p h er al j oi nt s f or t e n d er n e s s, s w elli n g, a n d r a n g e of 
m oti o n; e x a mi n ati o n of t h e s pi n e. C o n si d er pl ai n x- r a y/i m a gi n g t o e x cl u d e m et a st a s e s a n d e v al u at e j oi nt d am a g e 
( er o si o n s), if a p pr o pri at e
C o n si d er a ut oi m m u n e bl o o d p a n el i n cl u di n g A N A, R F, a n d a nti -C C P, a n d a nti -i nﬂa m m at or y m ar k er s ( E S R a n d 
C R P) if s y m pt o m s p er si st; if s y m pt o m s ar e s u g g e sti v e of r e a cti v e art hriti s or aff e ct t h e s pi n e, c o n si d er H L A B 2 7 
t e sti n g
G 2
C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; l a b or at or y t e st s a s a b o v e
C o n si d er U S ±
M RI of aff e ct e d j oi nt s if cli ni c all y i n di c at e d ( e. g. , p er si st e nt art hriti s u nr e s p o n si v e t o tr e at m e nt, 
s u s pi ci o n f or diff er e nti al di a g n o s e s s u c h a s m et a st ati c l e si o n s or s e pti c art hriti s)
C o n si d er e arl y r ef err al t o a r h e u m at ol o gi st, if t h er e i s j oi nt s w elli n g ( s y n o viti s) or if s y m pt o m s of art hr al gi a p er si st 
> 4 w e e k s
G 3 - 4
A s f or G 2
S e e k r h e u m at ol o gi st a d vi c e a n d r e vi e w
M o nit ori n g: P ati e nt s wit h i n ﬂa m m at or y art hriti s s h o ul d b e m o nit or e d wit h s eri al r h e u m at ol o gi c e x a mi n ati o n s, 
i n cl u di n g i nﬂa m m at or y m ar k er s, e v er y 4 - 6 w e e k s aft er tr e at m e nt i s i n stit ut e d
Gr a di n g
M a n a g e m e nt
All Gr a d e s
Cli ni ci a n s s h o ul d f oll o w r e p ort s of n e w j oi nt p ai n t o 
d et er mi n e w h et h er i n ﬂa m m at or y art hriti s i s pr e s e nt; 
q u e sti o n w h et h er s y m pt o m n e w si n c e r e c ei vi n g I C Pi
G 1: Mil d p ai n wit h i n ﬂa m m ati o n, er yt h e m a, or j oi nt 
s w elli n g
C o nti n u e I C Pi
I niti at e a n al g e si a wit h a c et a mi n o p h e n a n d/ or N S AI D s
G 2: M o d er at e p ai n a s s o ci at e d wit h si g n s of 
i nﬂa m m ati o n, er yt h e m a, or j oi nt s w elli n g, li miti n g 
i n str u m e nt al A D L
H ol d I C Pi a n d r e s u m e u p o n s y m pt o m c o ntr ol a n d o n 
pr e d ni s o n e ≤1 0 m g/ d 
E s c al at e a n al g e si a a n d c o n si d er hi g h er d o s e s of 
N S AI D s a s n e e d e d
If i n a d e q u at el y c o ntr oll e d, i niti at e pr e d ni s o n e or 
pr e d ni s ol o n e 1 0 -2 0 m g/ d or e q ui v al e nt f or 4 -6 w e e k s
If i m pr o v e m e nt, sl o w t a p er a c c or di n g t o r e s p o n s e 
d uri n g t h e n e xt 4- 6 w e e k s; if n o i m pr o v e m e nt aft er i niti al 
4- 6 w e e k s, tr e at a s G 3
If u n a bl e t o l o w er c orti c o st er oi d d o s e t o < 1 0 m g/ d aft er 
3 m o nt h s, c o n si d er D M A R D
C o n si d er i ntr a -arti c ul ar c orti c o st er oi d i nj e cti o n s f or l ar g e 
j oi nt s
R ef err al t o r h e u m at ol o g y
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 2 / 2 1 3
5. 0 M u s c ul o s k el et al T o xi citi e s
G 3 -4: S e v er e p ai n a s s o ci at e d wit h si g n s of 
i nﬂa m m ati o n, er yt h e m a, or j oi nt s w elli n g; irr e v er si bl e 
j oi nt d a m a g e; di s a bli n g; li miti n g s elf-c ar e A D L
F or G 3: H ol d I C Pi t e m p or aril y a n d m a y r e s u m e i n 
c o n s ult ati o n wit h r h e u m at ol o g y, if r e c o v er t o G 1 or l e s s
F or G 4: p er m a n e ntl y  di s c o nti n u e I C Pi
I niti at e or al pr e d ni s o n e 0. 5-1 m g/ k g
If f ail ur e of i m pr o v e m e nt aft er 4 w e e k s or w or s e ni n g i n 
m e a nti m e, c o n si d er s y nt h eti c or bi ol o gi c D M A R D
S y nt h eti c: m et h otr e x at e, l e ﬂu n o mi d e
Bi ol o gi c: c o n si d er a nti c yt o ki n e t h er a p y s u c h a s T N F- α
or I L - 6 r e c e pt or i n hi bit or s. ( N ot e: A s c a uti o n, I L-6 
i n hi biti o n c a n c a u s e i nt e sti n al p erf or ati o n; w hil e t hi s i s 
e xtr e m el y r ar e, it s h o ul d n ot b e u s e d i n p ati e nt s wit h 
c oliti s.) T e st f or vir al h e p atiti s B, C, a n d l at e nt/ a cti v e T B 
t e st pri or t o D M A R D tr e at me nt
R ef err al t o r h e u m at ol o g y
A d diti o n al c o n si d er ati o n s
E arl y r e c o g niti o n i s criti c al t o a v oi d er o si v e j oi nt d a m a g e
C orti c o st er oi d s c a n b e u s e d a s p art of i niti al t h er a p y i n i n ﬂa m m at or y art hriti s, b ut d u e t o li k el y pr ol o n g e d tr e at m e nt 
r e q uir e m e nt s, p h y si cia n s s h o ul d c o n si d er st arti n g c orti c o st er oi d- s p ari n g a g e nt s e arli er t h a n o n e w o ul d wit h ot h er 
ir A E s
Oli g o art hriti s c a n b e tr e at e d e arl y o n wit h i ntr a - arti c ul ar c orti c o st er oi d s; c o n si d er e arl y r ef err al.
C o n si d er P C P pr o p h yl a xi s f or p ati e nt s tr e at e d wit h hi g h - d o s e of c orti c o st er oi d s f or 1 2 w e e k s, a s p er l o c al 
g ui d eli n e s
5. 2 M y o siti s
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y m u s cl e i n ﬂa m m ati o n wit h w e a k n e s s a n d el e v at e d m u s cl e e n z y m e s ( C K). 
M u s cl e p ai n c a n b e pr e s e nt i n s e v er e c a s e s. C a n b e lif e- t hr e at e ni n g if re s pir at or y m u s cl e s or m y o c ar di u m ar e 
i n v ol v e d
Di a g n o sti c w or k -u p
C o m pl et e r h e u m at ol o gi c a n d n e ur ol o gi c hi st or y r e g ar di n g diff er e nti al di a g n o si s; r h e u m at ol o gi c a n d n e ur ol o gi c 
e x a mi n ati o n, i n cl u di n g m u s cl e str e n gt h; a n d e x a mi n ati o n of t h e s ki n f or ﬁn di n g s s u g g e sti v e of d er m at o m y o siti s. 
M u s cl e w e a k n e s s i s m or e t y pi c al of m y o siti s t h a n p ai n. C o n si d er pr e - e xi sti n g c o n diti o n s t h at c a n c a u s e si mil ar 
s y m pt o m s
Bl o o d t e sti n g t o e v al u at e m u s cl e i n ﬂa m m ati o n
C K, tr a n s a mi n a s e s ( A S T, A L T), L D H, a n d al d ol a s e c a n al s o b e el e v at e d
Tr o p o ni n t o e v al u at e m y o c ar di al i n v ol v e m e nt a n d ot h er c ar di a c t e sti n g, s u c h a s e c h o c ar di o gr a m, a s n e e d e d
I nﬂa m m at or y m ar k er s ( E S R a n d C R P)
C o n si d er E M G, i m a gi n g ( M RI), a n d/ or bi o p s y o n a n i n di vi d u al b a si s w h e n di a g n o si s i s u n c ert ai n a n d o v erl a p wit h
n e ur ol o gi c s y n dr o m e s, s u c h a s m y a st h e ni a gr a vi s, i s s u s p e ct e d
C o n si d er p ar a n e o pl a sti c a ut o a nti b o d y t e sti n g f or m y o siti s a n d n e ur ol o gi c c o n diti o n s, s u c h a s m y a st h e ni a gr a vi s 
M o nit ori n g: C K, E S R, C R P
G 1: C o m pl et e e x a mi n ati o n a n d l a b or at or y w or k- u p a s a b o v e
G 2: C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; a ut oi m m u n e m y o siti s bl o o d p a n el; E M G, M RI of aff e ct e d j oi nt s
E arl y r ef err al t o a r h e u m at ol o gi st or n e ur ol o gi st
G 3 -4: A s f or G 2
Ur g e nt r ef err al t o a r h e u m at ol o gi st or n e ur ol o gi st
Gr a di n g
M a n a g e m e nt
G 1: Mil d w e a k n e s s wit h or wit h o ut p ai n
C o nti n u e I C Pi
If C K i s el e v at e d a n d p ati e nt h a s m u s cl e w e a k n e s s, 
m a y off er or al c orti c o st er oi d s, a n d tr e at a s G 2
Off er a n al g e si a wit h a c et a mi n o p h e n or N S AI D s if t h er e 
ar e n o c o ntr ai n di c ati o n s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 3 / 2 1 3
5. 0 M u s c ul o s k el et al T o xi citi e s
G 2: M o d er at e w e a k n e s s wit h or wit h o ut p ai n, li miti n g 
a g e -a p pr o pri at e i n str u m e nt al A D L
H ol d I C Pi t e m p or aril y a n d m a y r e s u m e u p o n s y m pt o m 
c o ntr ol, if C K i s n or m al a n d pr e d ni s o n e d o s e, 1 0 m g; if 
w or s e n s, tr e at a s p er G 3
N S AI D s a s n e e d e d
R ef err al t o r h e u m at ol o gi st or n e ur ol o gi st
If C K i s el e v at e d 3 ti m e s or m or e, i niti at e pr e d ni s o n e or 
e q ui v al e nt at 0. 5 -1 m g/ k g
M a y r e q uir e p er m a n e nt di s c o nti n u ati o n of I C Pi i n m o st 
p ati e nt s wit h G 2 s y m pt o m s a n d o bj e cti v e ﬁn di n g s 
( el e v at e d e n z y m e s, a b n or m al E M G, a b n or m al m u s cl e 
M RI, or bi o p s y)
G 3 -4: S e v er e w e a k n e s s wit h or wit h o ut p ai n, li miti n g 
s elf -c ar e A D L
F or G 3: H ol d I C Pi u ntil G 1 or l e s s a n d p er m a n e ntl y 
di s c o nti n u e if a n y e vi d e n c e of m y o c ar di al i n v ol v e m e nt
F or G 4: p er m a n e ntl y  di s c o nti n u e I C Pi
C o n si d er h o s pit ali z ati o n f or s e v er e w e a k n e s s
R ef err al t o r h e u m at ol o gi st or n e ur ol o gi st
I niti at e pr e d ni s o n e 1 m g/ k g or e q ui v al e nt. C o n si d er 1-2 
m g/ k g of m et h yl pr e d ni s ol o n e I V or hi g h er - d o s e b ol u s if 
s e v er e c o m pr o mi s e ( w e a k n e s s s e v er el y li miti n g 
m o bilit y , c ar di a c, r e s pir at or y, dy s p h a gi a)
C o n si d er pl a s m a p h er e si s
C o n si d er I VI G t h er a p y
C o n si d er ot h er i m m u n o s u p pr e s s a nt t h er a p y, s u c h a s 
m et h otr e x at e, a z at hi o pri n e, or m y c o p h e n ol at e m of etil, if 
s y m pt o m s a n d C K l e v el s d o n ot i m pr o v e or w or s e n 
aft er 4 - 6 w e e k s; rit u xi m a b i s u s e d i n pri m ar y m y o siti s, 
b ut c a uti o n i s a d vi s e d gi v e n it s l o n g bi ol o gi c d ur ati o n
I n c a s e of m a n a g e m e nt wit h rit u xi m a b, I C Pi 
tr e at m e nt s h o ul d b e di s c o nti n u e d
A d diti o n al c o n si d er ati o n s: C a uti o n i s a d vi s e d wit h r e c h all e n gi n g
5. 3 P ol y m y al gi a -li k e S yn dr o m e
D e ﬁniti o n: C h ar a ct eri z e d b y m ar k e d p ai n a n d stiff n e s s i n pr o xi m al u p p er a n d/ or l o w er e xtr e miti e s a n d n o si g n s of 
tr u e m u s cl e i nﬂa m m ati o n s u c h a s C K el e v ati o n or E M G ﬁn di n g s of m y o siti s. N o tr u e m u s cl e w e a k n e s s, dif ﬁc ult y i n 
a cti v e m oti o n r el at e d t o p ai n
Di a g n o sti c w or k -u p
G 1
C o m pl et e r h e u m at ol o gi c hi st or y r e g ar di n g diff er e nti al di a g n o si s a n d e x a mi n ati o n of all j oi nt s a n d s ki n
C h e c k f or s y m pt o m s of t e m p or al art eriti s, s u c h a s h e a d a c h e or vi s u al di st ur b a n c e s; r ef er t o o p ht h al m ol o gi st if 
pr e s e nt, a n d c o n si d er t e m p or al art er y bi o p s y A N A, R F, a nti- C C P
C K t o e v al u at e diff er e nti al di a g n o si s of m y o siti s
I nﬂa m m at or y m ar k er s ( E S R, C R P)
M o nit ori n g: E S R, C R P
G 2: C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; a ut oi m m u n e t e st s a s r e q uir e d f or diff er e nti al di a g n o si s; e arl y 
r ef err al t o a r h e u m at ol o gi st
G 3 -4: A s f or G 2; s e e r h e u m at ol o gi st a d vi c e a n d r e vi e w
Gr a di n g
M a n a g e m e nt
G 1: Mil d stiff n e s s a n d p ai n
C o nti n u e I C Pi
I niti at e a n al g e si a wit h a c et a mi n o p h e n a n d/ or N S AI D s if 
t h er e ar e n o c o ntr ai n di c ati o n s
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 4 / 2 1 3
5. 0 M u s c ul o s k el et al T o xi citi e s
G 2: M o d er at e stiff n e s s a n d p ai n, li miti n g 
a g e -a p pr o pri at e i n str u m e nt al A D L
C o n si d er h ol di n g I C Pi a n d r e s u mi n g u p o n s y m pt o m 
c o ntr ol, pr e d ni s ol o n e < 1 0 m g; if w or s e n s, tr e at a s p er 
G 3
I niti at e pr e d ni s o n e 2 0 m g/ d or e q ui v al e nt; if s y m pt o m s 
i m pr o v e, st art t o t a p er d o s e aft er 3- 4 w e e k s
If n o i m pr o v e m e nt or n e e d f or hi g h er d o s a g e s aft er 
4 w e e k s, e s c al at e t o G 3 C o n si d er r ef err al t o 
r h e u m at ol o g y
G 3 -4: S e v er e stiff n e s s a n d p ai n, li miti n g s elf -c ar e A D L
F or G 3: H ol d I C Pi a n d m a y r e s u m e, i n c o n s ult ati o n wit h 
r h e u m at ol o g y, if r e c o v er t o G 1 or l e s s; h o w e v er, n ot e 
t h at c a s e s of t o xi cit y r et ur ni n g u p o n r e c h all e n g e h a v e 
b e e n r e p ort e d . I C Pi s h o ul d b e p er m a n e ntl y 
di s c o nti n u e d i n s u c h c a s e s
F or G 4: p er m a n e ntl y  di s c o nti n u e I C Pi
R ef err al t o r h e u m at ol o g y
S h o ul d i niti at e pr e d ni s o n e 2 0 m g/ d or e q ui v al e nt. If n o 
i m pr o v e m e nt or n e e d f or hi g h er d o s a g es f or pr ol o n g e d 
ti m e, m a y off er a c orti c o st er oi d-s p ari n g a g e nt s u c h a s 
m et h otr e x at e or I L - 6 i n hi biti o n wit h t o cili z u m a b
( N ot e: A s c a uti o n, I L- 6 i n hi biti o n c a n c a u s e i nt e sti n al 
p erf or ati o n; w hil e t hi s i s e xtr e m el y r ar e, it s h o ul d n ot b e 
u s e d i n p ati e nt s wit h c oliti s or GI m et a st a s e s). C o n si d er 
a d mi s si o n f or p ai n c o ntr ol
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A D L = a cti viti e s of d ail y li vi n g, A L T = al a ni n e a mi n otr a n sf er a s e, A N A = a nti n u cl e ar a nti b o di e s, C C P = citr ulli n at e d pr ot ei n 
a nti b o d y, C K = cr e ati n e ki n a s e, C R P = C -r e a cti v e pr ot ei n, D M A R D = di s e a s e-m o dif yi n g a ntir h e u m ati c dr u g, 
E M G = el e ctr o m y o gr a p h y, E S R = er yt hr o c yt e s e di m e nt ati o n r at e, 
, I L =i nt erl e u ki n, 
, I V =i ntr a v e n o u s, I VI G =i ntr a v e n o u s i m m u n o gl o b uli n, L D H =l a ct at e 
d e h y dr o g e n a s e, M RI = m a g n eti c r e s o n a n c e i m a gi n g, N S AI D = n o n st er oi d al a nti -i nﬂa m m at or y dr u g, P C P = P n e u m o c y sti s 
p n e u m o ni a, R F =r h e u m at oi d f a ct or, T B =t u b er c ul o si s, T N F =t u m or n e cr o si s f a ct or, U S = ultr a s o u n d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 5 / 2 1 3
T a ble A 6
M a n a ge me nt 
of Re n al I m m u ne-rel ate d A d verse E ve nts i n P a tie nts 
Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
6. 0 R e n al T o xi citi e s
N e p hriti s a n d r e n al d y sf u n cti o n: di a g n o si s a n d m o nit ori n g
F or a n y s u s p e ct e d i m m u n e - m e di at e d a d v er s e r e a cti o n s, e x cl u d e ot h er c a u s e s
M o nit or p ati e nt s f or el e v at e d s er u m cr e ati ni n e pri or t o e v er y d o s e
R o uti n e uri n al y si s i s n ot n e c e s s ar y, ot h er t h a n t o r ul e o ut U TI s, et c; n e p hr ol o g y m a y c o n si d er f urt h er
If n o p ot e nti al alt er n ati v e c a u s e of A KI i d e ntiﬁe d, f or e g o bi o p s y a n d pr o c e e d dir e ctl y wit h i m m u n o s u p pr e s si v e 
t h er a p y. S wift tr e at m e nt of a ut oi m m u n e c o m p o n e nt i m p ort a nt
6. 1 N e p hriti s
D e ﬁniti o n: I n ﬂa m m ati o n of t h e ki d n e y aff e cti n g t h e str u ct ur e
Gr a di n g
M a n a g e m e nt
G 1: Cr e ati ni n e l e v el i n cr e a s e
> U L N - 1. 5 x U L N
C o n si d er t e m p or aril y h ol di n g I C Pi, p e n di n g 
c o n si d er ati o n of p ot e nti al alt er n ati v e eti ol o gi e s (r e c e nt 
I V c o ntr a st, m e di c ati o n s, ﬂui d st at u s) a n d b a s eli n e r e n al 
f u n cti o n. A c h a n g e t h at i s still < 1. 5 U L N c o ul d b e 
m e a ni n gf ul
G 2: Cr e ati ni n e
> 1. 5 - 3. 0 x b a s eli n e; > 1. 5 - 3. 0 x U L N
H ol d I C Pi
C o n s ult n e p hr ol o g y
E v al u at e f or ot h er c a u s e s (r e c e nt I V c o ntr a st, 
m e di c ati o n s, ﬂui d st at u s, et c); if ot h er eti ol o gi e s r ul e d 
o ut, a d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e e q ui v al e nt s
If w or s e ni n g or n o i m pr o v e m e nt: 1 t o 2 m g/ k g/ d 
pr e d ni s o n e e q ui v al e nt s a n d p er m a n e ntl y di s c o nti n u e 
tr e at m e nt
If i m pr o v e d t o G 1 or l e s s, t a p er c orti c o st er oi d s o v er 4-6 
w e e k s. If n o r e c urr e n c e of c hr o ni c r e n al i n s uf ﬁci e n c y, 
di s c u s s r e s u m pti o n of I C Pi wit h p ati e nt aft er t a ki n g i nt o 
a c c o u nt t h e ri s k s a n d b e n e ﬁt s.
G 3: Cr e ati ni n e
> 3. 0 x b a s eli n e ; > 3. 0 - 6. 0 x U L N
P er m a n e ntl y di s c o nti n u e I C Pi
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; di al ysi s 
i n di c at e d; 
> 6. 0 x U L N 
P er m a n e ntl y  di s c o nti n u e I C Pi
C o n s ult n e p hr ol o g y
E v al u at e f or ot h er c a u s e s (r e c e nt I V c o ntr a st, 
m e di c ati o n s, ﬂui d st at u s, et c)
A d mi ni st er c orti c o st er oi d s (i niti al d o s e of 1 -2 m g/ k g/ d 
pr e d ni s o n e or e q ui v al e nt)
A d diti o n al c o n si d er ati o n s
M o nit or cr e ati ni n e w e e kl y
R e ﬂe x ki d n e y bi o p s y s h o u l d b e di s c o ur a g e d u ntil c orti c o st er oi d tr e at m e nt h a s b e e n att e m pt e d
6. 2 S y m pt o m ati c N e p hriti s: F oll o w -u p
Gr a di n g
M a n a g e m e nt
G 1
I m pr o v e d t o b a s eli n e, r e s u m e r o uti n e cr e ati ni n e 
m o nit ori n g
G 2
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 
3 w e e k s b ef or e r e s u mi n g tr e at m e nt wit h r o uti n e 
cr e ati ni n e m o nit ori n g If el e v ati o n s p er si st > 7 d a y s or 
w or s e n a n d n o ot h er c a u s e f o u n d, tr e at a s G 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 6 / 2 1 3
6. 0 R e n al T o xi citi e s
G 3
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 
4 w e e k s 
If el e v ati o n s p er si st > 3- 5 d a y s or w or s e n, c o n s i d er 
a d diti o n al i m m u n o s u p pr e s si o n ( e. g. , m y c o p h e n ol at e)
G 4
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 
4 w e e k s
If el e v ati o n s p er si st > 2- 3 d a y s or w or s e n, c o n si d er 
a d diti o n al i m m u n o s u p pr e s si o n ( e. g. , m y c o p h e n ol at e)
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A KI = a c ut e ki d n e y i nj ur y, G = gr a d e, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or,
 
I V =i ntr a v e n o u s, U L N = u p p er li mit of n or m al, U TI = uri nar y tr a ct i nf e cti o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 7 / 2 1 3
T a ble A 7
M a n a ge me nt 
of Ner v o us S yste m I m m u ne-rel ate d A d verse E ve nts i n 
P atie nts Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
7. 0 N er v o u s S y st e m T o xi citi e s
7. 1 M y a st h e ni a Gr a vi s
D e ﬁniti o n: F ati g a bl e or ﬂu ct u ati n g m u s cl e w e a k n e s s, g e n er all y m or e pr o xi m al t h a n di st al. Fr e q u e ntl y h a s o c ul ar 
a n d/ or b ul b ar i n v ol v e m e nt ( pt o si s, e xtr a o c ul ar m o v e m e nt a b n or m aliti e s r e s ulti n g i n d o u bl e vi si o n, d y s p h a gi a, 
d y s art hri a, f a ci al m u s cl e w e a k n e s s). M a y h a v e n e c k a n d/ or r e s pir at or y m u s cl e w e a k n e s s. ( N ot e: M a y o c c ur wit h 
m y o siti s a n d/ or m y o c ar diti s). R e s pir at or y s y m pt o m s m a y r e q uir e e v al u ati o n t o r ul e o ut p n e u m o niti s, m y o c ar diti s. 
Mill er Fi s h er v ari a nt of G uill ai n -B arr é s y n dr o m e ( o p ht h al m o p ar e si s) a n d t h e o c ul o b ul b ar m y o siti s ( pt o si s, 
o p ht h al m o p ar e si s, d y s p h a gi a, n e c k a n d r e s pir at or y w e a k n e s s) wit h I C Pi m a y h a v e o v erl a p pi n g s y m pt o m s
Di a g n o sti c w or k -u p
A C h R a n d a nti stri at e d m u s cl e a nti b o di e s i n bl o o d; if A C h R a nti b o di e s ar e n e g ati v e, c o n si d er m u s cl e s p e ci ﬁc 
ki n a s e a n d li p o pr ot ei n-r el at e d a nti b o di e s i n bl o o d. P ul m o n ar y f u n cti o n a s s e s s m e nt wit h NI F a n d V C
C P K, al d ol a s e, E S R, C R P f or p o s si bl e c o n c urr e nt m y o siti s
C o n si d er M RI of br ai n a n d/ or s pi n e, d e p e n di n g o n s y m pt o m s t o r ul e o ut C N S i n v ol v e m e nt b y di s e a s e or alt er n at e 
di a g n o si s
If r e s pir at or y i n s ufﬁci e n c y or el e v at e d C P K, tr o p o ni n T, p erf or m c ar di a c e x a mi n ati o n wit h E C G a n d T T E f or 
p o s si bl e c o n c o mit a nt m y o c ar diti s
N e ur ol o gi c c o n s ult ati o n
El e ctr o di a g n o sti c st u di e s, i n cl u di n g n e ur o m u s c ul ar j u n cti o n t e sti n g wit h r e p etiti v e sti m ul ati o n a n d/ or jitt er st u di e s, 
N C S t o e x cl u d e n e ur o p at h y, a n d n e e dl e E M G t o e v al u at e f or m y o siti s
Gr a di n g
M a n a g e m e nt
All gr a d e s
All gr a d e s w arr a nt w or k- u p a n d i nt er v e nti o n gi v e n 
p ot e nti al f or pr o gr e s si v e m y a st h e ni a gr a vi s t o l e a d t o 
r e s pir at or y c o m pro mi s e
N o G 1
G 2: S o m e s y m pt o m s i nt erf eri n g wit h A D L M G F A 
s e v erit y cl a s s 1 ( o c ul ar s y m pt o m s a n d ﬁn di n g s o nl y) 
a n d M G F A s e v erit y cl a s s 2 ( mil d g e n er ali z e d 
w e a k n e s s)
H ol d I C Pi a n d m a y r e s u m e i n G 2 p ati e nt s ( M G F A 1 a n d 
2) o nl y if s y m pt o m s r e s ol v e 
S h o ul d c o n s ult n e ur ol o g y
P yri d o sti g mi n e st arti n g at 3 0 m g or all y 3 ti m e s a d a y 
a n d gr a d u all y i n cr e a s e t o m a xi m u m of 1 2 0 m g or all y 
4 ti m e s a d a y a s t ol er at e d a n d b a s e d o n s y m pt o m s. 
A d mi ni st er c orti c o st er oi d s ( pr e d ni s o n e, 1 -1. 5 m g/ k g 
or all y d ail y) if s y m pt o m s G 2; w e a n b a s e d o n s y m pt o m 
i m pr o v e m e nt
G 3 -4: Li miti n g s elf -c ar e a n d ai d s w arr a nt e d, w e a k n e s s 
li miti n g w al ki n g, A N Y d y s p h a gi a, f a ci al w e a k n e s s, 
r e s pir at or y m u s cl e w e a k n e s s, or r a pi dl y pr o gr e s si v e 
s y m pt o m s, or M G F A s e v erit y cl a s s 3 -4 m o d er at e t o 
s e v er e g e n er ali z e d w e a k n e s s t o m y a st h e ni c cri si s
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt, m a y n e e d I C U -l e v el m o nit ori n g
N e ur ol o g y c o n s ult
C o nti n u e c orti c o st er oi d s a n d i niti at e I VI G 2 g/ k g I V o v er 
5 d a y s ( 0. 4 g/ k g/ d) or pl a s m a p h er e si s f or 5 d a y s
Fr e q u e nt p ul m o n ar y f u n cti o n a s s e s s m e nt
D ail y n e ur ol o gi c r e vi e w
A d diti o n al c o n si d er ati o n s
A v oi d m e di c ati o n s t h at c a n w or s e n m y a st h e ni a: β- bl o c k er s, I V m a g n e si u m, ﬂu or o q ui n ol o n e s, a mi n o gl y c o si d e s, 
a n d m a cr oli d e s. I niti all y a 5 - d a y c o ur s e of pl a s m a p h er e si s or a 2 g/ k g c o ur s e of I VI G ov er 5 d a y s
1- 2 m g/ k g m et h yl pr e d ni s ol o n e d ail y, w e a n b a s e d o n s y m pt o m i m pr o v e m e nt
P yri d o sti g mi n e, w e a n b a s e d o n i m pr o v e m e nt
I C Pi- a s s o ci at e d m y a st h e ni a gr a vi s m a y b e m o n o p h a si c, a n d a d diti o n al c orti c o st er oi d-s p ari n g a g e nt s m a y n ot b e 
r e q uir e d
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 8 / 2 1 3
7. 0 N er v o u s S y st e m T o xi citi e s
7. 2 G uill ai n - Barr é S y n dr o m e
D e ﬁniti o n: Pr o gr e s si v e, m o st oft e n s y m m etri c al m u s cl e w e a k n e s s wit h a b s e nt or r e d u c e d d e e p t e n d o n r e ﬂe x e s. 
Oft e n st art s wit h s e n s or y s y m pt o m s/ n e ur o p at hi c p ai n l o c ali z e d t o l o w er b a c k a n d t hi g h s. M a y i n v ol v e e xtr e miti e s 
(t y pi c all y a s c e n di n g we a k n e s s b ut n ot al w a y s), f a ci al, r e s pir at or y, a n d b ul b ar a n d o c ul o m ot or n er v e s. M a y h a v e 
d y sr e g ul ati o n of a ut o n o mi c n er v e s
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of s pi n e wit h or wit h o ut c o ntr a st (r ul e o ut c o m pr e s si v e l e si o n a n d e v al u at e f or n er v e
r o ot 
e n h a n c e m e nt/t hi c k e ni n g)
L u m b ar p u n ct ur e: C S F t y pi c all y h a s el e v at e d pr ot ei n a n d oft e n el e v at e d W B C s; e v e n t h o u g h t hi s i s n ot t y pi c all y 
s e e n i n cl a s si c G uill ai n -B arr é s y n dr o m e, c yt ol o g y s h o ul d b e s e nt wit h a n y C S F s a m pl e fr o m a p ati e nt wit h c a n c er.
S e r u m a nti b o d y t e st s f or G uill ai n-B arr é s y n dr o m e v ari a nt s ( G Q 1 b f or Mill er Fi s h er v ari a nt a/ w at a xi a a n d 
o p ht h al m o pl e gi a). El e ctr o di a g n o sti c st u di e s t o e v al u at e p ol y n e ur o p at h y
P ul m o n ar y f u n cti o n t e sti n g ( NI F/ V C)
Fr e q u e nt n e ur o c h e c k s
Gr a di n g
M a n a g e m e nt
All gr a d e s
W a rr a nt w or k- u p a n d i nt er v e nti o n gi v e n p ot e nti al f or 
pr o gr e s si v e G uill ai n - B arr é s y n dr o m e t o l e a d t o 
r e s pir at or y c o m pr o mi s e
N ot e: T h er e i s n o G 1 t o xi cit y
G 1: Mil d, n o n e
N A
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt
Di s c o nti n u e I C Pi
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d, 
w e a k n e s s, li miti n g w al ki n g, A N Y d y s p h a gi a, f a ci al 
w e a k n e s s, r e s pir at or y m u s cl e w e a k n e s s, or r a pi dl y 
pr o gr e s si v e s y m pt o m s
P er m a n e ntl y  di s c o nti n u e I C Pi. 
A d mi s si o n t o i n p ati e nt u nit wit h c a p a bilit y of r a pi d 
tr a n sf er t o I C U-l e v el m o nit ori n g. St art I VI G ( 0. 4 g/ k g/ d 
f or 5 d a y s f or a t ot al d o s e of 2 g/ k g) or pl a s m a p h er e si s. 
C orti c o st er oi d s ar e u s u all y n ot r e c o m m e n d e d f or 
i di o p at hi c G uill ai n-B arr é s y n dr o m e; h o w e v er, i n I C Pi -
r el at e d f or m s, a tri al i s r e a s o n a bl e ( m et h yl pr e d ni s ol o n e 
2- 4 m g/ k g/ d), f oll o w e d b y sl o w c orti c o st er oi d t a p er
P ul s e c orti c o st er oi d d o si n g ( m et h yl pr e d ni s ol o n e 1 g/ d 
f or 5 d a y s) m a y al s o b e c o n si d er e d f or G 3-4 al o n g wit h 
I VI G or pl a s m a p h er e si s
Fr e q u e nt n e ur o c h e c k s a n d p ul m o n ar y f u n cti o n 
m o nit ori n g
M o nit or f or c o n c urr e nt a ut o n o mi c d y sf u n cti o n
N o n - o pi oi d m a n a g e m e nt of n e ur o p at hi c p ai n
Tr e at m e nt of c o n sti p ati o n/il e u s
A d diti o n al c o n si d er ati o n s
Sl o w pr e d ni s o n e t a p er aft er c orti c o st er oi d p ul s e pl u s I VI G or pl a s m a p h er e si s. M a y r e q uir e r e p e at I VI G c o ur s e s
C a uti o n wit h r e c h all e n gi n g f or s e v er e c a s e s
7. 3 P eri p h er al N e ur o p at h y
D e ﬁniti o n: C a n pr e s e nt a s a s y m m etri c or s y m m etri c s e n s or y, m ot or, or s e n s or y m ot or d e ﬁcit. F o c al 
m o n o n e ur o p at hi e s, i n cl u di n g cr a ni al n e ur o p at hi e s ( e . g., f a ci al n e ur o p at hi e s/ B ell’ s p al s y) m a y b e pr e s e nt. 
N u m b n e s s a n d p ar e st h e si a s m a y b e p ai nf ul or p ai nl e s s. H y p o- or ar e ﬂe xi a or s e n s or y at a xi a m a y b e pr e s e nt
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 6 9 / 2 1 3
7. 0 N er v o u s S y st e m T o xi citi e s
Di a g n o sti c w or k -u p
G 1
S cr e e n f or r e v er si bl e n e ur o p at h y c a u s e s: di a b eti c s cr e e n, B 1 2, f ol at e, T S H, HI V, c o n s i d er s er u m pr ot ei n 
el e ctr o p h or e si s, a n d ot h er v a s c uliti c n e ur o p at h y a n d a ut oi m m u n e s cr e e n. N e ur ol o gi c c o n s ult ati o n
C o n si d er M RI of s pi n e wit h or wit h o ut c o ntr a st
G 2: i n a d diti o n t o a b o v e
M RI s pi n e a d vi s e d/ M RI of br ai n if cr a ni al n er v e C o n si d er E M G/ N C S
C o n s i d er n e ur ol o g y c o n s ult ati o n
G 3 -4: g o t o G uill ai n -B arr é s y n dr o m e al g orit h m
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e
L o w t hr e s h ol d t o h ol d I C Pi a n d m o nit or s y m pt o m s f or a 
w e e k If t o c o nti n u e, m o nit or v er y cl o s el y f or a n y 
s y m pt o m pr o gr e s si o n
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i . e., p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
H ol d I C Pi a n d r e s u m e o n c e r et ur n t o G 1
I niti al o b s er v ati o n O R i niti at e pr e d ni s o n e 0. 5-1 m g/ k g (if 
pr o gr e s si n g fr o m mil d)
N e ur o nti n, pr e g a b ali n, or d ul o x eti n e f or p ai n
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d, 
w e a k n e s s li miti n g w al ki n g or r e s pir at or y pr o bl e m s (i . e., 
l e g we a k n e s s, f o ot dr o p, r a pi dl y a s c e n di n g s e n s or y 
c h a n g e s). S e v er e m a y b e G uill ai n -B arr é s y n dr o m e a n d 
s h o ul d b e m a n a g e d a s s u c h
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
N e ur ol o gi c c o n s ult ati o n
I niti at e I V m et h yl pr e d ni s ol o n e 2-4 m g/ k g a n d pr o c e e d 
a s p er G uill ai n -B arr é s y n dr o m e m a n a g e m e nt
7. 4 A ut o n o mi c N e ur o p at h y
D e ﬁniti o n: N er v e s t h at c o ntr ol i n v ol u nt ar y b o dil y f u n cti o n s ar e d a m a g e d. T hi s m a y aff e ct bl o o d pr e s s ur e, 
t e m p er at ur e c o ntr ol, di g e sti o n, bl a d d er f u n cti o n, a n d s e x u al f u n cti o n. A c a s e of s e v er e e nt eri c n e ur o p at h y wit h 
I C Pi h a s b e e n r e p ort e d. C a n pr e s e nt wit h GI difﬁc ulti e s s u c h a s n e w s e v er e c o n sti p ati o n, n a u s e a, uri n ar y 
pr o bl e m s, s e x u al dif ﬁc ulti e s, s w e ati n g a b n or m aliti e s, sl u g gi s h p u pil r e a cti o n, a n d ort h o st ati c h y p ert e n si o n
Di a g n o sti c w or k -u p
A n e v al u ati o n b y n e ur ol o gi st or r el e v a nt s p e ci ali st, d e p e n di n g o n or g a n s y st e m, wit h t e sti n g t h at m a y i n cl u d e
S cr e e ni n g f or ot h er c a u s e s of a ut o n o mi c d y sf u n cti o n: di a b eti c s cr e e n, a dr e n al i n s uf ﬁci e n c y, HI V, p ar a pr ot ei n e mi a, 
a m yl oi d o si s, b ot uli s m; c o n si d er c hr o ni c di s e a s e s s u c h a s P ar ki n s o n’ s di s e a s e a n d ot h er a ut oi m m u n e s cr e e ni n g
A M  ort h o st ati c vit al s
C o n si d er el e ctr o di a g n o sti c st u di e s t o e v al u at e f or c o n c urr e nt p ol y n e ur o p at h y
C o n si d er p ar a n e o pl a sti c L a m b ert- E at o n m y a st h e ni c s y n dr o m e, a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s, a n d 
g a n gli o ni c A C h R a nti b o d y t e sti n g
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt
L o w t hr e s h ol d t o h ol d I C Pi a n d m o nit or s y m pt o m s f or a 
w e e k; if t o c o nti n u e, m o nit or v er y cl o s el y f or a n y 
s y m pt o m pr o gr e s si o n
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt
H ol d I C Pi a n d r e s u m e o n c e r et ur n t o G 1
I niti al o b s er v ati o n O R i niti at e pr e d ni s o n e 0. 5-1 m g/ k g (if 
pr o gr e s si n g fr o m mil d)
N e ur ol o gi c c o n s ult ati o n
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
I niti at e m et h yl pr e d ni s ol o n e 1 g d ail y f or 3 d a y s f oll o w e d 
b y or al c orti c o st er oi d t a p er N e ur ol o gi c c o n s ult ati o n
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 0 / 2 1 3
7. 0 N er v o u s S y st e m T o xi citi e s
7. 5 A s e pti c M e ni n giti s
D e ﬁniti o n: m a y pr e s e nt wit h h e a d a c h e, p h ot o p h o bi a, a n d n e c k stiff n e s s; oft e n af e bril e b ut m a y b e f e bril e. T h er e 
m a y b e n a u s e a/ v o miti n g. M e nt al st at u s s h o ul d b e n or m al ( di sti n g ui s h e s fr o m e n c e p h aliti s).
Di a g n o sti c w or k -u p
M RI of br ai n wit h or wit h o ut c o ntr a st, pl u s pit uit ar y pr ot o c ol
A M  c orti s ol, A C T H t o r ul e o ut a dr e n al i n s uf ﬁci e n c y
C o n si d er l u m b ar p u n ct ur e: m e a s ur e o p e ni n g pr e s s ur e; c h e c k c ell c o u nt a n d pr ot ei n gl u c o s e; a n d p erf or m Gr a m 
st ai n, c ult ur e, P C R f or H S V, a n d ot h er vir al P C R s d e p e n di n g o n s u s pi ci o n, c yt ol o g y
M a y s e e el e v at e d W B C c o u nt wit h n or m al gl u c o s e, n or m al c ult ur e, a n d Gr a m st ai n; m a y s e e r e a cti v e l y m p h o c yt e s 
or hi sti o c yt e s o n c yt ol o g y
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o u l d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i . e., p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er
t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n eﬁt s , co n si d er 
e m piri c al a nti vir al (I V a c y cl o vir) a n d a nti b a ct eri al 
t h er a p y u ntil C S F r e s ult s. O n c e b a ct eri al a n d vir al 
i nf e cti o n ar e n e g ati v e, m a y cl o s el y m o nit or off 
c orti c o st er oi d s, or c o n si d er or al pr e d ni s o n e 0. 5 - 1 m g/ k g 
or I V m et h yl pr e d ni s ol o n e 1 m g/ k g if m o d er at e/ s e v er e 
s y m pt o m s
7. 6 E n c e p h aliti s
D e ﬁniti o n: A s f or a s e pti c m e ni n giti s, n e e d t o e x cl u d e i nf e cti o u s c a u s e s, e s p e ci all y vir al (i . e., H S V).
C o nf u si o n, alt er e d b e h a vi or, h e a d a c h e s, s ei z ur e s, s h ort -t er m m e m or y l o s s, d e pr e s s e d l e v el of c o n s ci o u s n e s s, 
f o c al w e a k n e s s, s p e e c h a b n or m alit y
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of br ai n wit h or wit h o ut c o ntr a st m a y r e v e al T 2/ ﬂui d -att e n u at e d i n v er si o n r e c o v er y c h a n g e s t y pi c al of w h at i s 
s e e n i n a ut oi m m u n e e n c e p h al o p at hi e s or li m bi c e n c e p h aliti s or m a y b e n or m al
L u m b ar p u n ct ur e: c h e c k c ell c o u nt a n d pr ot ei n gl u c o s e, a n d p erf or m Gr a m st ai n, c ult ur e, P C R f or H S V a n d ot h er 
vir al P C R s d e p e n di n g o n s u s pi ci o n, c yt ol o g y, oli g o cl o n al b a n d s, a ut oi m m u n e e n c e p h al o p a t h y, a n d p ar a n e o pl a sti c 
p a n el s.
M a y s e e el e v at e d W B C c o u nt wit h l y m p h o c yti c pr e d o mi n a n c e a n d/ or el e v at e d pr ot ei n
E E G t o e v al u at e f or s u b cli ni c al s ei z ur e s
Bl o o d: m et a b oli c, C B C, E S R, C R P, A N C A (if s u s p e ct v a s c uliti c pr o c e s s), t h yr oi d p a n el i n cl u di n g T P O a n d
t h yr o gl o b uli n 
R ul e o ut c o n c urr e nt a n e mi a/t hr o m b o c yt o p e ni a, w hi c h c a n pr e s e nt wit h s e v er e h e a d a c h e s a n d c o nf u si o n
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i . e., p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er 
t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n eﬁt s
A s a b o v e f or a s e pti c m e ni n giti s s u g g e st c o n c urr e nt I V 
a c y cl o vir u ntil P C R r e s ult s o bt ai n e d a n d n e g ati v e
Tri al of m et h yl pr e d ni s ol o n e 1 -2 m g/ k g
If s e v er e or pr o gr e s si n g s y m pt o m s or oli g o cl o n al b a n d s 
pr e s e nt, c o n si d er p ul s e c orti c o st er oi d s: 
m et h yl pr e d ni s ol o n e 1
g I V d ail y f or 3 -5 d a y s pl u s I VI G 
2 g/ k g o v er 5 d a y s
If p o siti v e f or a ut oi m m u n e e n c e p h al o p at h y a nti b o d y a n d 
li mit e d or n o i m pr o v e m e nt, c o n si d er rit u xi m a b or 
pl a s m a p h er e si s i n c o n s ult ati o n wit h n e ur ol o g y .
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 1 / 2 1 3
7. 0 N er v o u s S y st e m T o xi citi e s
7. 7 Tr a n s v er s e M y eliti s
D e ﬁniti o n: A c ut e or s u b a c ut e w e a k n e s s or s e n s or y c h a n g e s bil at er al, oft e n wit h i n cr e a s e d d e e p t e n d o n r e ﬂe x e s
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of s pi n e ( wit h t hi n a xi al c ut s t hr o u g h t h e r e gi o n of s u s p e ct e d a b n or m alit y) a n d M RI of br ai n
L u m b ar p u n ct ur e: c ell c o u nt, pr ot ei n, gl u c o s e, oli g o cl o n al b a n d s, vir al P C R s, c yt ol o g y, o n c o n e ur al a nti b o di e s 
Bl o o d: B 1 2, HI V, R P R, A N A, R o/ L a, T S H, a q u a p ori n -4 I g G
E v al u ati o n f or uri n ar y r et e nti o n, c o n sti p ati o n
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i . e., p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
P er m a n e ntl y di s c o nti n u e I C Pi
M et h yl pr e d ni s ol o n e 2 m g/ k g
Str o n gl y c o n si d er hi g h er d o s e s of 1 g/ d f or 3- 5 d a y s 
Str o n gl y c o n si d er I VI G
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A C h R = a c et yl c h oli n e r e c e pt or, A C T H = a dr e n o c orti c otr o pi c h or m o n e, A D L = a cti viti e s of d ail y li vi n g, A N A = a nti n u cl e ar 
a nti b o di e s, A N C A = a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s, C B C = c o m pl et e bl o o d c o u nt, C N S = c e ntr a l n er v o u s s y st e m, 
C P K = cr e ati n e p h o s p h o ki n a s e, C R P = C- r e a cti v e pr ot ei n, C S F = c er e br o s pi n al fl ui d, E C G = el e ctr o c ar di o gr a m, 
E M G = el e ctr o m y o gr a p h y, E S R = er yt hr o c yt e s e di m e nt ati o n r at e, HI V = h u m a n i m m u n o d efi ci e n c y s y n dr o m e, 
H S V = h er p e s si m pl e x vir u s, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, I C U =i nt e n si v e c ar e u nit, I g G =i m m u n o gl o b uli n G, 
I V =i ntr a v e n o u s, I VI G =i ntr a v e n o u s i m m u n o gl o b uli n, ir A E =i m m u n e-r el at e d a d v er s e e v e nt, M G F A = M y a st h e ni a Gr a vi s 
F o u n d ati o n of A m eri c a, M RI = m a g n eti c r e s o n a n c e i m a gi n g, N A = n ot a p pli c a bl e, N C S = n er v e c o n d u cti o n st u d y, 
NI F = n e g ati v e i n s pir at or y f or c e, P C R = p ol y m er a s e c h ai n r e a cti o n, R P R =r a pi d pl a s m a r e g ai n, T P O =t h yr oi d p er o xi d a s e, 
T S H =t h yr oi d -sti m ul ati n g h or m o n e, T T E =tr a n st h or a ci c e c h o c ar di o gr a m, V C = vit al c a p a cit y, W B C = w hit e bl o o d c ell.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 2 / 2 1 3
T a ble A 8
M a n a ge me nt 
of He m at ol o gic 
I m m u ne-rel ate d A d verse 
E ve nts 
i n 
P atie nts Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
8. 0 H e m at ol o gi c T o xi citi e s
8. 1 A ut oi m m u n e H e m ol y ti c A n e mi a
D e ﬁniti o n: A c o n diti o n i n w hi c h R B C s ar e d e str o y e d a n d r e m o v e d fr o m t h e bl o o d str e a m b ef or e t h eir n or m al 
lif e s p a n i s o v er. S y m pt o m s i n cl u d e w e a k n e s s, p al e n e s s, j a u n di c e, d ar k- c ol or e d uri n e, f e v er, i n a bilit y t o d o p h y si c al 
a cti vit y, a n d h e art m ur m ur
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( wit h s p e ci al c o n si d er ati o n of hi st or y of n e w dr u g s a n d i n s e ct, s pi d er, or s n a k e 
bit e s)
Bl o o d c h e mi str y, C B C wit h e vi d e n c e of a n e mi a, m a cr o c yt o si s, e vi d e n c e of h e m ol y si s o n p eri p h er al s m e ar; L D H, 
h a pt o gl o bi n, bilir u bi n, r eti c ul o c yt e c o u nt, fr e e H g b DI C p a n el, w hi c h c o ul d i n cl u d e P T, I N R, i nf e cti o u s c a u s e s
A ut oi m m u n e s er ol o g y
P ar o x y s m al n o ct ur n al h e m o gl o bi n uri a s cr e e ni n g
Dir e ct a n d i n dir e ct bilir u bi n; L D H; dir e ct a g gl uti ni n t e st; a n d if n o o b vi o u s c a u s e, b o n e m arr o w a n al y si s, c yt o g e n eti c 
a n al y si s t o e v al u at e f or m y el o d y s pl a sti c s y n dr o m e s
E v al u ati o n f or vir al/ b a ct eri al ( m y c o pl a s m a, et c) c a u s e s of h e m ol y si s st u di e s
Pr ot ei n el e ctr o p h or e si s, cr y o gl o b uli n a n al y si s
W o r k-u p f or b o n e m arr o w f ail ur e s y n dr o m e if r efr a ct or y, i n cl u di n g B 1 2, f ol at e, c o p p er, p ar v o vir u s, ir o n, t h yr oi d, 
i nf e cti o n
Gl u c o s e - 6-p h o s p h at e d e h y dr o g e n a s e
E v al u ati o n of c o m m o n dr u g c a u s e s (ri b a viri n, rif a m pi n, d a p s o n e, i nt erf er o n, c e p h al o s p ori n s, p e ni cilli n s, N S AI D s, 
q ui ni n e/ q ui ni di n e, ﬂu d ar a bi n e, ci pr o ﬂo x a ci n, l or a z e p a m, di cl of e n a c, et c)
A s s e s s m e nt of m et h e m o gl o bi n e mi a
Gr a di n g
M a n a g e m e nt
G 1: H g b < L L N t o 1 0. 0 g/ d L; < L L N t o 6. 2 m m ol/ L; 
< L L N t o 1 0 0 g/ L
C o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -u p a n d 
l a b or at or y e v al u ati o n
G 2: H g b < 1 0. 0 t o 8. 0 g/ d L; < 6. 2 t o 4. 9 m m ol/ L; <
1 0 0 
t o 8 0 g/ L
H ol d I C Pi a n d str o n gl y c o n si d er p er m a n e nt 
di s c o nti n u ati o n
A d mi ni st er 0. 5 - 1 m g/ k g/ d pr e d ni s o n e e q ui v al e nt s
G 3: H g b < 8. 0 g/ d L; < 4. 9 m m ol/ L; < 8 0 g/ L; tr a n sf u si o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
S h o ul d u s e cli ni c al j u d g m e nt a n d c o n si d er a d mitti n g t h e 
p ati e nt
H e m at ol o g y c o n s ult
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s/ s p e e d of d e v el o p m e nt)
If w or s e ni n g or n o i m pr o v e m e nt, 1-2 m g/ k g/ d 
pr e d ni s o n e e q ui v al e nt s a n d p er m a n e ntl y di s c o nti n u e 
I C Pi tr e at m e nt
C o n si d er R B C tr a n sf u si o n p er e xi sti n g g ui d eli n e s; d o 
n ot tr a n sf u s e m or e t h a n t h e mi ni m u m n u m b er of R B C 
u nit s n e c e s s ar y t o r eli e v e s y m pt o m s of a n e mi a or t o 
r et ur n a p ati e nt t o a s af e H g b r a n g e ( 7-8 g/ d L i n st a bl e, 
n o n c ar di a c i n p ati e nt s)
S h o ul d off er p ati e nt s s u p pl e m e nt ati o n wit h f oli c a ci d 
1 m g o n c e d ail y
G 4: Lif e -t hr e at eni n g c o n s e q u e n c e s, ur g e nt i nt er v e nti o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
H e m at ol o g y c o n s ult
I V pr e d ni s o n e c orti c o st er oi d s 1-2 m g/ k g/ d
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 3 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
If n o i m pr o v e m e nt or if w or s e ni n g w hil e o n 
c orti c o st er oi d s or s e v er e s y m pt o m s o n pr e s e nt ati o n, 
i niti at e ot h er i m m u n o s u p pr e s si v e dr u g s, s u c h a s 
rit u xi m a b, I VI G, c y cl o s p ori n A, a n d m y c o p h e n ol at e 
m of etil
R B C tr a n sf u si o n p er e xi sti n g g ui d eli n e s; di s c u s s wit h 
bl o o d b a n k t e a m pri or t o tr a n sf u si o n s t h at a p ati e nt wit h 
p o s si bl e I C Pi s eri o u s A E i s i n h o u s e
A d diti o n al c o n si d er ati o n s: M o nit or H g b l e v el s o n a w e e kl y b a si s u ntil t h e c orti c o st er oi d t a p eri n g pr o c e s s i s 
c o m pl et e; t h er e aft er, l e s s fr e q u e nt t e sti n g i s n e e d e d
8. 2 A c q uir e d T T P
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y t h e pr e s e n c e of mi cr o a n gi o p at hi c h e m ol yti c a n e mi a, t hr o m b o c yt o p e ni c 
p ur p ur a, f e v er, r e n al a b n or m aliti e s, a n d n e ur ol o gi c a b n or m aliti e s, s u c h a s s ei z ur e s, h e mi pl e gi a, a n d vi s u al 
di st ur b a n c e s. It i s a n a c ut e or s u b a c ut e c o n diti o n
Di a g n o sti c w or k -u p
Hi st or y wit h s p e ci ﬁc q u e sti o n s r el at e d t o dr u g e x p o s ur e ( e . g., c h e m ot h er a p y, sir oli m u s, t a cr oli m u s, O p a n a 
e xt e n d e d r el e a s e, a nti bi oti c s, q ui ni n e), p h y si c al e x a mi n ati o n, p eri p h er al s m e ar
A D A M T S 1 3 a cti vit y l e v el a n d i n hi bit or tit er
L D H, h a pt o gl o bi n, r eti c ul o c yt e c o u nt, bilir u bi n, uri n al y si s t o r ul e o ut ot h er c a u s e s
P T, a cti v at e d P T T, ﬁbri n o g e n
Bl o o d gr o u p a n d a nti b o d y s cr e e n, dir e ct a nti gl o b uli n t e st, C M V s er ol o g y
C o n si d er C T/ M RI br ai n, e c h o c ar di o gr a m, E C G
Vir al st u di e s
N ot e: T hi s di s or d er i s u s u all y a s s o ci at e d wit h a s e v er e dr o p i n pl at el et s a n d h e m ol y si s/ a n e mi a pr e ci pit o u sl y
Gr a di n g
M a n a g e m e nt
All gr a d e s
T h e ﬁr st st e p i n t h e m a n a g e m e nt of T T P i s a hi g h i n d e x 
of s u s pi ci o n f or t h e di a g n o si s a n d ti m el y r e c o g niti o n; 
h e m at ol o g y c o n s ult s h o ul d i m m e di at el y b e c all e d, a s 
d el a y i n i d e nti ﬁc ati o n i s a s s o ci at e d wit h i n cr e a s e d 
m ort alit y/ m or bi dit y
I niti all y, t h e p ati e nt s h o ul d b e st a bili z e d a n d a n y criti c al 
or g a n d y sf u n cti o n s h o ul d b e st a bili z e d
G 1: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut a n e mi a, r e n al i n s uf ﬁci e n c y, or 
t hr o m b o c yt o p e ni a cli ni c all y
G 2: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut cli ni c al c o n s e q u e n c e wit h G 2 a n e mi a a n d 
t hr o m b o c yt o p e ni a
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er 
t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n e ﬁt s, n oti n g t h at 
t h er e ar e c urr e ntl y n o d at a t o r e c o m m e nd r e st arti n g 
I C Pi t h er a p y
H e m at ol o g y c o n s ult
A d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e
G 3: L a b or at or y ﬁn di n g s wit h cli ni c al c o n s e q u e n c e s ( G 3 
t hr o m b o c yt o p e ni a, a n e mi a, r e n al i n s ufﬁci e n c y > 2)
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s ( e. g., C N S 
h e m orr h a g e or t hr o m b o si s/ e m b oli s m or r e n al f ail ur e)
F or G 3: H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt 
o nl y aft er t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n e ﬁt s, 
n oti n g t h at t h er e ar e c urr e ntl y n o d at a t o r e c o m m e n d 
r e st arti n g I C Pi t h er a p y
F or G 4: p er m a n e ntl y  di s c o nti n u e IC Pi
H e m at ol o g y c o n s ult
I n c o nj u n cti o n wit h h e m at ol o g y, i niti at e P E X a c c or di n g 
t o e xi sti n g g ui d eli n e s wit h f urt h er P E X d e p e n d e nt o n 
cli ni c al pr o gr e s s
A d mi ni st er m et h yl pr e d ni s ol o n e 1 g I V d ail y f or 3 d a y s, 
wit h t h e ﬁr st d o s e t y pi c all y a d mi ni st er e d i m m e di at el y 
aft er t h e ﬁr st P E X
M a y off er rit u xi m a b
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 4 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
I n c a s e of m a n a g e m e nt wit h rit u xi m a b, I C Pi 
tr e at m e nt will b e di s c o nti n u e d
8. 3 H e m ol y ti c U r e mi c S y n dr o m e
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y a f or m of t hr o m b oti c mi cr o a n gi o p at h y wit h r e n al f ail ur e, h e m ol yti c a n e mi a, 
a n d s e v er e t hr o m b o c yt o p e ni a. Si g n s a n d s y m pt o m s of h e m ol yti c ur e mi c s y n dr o m e c a n i n cl u d e:
Bl o o d y di arr h e a
D e cr e a s e d uri n ati o n or bl o o d i n t h e uri n e
A b d o mi n al p ai n, v o miti n g, a n d o c c a si o n all y f e v er
P all or
S m all, u n e x pl ai n e d br ui s e s or bl e e di n g fr o m t h e n o s e a n d m o ut h
F ati g u e a n d irrit a bilit y
C o nf u si o n or s ei z ur e s
Hi g h bl o o d pr e s s ur e
S w elli n g of t h e f a c e, h a n d s, f e et, or e ntir e b o d y
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al c o n si d er ati o n f or n e w hi st or y of hi g h -ri s k dr u g s, h y p ert e n si o n, or c ar di a c 
c a u s e s) C B C wit h i n di c e s
Bl o o d s m e ar m or p h ol o g y. N ot e t h at t h e pr e s e n c e of s c hi st o c yt e s o n s m e ar i s criti c al f or di a g n o si s.
S er u m cr e ati ni n e
A D A M T S 1 3 (t o r ul e o ut T T P)
H o m o c y st ei n e/ m et h yl m al o ni c a ci d
C o m pl e m e nt t e sti n g C 3, C 4, C H 5 0 ( c o m pl e m e nt i n hi bit or y a nti b o di e s f or s u s p e ct e d f a mili al)
E v al u at e r eti c ul o c yt e c o u nt a n d m e a n c or p u s c ul ar v ol u m e
E v al u ati o n of i nf e cti o u s c a u s e, i n cl u di n g s cr e e ni n g f or E B V, C M V, H H V 6
E v al u ati o n f or n utriti o n al c a u s e s of m a cr o c yt o si s ( B 1 2 a n d f ol at e)
P a n cr e ati c e n z y m e s
E v al u ati o n f or di arr h e al c a u s e s, S hi g a t o xi n, E s c h eri c hi a c oli O 1 5 7, et c
Dir e ct a nti b o d y t e st ( C o o m b s t e st), h a pt o gl o bi n, L D H, a n d ot h er eti ol o gi e s of a n e mi a
E v al u ati o n f or c o m m o n dr u g s c a u si n g h e m ol y si s (t a cr oli m u s, c y cl o s p ori n e, sir oli m u s , et c)
E v al u ati o n f or c o n c urr e nt c o nf u si o n
Gr a di n g
M a n a g e m e nt
G 1 -2: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut cli ni c al c o n s e q u e n c e s of a n e mi a, 
t hr o m b o c yt o p e ni a Gr a d e 2
G 3: L a b or at or y ﬁn di n g s wit h cli ni c al c o n s e q u e n c e s 
( e. g., r e n al i n s ufﬁci e n c y, p et e c hi a e)
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s ( e. g., C N S 
t hr o m b o si s/ e m b oli s m or r e n al f ail ur e)
F or G 1 a n d G 2 : C o nti n u e I C Pi wit h cl o s e cli ni c al 
f oll o w-u p a n d l a b or at or y e v al u ati o n
S u p p orti v e c ar e
F or G 3 a n d G 4: P er m a n e ntl y di s c o nti n u e I C Pi
B e gi n t h er a p y wit h e c uli z u m a b t h er a p y 9 0 0 m g w e e kl y 
f or 4 d o s e s, 1 2 0 0 m g W e e k 5, t h e n 1 2 0 0 m g e v er y 
2 w e e k s
R e d bl o o d tr a n sf u si o n a c c or di n g t o e xi sti n g g ui d eli n e s
8. 4 A pl a sti c A n e mi a
D e ﬁniti o n: C o n diti o n i n w hi c h t h e b o d y st o p s pr o d u ci n g e n o u g h n e w bl o o d c ell s 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( cl o s e att e nti o n t o m e di c ati o n s, e x p o s ur e t o r a di ati o n, t o xi n s, r e c e nt vir al 
i nf e cti o n s), C B C, s m e ar, r eti c ul o c yt e c o u nt
Vir al st u di e s, i n cl u di n g C M V, H H V 6, E B V, p ar v o vir u s
N utriti o n al a s s e s s m e nt s i n cl u di n g B 1 2, f ol at e, ir o n, c o p p er, c er ul o pl a s mi n, vit a mi n D
S er u m L D H, r e n al f u n cti o n
W o r k-u p f or i nf e cti o u s c a u s e s
I d e ntif y m arr o w h y p o/ a pl a si a
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 5 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
B o n e m arr o w bi o p s y a n d a s pir at e a n al y si s
P eri p h er al bl o o d a n al y si s, i n cl u di n g n e utr o p hil c o u nt, pr o p orti o n of G PI -n e g ati v e c ell s b y ﬂo w f or P N H
Fl o w c yt o m etr y t o e v al u at e l o s s of G PI -a n c h or e d pr ot ei n s
T y p e a n d s cr e e n p ati e nt f or tr a n sf u si o n s a n d n otif y bl o o d b a n k t h at all tr a n sf u si o n s n e e d t o b e irr a di at e d a n d 
ﬁlt er e d
Gr a di n g
M a n a g e m e nt
G 1: N o n s e v er e, < 0. 5 p ol y m or p h o n u cl e ar c ell s × 1 0 9 / L 
h y p o c ell ul ar m arr o w, wit h m arr o w c ell ul arit y < 2 5 %, 
p eri p h er al pl at el et c o u nt > 2 0, 0 0 0, r eti c ul o c yt e c o u nt 
< 2 0, 0 0 0
H ol d I C Pi a n d pr o vi d e gr o wt h f a ct or s u p p ort a n d cl o s e 
cli ni c al f oll o w -u p, a n d l a b or at or y e v al u ati o n 
S u p p orti v e tr a n sf u si o n s a s p er l o c al g ui d eli n e s
G 2: S e v er e, h y p o c ell ul ar m arr o w < 2 5 % a n d 2 of t h e 
f oll o wi n g: A N C < 5 0 0, p eri p h er al pl at el et > 2 0, 0 0 0, a n d 
r eti c ul o c yt e < 2 0, 0 0 0
H ol d I C Pi a n d pr o vi d e gr o wt h f a ct or s u p p ort a n d cl o s e 
cli ni c al l a b or at or y e v al u ati o n s d a il y
A d mi ni st er A T G + c y cl o s p ori n e; H L A t y pi n g a n d 
e v al u ati o n f or b o n e m arr o w tr a n s pl a nt ati o n if p ati e nt i s 
c a n di d at e; all bl o o d pr o d u ct s s h o ul d b e irr a di at e d a n d 
ﬁlt er e d
S u p p orti v e c ar e wit h gr a n ul o c yt e c ol o n y -sti m ul ati n g 
f a ct or m a y b e a d d e d i n a d diti o n
G 3- 4: V er y s e v er e, A N C > 2 0 0, pl at el et c o u nt > 2 0, 0 0 0, 
r eti c ul o c yt e c o u nt > 2 0, 0 0 0, pl u s h y p o c ell ul ar m arr o w 
> 2 5 %
F or G 3: H ol d I C Pi a n d m o nit or w e e kl y f or i m pr o v e m e nt; 
if n ot r e s ol v e d, di s c o nti n u e tr e at m e nt u ntil A E h a s 
r e v ert e d t o G 1. 
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
H e m at ol o g y c o n s ult, gr o wt h f a ct or s u p p ort
H or s e A T G pl u s c y cl o s p ori n e
If n o r e s p o n s e, r e p e at i m m u n o s u p pr e s si o n wit h r a b bit 
A T G pl u s c y cl o s p ori n e, c y cl o p h o s p h a mi d e
F or r efr a ct or y p ati e nt s, c o n si d er eltr o m b o p a g pl u s 
s u p p orti v e c ar e
8. 5 L y m p h o p e ni a
D e ﬁniti o n: A n a b n or m all y l o w l e v el of l y m p h o c yt e s i n P B; f or a d ult s, c o u nt s of < 1, 5 0 0/ m m 3 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al att e nti o n f or l y m p h o c yt e -d e pl eti n g t h er a p y s u c h a s ﬂu d ar a bi n e, A T G, 
c orti c o st er oi d s, c yt ot o xi c c h e m ot h er a p y, r a di ati o n e x p o s ur e, et c, a s w ell a s hi st or y of a ut oi m m u n e di s e a s e, f a mil y 
hi st or y of a ut oi m m u n e di s e a s e) 
E v al u ati o n of n utriti o n al st at e a s c a u s e
S pl e e n si z e
C B C wit h diff er e nti al, p eri p h er al s m e ar a n d r eti c ul o c yt e c o u nt s
C X R f or e v al u ati o n of pr e s e n c e of t h y m o m a
B a ct eri al c ult ur e s a n d e v al u ati o n f or i nf e cti o n (f u n g al, vir al, b a ct eri al s p e ci ﬁc all y C M V/ HI V)
Gr a di n g
M a n a g e m e nt
G 1 -2: 5 0 0 -1, 0 0 0 P B l y m p h o c yt e c o u nt
G 3: 2 5 0 -4 9 9 P B l y m p h o c yt e c o u nt
G 4: < 2 5 0 P B l y m p h o c yt e c o u nt
C o nti n u e I C Pi f or G 1 t o G 2
F or G 3 si n gl e l a b or at or y val u e s o ut of n or m al r a n g e 
wit h o ut a n y  cli ni c al c orr el at e s, h ol d tr e at m e nt u ntil 
r e s ol uti o n t o G 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 6 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
F or G 4, f or si n gl e l a b or at or y v al u e s o ut of n or m al 
r a n g e wit h o ut a n y cli ni c al c orr el at e s, p er m a n e nt 
tr e at m e nt di s c o nti n u ati o n i s n ot r e q uir e d. Tr e at m e nt 
s h o ul d b e h el d u ntil t h e eti ol o g y  i s d et er mi n e d. 
P er m a n e nt tr e at m e nt di s c o nti n u ati o n w ill o nl y b e 
r e q uir e d, if l ym p h o p e ni a i s c o n si d er e d of 
i m m u n e-r el at e d i n n at ur e, n o cl e ar alt er n ati v e 
e x pl a n ati o n e xi st s f or t h e e v e nt, a n d G 4 
l ym p h o p e ni a d o e s n ot r e s ol v e wit hi n 1 4 d a y s. If t h e 
e v e nt i s n ot c o n si d er e d i m m u n e -r el at e d a n d 
r e s ol v e s t o G ≤1 r e st arti n g tr e at m e nt m a y b e 
c o n si d er e d.
C h e c k C B C w e e kl y f or m o nit ori n g, i niti ati o n of C M V 
s cr e e ni n g 
C o n si d er h ol di n g I C Pi
I niti at e M y c o b a ct eri u m a vi u m
c o m pl e x pr o p h yl a xi s a n d 
P n e u m o c y sti s jir o v e cii pr o p h yl a xi s, C M V s cr e e ni n g. 
HI V/ h e p atiti s s cr e e ni n g if n ot alr e a d y d o n e
M a y c o n si d er E B V t e sti n g if e vi d e n c e of 
l y m p h a d e n o p at h y/ h e p atiti s, f e v er s, h e m ol y si s 
c o n si st e nt wit h l y m p h o pr olif er ati v e di s e a s e
8. 6 I m m u n e T hr o m b o c y t o p e ni a
D e ﬁniti o n: A n a ut oi m m u n e di s or d er c h ar a ct eri z e d b y i m m u n ol o gi c d e str u cti o n of ot h er wi s e n or m al pl at el et s 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al att e nti o n f or l y m p h o c yt e -d e pl eti n g t h er a p y, s u c h a s ﬂu d ar a bi n e, A T G, 
c orti c o st er oi d s, c y t ot o xi c t h er a p y) F a mil y hi st or y of a ut oi m m u nit y or p er s o n al hi st or y of a ut oi m m u n e di s e a s e
Hi st or y of vir al ill n e s s
C B C
P eri p h er al bl o o d s m e ar, r eti c ul o c yt e c o u nt
B o n e m arr o w e v al u ati o n o nl y if a b n or m aliti e s i n t h e a b o v e t e st r e s ult s a n d f urt h er i n v e sti g ati o n i s n e c e s s ar y f or a 
di a g n o si s
P ati e nt s wit h n e wl y di a g n o s e d i m m u n e t hr o m b o c yt o p e ni a s h o ul d u n d er g o t e sti n g f or HI V, h e p atiti s C vir u s, 
h e p atiti s B vir u s, a n d H eli c o b a ct er p yl ori . Dir e ct a nti g e n t e st s h o ul d b e c h e c k e d t o r ul e o ut c o n c urr e nt E v a n s 
s y n dr o m e
N utriti o n al e v al u ati o n
B o n e m arr o w e v al u ati o n if ot h er c ell li n e s aff e ct e d a n d c o n c er n f or a pl a sti c a n e mi a
Gr a di n g
M a n a g e m e nt
G 1: Pl at el et c o u nt < 1 0 0/ µ L
G 2: Pl at el et c o u nt < 7 5/ µ L
C o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -u p a n d 
l a b or at or y e v al u ati o n
H ol d I C Pi b ut m o nit or f or i m pr o v e m e nt; if n ot r e s ol v e d, 
i nt err u pt tr e at m e nt u ntil A E h a s r e v ert e d t o G 1
A d mi ni st er pr e d ni s o n e 1 m g/ k g/ d ( d o s a g e r a n g e: 
0. 5 - 2 m g/ k g/ d) or all y f or 2 -4 w e e k s aft er w hi c h t h e 
m e di c ati o n s h o ul d b e t a p er e d o v er 4 -6 w e e k s t o t h e 
l ow e st eff e cti v e d o s e
I VI G m a y b e u s e d i n c o nj u n cti o n wit h c orti c o st er oi d s if a 
m or e -r a pi d i n cr e a s e i n pl at el et c o u nt i s r e q uir e d
G 3: Pl at el et c o u nt < 5 0/ µ L
H ol d I C Pi b ut m o nit or f or i m pr o v e m e nt; if n ot r e s ol v e d, 
i nt err u pt tr e at m e nt u ntil A E h a s r e v ert e d t o G 1
G 4: Pl at el et c o u nt < 2 5/ µ L
P er m a n e ntl y  di s c o nti n u e I C Pi
H e m at ol o g y c o n s ult
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 7 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s) a n d p er m a n e ntl y di s c o nti n u e tr e at m e nt
I VI G u s e d wit h c orti c o st er oi d s w h e n a m or e-r a pi d 
i n cr e a s e i n pl at el et c o u nt i s re q uir e d
If I VI G i s u s e d, t h e d o s e s h o ul d i niti all y b e 1 g/ k g a s a 1-
ti m e d o s e. T hi s d o s a g e m a y b e r e p e at e d if n e c e s s ar y
If pr e vi o u s tr e at m e nt wit h c orti c o st er oi d s a n d/ or I VI G 
u n s u c c e s sf ul, s u b s e q u e nt tr e at m e nt m a y i n cl u d e 
rit u xi m a b, t hr o m b o p oi eti n r e c e pt or a g o ni st s, or m or e 
p ot e nt i m m u n o s u p pr e s si o n ( Fr o m A m eri c a n S o ci et y of 
H e m at ol o g y g ui d eli n e o n i m m u n e t hr o m b o c yt o p e ni a 9 7; 
c o n s ult f or f urt h er d et ail s)
8. 7 A c q uir e d H e m o p hili a
D e ﬁniti o n: Di s or d er c a u s e d b y t h e d e v el o p m e nt of a ut o a nti b o di e s (i n hi bit or s) dir e ct e d a g ai n st pl a s m a c o a g ul ati o n 
f a ct or s 
Di a g n o sti c w or k -u p
F ull bl o o d c o u nt t o a s s e s s pl at el et n u m b er, ﬁbri n o g e n, P T, P T T, I N R; t h e t y pi c al ﬁn di n g i n p ati e nt s wit h a c q uir e d 
h e m o p hili a A i s a pr ol o n g e d a cti v at e d P T T wit h a n or m al P T
M RI, C T, a n d ultr a s o n o gr a p h y m a y b e i n di c at e d t o l o c ali z e, q u a ntif y, a n d s eri all y m o nit or t h e l o c ati o n a n d 
r e s p o n s e of bl e e di n g 
M e di c ati o n r e vi e w t o a s s e s s f or alt er n ati v e c a u s e s
D et er mi n ati o n of B et h e s d a u nit l e v el of i n hi bit or
Gr a di n g
M a n a g e m e nt
G 1: Mil d, 5 % -4 0 % of n or m al f a ct or a cti vit y i n bl o o d, 
0. 0 5 - 0. 4 I U/ m L of w h ol e bl o o d
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er 
t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n eﬁt s
A d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e
Tr a n sf u si o n s u p p ort a s r e q uir e d
Tr e at m e nt of bl e e di n g di s or d er s wit h h e m at ol o g y 
c o n s ult
G 2: M o d er at e, 1 % - 5 % of n or m al f a ct or a cti vit y i n bl o o d, 
0. 0 1 - 0. 0 5 I U/ m L of w h ol e bl o o d
H e m at ol o g y c o n s ult
A d mi ni str ati o n of f a ct or r e pl a c e m e nt ( c h o i c e b a s e d o n 
B et h e s d a u nit of tit er)
A d mi ni st er 1 m g/ k g/ d pr e d ni s o n e, ± rit u xi m a b ( d o s e, 
3 7 5 m g/ m
2 w e e kl y f or 4 w e e k s) a n d/ or 
c y cl o p h o s p h a mi d e ( d o s e, 1 -2 m g/ k g/ d); c h oi c e of 
rit u xi m a b or c y cl o p h o s p h a mi d e i s p ati e nt s p e ciﬁc a n d 
s h o ul d b e d o n e wit h a s si st a n c e of h e m at ol o g y c o n s ult; 
pr e d ni s o n e, rit u xi m a b, a n d c y cl o p h o s p h a mi d e s h o ul d 
b e gi v e n f or at l e a st 5 w e e k s
F a ct or s s h o ul d b e pr o vi d e d t o i n cr e a s e l e v el d uri n g 
bl e e di n g e pi s o d e s, wit h c h oi c e of f a ct or b a s e d o n 
pr e s e n c e or a b s e n c e of i n hi bit or
G 3 -4: S e v er e, < 1 % of n or m al f a ct or a cti vit y i n bl o o d, < 
0. 0 1 I U/ m L of w h ol e bl o o d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
H e m at ol o g y c o n s ult
A d mi ni str ati o n of f a ct or r e pl a c e m e nt, c h oi c e b a s e d o n 
B et h e s d a u nit l e v el of i n hi bit or B y p a s si n g a g e nt s m a y 
b e u s e d (f a ct or VII, f a ct or VIII i n hi bit or b y p a s s a cti vit y); 
c a uti o n s h o ul d b e t a k e n i n t h e el d erl y a n d t h o s e wit h 
c or o n ar y art er y di s e a s e
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 8 / 2 1 3
8. 0 H e m at ol o gi c T o xi citi e s
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s) ± rit u xi m a b ( d o s e, 3 7 5 m g/ m2 w e e kl y f or 
4 w e e k s) a n d/ or c y cl o p h o s p h a mi d e ( d o s e, 1- 2 m g/ k g/ d).
Tr a n sf u si o n s u p p ort a s r e q uir e d f or bl e e di n g
If w or s e ni n g or n o i m pr o v e m e nt a d d c y cl o s p ori n e or 
i m m u n o s u p pr e s si o n/i m m u n o a d s or pti o n
A d diti o n al c o n si d er ati o n s: T h e A m eri c a n H e art A s s o ci ati o n r e q uir e s s p e ci ali st cli ni c al a n d l a b or at or y e x p erti s e. 
C o n s ult a n d/ or tr a n sf er t o a s p e ci ali st c e nt er i s oft e n a p pr o pri at e. If c o n s ult ati o n wit h o r tr a n sf er t o a h e m o p hili a 
c e nt er i s n ot i m m e di at el y p o s si bl e, t h e n i n v e sti g ati o n a n d tr e at m e nt s h o ul d b e i niti at e d w hil e a li ai s o n i s b ei n g 
e st a bli s h e d
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m en d ati o n s ar e m o d er at e
A E = a d v er s e e v e nt, A N C = a b s ol ut e n e utr o p hil c o u nt, A N C A = a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s, 
A T G = a nti -t h y m o c yt e gl o b uli n, C B C = c o m pl et e bl o o d c o u nt, C M V = c yt o m e g al o vir u s, C N S = c e ntr al n er v o u s s y st e m, 
C T = c o m p ut e d t o m o gr a p h y, C X R = c h e st x- r a y, DI C = di s s e mi n at e d i ntr a v a s c ul ar c o a g ul ati o n, E B V = E p st ei n-B arr vir u s, 
E C G = el e ctr o c ar di o gr a m, G = gr a d e, G PI = gl y c o s yl p h o s p h ati d yli n o sit ol, H g b = h e m o gl o bi n, H H V 6 = h u m a n h er p e s vir u s 
6, HI V = h u m a n i m m u n o d efi ci e n c y vir u s, H L A = h u m a n l e u k o c yt e a nti g e n, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, 
I N R =i nt er n ati o n al n or m ali z e d r ati o, ir A E =i m m u n e-r el at e d a d v er s e e v e nt, I V =i ntr a v e n o u s, I VI G =i ntr a v e n o u s 
i m m u n o gl o b uli n, L D H =l a ct at e d e h y dr o g e n a s e, L L N =l o w er li mit of n or m al, M RI = m a g n eti c r e s o n a n c e i m a gi n g, 
N S AI D = n o n st er oi d al a nti -i nﬂa m m at or y dr u g, P B = p eri p h er al bl o o d, P E X = pl a s m a e x -c h a n g e, P N H = p ar o x y s m al 
n o ct ur n al h e m o gl o bi n uri a, P T = pr ot hr o m bi n ti m e, P T T = p arti al t hr o m b o pl a sti n ti m e, R B C =r e d bl o o d c ell, 
T T P =t hr o m b oti c t hr o m b o c yt o p e ni c p ur p ur a.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 7 9 / 2 1 3
T a ble A 9  
M a n a ge me nt of C ar di o v asc ul ar I m m u ne-rel ate d A d verse E ve nts i n 
P atie nts Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors 
9. 0 C ar di o v a s c ul ar T o xi citi e s
9. 1 M y o c ar diti s, P eri c ar diti s, Arr h yt h mi a s, I m p air e d V e ntri c ul ar F u n cti o n wit h H e art F ail ur e a n d V a s c uliti s
D e ﬁnit i o n: Si g n s a n d s y m pt o m s m a y i n cl u d e c h e st p ai n, arr h yt h mi a, p al pit ati o n s, p eri p h er al e d e m a, pr o gr e s si v e or 
a c ut e d y s p n e a, pl e ur al eff u si o n, f ati g u e
Di a g n o sti c w or k -u p
At b a s eli n e
E C G
C o n si d er tr o p o ni n, e s p e ci all y i n p ati e nt tr e at e d wit h c o m bi n ati o n i m m u n e t h er a pi e s u p o n si g n s/ s y m pt o m s 
( c o n si d er c ar di ol o g y c o n s ult)
E C G
Tr o p o ni n
B N P E c h o c ar di o gr a m C X R
A d diti o n al t e sti n g t o b e g ui d e d b y c ar di ol o g y a n d m a y i n cl u d e
Str e s s t e st
C ar di a c c at h eri z ati o n
C ar di a c M RI
Gr a di n g
M a n a g e m e nt
G 1: A b n or m al c ar di a c bi o m ar k er t e sti n g, i n cl u di n g 
a b n or m al E C G
G 2: A b n or m al s cr e e ni n g t e st s wit h mil d s y m pt o m s
G 3: M o d er at el y a b n or m al t e sti n g or s y m pt o m s wit h mil d 
a cti vit y
G 4: M o d er at e t o s e v er e d e c o m p e n s ati o n, I V m e di c ati o n 
or i nt er v e nti o n r e q uir e d, lif e -t hr e at e ni n g c o n diti o n s
All g r a d e s w arr a nt w or k- u p a n d i nt er v e nti o n gi v e n 
p ot e nti al f or c ar di a c c o m pr o mi s e
C o n si d er t h e f oll o wi n g:
F or G 1: H ol d I C Pi 
F or G 2, G 3, a n d G 4: P er m a n e ntl y di s c o nti n u e I C Pi
F or G 1 -G 4 : Hi g h -d o s e c orti c o st er oi d s ( 1 -2 m g/ k g of 
pr e d ni s o n e) i niti at e d r a pi dl y ( or al or I V d e p e n di n g o n 
s y m pt o m s)
A d mit p ati e nt, c ar di ol o g y c o n s ult ati o n
I m m e di at e tr a n sf er t o a c or o n ar y c ar e u nit f or p ati e nt s 
wit h el e v at e d tr o p o ni n or c o n d u cti o n a b n or m aliti e s
I n p ati e nt s wit h o ut a n i m m e di at e r e s p o n s e t o hi g h-d o s e 
c orti c o st er oi d s, c o n si d er e arl y i n stit uti o n of c ar di a c 
tr a n s pl a nt r ej e cti o n d o s e s of c orti c o st er oi d s 
( m et h yl pr e d ni s ol o n e 1 g e v er y d a y) a n d t h e a d diti o n of 
eit h er m y c o p h e n ol at e, i n ﬂi xi m a b, or a nti -t h y m o c yt e 
gl o b uli n
Q u alif yi n g st at e m e nt: Tr e at m e nt r e c o m m e n d ati o n s ar e b a s e d o n a n e c d ot al e vi d e n c e a n d t h e lif e -t hr e at e ni n g 
n at ur e of c ar di o v a s c ul ar c o m pli c ati o n s. T h e a p pr o pri at e n e s s of r e c h all e n gi n g r e m ai n s u n k n o w n. N ot e t h at 
i nﬂi xi m a b h a s b e e n a s s o ci at e d wit h h e art f ail ur e a n d i s c o ntr ai n di c at e d at hi g h d o s e s i n p ati e nt s wit h m o d er at e -
s e v er e h e art f ail ur e
9. 2 V e n o u s T hr o m b o e m b oli s m
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y o c cl u si o n of a v e s s el b y a t hr o m b u s t h at h a s mi gr at e d fr o m a di st al sit e vi a 
t h e bl o o d str e a m. Cli ni c al si g n s a n d s y m pt o m s ar e v ari a bl e a n d m a y i n cl u d e p ai n, s w elli n g, i n cr e a s e d s ki n v ei n 
vi si bilit y, er yt h e m a, a n d c y a n o si s a c c o m p a ni e d b y u n e x pl ai n e d f e v er f or D V T a n d d y s p n e a, pl e uriti c p ai n, c o u g h, 
w h e e zi n g, or h e m o pt y si s f or P E
Di a g n o sti c w or k -u p
E v al u ati o n of si g n s a n d s y m pt o m s of P E or D V T m a y i n cl u d e Cli ni c al pr e d i cti o n r ul e t o str atif y p ati e nt s wit h 
s u s p e ct e d v e n o u s t hr o m b o e m b oli s m V e n o u s ultr a s o u n d f or s u s p e ct e d D V T
C T P A f or s u s p e ct e d P E
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 0 / 2 1 3
9. 0 C ar di o v a s c ul ar T o xi citi e s
C a n al s o c o n si d er D -di m er f or l o w -ri s k p ati e nt s b a s e d o n ri s k str atiﬁc ati o n b y cli ni c al pr e di cti o n r ul e f or D V T/ P E 
w h e n C T or D o p pl er ar e n ot a v ail a bl e or a p pr o pri at e
V e ntil ati o n/ p erf u si o n s c a n i s al s o a n o pti o n w h e n C T P A i s n ot a p pr o pri at e
C o n si d er ot h er t e sti n g, i n cl u di n g E C G, C X R, B N P a n d tr o p o ni n l e v el s, a n d art eri al bl o o d g a s
Gr a di n g
M a n a g e m e nt
G 1: V e n o u s t hr o m b o si s ( e . g., s u p er ﬁci al t hr o m b o si s)
C o nti n u e I C Pi
W a r m c o m pr e s s
Cli ni c al s ur v eill a n c e
G 2: V e n o u s t hr o m b o si s ( e . g., u n c o m pli c at e d D V T), 
m e di c al i nt er v e nti o n i n di c at e d
G 3: T hr o m b o si s ( e . g., u n c o m pli c at e d P E [ v e n o u s], 
n o n e m b oli c c ar di a c m ur al [ art eri al] t hr o m b u s), m e di c al 
i nt er v e nti o n i n di c at e d
H ol d I C Pi u ntil A E r e v ert s b a c k t o G 1 or l e s s. If r e v ert s 
t o G 2, u s e b e n efit-ri s k a s s e s s m e nt f or I C Pi c o nti n u ati o n 
C o n si d er c o n s ult fr o m c ar di ol o g y or ot h er r el e v a nt 
s p e ci alti e s
L M W H  i s s u g g e st e d o v er V K A, d a bi g atr a n, ri v ar ox a b a n, 
a pi x a b a n, or e d o x a b a n f or i niti al a n d l o n g -t er m 
tr e at m e nt
I V h e p ari n i s a n a c c e pt a bl e alt er n ati v e f or i niti al u s e, 
a n d or al a nti c o a g ul a nt s ar e a c c e pt a bl e f or t h e l o n g -t er m
G 4: Lif e -t hr e at e ni n g ( e. g., P E, c er e br o v a s c ul ar e v e nt, 
art eri al i n s ufﬁci e n c y), h e m o d y n a mi c or n e ur ol o gi c 
i n st a bilit y, ur g e nt i nt er v e nti o n i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt a n d m a n a g e m e nt a c c or di n g t o C H E S T, 
A C C, a n d/ or A H A g ui d eli n e s a n d wit h g ui d a n c e fr o m 
c ar di ol o g y
R e s pir at or y a n d h e m o d y n a mi c s u p p o rt
L M W H  i s s u g g e st e d o v er V K A, d a bi g atr a n, ri v ar o x a b a n, 
a pi x a b a n, or e d o x a b a n f or i niti al a n d l o n g -t er m 
tr e at m e nt
I V h e p ari n i s a n a c c e pt a bl e alt er n ati v e f or i niti al u s e, 
a n d or al a nti c o a g ul a nt s ar e a c c e pt a bl e f or t h e l o n g -t er m
F urt h er cli ni c al m a n a g e m e nt a s i n di c at e d b a s e d o n 
s y m pt o m s
A d diti o n al c o n si d er ati o n s
W h il e it m a y b e i m p o s si bl e t o d et er mi n e t h e eti ol o g y of t hr o m b o e m b oli c di s e a s e i n p ati e nt s wit h a d v a n c e d c a n c er 
a n d t h e r ol e, if a n y, t h at I C Pi tr e at m e nt pl a y s, it i s r e a s o n a bl e t o r e m o v e t h e p ot e nt i al i n citi n g a g e nt s gi v e n t h e 
s e v erit y a n d lif e -t hr e at e ni n g p ot e nti al of G 4 c o m pli c ati o n s. Cli ni ci a n s ar e t o u s e cli ni c al j u d g m e nt a n d t a k e i nt o 
a c c o u nt t h e ri s k s a n d b e n e ﬁt s w h e n d e ci di n g w h et h er t o di s c o nti n u e I C Pi tr e at m e nt.
A nti c o a g ul a nt t h er a p y d ur ati o n s h o ul d c o nti n u e f or a mi ni m u m of 9 -1 2 m o nt h s t o i n d e ﬁnit el y f or a cti v e c a n c er 
u nl e s s p ati e nt i s a s y m pt o m ati c, d oi n g w ell, or i n r e mi s si o n
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A C C = A m eri c a n C oll e g e of C ar di ol o g y, A H A = A m eri c a n H e art A s s o ci ati o n, B N P = br ai n n atri ur eti c p e pti d e, 
C T = c o m p ut e d t o m o gr a p h y, C T P A = c o m p ut e d t o m o gr a p h y p ul m o n ar y a n gi o gr a p h y, C X R = c h e st x -r a y, D V T = d e e p v ei n 
t hr o m b o si s, E C G = el e ctr o c ar di o gr a m, G = gr a d e, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, 
 
, I V =i ntr a v e n o u s, L MW H =l o w -m ol e c ul ar - w ei g ht h e p ari n, M RI = m a g n eti c r e s o n a n c e i m a gi n g, P E = p ul m o n ar y 
e m b oli s m, V K A = vit a mi n K a g o ni st.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 1 / 2 1 3
T a ble A 1 0
M a n a ge me nt 
of Oc ul ar
I m m u ne-rel ate d A d verse E ve nts i n P atie nts 
Tre ate d wit h I m m u ne C hec k p oi nt I n hi bit ors
1 0. 0 O c ul ar T o xi citi e s
C o u n s el all p ati e nt s t o i nf or m t h eir h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e a n y of t h e f oll o wi n g o c ul ar 
s y m pt o m s
Bl urr e d vi si o n
C h a n g e i n c ol or vi si o n
P h ot o p h o bi a
Di st orti o n
S c ot o m a s
Vi s u al ﬁel d c h a n g e s, d o u bl e vi si o n, t e n d er n e s s
P ai n wit h e y e m o v e m e nt 
E y eli d s w elli n g 
Pr o pt o si s
E v al u ati o n, u n d er t h e g ui d a n c e of o p ht h al m ol o g y
C h e c k vi si o n i n e a c h e y e s e p ar at el y
C ol or vi si o n
R e d r e ﬂe x
P u pil si z e, s h a p e, a n d r e a cti vit y
F u n d o s c o pi c e x a mi n ati o n
I n s p e cti o n of a nt eri or p art of e y e wit h p e nli g ht
Pri or c o n diti o n s
E x cl u d e p ati e nt s wit h hi st or y of a cti v e u v eiti s
Hi st or y of r e c urr e nt u v eiti s r e q uiri n g s y st e mi c i m m u n o s u p pr e s si o n or c o nti n u o u s l o c al t h er a p y
A d diti o n al c o n si d er ati o n s
O c ul ar ir A E s ar e m a n y ti m e s s e e n i n t h e c o nt e xt of ot h er or g a n ir A E s
Hi g h l e v el of cli ni c al s u s pi ci o n a s s y m pt o m s m a y n ot al w a y s b e a s s o ci at e d wit h s e v erit y 
B e st t o tr e at aft er o p ht h al m ol o gi st e y e e x a mi n ati o n
1 0. 1 U v eiti s/I riti s
D e ﬁniti o n: I n ﬂa m m ati o n of t h e mi d dl e l a y er of t h e e y e 
Di a g n o sti c w or k -u p: a s p er a b o v e
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c
C o nti n u e I C Pi
R ef er t o o p ht h al m ol o g y wit hi n 1 w e e k
Arti ﬁci al t e ar s
G 2: M e di c al i nt er v e nti o n r e q uir e d, a nt eri or u v eiti s
H ol d I C Pi t e m p or aril y u ntil aft er o p ht h al m ol o g y c o n s ult
Ur g e nt o p ht h al m ol o g y r ef err al
T o pi c al c orti c o st er oi d s, c y cl o pl e gi c a g e nt s, s y st e mi c 
c orti c o st er oi d s
M a y r e s u m e I C Pi tr e at m e nt o n c e off s y st e mi c 
c orti c o st er oi d s, w hi c h ar e p ur el y i n di c at e d f or o c ul ar 
a d v er s e eff e ct s or o n c e c orti c o st er oi d s f or ot h er 
c o n c urr e nt s y st e mi c ir A E s ar e r e d u c e d t o ≤1 0 m g; 
c o nti n u e d t o pi c al/ o c ul ar c orti c o st er oi d s ar e p er mitt e d 
w h e n r e s u mi n g t h er a p y t o m a n a g e a n d mi ni mi z e l o c al 
t o xi cit y 
R e -tr e at aft er r et ur n t o G 1 or l es s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 2 / 2 1 3
1 0. 0 O c ul ar T o xi citi e s
G 3: P o st eri or or p a n u v eiti s
P er m a n e ntl y di s c o nti n u e I C Pi
Ur g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d 
i ntr a vitr e al/ p eri o c ul ar/t o pi c al c orti c o st er oi d s
G 4: 2 0/ 2 0 0 or w or s e
P er m a n e ntl y di s c o nti n u e I C Pi
E m er g e nt o p ht h al m ol o g y r ef err al
S y st e mi c c orti c o st er oi d s (I V pr e d ni s o n e 1 -2 m g/ k g or 
m et h yl pr e d ni s ol o n e 0. 8 -1. 6 m g/ k g) a n d 
i ntr a vitr e al/ p eri o c ul ar/t o pi c al c orti c o st er oi d s p er 
o p ht h al m ol o gi st o pi ni o n
A d diti o n al c o n si d er ati o n s: C o n si d er u s e of i n ﬂi xi m a b or ot h er T N F - α bl o c k er s i n c a s e s t h at ar e s e v er e a n d 
r efr a ct or y t o st a n d ar d tr e at m e nt
1 0. 2 E pi s cl eriti s
D e ﬁniti o n: I n ﬂa m m at or y c o n diti o n aff e cti n g t h e e pi s cl er al ti s s u e b et w e e n t h e c o nj u n cti v a a n d t h e s cl er a t h at o c c ur s 
i n t h e a b s e n c e of a n i nf e cti o n 
Di a g n o sti c w or k -u p: A s p er 1 0. 0
Gr a d i n g
M a n a g e m e nt
G 1: A s y m pt o m ati c
C o nti n u e I C Pi
R ef er t o o p ht h al m ol o g y wit hi n 1 w e e k
Arti ﬁci al t e ar s
G 2: Vi si o n 2 0/ 4 0 or b ett er
H ol d I C Pi t h er a p y t e m p or aril y u ntil aft er o p ht h al m ol o g y 
c o n s ult
Ur g e nt o p ht h al m ol o g y r ef err al
T o pi c al c orti c o st er oi d s, c y cl o pl e gi c a g e nt s, s y st e mi c 
c orti c o st er oi d s
G 3: S y m pt o m ati c a n d vi si o n w or s e t h a n 2/ 4 0
P er m a n e ntl y di s c o nti n u e I C Pi
Ur g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d t o pi c al c orti c o st er oi d s wit h 
c y cl o pl e gi c a g e nt s
G 4: 2 0/ 2 0 0 or w or s e
P er m a n e nt l y di s c o nti n u e I C Pi
E m er g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d t o pi c al c orti c o st er oi d s wit h 
c y cl o pl e gi c a g e nt s
A d diti o n al c o n si d er ati o n s: C o n si d er u s e of i n ﬂi xi m a b or ot h er T N F - α bl o c k er s i n c a s e s t h at ar e s e v er e a n d 
r efr a ct or y t o st a n dar d tr e at m e nt
1 0. 3 Bl e p h ariti s
D e ﬁniti o n: I n ﬂa m m ati o n of t h e e y eli d t h at aff e ct s t h e e y el a s h e s or t e ar pr o d u cti o n 
Di a g n o sti c w or k -u p: A s p er 1 0. 0
Gr a di n g
M a n a g e m e nt
N o f or m al gr a di n g s y st e m
W a r m c o m pr e s s e s a n d l u bri c ati o n dr o p s
C o nti n u e t h er a p y u nl e s s p er si st e nt a n d s eri o u s
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
G = gr a d e, I C Pi =i m m u n e c h e c k p oi nt i n hi bit or, ir A E =i m m u n e -r el at e d a d v er s e e v e nt, I V =i ntr a v e n o u s, T N F =t u m or 
n e cr o si s f a ct or.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 3 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 4 / 2 1 3
A p pe n di x 1 0
C o u ntr y -s pecific Re q uire me nts
Wit h t he f ollo wi n g e xce pti o ns, all c o u ntr y-s pecific pr ot oc ol re q uire me nts are o utli ne d wit hi n t he 
pr ot oc ol.
J a p a n
I n Ja pa n, all partici pa nts e nr olle d i n t he safet y r u n -i n c o h ort m ust u n der g o i n -h o use o bser vati o n i n 
a h os pital setti n g f or u ntil at least 2 4 h o urs after t he first a d mi nistrati o n of t he st u d y  i nter ve nti o n. 
T hereafter, h os pitalizati o n ca n be e xte n de d t o u p u ntil t he e n d of t he D L T e val uati o n peri o d if it is 
a p pr o priate f or t he safet y of t he partici pa nt. See als o Secti o ns 4. 1. 1 a n d 6. 6. 2 .
I n Ja pa n, if t he st u d y is n ot e x pa n de d t o t he pla n ne d N = 5 0 0 part, it is re gar de d t hat t he efficac y of 
bi ntraf us p alfa is n ot c o nfir me d statisticall y thr o u g h o ut t his st u d y, as st u d y is a c o nfir mat or y st u d y.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 5 / 2 1 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 6 / 2 1 3
A p pe n di x 1 1  
Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors ( R E CI S T) 
Versi o n 1. 1
T he te xt bel o w was o btai ne d fr o m t he f oll o wi n g refere nce:  Eise n ha uer 2 0 0 9 .
Defi niti o ns
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y  usi n g t he i nter nati o nal criteria pr o p ose d 
b y  the R E CI S T C o m mittee ( Versi o n 1. 1). C ha n ges i n o nl y  the lar gest dia meter ( u ni di me nsi o nal 
meas ure me nt) of t he t u m or lesi o ns are use d i n t he R E CI S T criteria. N ote: Lesi o ns are eit her 
meas ura ble or n o n- meas ura ble usi n g t he criteria pr o vi de d bel o w. T he ter m “e val ua ble” i n 
refere nce t o meas ura bilit y  will n ot be use d beca use it d oes n ot pr o vi d e a d diti o nal mea ni n g or 
acc urac y.
Meas ura ble Disease
T u m or lesi o ns: M ust be acc uratel y meas 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  CT sca n (irres pecti ve of sca n ner t ype) a n d M RI  (n o less t ha n d o u ble t he slice 
t hic k ness a n d a mi ni m u m of 1 0 m m)

1 0 m m cali per meas ure me nt b y  cli nical e xa m ( w he n s u perficial)

2 0 m m b y  c hest X-ra y (if clearly defi ne d a n d s urr o u n de d b y aerate d l u n g).
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 ly m p h n o de 
m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y  C T sca n ( C T sca n slice t hic k ness rec o m me n de d 
t o be n o greater t ha n 5 m m). At Baseli ne a n d i n F oll o w - u p, o nl y  the s h ort a xis will be meas ure d 
a n d f oll o we d.
N o n- meas ura ble Disease
All ot her lesi o ns ( or sites of disease), i ncl u di n g s mall lesi o ns (l o n gest dia meter ≥1 0 t o < 1 5 m m 
wit h c o n ve nti o nal tec h ni q ues or < 1 0 m m usi n g s piral C T sca n), are c o nsi dere d n o n- meas ura ble 
disease. Le pt o me ni n geal disease, ascites, p le ural or pericar dial eff usi o n, i nfla m mat or y breast 
disease, l ym 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 me gal y 
i de ntifie d b y p h ysical e xa mi nati o n 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 are 
all n o n-meas ura b le.
B o ne lesi o ns:

B o ne sca n, P E T sca n, or plai n fil ms are n ot c o nsi dere d a de q uate i ma gi n g tec h ni q ues t o 
meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m t he prese nce or 
disa p peara nce of b o ne lesi o ns.

L yt ic b o ne lesi o ns or mi xe d l ytic-blastic lesi o ns, wit h i de ntifia ble s oft tiss ue c o m p o ne nts, 
t hat ca n be e val uate d b y  cr oss-secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI  ca n b e 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 7 / 2 1 3
c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of 
meas ura bilit y  descri be d a bo ve.

Blastic b o ne lesi o ns are n o n- meas ura ble.
Cystic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be 
c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n- meas ura ble) si nce t he y are, 
b y  defi niti o n, si m ple c ysts.

C y stic lesi o ns t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble 
lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y  descri be d a b o ve. H o we ver, if 
n o n- c ystic lesi o ns are prese nt i n t he sa me partici pa nt, t hese are preferre d for selecti o n as 
tar get lesi o ns.
Lesi o ns wit h pri or l oc al tre at me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her l ocal 
re gi o nal t hera p y, are us uall y  not c o nsi dere d meas ura ble u nless t here has bee n de m o nstrate d 
pr o gressi o n i n t he lesi o n. St u d y  pr ot oc ols s h o ul d detail t he c o n diti o ns u n der w hic h s uc h 
lesi o ns w o ul d be c o nsi dere d meas ura ble.
Tar get Lesi o ns
All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, s h o ul d be 
i de ntifie d as t ar get lesi o ns a n d rec or de d a n d meas ure d at Baseli ne. Tar get lesi o ns s h o ul d be 
selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re peate d 
meas ure me nts.
L y m p h n o des merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h m a y  be 
visi ble b y  ima gi n g e ve n if n ot i n v ol ve d b y  tu m or. Pat h ol o gical n o des w hic h are defi ne d as 
meas ura ble a n d m a y  be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis of 
≥1 5 m m b y  CT sca n. O nl y  the s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m. T he 
s h ort a xis of t he n o de is t he dia meter n or mally use d b y  ra di ol o gists t o j u d ge if a n o de is i n v ol ve d 
b y  soli d t u m or. N o dal size is n or mall y re p orte d as 2 di me nsi o ns i n t he pla ne i n w hic h t he i ma ge is 
o btai ne d (f or C T sca n t his is al m ost al wa y s t he a xial pla ne; f or M RI t he pla ne of ac q uisiti o n ma y 
be a xial, sa gittal, or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or e xa m ple, a n 
a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of 2 0 m m a n d q ualifies 
as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o ul d be rec or de d as t he n o de 
meas ure me nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥1 0 m m b ut < 1 5 m m) s h o ul d 
be c o nsi dere d n o n- tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-
pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.
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 orte d as t he baseli ne s u m dia meters. If l ym p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. T he baseli ne 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 8 / 2 1 3
s u m dia meters will be use d as refere nce t o f urt her c haracterize a n y objecti 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 -tar get Lesi o ns
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l ym 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 re 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 i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( m ore details t o f oll o w). I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e. g., ‘ m ulti ple e nlar ge d pel vic l ym p h 
n o des’ or ‘ m ulti ple li ver metastases’). 
G UI D E LI N E S F O R E V A L U A TI O N O F M E A S U R A B L E DI S E A S E
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y assesse d. All 
Baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d ne ver m ore 
t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt.
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be us e d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at Baseli ne a n d d uri n g f oll o w-u p. I ma gi n g base d e val uati o n s h o ul d 
al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xami nati o n.
N o p h ot o gra p hs, n o s ki n lesi o n meas ure me nt b y  cali pers a n d n o meas ure me nts o n c hest X -ra y will 
be d o ne i n t his st u d y .
C T, M RI: C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns selecte d 
f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n 
t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. As is descri be d i n A p pe n di x II of t he 
ori gi nal s o urce article cite d a b o ve, w he n C T sca ns ha ve slice t hic k ness greater t ha n 5 m m, t he 
mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. M RI  is als o acce pta ble 
i n certai n sit uati o ns (e. g., f or b o dy sca ns). 
Ultr as o u n d: Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure me n t. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vie w at a later date a n d, beca use t he y are o perat or de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m 1 assess me nt t o t he ne xt.
If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n b y C T or M RI 
is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI m a y be use d i nstea d of C T i n 
selecte d i nsta nces.
E n d osc o p y, l a p ar osc o p y: T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is n ot 
a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n bi o psies 
are o btai ne d or t o deter mi ne rela pse i n st u dies w here rec urre nce f oll o wi n g C R or s ur gical resecti o n 
is a n e n d p oi nt.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 8 9 / 2 1 3
T u m or m a r kers: T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit; h o we ver, t he y m ust n or malize f or a partici pa nt 
t o be c o nsi dere d i n C R. Beca use t u m or ma r kers are disease s pecific, i nstr ucti o ns f or t heir 
meas ure me nt s h o ul d be i nc or p orate d i nt o pr ot oc ols o n a disease s pecific basis. S pecific g ui deli nes 
f or b ot h C A-1 2 5 res p o nse (i n rec urre nt o varia n ca ncer) a n d pr ostate -s pecific a nti ge n res p o nse (i n 
rec urre nt pr ostate ca ncer), ha ve bee n p u blis he d. I n a d diti o n, t he G y nec ol o gic Ca ncer I nter gr o u p 
has de vel o pe d C A - 1 2 5 pr o gressi o n criteria w hic h are t o be i nte grate d wit h o bjecti ve t u m or 
assess me nt f or use i n first -li ne st u dies i n o varia n ca ncer.
C yt ol o g y, hist ol o g y: T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare 
cases if re q uire d b y pr ot oc ol (e. g., resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell t u m ors, w here 
k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n t o be a p ote n tial a d verse 
e ve nt ( A E) of treat me nt (e. g., wit h certai n ta xa ne c o m p o u n ds or a n gi o ge nesis i n hi bit ors), t he 
c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns d uri n g 
treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse or sta ble disease
(S D ) i n or der t o differe ntiate bet wee n res p o nse ( or S D) a n d P D.
R E S P O N S E C RI T E RI A
E val uati o n of Tar get Lesi o ns
C R: Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l ym 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.
P R: At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere nce t he 
baseli ne s u m dia meters. 
P D: At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere nce t he 
s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if t hat is t he s mallest o n st u d y). In a d diti o n 
t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 
5 m m. ( N ote: t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n). 
S D: Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o q ualif y f or P D, ta ki n g 
as refere nce t he s mallest s u m dia meters w hile o n st u d y . 
Ly m p h n o des. L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he Baseli ne e xa mi nati o n), e ve n 
if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l ym p h n o des are i ncl u de d as 
tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y  not be zer o e ve n if C R criteria are met, si nce a n or mal 
l ym p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. Case re p ort f or ms ( C R Fs) or ot her data 
c ollecti o n met h o ds ma y  t heref ore be desi g ne d t o ha ve tar get n o dal lesi o ns rec or de d i n a se parate 
secti o n w here, i n or der t o q ualif y for C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. F or P R, 
S D, a n d P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m of tar get 
lesi o ns.
T ar get lesi o ns t h at bec o me ‘t o o s m all t o me as ure’.
W hile 
o n st u d y, all lesi o ns ( n o dal a n d 
n o n- n o dal) rec or de d at Baseli ne s h o ul d ha ve t heir act ual meas ure me nts 
rec or de d at eac h 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 0 / 2 1 3
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g., 2 m m). H o we ver, s o meti mes lesi o ns or l y m p h 
n o des w hic h are rec or de d as tar get lesi o ns at Baseli ne bec o me s o fai nt o n C T sca n t hat t he 
ra di ol o gist m a y  not feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as bei n g 
‘t o o s mall t o meas ure’. W he n t his occ urs, it is i m p orta nt t hat a val ue be rec or de d o n t he e C R F. If 
it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he meas ure me nt s h o ul d 
be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is fai ntly see n b ut t o o s mall t o 
meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d. ( N ote: It is less li kel y that t his r ule will be 
use d f or l ym p h n o des si nce t he y us ually ha ve a defi na ble size w he n n or mal a n d are fre q ue ntly 
s urr o u n de d b y  fat, s uc h as i n t he retr o perit o ne u m; h o we ver, if a l ym p h n o de is belie ve d t o be 
prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a d efa ult val ue of 5 m m s h o ul d be assi g ne d i n 
t his circ u msta nce as well). T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut 
s h o ul d n ot be c ha n ge d wit h var y i n g C T slice t hic k ness). T he meas ure me nt of t hese lesi o ns is 
p ot e ntiall y no n- re pr o d uci ble; t heref ore, pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses 
or pr o gressi o ns base d u p o n meas ure me nt err or. T o reiterate, h o we ver, if t he ra di ol o gist is a ble t o 
pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if i t is bel o w 5 m m.
Lesi o ns t h at s plit or c o alesce o n tre at me nt. W he n 
n o n- n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 
Si milarl y , as lesi o ns c oalesce, a pla ne bet wee n the m ma y  be mai ntai ne d t hat w o ul d ai d i n o btai ni n g 
ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr uly c oalesce d s uc h 
t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n t his i nsta nce s h o ul d be t he 
ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’.
E val uati o n of N o n -tar get Lesi o ns
W hile s o me n o n- tar get lesi o ns ma y  act uall y be meas ura ble, t he y nee d n ot be meas ure d a n d i nstea d 
s h o ul d be assesse d o nly q ualitati vel y  at t he ti me p oi nts s pecifie d i n t he pr ot oc ol. 
C R: Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n of t u m or mar ker le vel. All l ym 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). 
N o n -C R/ N o n -P D: Persiste nce of 1 or m ore n o n- tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le vel a b o ve t he n or mal li mits.
P D: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n- tar get lesi o ns. ( N ote: t he 
a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n). 
W h e n t he p artici p a nt als o h as me as ur a ble dise ase. I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal 
pr o gressi o n’ o n t he basis of t he n o n- tar get disease, t here m ust be a n o verall le vel of s u bsta ntial 
w orse ni n g i n n o n -tar get disease s uc h t hat, e ve n i n t he prese nce of S D or partial res p o nse i n tar get 
disease, t he o verall t u m or b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y. A 
m o dest ‘i ncrease’ i n t he size of 1 or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y f or 
u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n s olel y on t he basis of 
c ha n ge i n n o n-tar get disease i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y 
rare.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 1 / 2 1 3
W h e n t he p artici p a nt h as o nly n o n- me as ur a ble dise ase. T his circ u msta nce arises i n s o me P hase III 
st u dies w he n it is n ot a criteri o n of st ud y  entr y  to ha ve meas ura ble disease. T he sa me ge neral 
c o nce pt a p plies here as n ote d a b o ve; h o we ver, i n t his i nsta nce t here is n o meas ura ble disease 
assess me nt t o fact or i nt o t he i nter pretati o n of a n i ncrease i n n o n- meas ura ble disease b ur de n. 
Beca use w orse n i n g i n n o n -tar get disease ca n n ot be easil y qua ntifie d ( by defi niti o n: if all lesi o ns 
are tr ul y no n- meas ura ble), a usef ul test t hat ca n be a p plie d w he n assessi n g partici pa nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall disease b ur d e n base d o n t he c ha n ge 
i n n o n- meas ura ble disease is c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o 
declare P D f or meas ura ble disease: i.e., a n i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 
7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a meas ura ble lesi o n). 
E xa m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge’, a n i ncrease i n 
l ym p ha n gitic disease fr o m l ocalize d t o wi des prea d, or ma y  be descri be d i n pr ot oc ols as ‘s ufficie nt 
t o re q uire a c ha n ge i n t hera py’.  If ‘ u ne q ui v ocal pr o gressi o n’ is see n, t he partici pa nt s h o ul d be 
c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal t o ha ve o bjecti ve criteria 
t o a p pl y to n o n- meas ura ble disease, t he ver y  nat ure of t hat di sease ma kes it i m p ossi ble t o d o s o; 
t heref ore, t he i ncrease m ust be s u bsta ntial.
Ne w Lesi o ns
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me c o m me nts 
o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he i de ntificati o n of 
ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal: i.e., n ot 
attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g m o dalit y, or fi n di n gs t h o u g ht 
t o re prese nt s o met hi n g ot her tha n t u m or (e. g., s o me ‘ ne w’ b o ne lesi o ns ma y  be si m pl y heali n g or 
flare of pre -e xisti n g lesi o ns). T his is partic ularl y i m p orta nt w he n t he partici pa nt’s Baseli ne lesi o ns 
s h o w partial or C R. F or e xa m ple, necr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as 
a ‘ ne w’ c ystic lesi o n, w hic h it is n ot. 
A lesi o n i de ntifie d o n a f oll o w-u p st u d y in a n a nat o mical l ocati o n t hat was n ot sca n ne d at Baseli ne 
is c o nsi dere d a ne w lesi o n a n d will i n dicate P D. A n e xa m ple of t his is t he partici pa nt w h o has 
visceral disease at Baseli ne a n d w hile o n st u d y has a brai n C T or M RI  or dere d w hic h re veals 
metastases. T he partici pa nt’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n if he/s he 
di d n ot ha ve brai n i ma gi n g at Baseli ne.
If a ne w lesi o n is e q ui v ocal, e. g., beca use of its s mall size, c o nti n ue d t hera py a n d f oll o w-u p 
e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is defi nitel y 
a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.
W hile
fl u de o xy gl uc ose p ositr o n e missi o n t o m o gra p hy ( F D G-P E T) res p o nse assess me nts nee d 
a d diti o nal st u dies, it is s o meti mes reas o na ble t o i nc or p orate t he use of F D G -P E T sca n ni n g t o 
c o m ple me nt C T sca n ni n g i n assess me nt of pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ disease). Ne w 
lesi o ns o n t he basis of F D G- P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m:
a.
Ne gati ve F D G -P E T at Baseli ne, wit h a p ositi ve F D G -P E T at f oll o w -u p is a si g n of P D base d 
o n a ne w lesi o n.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 2 / 2 1 3
b.
N o F D G -P E T at Baseli ne a n d a p osit i ve F D G -P E T at f oll o w-u p: If t he p ositi ve F D G -P E T at 
f oll o w- u p c orres p o n ds t o a ne w site of disease c o nfir me d b y  CT, t his is P D. If t he p ositi ve 
F D G -P E T at f oll o w- u p is n ot c o nfir me d as a ne w site of disease o n C T, a d diti o nal f oll o w- u p 
C T sca ns are nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat site (if s o, t he 
date of P D will be t he date of t he i nitial a b n or mal F D G -P E T sca n). If t he p ositi ve F D G -P E T 
at f oll o w-u p c orres p o n ds t o a pre -e xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he 
basis of t he a nat o mic i ma ges, t his is n ot P D.
E val uati o n of Best O verall Res p o nse
T he best o verall res p o nse ( B O R) is t he best res p o nse rec or de d fr o m t he start of t he st u d y 
i nter ve nti o n u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n. O n 
occasi o n, a res p o nse ma y n ot be d oc u me nte d u ntil after t he e n d of t he ra py, s o pr ot oc ols s h o ul d be 
clear if p ost treat me nt assess me nts are t o be c o nsi dere d i n deter mi nati o n of B O R. Pr ot oc ols m ust 
s pecif y h o w a ny ne w t hera p y i ntr o d uce d bef ore pr o gressi o n will affect best res p o nse desi g nati o n. 
T he partici pa nt’s B O R assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n- tar get disease 
a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns. F urt her m ore, de pe n di n g o n 
t he nat ure of t he st u d y an d t he pr ot oc ol re q uire me nts, it ma y  als o re q uire c o nfir mat or y 
meas ure me nt. S pecificall y , i n n o n -ra n d o mize d st u dies w here res p o nse is t he pri mar y  en d p oi nt, 
c o nfir mati o n of P R or C R is nee de d t o dee m eit her 1 t he ‘ B O R’. 
T he B O R is deter mi ne d o nce all t he data f or t he partici pa nt is k n o w n. Best res p o nse deter mi nati o n 
i n st u dies w here c o nfir mati o n of c o m plete or P R is n ot re q uire d: Best res p o nse i n t hese st u dies is 
defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a partici pa nt w h o has S D at first 
assess me nt, P R at sec o n d assess me nt, a n d P D o n last assess me nt ha s a B O R of P R). W he n S D is 
belie ve d t o be best res p o nse, it m ust als o meet t he pr ot oc ol -s pecifie d mi ni m u m ti me fr o m baseli ne. 
If t he mi ni m u m ti me is n ot met w he n S D is ot her wise t he best ti me p oi nt res p o nse, t he partici pa nt’s 
best res p o nse de pe n ds o n t he su bse q ue nt assess me nts. F or e xa m ple, a partici pa nt w h o has S D at 
first assess me nt, P D at sec o n d a n d d oes n ot meet mi ni m u m d urati o n f or S D, will ha ve a best 
res p o nse of P D. T he sa me partici pa nt l ost t o f oll o w- u p after t he first S D assess me nt w o ul d be 
c o nsi dere d i ne val ua ble.
T ar g et L e si o n s
N o n -t ar g et L e si o n s
N e w  L e si o n s
O v er all R e s p o n s e
C R
C R
N o
C R
C R
C R
N o n -C R/ n o n -P D
N ot E v al u at e d
N o
N o
P arti al r e s p o n s e
P arti al r e s p o n s e
P arti al r e s p o n s e
N o n - P D or n ot all e v al u at e d
N o
P arti al r e s p o n s e
S D
N o n - P D or n ot all e v al u at e d
N o
S D
N ot all e v al u at e d
N o n -P D
N o
N E
P D
A n y
Y e s or N o
P D
A n y
P D
Y e s or N o
P D
A n y
A n y
Y e s
P D
C R = c o m pl et e r e s p o n s e, N E = n ot e v al u a bl e, S D = st a bl e di s e a s e, P D = pr o gr e s si v e di s e a s e.
S e e t e xt f or m or e d et ail s.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 3 / 2 1 3
N ote:
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o ‘ n or mal’ 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o versta te pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns t hat partici pa nts wit h C R ma y  
n ot ha ve a t otal s u m of ‘zer o’ o n t he e C R F. 
I n st u dies w here c o nfir mati o n of res p o nse is re q uire d, re peate d ‘ N E’ ti me p oi nt assess me nts ma y 
c o m plicate best res p o nse deter mi nati o n. T he a nal ysis pla n f or t he st u d y must a d dress h o w missi n g 
data/assess me nts will be a d dresse d i n deter mi nati o n of res p o nse a n d pr o gressi o n. F or e xa m ple, i n 
m ost st u dies, it is reas o na ble t o c o nsi der a parti ci pa nt wit h ti me p oi nt res p o nses of P R -N E -P R as 
a c o nfir me d res p o nse.
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of P D at t hat ti me s h o ul d be re p orte d as ‘s ym pt o matic deteri or ati o n’. 
E ver y  eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of 
treat me nt. Sy m pt o matic deteri orati o n is n ot a descri pt or of a n o bjecti ve res p o nse; it is a reas o n f or 
st o p pi n g st u d y t hera p y. 
C o n diti o ns t hat defi ne ‘earl y pr o gressi o n, earl y deat h, a n d i ne val ua bilit y’ are st u d y-s pecific a n d 
s h o ul d be clearl y descri be d i n eac h pr ot oc ol ( de pe n di n g o n treat me nt d urati o n, a n d treat me nt 
peri o dicit y ).
I n s o me circ u msta nces it ma y  be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. W he n 
t he e val uati o n of C R de pe n ds u p o n t his deter mi nati o n, it is rec o m me n de d t hat t he resi d ual lesi o n 
be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) bef ore assi g ni n g a stat us of C R. T he use of F D G -P E T 
ma y  be use d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y  in cases w here a resi d ual 
ra di o gra p hic a b n or malit y is t h o u g ht t o re prese nt fi br osis or scarri n g. T he use of F D G-P E T i n t his 
circ u msta nce s h o ul d be pr os pecti vely descri be d i n t he pr ot oc ol a n d s u p p orte d b y  disease s pecific 
me dical literat ure f or t he i n dicati o n. H o we ver, it m ust be ac k n o wle d ge d t hat b ot h a p pr oac hes ma y 
lea d t o false p ositi ve C R d ue t o li mitati o ns of F D G-P E T a n d bi o ps y  res ol uti o n/se nsiti vit y.
F or e q ui v ocal fi n di n gs of pr o gressi o n (e. g., ver y  s mall a n d u ncertai n ne w lesi o ns; c y stic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y  co nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w he n pr o gressi o n was s us pecte d.
C O N FI R M A T O R Y M E A S U R E M E N T/ D U R A TI O N O F R E S P O N S E
C o nfir mati o n
I n n o n-ra n d o mize d st u dies w here res p o nse is t he pri mar y e n d p oi nt, c o nfir mati o n of P R a n d C R is 
re q uire d t o e ns ure t he res p o nses i de ntifie d are n ot t he res ult of meas ure me nt err or. T his will als o 
per mit a p pr o priate i nter pretati o n of res ults i n t he c o nte xt of hist orical data w here res p o nse has 
tra diti o nall y re q uire d c o nfir mati o n i n s uc h st u dies. H o we ver, i n all ot her circ u msta nces, i. e., i n 
ra n d o mize d st u dies ( P hase II or III) or st u dies where S D or pr o gressi o n are t he pri mar y e n d p oi nts, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 4 / 2 1 3
c o nfir mati o n of res p o nse is n ot re q uire d si nce it will n ot a d d val ue t o t he i nter pretati o n of t he st u d y 
res ults. H o we ver, eli mi nati o n of t he re q uire me nt f or res p o nse c o nfir mati o n ma y  increase t he 
i m p orta nce of ce ntral re vie w t o pr otect a gai nst bias, i n partic ular i n st u dies w hic h are n ot bli n de d.
I n t he case of S D, meas ure me nts m ust ha ve met t he S D criteria at least o nce after st u d y e ntr y at a 
mi ni m u m i nter val (i n ge neral n ot less t ha n 6 t o 8 wee ks) t hat is defi ne d i n t he st u d y  pr ot oc ol.
D urati o n of O verall Res p o nse
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or P D is o bjecti vel y 
d oc u m e nte d (ta ki n g as refere nce f or P D t he s mallest meas ure me nts rec or de d o n st u d y ).
T he d urati o n of o verall C R is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or C R 
u ntil t he first date t hat rec urre nt disease is o bjecti vel y d oc u me nte d. 
D urati o n of Sta ble Disease
Sta ble disease is meas ure d fr o m t he start of t he treat me nt (i n ra n d o mize d st u dies, fr o m date of 
ra n d o mizati o n) u ntil t he criteria f or pr o gressi o n are met, ta ki n g as refere nce t he s mallest s u m o n 
st u d y (if t he baseli ne s u m is t he s mallest, t his is t he refere nce f or calc ulati o n of P D).
T he cli nical rele va nce of t he d urati o n of S D varies i n differe nt st u dies a n d diseases. If t he 
pr o p orti o n of partici pa nts ac hie vi n g S D f or a mi ni m u m peri o d of ti me is a n e n d p oi nt of i m p orta nce 
i n a partic ular st u d y, t he pr ot oc ol s h o ul d s pecif y the mi ni mal ti me i nter val re q uire d bet wee n 
2 meas ure me nts f or deter mi nati o n of S D.
N ote: T he D O R a n d S D as well as t he P F S are i nfl ue nce d b y  the fre q ue nc y of f oll o w- u p after 
baseli ne e val uati o n. It is n ot i n t he sc o pe of this g ui deli ne t o defi ne a sta n dar d f oll o w- u p fre q ue nc y. 
T he fre q ue nc y sh o ul d ta ke i nt o acc o u nt m a n y  para meters i ncl u di n g disease t ypes a n d sta ges, 
treat me nt peri o dicit y , a n d sta n dar d practice. H o we ver, t hese li mitati o ns of t he precisi o n of t he 
meas ure d e n d p oi nt s h o ul d be ta ke n i nt o acc o u nt if c o m paris o ns bet wee n st u dies are t o be ma de.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 5 / 2 1 3
A p pe n di x 1 2
Pr ot oc ol A me n d me nt Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is pr o vi de d o n t he title pa ge .
Pr ot oc ol Versi o n 4. 0 ( 2 0 A pril 2 0 2 1 )
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  dri ver f or t his a me n d me nt is t o s pecif y t hat efficac y data fr o m t he first 1 5 0 a nti bi otics -
nai ve partici pa nts e nr olle d i n P hase II will be use d f or t he decisi o n o n t he e x pa nsi o n i nt o P hase 
III. I n a d diti o n, a d ose m o dificati o n of bi ntraf us p alfa/ place b o f or ma na ge me nt of blee di n g e ve nts 
has bee n a d de d.
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e
R e m o v e d “ M e di c al R e s p o n si bl e”, 
“ A m e n d m e nt N u m b er”, a n d 
“ R e pl a c e s V er si o n” fi el d s  
T o b e c o n si st e nt wit h c urr e nt S p o n s or 
pr ot o c ol t e m pl at e ( V er si o n 1 5)
Titl e P a g e
C h a n g e d d et ail s of M e di c al M o nit or 
D et ail s r el at e d t o M e di c al M o nit or 
r e s p o n si bl e f or t h e st u d y h a v e b e e n 
u p d at e d. 
1. 1 S y n o p si s
1. 2 S c h e m a: Fi g ur e 1 O v er all 
St u d y D e si g n S c h e m a
4. 1 O v er all D e si g n
Fi g ur e 2 O utli n e of R a n d o mi z e d, 
D o u bl e -bli n d St u d y D e si g n
9. 3. 1 A n al y si s f or t h e A d a p t ati o n 
D e ci si o n
S e cti o n 9. 5. 4 S e q u e n c e of 
A n al y s e s, T a bl e 2 6 S e q u e n c e of 
Pl a n n e d A n al y s e s
A n a d diti o n al crit eri o n h a s b e e n 
a d d e d t o t h e d efi niti o n of t h e 
effi c a c y a n al y si s s et to b e u s e d f or 
t h e a n al y si s f or d e ci si o n o n t h e 
e x p a n si o n t o P h a s e III s a m pl e si z e.
Si n c e St u d y Pr ot o c ol V er si o n 3. 0 
( d at e d 2 7 J ul y 2 0 2 0), p ati e nt s wit h 
s y st e mi c a nti bi oti c s tr e at m e nt d uri n g 
s cr e e ni n g w er e e x cl u d e d a n d 
t h er ef or e, t h e f ull P h a s e III s a m pl e 
s i z e i s e x p e ct e d t o b e l ar g el y 
a nti bi oti c s -n a iv e. T h e crit eri o n of 
b ei n g a nti bi oti c s -n a iv e h a s b e e n 
a d d e d t o t h e d efi niti o n of t h e effi c a c y 
a n al y si s s et t o b e u s e d f or t h e 
a n al y si s f or d e ci si o n o n t h e 
e x p a n si o n t o P h a s e III s a m pl e si z e i n 
or d er t o h a v e a p o p ul ati o n m or e 
r e pr e s e nt ati v e of t h e a nti ci p at e d 
p o p ul ati o n i n t h e f ull P h a s e III s a m pl e 
si z e .
1. 1 S y n o p si s
9. 3. 1 A n al y si s f or t h e A d a pt ati o n 
D e ci si o n
9. 3. 3
P o w er a n d T y p e I Err or 
C o ntr ol T a bl e 1 9
F utilit y crit eri o n h a s b e e n i ntr o d u c e d 
f or e x p a n si o n d e ci si o n a n d O v er all 
S ur vi v al ( O S) a n al y si s.
T h e f utilit y crit eri o n will ai d t h e 
I n d e p e n d e nt D at a M o nit ori n g 
C o m mitt e e (I D M C) wit h t h eir 
r e c o m m e n d ati o n t o st o p t h e st u d y 
e arl y f or f utilit y , if a p pli c a bl e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 6 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 1 S y n o p si s
4. 1. 2 R a n d o mi z e d, D o u bl e -bli n d 
P art
8. 2. 4. 2 I n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e
A d e s cri pti o n h a s b e e n a d d e d t o 
pr o vi d e cl arit y o n t h e t y p e of st u d y 
p o p ul ati o n t o b e a n al y z e d f or 
effi c a c y a n d s af et y a n al y si s f or 
e x p a n si o n i nt o P h a s e III. T hi s 
cl arifi c ati o n w o ul d al s o h el p I D M C ’ s
a s s e s s m e nt of effi c a c y a n d s af et y 
d at a a n d t o pr o vi d e t h eir
r e c o m m e n d ati o n f or e x p a n si o n i nt o 
t h e P h a s e III.
A c c u m ul ati n g e vi d e n c e s h o w s t h at 
a nti bi oti c s u s e d b ef or e c h e c k p oi nt 
i n hi bit or s ar e a s s o ci at e d wit h p o or 
pr o g n o si s. St u d y Pr ot o c ol V er si o n 3. 0 
a m e n d e d e x cl u si o n crit eri a t o 
p arti ci p a nt s wit h s y st e mi c a nti bi oti c 
u s e d uri n g S cr e e ni n g, l e a di n g t o a f ull 
P h a s e III s a m pl e si z e of l ar g el y 
a nti bi oti c s -n aï v e p arti ci p a nt s. I n or d er 
t o h a v e a p o p ul ati o n m or e 
r e pr e s e nt ati v e of t h e a nti ci p at ed 
o v er all st u d y p o p ul ati o n, t h e 
a d a pt ati o n d e ci si o n will b e b a s e d o n 
a nti bi oti c s -n a iv e p arti ci p a nt s .
1. 3 S c h e d ul e of A cti viti e s T a bl e 1 
a n d T a bl e 2
S e cti o n 1 1 A p p e n di x 6 T a bl e E
A cl arifi c ati o n h a s b e e n pr o vi d e d o n 
m e a s ur e s t o b e t a k e n w h e n 
H e p atiti s B t e st p o siti vit y i s r e p ort e d 
at S cr e e ni n g.
T h e ai m of 6 w e e k s f oll o w -u p if o n e or 
m or e of H B -s urf a c e a nti g e n, H B -c or e 
a nti b o d y or H B - s urf a c e a nti b o d y t e st 
i s p o siti v e, i s t o t e st t h e p ot e nti al 
r e a cti v ati o n of H B V, alt h o u g h t h e ri s k 
i s v er y l o w.
1. 3 S c h e d ul e of A cti viti e s T a bl e 1 
a n d T a bl e 2
A n ot e h a s b e e n a d d e d r el at e d t o 
P ati e nt R e p ort e d O ut c o m e ( P R O) 
Q u e sti o n n air e s c o m pl eti o n i n c a s e 
of st u d y tr e at m e nt i nt err u pti o n.
A d diti o n of n ot e will h el p a s s e s s m e nt 
of P R O s i n c a s e of d o s e d el a y or 
i nt err u pti on d uri n g t h e st u d y.
1. 3 S c h e d ul e of A cti viti e s T a bl e 3 
a n d T a bl e 4
A n ot e h a s b e e n a d d e d o n a nti dr u g 
 a n d 
p h ar m a c o ki n eti c ( P K ) s a m pli n g
T h e n ot e will cl arif y t h e r e q uir e m e nt 
of pr e -d o s e  
 a n d P K s a m pl e s 
w h e n d o si n g i s d ef err e d at t h e vi sit or 
w h e n n o vi sit t a k e s pl a c e.
2. 3 B e n efit/ Ri s k A s s e s s m e nt
D er m at ol o gi c a d v er s e e v e nt s ( A E s) 
ar e r e cl a s sifi e d a s i m p ort a nt 
i d e ntifi e d ri s ks .
T h e ri s k r e cl a s sifi c ati o n w a s b a s e d o n 
i n d e pt h a n al y si s of a p o ol e d s af et y 
d at a s et of N = 7 6 5 p arti ci p a nt s w h o 
r e c ei v e d bi ntr af u s p alf a m o n ot h er a p y 
at 1 2 0 0 m g Q 2 W
4. 1 O v er all D e si g n
A n ot e h a s b e e n a d d e d t o g ui d e i n 
c h e c ki n g e nr oll m e nt of t h e st u d y 
p o p ul ati o n.
T h e m o nit ori n g of e nr oll m e nt will 
e n s ur e t h at a st u d y p o p ul ati o n i s 
o bt ai n e d, w hi c h i s r e pr e s e nt ati v e 
a cr o s s t h e p arti ci p ati n g gl o b al r e gi o n s 
(f or e. g., A si a n v er s u s n o n -A si a n 
c o u ntri e s) .
4. 3. 2 Bi ntr af u s p alf a wit h 
C h e m ot h er a p y
E dit s ar e d o n e t o hi g hli g ht d o s e 
m o difi c ati o n of t h e st u d y i nt er v e nti o n 
i n a s p e cifi c c o n diti o n.
T h e s e e dit s will h el p f urt h er 
u n d er st a n di n g of c o n diti o n s f or d o s e 
m o difi c ati o n of t h e st u d y i nt er v e nti o n.
5 St u d y P o p ul ati o n
A p p e n di x 2
E dit s ar e d o n e r el at e d t o i nf or m e d 
c o n s e nt pr o c e s s .
T o b e c o n si st e nt wit h c urr e nt S p o n s or 
pr ot o c ol t e m pl at e ( V er si o n 1 5)
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 7 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
5. 1 I n cl u si o n Crit eri a
I n cl u si o n crit eri o n n u m b er 2 h a s 
b e e n u p d at e d
T h e crit eri o n h a s b e e n u p d at e d t o 
pr o vi d e m or e cl arit y o n e x cl u si o n of 
p a rti ci p a nt s wit h hi st ol o gi c al s u bt y p e 
s u c h a s s ar c o m at oi d t u m or or H C C 
mi x e d s u bt y p e f or w hi c h g e m cit a bi n e 
a n d ci s pl ati n tr e at m e nt ar e n ot 
c o n si d er e d a s t h e st a n d ar d of c ar e .
5. 2 E x cl u si o n Crit eri a
E x cl u si o n crit eri o n n u m b er 5 h a s 
b e e n e dit e d. Cl arifi c ati o n h a s b e e n 
pr o vi d e d t o e n s ur e e x cl u si o n of 
p arti ci p a nt s w h o r e q uir e a nti bi oti c 
tr e at m e nt a n d s y st e mi c t h er a p y 
d uri n g t h e s cr e e ni n g p eri o d
T o d efi n e t h e p eri o d m or e cl e arl y a n d 
e n s ur e c o n si st e nt w or di n g a cr o s s t h e 
2 e x cl u si o n crit eri a t o a v oi d a m bi g uit y 
d u e t o i m pr e ci s e w or di n g.
5. 2 E x cl u si o n Crit eri a
E x cl u si o n crit eri o n n u m b er 1 3 h a s 
b e e n u p d at e d f or pri or a dj u v a nt 
t h er a p y d ur ati o n
T h e s p e cifi c ati o n f or pri or a dj u v a nt 
t h er a p y d ur ati o n will h el p t o s el e ct 
p arti ci p a nt s f or t h e st u d y.
6. 4 St u d y I nt er v e nti o n 
C o m pli a n c e
A s e nt e n c e h a s b e e n a d d e d r el at e d 
t o d o s e m o difi c ati o n of t h e st u d y 
i nt er v e nti o n.
T h e i nf or m ati o n will ai d i n 
d o c u m e nt ati o n of d o s e m o difi c ati o n, if 
a n y d uri n g t h e st u d y i n t h e el e ctr o ni c 
c a s e r e p ort f or m ( e C R F).
6. 5. 3 Pr o hi bit e d M e di ci n e s
V a c c i n e a d mi ni str ati o n crit eri o n h a s 
b e e n r e vi s e d.
T h e crit eri o n w a s r e vi s e d t o pr o vi d e 
cl arit y o n w hi c h v a c ci n e s ar e all o w e d 
or pr o hi bit e d f or t h e st u d y p arti ci p a nt s 
d uri n g t h e c o n d u ct of t h e st u d y . 
6. 6. 1 D o si n g I n str u cti o n s
D et ail s ar e a d d e d o n st u d y 
tr e at m e nt a d mi ni str ati o n.
E dit s ar e d o n e i n t hi s s e cti o n t o 
i n di c at e d o s e m o difi c ati o n of 
bi ntr af u s p alf a/ pl a c e b o t o 1 2 0 0 m g 
i s all o w e d i n t h e st u d y.
T h e d et ail s will h el p 
i n v e sti g at or/ d e si g n e e o n e n s uri n g 
ti mi n g of t h e st u d y tr e at m e nt 
a d mi ni str ati o n.
T hi s will h el p t h e I n v e sti g at or t o 
u n d er st a n d d o s e m o difi c ati o n of 
bi ntr af u s p alf a/ pl a c e b o i s all o w e d i n 
t h e st u d y t o m a n a g e bl e e di n g e v e nt s.
6. 6. 3 Tr e at m e nt M o difi c ati o n
T a bl e 7
Titl e h a s b e e n m o difi e d a n d a n ot e 
a d d e d o n h a n dli n g of ot h er A E s 
( e. g., i nf e cti o n s).
A s e nt e n c e h a s b e e n d el et e d 
r el at e d t o d o s e m o difi c ati o n i n c a s e 
of s e v er al t o xi citi e s.
E dit s ar e d o n e i n t hi s s e cti o n t o 
i n di c at e d o s e m o difi c ati o n of 
bi ntr af u s p alf a/ pl a c e b o t o 1 2 0 0 m g 
i s all o w e d i n t h e st u d y.
I nf or m ati o n r el at e d t o d o s e 
m o d ifi c ati o n of bi ntr af u s p 
alf a/ pl a c e b o t o 1 2 0 0 m g f or 
m a n a g e m e nt of bl e e di n g e v e nt s h a s 
b e e n a d d e d i n t h e t a bl e
T h e n ot e a d d e d will h el p i n h a n dli n g 
ot h er A E s s u c h a s i nf e cti o n s.
T h e s e nt e n c e h a s b e e n d el et e d t o 
a v oi d r e p etiti o n of t h e i nf or m ati o n 
pr e s e nt e d i n t h e s e cti o n.
T hi s will h el p t h e I n v e sti g at or t o 
u n d er st a n d d o s e m o difi c ati o n of 
bi ntr af u s p alf a/ pl a c e b o i s all o w e d i n 
t h e st u d y t o m a n a g e bl e e di n g e v e nt s.
6. 6. 3. 2 G e m cit a bi n e a n d/ or 
Ci s pl ati n -r el at e d A d v er s e Dr u g 
R e a cti o n s
A n ot e h a s b e e n i ntr o d u c e d r el at e d 
t o r e s ol uti o n of a n e mi a.
T h e n ot e will h el p t o a s s e s s if t h e 
st u d y i nt er v e nti o n s h o ul d b e 
c o nti n u e d i n c a s e a n e mi a d o e s n ot 
r e s ol v e fr o m Gr a d e 2 t o Gr a d e ≤ 1
6. 6. 4 D o s e M o difi c ati o n of 
G e m cit a bi n e, Ci s pl ati n, a n d 
Bi ntr af u s p alf a/ Pl a c e b o f or R e n al 
Im p air m e nt
S p e cifi c ati o n s o n cr e ati n e cl e ar a n c e 
h a v e b e e n a d d e d f or a d mi ni str ati o n 
of g e m cit a bi n e a n d ci s pl ati n.
T h e crit eri o n will h el p t o t a k e d e ci si o n 
o n d o s e m o difi c ati o n of g e m cit a bi n e 
a n d ci s pl ati n i n c a s e of r e n al t o xi cit y.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 8 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
6. 9 M a n a g e m e nt of A d v er s e
E v e nt s of S p e ci al I nt er e st a n d 
ot h er P ot e nti al Ri s k s
S e cti o n 1 1 A p p e n di c e s, 
A p p e n di x 4
Ri s k r e c at e g ori z ati o n h a s b e e n d o n e 
a n d t h e li st of e v e nt s h a s b e e n 
u p d at e d a c c or di n gl y
T h e ri s k r e -cl a s sifi c ati o n w a s b a s e d 
o n i n d e pt h a n al y si s of a p o ol e d 
s af et y d at a s et of N = 7 6 5 p arti ci p a nt s 
w h o r e c ei v e d bi ntr af u s p alf a 
m o n ot h er a p y at 1 2 0 0 m g Q 2 W.
6. 9. 1 I nf u si o n-r el at e d R e a cti o n s 
I n cl u di n g I m m e di at e 
H y p er s e n siti vit y
I nf u si o n r el at e d r e a cti o n s ar e 
r e cl a s sifi e d fr o m “i m p ort a nt 
i d e ntifi e d ri s k s” t o “i d e ntifi e d ri s k” f or 
bi ntr af u s p alf a.
6. 9. 2 I m m u n e-r el at e d A d v er s e 
E v e nt s
Ri s k r e cl a s sifi c ati o n h a s b e e n d o n e 
a n d t h e li st of e v e nt s h a s b e e n 
u p d at e d a c c or di n gl y
6. 9. 3 T G F β i n hi biti o n m e di at e d 
S ki n R e a cti o n s
Ri s k r e c at e g ori z ati o n h a s b e e n 
d o n e .
6. 9. 4 A n e mi a
T er m tr e at m e nt -r el at e d a n e mi a 
e v e nt s h a s b e e n r e vi s e d t o a n e mi a 
a n d r e cl a s sifi e d fr o m “i m p ort a nt 
p ot e nti al ri s k ” t o “i m p ort a nt i d e ntifi e d 
ri s k” f or bi ntr af u s p alf a. Al s o, d et ail s 
ar e u p d at e d f or m a n a g e m e nt of 
a n e mi a.
6. 9. 5 Bl e e di n g E v e nt s
Bl e e di n g e v e nt s ar e r e cl a s sifi e d 
fr o m “p ot e nti al ri s k ” t o “i m p ort a nt 
i d e ntifi e d ri s k” f or bi ntr af u s p alf a
6. 9. 6. 1 I m p air e d W o u n d H e ali n g
T h e ri s k n a m e “Alt e r ati o ns i n Wo u n d 
H e ali n g or R e p air of Ti s s u e 
D a m a g e ” h a s b e e n c h a n g e d t o 
“I m p air e d W o u n d H e ali n g ”.
6. 9. 1 I nf u si o n -r el at e d R e a cti o n s 
I n cl u di n g I m m e di at e 
H y p er s e n siti vit y
F urt h er d et ail s ar e a d d e d o n 
tr e at m e nt m o difi c ati o n f or Gr a d e 3 
or Gr a d e 4 i nf u si o n r el at e d r e a cti o n s 
i n cl u di n g i m m e di at e h y p er s e n siti vit y
T h e d et ail s a d d e d o n tr e at m e nt 
m o difi c ati o n will h el p i n r e s ol uti o n of 
t h e e v e nt. 
6. 9. 4 A n e mi a
F urt h er d et ail s h a v e b e e n a d d e d i n 
g e n er al g ui d a n c e f or a n e mi a 
m a n a g e m e nt a n d e v al u ati o n.
T h e g ui d a n c e w ill h el p I n v e sti g at or t o 
t a k e d e ci si o n o n c o nti n u ati o n of st u d y 
i nt er v e nti o n a d mi ni str ati o n i n c a s e of 
a n e mi a.
6. 9. 5 Bl e e di n g E v e nt s
D et ail s h a v e b e e n a d d e d wit h 
r e g ar d s t o a cti o n t o b e t a k e n o n t h e 
st u d y i nt er v e nti o n i n c a s e of r a pi d 
d e cr e a s e of h e m o gl o b i n ( H g b) a n d
Gr a d e 1 or gr e at er bl e e di n g e v e nt s.
T h e s e d et ail s will h el p t h e 
I n v e sti g at or i n u n d er st a n di n g st u d y 
tr e at m e nt i nt err u pti o n, m o difi c ati o n or 
r e-e s c al ati o n i n c a s e of r a pi d 
d e cr e a s e of H g b a n d Gr a d e 1 or 
gr e at er bl e e di n g e v e nt s d uri n g t h e 
st u d y.
7. 1. 1 P er m a n e nt Tr e at m e nt 
Di s c o nti n u ati o n
A p ar a gr a p h h a s b e e n d el et e d, 
w hi c h i s r el at e d t o t u m or 
a s s e s s m e nt a n d ot h er a s s e s s m e nt s 
i n c a s e of pr e m at ur e wit h dr a w al 
fr o m t h e st u d y i nt er v e nti o n f or 
r e a s o n s ot h er t h a n P D.
T h e p ar a gr a p h h a s b e e n d el et e d t o 
a v oi d r e d u n d a n c y of i nf or m ati o n 
pr e s e nt e d i n t h e s e cti o n.
7. 1. 2
Tr e at m e nt B e y o n d I niti al 
Pr o gr e s si o n
Cl arifi c ati o n pr o vi d e d f or a d a pti o n 
d e ci si o n a n al y si s.
T h e a d diti o n al w or di n g s will pr o vi d e 
m or e cl arit y o n a d a pti o n d e ci si o n 
a n al y si s.
7. 3 L o st t o F oll o w u p
E dit s ar e d o n e r el at e d t o L o st t o 
F oll o w -u p i nf or m ati o n.
T o b e c o n si st e nt wit h c urr e nt S p o n s or 
pr ot o c ol t e m pl at e ( V er si o n 1 5)
8. 1. 1
T u m or R e s p o n s e
A nti bi oti c s -n ai v e crit eri o n h a s b e e n 
T o e n s ur e p arti ci p a nt s r e pr e s e nt ati v e 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
1 9 9 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
a d d e d
of t h e crit eri o n a d d e d f or t h e a d a pti o n 
d e ci si o n.
1 0 R ef er e n c e s
N e w r ef er e n c e h a s b e e n a d d e d
N e w r ef er e n c e s h a v e b e e n a d d e d t o 
f urt h er e n h a n c e u n d er st a n di n g a b o ut:
s t o p pi n g b o u n d ari e s f or n o n-bi n di n g 
f utilit y a n al y si s.
O ut c o m e of u s e of a nti bi oti c s b ef or e 
tr e at m e nt wit h c h e c k p oint i n hi bit or s.
N ot e: Mi n or c h a n g e s h a v e b e e n p erf or m e d t hr o u g h o ut t h e pr ot o c ol t o a d dr e s s c o n si st e n c y p ert ai ni n g t o m aj or 
c h a n g e s d o n e i n t h e pr ot o c ol or t o a d d f urt h er cl arit y a n d pr e ci si o n .
Pr ot oc ol Versi o n 3. 0 ( 2 7 J ul y 2 0 2 0 )
T his a me n d me nt is c o nsi dere d a s u bsta ntial a me n d me nt base d o n t he criteria i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  pur p ose of t his a me n d me nt is t o all o w t he c o nti n ue d recr uit me nt at t he ti me 1 5 0 
partici pa nts are ra n d o mize d as rec o m me n de d b y  
EM A 
F oll o w -u p Pr ot oc ol Assista nce 
( E M E A/ H/ S A/ 3 9 3 4/ 2/ F U/ 1/ 2 0 1 9/ P A/II).
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e
A p p e n di x 1 3, S p o n s or Si g n at ur e 
P a g e
A p p e n di x 1 4, C o or di n ati n g 
I n v e sti g at or Si g n at ur e P a g e
A p p e n di x 1 5, Pri n ci p al 
I n v e sti g at or Si g n at ur e P a g e
A d d e d t h e Cli ni c al Tri al s. g o v n u m b er
F or tr a n s p ar e n c y a n d e a s y tr a c k.
Titl e P a g e
7. 2 P arti ci p a nt 
Di s c o nti n u ati o n/ Wi t h dr a w al fr o m 
t h e St u d y
8 St u d y A s s e s s m e nt s a n d 
Pr o c e d ur e s
8. 5 P h ar m a c o ki n eti c s
9. 5. 3 Ot h er A n al y s e s
A p p e n di x 2, St u d y G o v er n a n c e
A d d e d a d diti o n al t e xt or m o difi e d t h e 
pr e vi o u s t e xt 
T o u p d at e w or di n g t o b e c o n si st e nt 
wi t h c urr e nt S p o n s or pr ot o c ol 
t e m pl at e ( V er si o n 1 4).
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 0 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 1 S y n o p si s
1. 2 O v er all St u d y D e si g n S c h e m a
( Fi g ur e 1)
4. 1 O v er all D e si g n
4. 1. 2 R a n d o mi z e d, D o u bl e -bli n d 
P art (Fi g ur e 2 )
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
4. 4 E n d of St u d y D efi niti o n
9. 3 S a m pl e Si z e D et er mi n ati o n
9. 3. 1 A n al y si s f or t h e A d a pt ati o n 
D e ci si o n
9. 3. 2 Pr o b a bilit y of St u d y 
E x p a n si o n
9. 3. 3 P o w er a n d T y p e I Err or 
C o ntr ol ( T a bl e 1 9) 
9. 5. 1 Effi c a c y A n al y s e s ( T a bl e 2 4)
9. 5. 4 S e q u e n c e of A n al y si s 
( T a bl e 2 6)
- U p d at e d m a xi m al n u m b er of 
p arti ci p a nt s f or P h a s e II 
- U p d at e d t e xt t o cl arif y t h at i niti al 
1 5 0 p arti ci p a nt s r e cr uit e d i n P h a s e II 
will b e a n al y z e d f or a n e x p a n si o n 
d e ci si o n i nt o P h a s e III
- U p d at e d a mi ni m u m f oll o w-u p 
p eri o d at l e a st 1 9 w e e k s f or t h e fir st 
1 5 0 p arti ci p a nt s r a n d o mi z e d i s 
i n cl u d e d
- U p d at e d Fi g ur e 1 a n d 2
- U p d at e d a s s u m pti o n s of s a m pl e 
si z e c al c ul ati o n (i. e., n u m b er of 
p arti ci p a nt s a n d ti m e p eri o d s).
- U p d at e d t e xt t o all o w c o nti n u e d 
p arti ci p a nt r e cr uit m e nt wit h o ut p a u s e 
pri or t o a d a pt ati o n d e ci si o n a s 
r e c o m m e n d e d b y E M A Foll o w -u p 
Pr ot o c ol A s si st a n c e 
( E M E A/ H/ S A/ 3 9 3 4/ 2/ F U/ 1/ 2 0 1 9/ P A/II)
-  U p d at e d f oll o w - u p p eri o d t o all o w 
f or d at a m at urit y t o o b s er v e c o nfir m e d 
r e s p o n s e.
1. 1 S y n o p si s
8. 2. 4. 2 I n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e
8. 2. 4. 3 I n d e p e n d e nt R e vi e w 
C o m mitt e e a n d t hr o u g h o ut t h e 
pr ot o c ol, a s a p pli c a bl e
A d d e d t h e i nf or m ati o n a b o ut t h e 
I n d e p e n d e nt D at a M o nit ori n g 
C o m mitt e e (I D M C) a n d I n d e p e n d e nt 
R e vi e w C o m mitt e e (I R C) 
r e s p o n si bilit y f or P h a s e II a n d 
P h a s e III st u d y 
- T o b e ali g n e d wit h I D M C St ati sti c al 
A n al y si s Pl a n
- T o pr o vi d e d et ail s a b o ut t h e I D M C 
r e s p o n si bilit y.
1. 3 S c h e d ul e of A cti viti e s a n d 
t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
Cl arifi e d t h at pr o c e d ur e s a n d 
a cti viti e s s h o ul d b e s c h e d ul e d fr o m 
W e e k 1, D a y 1 ( W 1 D 1)
F or cl arit y
U p d at e d n ot e f or I n cl u si o n/ e x cl u si o n 
crit eri a
F or cl arit y
U p d at e d n ot e f or Pr e m e di c ati o n a n d 
bi ntr af u s p alf a / pl a c e b o 
a d mi ni str ati o n
T o k e e p t h e d o s e i nt e n sit y of 
bi ntr af u s p alf a/ pl a c e b o w h e n d o si n g 
fl e xi bilit y i s n e e d e d
U p d at e d n ot e f or 
Pr e m e di c ati o n/ h y dr ati o n a n d 
g e m cit a bi n e/ ci s pl ati n
F or cl arit y
U p d at e d n ot e f or F ull c h e mi str y a n d 
h e m at ol o g y a n d C or e c h e mi str y a n d 
h e m at ol o g y
T o cl arif y t h e ti mi n g t h at l a b or at or y 
t e st s m u st b e r e vi e w e d b ef or e d o si n g
U p d at e d n ot e f or Uri n al y si s
T o cl arif y t h at o nl y di p sti c k i s r e q uir e d 
e v e n if di p sti c k i s a c c o m p a ni e d wit h 
mi cr o s c o p y.
U p d at e d n ot e f or T u m or e v al u ati o n 
T o cl arif y a n d m o dif y t h e t u m or 
e v al u ati o n wi n d o w fr o m ± 3 d a y s t o 
± 7 d a y s ( e x c e pt w e e k 7, w h e n t h e 
wi n d o w i s -0 t o + 7 d a y s)
U p d at e d t h e wi n d o w f or S af et y 
F ol l o w-u p Vi sit 2 8 d a y s fr o m ± 5 t o 
± 7 D a y s Aft er L a st Tr e at m e nt
T o all o w a n e xt e n si o n 
U p d at e d n ot e s a n d O bj e cti v e 
r e s p o n s e t o s u b s e q u e nt ( 2 L) 
tr e at m e nt i n T a bl e 2
T o cl arif y t h e r a di ol o gi c al a s s e s s m e nt 
i n L o n g-t er m F oll o w-u p f or 
p arti ci p a nt s t h at st art e d s u b s e q u e nt 
a nti c a n c er t h er a p y
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 1 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
U p d at e d n ot e f or Li q ui d bi o p s y 
( pl a s m a)
R e m o v e d ti m e -wi n d o w of li q ui d 
bi o p s y pri or t o d o si n g to str e a mli n e 
t h e pr o c e d ur e
5. 2 E x cl u si o n Crit eri a
U p d at e d e x cl u si o n crit eri a 2 a n d 5
T o cl arif y t h e ti mi n g 
U p d at e d e x cl u si o n crit eri o n 5
T o cl arif y e x cl u si o n crit eri a f or 
p arti ci p a nt s wit h bili ar y o b str u cti o n
U p d at e d e x cl u si o n crit eri o n 1 6
F or c o n si st e n c y wit h S e cti o n 6. 5. 4
5. 4 S cr e e n F ail ur e s
A d diti o n of r e q uir e m e nt of r e -bi o p s y 
a s a crit eri a of di s c u s si o n wit h 
M e di c al M o nit or f or s cr e e ni n g 
wi n d o w e xt e n si o n
F or cl arit y
6. 1 St u d y I nt er v e nti o n( s) 
A d mi ni str ati o n ( T a bl e 6)
Bi ntr af u s p alf a w a s i n cl u d e d a s t h e 
i nt er n ati o n al n o n pr o pri et ar y n a m e 
f or M 7 8 2 4
F or c o n si st e n c y a cr o s s t h e 
d e v el o p m e nt pr o gr a m
6. 5. 3 Pr o hi bit e d M e di ci n e s
Cl arifi e d pr o p h yl a cti c u s e of st er oi d
T o all o w l o c al g ui d a n c e 
6. 6. 1 D o si n g I n str u cti o n s
Cl arifi e d a d mi ni str ati o n of 
c h e m ot h er a p y
T o all o w l o c al pr a cti c e f or 
g e m cit a bi n e a n d ci s pl ati n 
a d mi ni str ati o n
6. 6. 3. 2 G e m cit a bi n e a n d/ or 
Ci s pl ati n -r el at e d A d v er s e Dr u g 
R e a cti o n s
Cl arifi e d t h e d o s e m o difi c ati o n f or 
n e utr o p e ni a a n d t hr o m b o c yt o p e ni a 
i n t h e ca s e of g e m cit a bi n e a n d/ or 
ci s pl ati n -r el at e d a d v er s e dr u g 
r e a cti o n s.
F or cl arit y
6. 6. 4 D o s e M o difi c ati o n of 
G e m cit a bi n e, Ci s pl ati n, a n d 
Bi ntr af u s p alf a/ Pl a c e b o f or R e n al 
I m p air m e nt
A d d e d cl arifi c ati o n a b o ut t h e 
cr e ati ni n e cl e ar a n c e ( Cr Cl) 
c al c ul ati o n
F or c l arit y
6. 6. 5 Di s e a s e S p e cifi c Ri s k: 
H e p ati c I m p air m e nt
A d d e d a cl arifi c ati o n t h at 
im m u n e -r el at e d c h ol a n giti s s h o ul d 
F or cl arit y
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 2 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
b e diff er e nti at e d if m e di c all y 
i n di c at e d
6. 8 S p e ci al Pr e c a uti o n s
C o n si d er e d ci s pl ati n f or s u b s e q u e nt 
i nf u si o n
F or cl arit y
6. 9. 1 I nf u si o n -r el at e d R e a cti o n s 
I n cl u di n g I m m e di at e 
H y p er s e n siti vit y ( T a bl e 1 4)
A d d e d cl arifi c ati o n a b o ut t h e or d er 
of i nf u si o n
F or cl arit y
7. 1. 2 Tr e at m e nt B e y o n d I niti al 
Pr o gr e s si o n
- R e m o v e d t h e i nf or m ati o n a b o ut 
r e gr e s si o n a n d cl arifi e d t h e t e xt 
r el at e d t o t h e c o nti n u ati o n of 
g e m cit a bi n e a n d ci s pl ati n u ntil 
c o nfir m e d p r o gr e s si v e di s e a s e ( P D).
- Cl arifi e d t h at r a di ol o gi c al i m a g e s 
will b e c oll e ct e d fr o m all p arti ci p a nt s 
a n d t h e s e will b e a s s e s s e d b y I R C if 
r e q uir e d.
T o si m plif y t h e tr e at m e nt d e ci si o n 
tr e e f or tr e at m e nt b e y o n d pr o gr e s si o n
7. 1. 3 Tr e at m e nt B e y o n d 
C o nfir m e d Pr o gr e s si o n a n d 
t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
- D el et e d i nf or m ati o n a b o ut 
tr e at m e nt b e y o n d c o nfir m e d 
pr o gr e s si o n
- U p d at e d Fi g ur e 3
T o si m plif y t h e st u d y pr ot o c ol aft er 
t he pr o gr e s si o n p eri o d. I n a d diti o n, it 
i s n ot r e a s o n a bl e t o all o w f urt h er 
tr e at m e nt aft er c o nfir m e d P D f or t h e 
c o m p ar at or ar m w hi c h d o e s n ot 
i n cl u d e i m m u n ot h er a p y.
8. 1. 1 T u m or R e s p o n s e
A p p e n di x 1 1, R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d 
T u m or s ( R E CI S T) V er s i o n 1. 1
t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
- Cl arifi e d t h e M RI ar e a s
- R e m o v e d t h e i nf or m ati o n f or 
c e ntr al i m a gi n g r e a d a n d 
i nt er pr et ati o n f or all s c a n
- A d d e d R E CI S T 1. 1 a s 
A p p e n di x 1 1.
- Cl arifi e d t h at r a di ol o gi c al i m a g e s 
c oll e ct e d fr o m t h e r e m ai ni n g 
3 5 0 p arti ci p a nt s m u st b e s u b mitt e d.
- F or cl arit y
- T o c orr e ct i n c o n si st e n c y. C e ntr al 
I m a gi n g i s o nl y f or P h a s e II.
- F or c o n si st e n c y a cr o s s t h e 
d e v el o p m e nt pr o gr a m
8. 2. 1 P h y si c al E x a mi n ati o n s a n d 
Vit al Si g n s
R e m o v e d t h e s p e cifi c i nf or m ati o n 
a b o ut t h e r e a di n g s of bl o o d 
pr e s s ur e a n d p ul s e 
F or c o n si st e n c y a cr o s s t h e 
d e v el o p m e nt pr o gr a m
8. 2. 4. 1 S af et y M o nit ori n g 
C o m mitt e e
U p d at e d s e cti o n
F or cl arit y
9. 5. 1 Effi c a c y A n al y s e s
( T a bl e 2 4)
U p d at e d d ur ati o n of r e s p o n s e
( D O R) e n d p oi nt t o b e ali g n e d wit h 
o bj e cti v e s
F or c o n si st e n c y
A p p e n di x 8, M a n a g e m e nt of 
I m m u n e-r el at e d A d v er s e E v e nt s 
( T a bl e A 2)
T o r e m o v e t h e i nf or m ati o n t h at 
V e d oli z u m a b i s n ot a p pr o v e d i n 
J a p a n
T o r e vi s e a n d pr o vi d e c orr e ct 
i nf or m ati o n si n c e V e d oli z u m a b i s 
alr e a d y a p pr o v e d i n J a p a n f or t h e 
tr e at m e nt of Ul c er ati v e c oliti s (fr o m 
2 0 1 8) a n d Cr o h n´ s di s e a s e
A p p e n di x 1 0, C o u ntr y -s p e cifi c 
r e q uir e m e nt s
A d d e d i nf or m ati o n a b o ut J a p a n a n d 
K or e a n/ T ai w a n s p e cifi c 
r e q uir e m e nt s
F or cl arit y a n d t o e x pl ai n t h at t h e 
2 P R O it e m s c a n o nl y b e 
i m pl e m e nt e d o n c e t h e l o c al l a n g u a g e 
v er si o n s ar e a v ail a bl e a n d a p pr o v e d 
b y t h e Et hi c s C o m mitt e e/ In stit uti o n al 
R e vi e w B o ar d ( E C/I R B)
T hr o u g h o ut t h e pr ot o c ol
Mi n or e dit ori al a n d f or m atti n g 
r e vi si o n s; c orr e cti o n of mi n or 
t y p o gr a p hi c al err or s
T o m a k e mi n or r e vi si o n s f or 
c orr e ct n e s s, r e a d a bilit y, c o n si st e n c y 
of l a n g u a g e a cr o s s t h e bi ntr af u s p alf a 
d e v el o p m e nt pr o gr a m, a n d f or 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 3 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
c o m pli a n c e wit h c urr e nt S p o n s or 
g ui d eli n e s
Pr ot oc ol Versi o n 2. 1 ( 0 3 Dece m ber 2 0 1 9)
T his a me n d me nt is c o nsi dere d a s u bsta ntial a me n d me nt base d o n t he criteria i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
 
 
 
 
 
T he ke y  c ha n ges i nc or p orate d are:

T o descri be a si n gle pri mar y  en d p oi nt ( o verall s ur vi val) i n t he ra n d o mize d, d o u ble -bli n d part 
of t he st u d y  rat her t ha n d ual pri mar y e n d p oi nts

T o re m o ve t he re q uire me nt f or i nitial pr o gressi ve disease as deter mi ne d b y t he I n vesti gat or t o 
be verifie d b y a n I n de pe n de nt Re vie w C o m mittee (I R C) 

T he a nal ys is of pr o gressi o n -free s ur vi val (P F S ) a n d ot her t u m or -base d efficac y en d p oi nts will 
n o w be base d o n I n vesti gat or assess me nt; a nal ysis base d o n I RC
assess me nt will o nl y  be 
perf or me d if t he st u d y  is n ot e x pa n de d t o P hase III

T o ac k n o wle d ge t hat, f or t he p ur p oses of mar keti n g a ut h orizati o n i n Ja pa n, if t he st u d y is n ot 
e x pa n de d i nt o P hase III, it will n ot be acce pta ble as a c o nfir mat or y st u d y  

T o pr o vi de a d diti o nal i nf or mati o n o n t he p o wer t o detect differe nces i n efficac y am o n g t he 
differe nt biliar y  tract ca ncer a nat o mical s u b gr o u ps

T o e xcl u de pa rtici pa nts wit h hist or y  of blee di n g diat hesis a n d pr o vi de f urt her g ui da nce o n d ose 
m o dificati o ns f or blee di n g e ve nts acc or di n g t o N CI -C T C A E se verity gra d e a n d site of blee di n g

T o i ncl u de a d diti o nal patie nt -re p orte d o utc o me meas ures t o e na ble partici pa nts’ e x perie nce of 
t he st u d y i nter ve nti o n t o be f urt her c haracterize d

T o all o w c he m ot hera p y t o be gi ve n o n Da y 1 5 of a gi ve n c ycle if a d mi nistrati o n o n Da y 1 or 
D a y 8 was n ot p ossi ble.
C ha n ges i m ple me nted i n t his pr ot oc ol a me n d me nt will o nl y  be i m ple me nte d at eac h site f oll o wi n g 
re vie w/fa v ora ble o pi ni o n 
of 
t he a me n d me nt b y  the 
res p o nsi ble I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee, as i n dicate d i n A p pe n di x 2 . Sites s h o ul d e ns ure t he y are 
f ollo wi n g t he a p pr o priate a p pr o ve d pr ot oc ol versi o n at a n y  gi ve n ti me, partic ularly w it h res pect t o 
t he recr uit me nt of partici pa nts i n t he o pe n-la bel, safety r u n -i n part.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 4 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 1 S y n o p si s
4. 2 S ci e ntifi c R at i o n al e f or St u d y 
D e si g n
9. 1 St ati sti c al H y p ot h e s e s
9. 3 S a m pl e Si z e D et er mi n ati o n
9. 5 St ati sti c al A n al y s e s
T a bl e 5, T a bl e 2 4, a n d T a bl e 2 6, 
a n d t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
c h a n g e d fr o m a pri m ar y t o a 
s e c o n d ar y e n d p oi nt
If t h e a d a pt ati o n d e ci si o n r e s ult s i n t h e 
f ull P h a s e III s a m pl e si z e (N = 5 0 0), t h e 
I n v e sti g at or will b e c o m e t h e m ai n 
a s s e s s or f or P F S
T o h a v e o v er all s ur vi v al ( O S) a s 
a si n gl e pri m ar y e n d p oi nt
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
Fi g ur e 3
5 . 1 I n cl u si o n Crit eri a
6. 5. 4 Ot h er I nt er v e nti o n s
7. 1 Di s c u s si o n of St u d y 
I nt er v e nti o n 
T a bl e 1 6
8. 1. 1 T u m or R e s p o n s e, a n d 
t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
R e m o v al of v erifi c ati o n of pr o gr e s si v e 
di s e a s e ( P D) b y a n I n d e p e n d e nt 
R e vi e w C o m mitt e e (I R C) f oll o wi n g 
I n v e sti g at or d et er mi n e d P D
V erifi c ati o n of P D b y a n I R C w a s 
i ntr o d u c e d a s a q u alit y m e a s ur e 
f or t h e pri m ar y e n d p oi nt, P F S 
p er I R C. W it h P F S h a vi n g b e e n 
d e m ot e d t o a s e c o n d ar y 
e n d p oi nt, t hi s i s n o l o n g er 
r e q uir e d
4. 4 E n d of St u d y D efi niti o n
U p d at e d e n d of st u d y d efi niti o n wit h 
d at a c ut off f or pri m ar y O S a n al y si s f or 
P h a s e III a n d P h a s e II st u d y
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
9. 2 Hi er ar c hi c al T e sti n g Pr o c e d ur e
Pr o vi si o n of hi er ar c hi c al t e sti n g 
pr o c e d ur e s f or t h e e n d p oi nt s O S, P F S, 
a n d o bj e cti v e r e s p o n s e r at e
R e q uir e d d u e t o t h e c h a n g e 
fr o m d u al pri m ar y e n d p oi nt s t o a 
si n gl e pri m ar y e n d p oi nt
9. 5. 1 Effi c a c y A n al y s e s ( T a bl e 2 4)
Cl arifi c ati o n of t h e a n al y s e s u s e d f or 
t e sti n g n ull h y p ot h e si s
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
9. 5. 4 S e q u e n c e of A n al y s e s
Cl arifi c ati o n of t h e s e q u e n c e of 
a n al y s e s
R e q uir e d d u e t o t h e c h a n g e 
fr o m d u al pri m ar y e n d p oi nt s t o a 
si n gl e pri m ar y e n d p oi nt
A p p e n di x 1 0 C o u ntr y -s p e cifi c 
R e q uir e m e nt s
E x pl a n ati o n t h at i n J a p a n, if t h e st u d y i s 
n ot e x p a n d e d i nt o P h a s e III , it i s n ot 
e x p e ct e d t o s ati sf y t h e c o n diti o n of a 
c o nfir m at or y st u d y
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
1. 1 S y n o p si s
4. 1. 1 O p e n -l a b el, S af et y R u n-i n 
P art
Cl arifi c ati o n t h at p arti ci p a nt s will b e 
r e cr uit e d s e q u e nti all y i n e a c h c o h ort of 
t h e o p e n-l a b el, s af et y r u n -i n p art
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
1. 1 S y n o p si s
4. 1. 2 R a n d o mi z e d, D o u bl e -bli n d 
P art 
6. 3. 1 St u d y I nt er v e nti o n 
A s si g n m e nt
T a bl e 2 4
T h e d efi niti o n of t h e str atifi c ati o n f a ct or 
r el ati n g t o cl a s sifi c ati o n of bili ar y tr a ct 
c a n c er ( B T C) at di a g n o si s h a s b e e n 
r efi n e d
T o e n s ur e all p ot e nti al 
di a g n o s e s of B T C at di a g n o si s 
ar e c a pt ur e d wit hi n t h e d efi niti o n 
of t h e r el at e d str atifi c ati o n f a ct or
9. 3. 4 S u b gr o u p A n al y s e s f or 
Bili ar y Tr a ct C a n c er S u bt y p e s
T a bl e 2 0, T a bl e 2 1, T a bl e 2 2, a n d 
T a bl e 2 4
I nf or m ati o n pr o vi d e d r e g ar di n g t h e 
p o w er t o d et e ct diff er e n c e s i n effi c a c y 
a m o n g t h e a n at o mi c al B T C s u b gr o u p s
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
5. 1 I n cl u si o n Crit eri a
T e xt a d d e d t o e n s ur e t h e hi st ol o gi c al 
ori gi n of a m p ull ar y c ar ci n o m a s i s 
r e c or d e d
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 5 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
5. 2 E x cl u si o n Crit eri a
6. 6. 3. 1 Bi ntr af u s p alf a/ Pl a c e b o -
r el at e d A d v er s e Dr u g R e a cti o n s
6. 9. 5. 1 M a n a g e m e nt of Bl e e di n g 
E v e nt s
E x cl u si o n of p arti ci p a nt s wit h 
r el e v a nt pri or/ c urr e nt m e di c al hi st or y 
of bl e e di n g e v e nt s. 
I nf or m ati o n pr o vi d e d r e g ar di n g t h e 
m a n a g e m e nt of bl e e di n g e v e nt s d uri n g 
st u d y i nt er v e nti o n
T o e x cl u d e p arti ci p a nt s wit h 
hi st or y of bl e e di n g di at h e si s 
or r e c e nt m aj or bl e e di n g 
e v e nt s
T o pr o vi d e g ui d eli n e s f or t h e 
m a n a g e m e nt of bl e e di n g e v e nt s 
a n d i n di c ati o n s f or w h e n 
p arti ci p a nt s s h o ul d h a v e st u d y 
i nt er v e nti o n h el d or di s c o nti n u e d
1. 3 S c h e d ul e of A cti viti e s, 
T a bl e 1 a n d T a bl e 2
T a bl e 6
6. 6. 1 D o si n g I n str u cti o n s
D o si n g i n str u cti o n s a m e n d e d t o all o w a 
mi s s e d d o s e of c h e m ot h er a p y o n D a y 1 
or D a y 8 of a gi v e n c y cl e t o b e 
a d mi ni st er e d o n D a y 1 5 of t h e s a m e 
c y cl e
T o m ai nt ai n d o s e i nt e n sit y of 
c h e m ot h er a p y w h er e p o s si bl e
6. 6. 3. 1 Bi ntr af u s p Alf a/ Pl a c e b o -
r el at e d A d v er s e Dr u g R e a cti o n s
6. 9. 3 S ki n A d v er s e E v e nt s
I nf or m ati o n r e g ar di n g t h e m a n a g e m e nt 
of bi ntr af u s p alf a / pl a c e b o-r el at e d 
a d v er s e dr u g r e a cti o n s a n d t h e 
m a n a g e m e nt of s ki n a d v er s e e v e nt s 
h a s b e e n u p d at e d
T o e n s ur e g ui d a n c e i s 
c o n si st e nt wit h l a n g u a g e u s e d 
a cr o s s t h e b i ntr af u s p alf a
d e v el o p m e nt pr o gr a m
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 6 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
T hr o u g h o ut t h e pr ot o c ol
Pr ot o c ol r e q uir e m e nt s cl arifi e d f or: 
p r e g n a n c y t e sti n g; h e p atiti s ; in cl u si o n 
crit eri a 3 a n d 4; d o si n g in str u cti o n s ;
a nti - e m e si s tr e at m e nt; pati e nt -r e p ort e d 
o ut c o m e s ; a n d T a bl e s A, B , E, a n d F
T o i m pl e m e nt p r ot o c ol 
cl arifi c ati o n s o utli n e d i n t h e 
M S 2 0 0 6 4 7 _ 0 0 5 5 Cl arifi c ati o n 
L ett er, d at e d 2 2 J ul y 2 0 1 9
T hr o u g h o ut t h e pr ot o c ol
Pr ot o c ol r e q uir e m e nt s cl arifi e d f or: 
i n cl u si o n crit eri o n 1; e x cl u si o n crit eri a 5 
a n d 1 8; m a n a g e m e nt of e m e si s; 
m a n a g e m e nt of bili ar y tr a ct o b str u cti o n; 
a n d r e pl a c e m e nt of p arti ci p a nt s i n t h e 
o p e n -l a b el, s af et y r u n-i n p art. 
A s s u m pti o n s f or s a m pl e si z e 
c al c ul ati o n al s o cl arifi e d
Pr ot o c ol cl arifi c ati o n s
T hr o u g h o ut t h e pr ot o c ol
“ M 7 8 2 4” h a s b e e n r e pl a c e d b y t h e 
i nt er n ati o n al n o n pr o pri et ar y n a m e, 
“ bi ntr af u s p alf a” t hr o u g h o ut t h e pr oto c ol
T o e n s ur e c o n si st e n c y wit h 
ot h er r e g ul at or y d o c u m e nt s i n 
t h e bi ntr af u s p alf a d e v el o p m e nt 
pr o gr a m
T hr o u g h o ut t h e pr ot o c ol
Mi n or e dit ori al a n d f or m atti n g r e vi si o n s; 
c orr e cti o n of mi n or t y p o gr a p hi c al err or s
T o m a k e m i n or r e vi si o n s f or 
c orr e ct n e s s, r e a d a bilit y, 
c o n si st e n c y of l a n g u a g e a cr o s s 
t h e bi ntr af u s p alf a d e v el o p m e nt 
pr o gr a m, a n d f or c o m pli a n c e 
wit h c urr e nt S p o n s or g ui d eli n e s
Pr ot oc ol Versi o n 2. 0 ( 1 1 Oct o ber 2 0 1 9)
T his a me n d me nt is c o nsi dere d a s u bsta ntial a me n d me nt base d o n t he criteria i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  pur p ose of t his a me n d me nt is t o a d dress fee d bac k o n Versi o n 1. 0 of t he pr ot oc ol fr o m 
re gi o nal a n d nati o n al re g ulat or y age ncies ( E ur o pea n Me dici nes A ge nc y , t he U S F o o d a n d Dr u g 
A d mi nistrati o n, a n d t he P har mace utical a n d Me dical De vices A ge nc y i n Ja pa n). T he ke y c ha n ges 
i nc or p orate d are:

T o descri be a si n gle pri mar y  en d p oi nt ( o verall s ur vi val) i n t he ra n d o mized, d o u ble -bli n d part 
of t he st u d y  rat her t ha n d ual pri mar y e n d p oi nts

T o re m o ve t he re q uire me nt f or i nitial pr o gressi ve disease as deter mi ne d b y t he I n vesti gat or t o 
be verifie d b y a n I n de pe n de nt Re vie w C o m mittee (I R C) 

T he a nal ys is of pr o gressi o n -free s ur vi val (P F S ) a n d ot her t u m or -base d efficac y en d p oi nts will 
n o w be base d o n I n vesti gat or assess me nt; a nal ysis base d o n I RC assess me nt will o nl y  be 
perf or me d if t he st u d y  is n ot e x pa n de d t o P hase III
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 7 / 2 1 3

T o ac k n o wle d ge t hat, f or t he p ur p oses of mar keti n g a ut h orizat i o n i n Ja pa n, if t he st u d y is n ot 
e x pa n de d i nt o P hase III, it will n ot be acce pta ble as a c o nfir mat or y st u d y  

T o pr o vi de a d diti o nal i nf or mati o n o n t he p o wer t o detect differe nces i n efficac y am o n g t he 
differe nt biliar y  tract ca ncer a nat o mical s u b gr o u ps

T o e xcl u de partici pa nts wit h hist or y  of blee di n g diat hesis a n d pr o vi de f urt her g ui da nce o n d ose 
m o dificati o ns f or blee di n g e ve nts acc or di n g t o N CI -C T C A E se verity gra d e a n d site of blee di n g

T o i ncl u de a d diti o nal patie nt -re p orte d o utc o me meas ures t o e na ble par tici pa nts’ e x perie nce of 
t he st u d y i nter ve nti o n t o be f urt her c haracterize d

T o all o w c he m ot hera p y t o be gi ve n o n Da y 1 5 of a gi ve n c ycle if a d mi nistrati o n o n Da y 1 or 
D a y 8 was n ot p ossi ble.
C ha n ges i m ple me nte d i n t his pr ot oc ol a me n d me nt will o nl y  be i m pleme nte d at eac h site f oll o wi n g 
re vie w/fa v ora ble o pi ni o n 
of 
t he a me n d me nt b y  the 
res p o nsi ble I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee, as i n dicate d i n A p pe n di x 2. Sites s h o ul d e ns ure t he y are 
f oll o wi n g t he a p pr o priate a p pr o ve d pr ot oc ol versi o n at a n y gi ve n ti me, partic ularly w it h res pect t o 
t he recr uit me nt of partici pa nts i n t he o pe n-la bel, safety r u n-i n part.
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 1 S y n o p si s
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
9. 1 St ati sti c al H y p ot h e s e s
9. 3 S a m pl e Si z e D et er mi n ati o n
9. 5 St ati sti c al A n al y s e s
T a bl e 5, T a bl e 2 4, a n d T a bl e 2 6, 
a n d t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
c h a n g e d fr o m a pri m ar y t o a s e c o n d ar y 
e n d p oi nt
If t h e a d a pt ati o n d e ci si o n r e s ult s i n t h e 
f ull P h a s e III s a m pl e si z e ( N = 5 0 0), t h e 
I n v e sti g at or will b e c o m e t h e m ai n 
a s s e s s or f or P F S
T o h a v e o v er all s ur vi v al ( O S) a s 
a si n gl e pri m ar y e n d p oi nt
4. 2 S ci e ntifi c R ati o n al e f or St u d y 
D e si g n
Fi g ur e 3
5. 1 I n cl u si o n Crit eri a
6. 5. 4 Ot h er I nt er v e nti o n s
7. 1 Di s c u s si o n of St u d y I nt er v e nti o n 
T a bl e 1 6
8. 1. 1 T u m or R e s p o n s e, a n d 
t hr o u g h o ut t h e pr ot o c ol, a s 
a p pli c a bl e
R e m o v al of v erifi c ati o n of pr o gr e s si v e 
di s e a s e ( P D) b y a n I n d e p e n d e nt 
R e vi e w C o m mitt e e (I R C) f oll o wi n g 
I n v e sti g at or d et er mi n e d P D
V erifi c ati o n of P D b y a n I R C w a s 
i ntr o d u c e d a s a q u alit y m e a s ur e 
f or t h e pri m ar y e n d p oi nt, P F S 
p er I R C. W it h P F S h a vi n g b e e n 
d e m ot e d t o a s e c o n d ar y 
e n d p oi nt, t hi s i s n o l o n g er 
r e q uir e d
4. 4 E n d of St u d y D efi niti o n
U p d at e d e n d of st u d y d efi niti o n wit h 
d at a c ut off f or pri m ar y O S a n al y si s f or 
P h a s e III a n d P h a s e II st u d y
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
9. 2 Hi er ar c hi c al T e sti n g Pr o c e d ur e
Pr o vi si o n of hi er ar c hi c al t e sti n g 
pr o c e d ur e s f or t h e e n d p oi nt s O S, P F S, 
a n d o bj e cti v e r e s p o n s e r at e
R e q uir e d d u e t o t h e c h a n g e 
fr o m d u al pri m ar y e n d p oi nt s t o a 
si n gl e pri m ar y e n d p oi nt
9. 5. 1 Effi c a c y A n al y s e s ( T a bl e 2 4)
Cl arifi c ati o n of t h e a n al y s e s u s e d f or 
t e sti n g n ull h y p ot h e si s
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
9. 5. 4 S e q u e n c e of A n al y s e s
Cl arifi c ati o n of t h e s e q u e n c e of 
a n al y s e s
R e q uir e d d u e t o t h e c h a n g e 
fr o m d u al pri m ar y e n d p oi nt s t o a 
si n gl e pri m ar y e n d p oi nt
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 8 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
A p p e n di x 1 0 C o u ntr y -s p e cifi c 
R e q uir e m e nt s
E x pl a n ati o n t h at i n J a p a n, if t h e st u d y i s 
n ot e x p a n d e d i nt o P h a s e III, it i s n ot 
e x p e ct e d t o s ati sf y t h e c o n diti o n of a 
c o nfir m at or y st u d y
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
1. 1 S y n o p si s
4. 1. 1 O p e n -l a b el, S af et y R u n-i n 
P art
Cl arifi c ati o n t h at p arti ci p a nt s will b e 
r e cr uit e d s e q u e nti all y i n e a c h c o h ort of 
t h e o p e n-l a b el, s af et y r u n-i n p art
T o a d dr e s s r e g ul at or y a g e n c y 
f e ed b a c k
1. 1 S y n o p si s
4. 1. 2 R a n d o mi z e d, D o u bl e -bli n d 
P art 
6. 3. 1 St u d y I nt er v e nti o n A s si g n m e nt
T a bl e 2 4
T h e d efi niti o n of t h e str atifi c ati o n f a ct or 
r el ati n g t o cl a s sifi c ati o n of bili ar y tr a ct 
c a n c er ( B T C) at di a g n o si s h a s b e e n 
r efi n e d
T o e n s ur e all p ot e nti al
di a g n o s e s of B T C at di a g n o si s 
ar e c a pt ur e d wit hi n t h e d efi niti o n 
of t h e r el at e d str atifi c ati o n f a ct or
9. 3. 4 S u b gr o u p A n al y s e s f or Bili ar y 
Tr a ct C a n c er S u bt y p e s
T a bl e 2 0, T a bl e 2 1, T a bl e 2 2, a n d 
T a bl e 2 4
I nf or m ati o n pr o vi d e d r e g ar di n g t h e 
p o w er t o d et e ct diff er e n c e s i n effi c a c y 
a m o n g t h e a n at o mi c al B T C s u b gr o u p s
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
5. 1 I n cl u si o n Crit eri a
T e xt a d d e d t o e n s ur e t h e hi st ol o gi c al 
ori gi n of a m p ull ar y c ar ci n o m a s i s 
r e c or d e d
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
5. 2 E x cl u si o n Crit eri a
6. 6. 3. 1 Bi ntr af u s p alf a/ Pl a c e b o -
r el at e d A d v er s e Dr u g R e a cti o n s
6. 9. 5. 1 M a n a g e m e nt of Bl e e di n g 
E v e nt s
E x cl u si o n of p arti ci p a nt s wit h r el e v a nt 
pri or/ c urr e nt m e di c al hi st or y of bl e e di n g 
e v e nt s. 
I nf or m ati o n pr o vi d e d r e g ar di n g t h e 
m a n a g e m e nt of bl e e di n g e v e nt s d uri n g 
st u d y i nt er v e nti o n
T o e x cl u d e p arti ci p a nt s wit h 
hi st or y of bl e e di n g di at h e si s or 
r e c e nt m aj or bl e e di n g e v e nt s
T o pr o vi d e g ui d eli n e s f or t h e 
m a n a g e m e nt of bl e e di n g e v e nt s 
a n d i n di c ati o n s f or w h e n 
p arti ci p a nt s s h o ul d h a v e st u d y 
i nt er v e nti o n h el d or di s c o nti n u e d
1. 3 S c h e d ul e of A cti viti e s, T a bl e 1 
a n d T a bl e 2
T a bl e 6
6. 6. 1 D o si n g I n str u cti o n s
D o si n g i n str u cti o n s a m e n d e d t o all o w a 
mi s s e d d o s e of c h e m ot h er a p y o n D a y 1 
or D a y 8 of a gi v e n c y cl e t o b e 
a d mi ni st er e d o n D a y 1 5 of t h e s a m e 
c y cl e
T o m ai nt ai n d o s e i nt e n sit y of 
c h e m ot h er a p y w h er e p o s si bl e
6. 6. 3. 1 Bi ntr af u s p Alf a/ Pl a c e b o-
r el at e d A d v er s e Dr u g R e a cti o n s
I nf or m ati o n r e g ar di n g t h e m a n a g e m e nt 
of bi ntr af u s p alf a / pl a c e b o-r el at e d 
T o e n s ur e g ui d a n c e i s 
c o n si st e nt wit h l a n g u a g e u s e d 
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 0 9 / 2 1 3
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
6. 9. 3 S ki n A d v er s e E v e nt s
a d v er s e dr u g r e a cti o n s a n d t h e 
m a n a g e m e nt of s ki n a d v er s e e v e nt s 
h a s b e e n u p d at e d
a cr o s s t h e b i ntr af u s p alf a
d e v el o p m e nt pr o gr a m
T hr o u g h o ut t h e pr ot o c ol
Pr ot o c ol r e q uir e m e nt s cl arifi e d f or: 
p r e g n a n c y t e sti n g; h e p atiti s ; in cl u si o n 
crit eri a 3 a n d 4; d o si n g in str u cti o n s ;
a nti - e m e si s tr e at m e nt; pati e nt -r e p ort e d 
o ut c o m e s ; a n d T a bl e s A, B , E, a n d F
T o i m pl e m e nt p r ot o c ol 
cl arifi c ati o n s o utli n e d i n t h e 
M S 2 0 0 6 4 7 _ 0 0 5 5 Cl arifi c ati o n 
L ett er, d at e d 2 2 J ul y 2 0 1 9
T hr o u g h o ut t h e pr ot o c ol
Pr ot o c ol r e q uir e m e nt s cl arifi e d f or: 
i n cl u si o n crit eri o n 1; e x cl u si o n crit eri a 5 
a n d 1 8; m a n a g e m e nt of e m e si s; 
m a n a g e m e nt of bili ar y tr a ct o b str u cti o n; 
a n d r e pl a c e m e nt of p arti ci p a nt s i n t h e 
o p e n -l a b el, s af et y r u n-i n p art. 
A s s u m pti o n s f or s a m pl e si z e 
c al c ul ati o n al s o cl arifi e d
Pr ot o c ol cl arifi c ati o n s
T hr o u g h o ut t h e pr ot o c ol
“ M 7 8 2 4” h a s b e e n r e pl a c e d b y t h e 
i nt er n ati o n al n o n pr o pri et ar y n a m e, 
“ bi ntr af u s p alf a” t hr o u g h o ut t h e pr ot o c ol
T o e n s ur e c o n si st e n c y wit h 
ot h er r e g ul at or y d o c u m e nt s i n 
t h e bi ntr af u s p alf a d e v el o p m e nt 
pr o gr a m
T hr o u g h o ut t h e pr ot o c ol
Mi n or e dit ori al a n d f or m atti n g r e vi si o n s; 
c orr e cti o n of mi n or t y p o gr a p hi c al err or s
T o m a k e m i n or r e vi si o n s f or
c orr e ct n e s s, r e a d a bilit y, 
c o n si st e n c y of l a n g u a g e a cr o s s 
t h e bi ntr af u s p alf a d e v el o p m e nt 
pr o gr a m, a n d f or c o m pli a n c e 
wit h c urr e nt S p o n s or g ui d eli n e s
Pr ot oc ol Versi o n 1. 1 ( 1 9 Se pte m ber 2 0 1 9)
T his a me n d me nt is c o nsi dere d n o ns u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 
2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n beca use it neit her 
si g nifica ntly i m pacts t he safet y or p h y sical/ me ntal i nte grit y of t he partici pa nts n or t he scie ntific 
i nte grity of t he st u d y.
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  pur p ose of t his a me n d me nt is t o a d dress fee d bac k a n d q uesti o ns o n Versi o n 1. 0 of 
t he pr ot oc ol recei ve d d uri n g E ur o pea n V H P pr oce d ure. T he ke y  c ha n ges i nc or p orate d are:

Re visi o n a n d clarificati o n of i ncl usi o n a n d e xcl usi o n criteria t o ass ure partici pa nt safet y

Clarificati o n of t he ma na ge me nt of st u d y  partici pa nts at t he e n d of st u d y
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 1 0 / 2 1 3

Re visi o n of t he criteria f or Gra de 3 M 7 8 2 4/ place b o -relate d a d verse dr u g reacti o ns t hat d o n ot 
re q uire disc o nti n uati o n of st u d y i nter ve nti o n.
C ha n ges i m ple me nte d i n t his pr ot oc ol a me n d me nt will o nl y  be i m ple me nte d at eac h site f oll o wi n g 
re vie w/fa v ora ble o pi ni o n 
of 
t he a me n d me nt b y  the 
res p o nsi ble I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee, as i n dicate d i n A p pe n di x 2. S ites s h o ul d e ns ure t he y are 
f oll o wi n g t he a p pr o priate a p pr o ve d pr ot oc ol versi o n at a n y gi ve n ti me, partic ularly w it h res pect t o 
t he recr uit me nt of partici pa nts i n t he o pe n-la bel, safety- r u n-i n part.
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
5. 1 I n cl u si o n Crit eri a
R e vi si o n of i n cl u si o n crit eri a 8 a n d 1 4 
wit h r e s p e ct t o h e m at ol o gi c al f u n cti o n 
a n d s e x u al a cti vit y/ e g g d o n ati o n, 
r e s p e cti v el y
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
5. 2 E x cl u si o n Crit eri a
R e vi si o n of e x cl u si o n crit eri o n 5 wit h 
r e s p ect t o a cti v e vir al i nf e cti o n r e q uiri n g 
s y st e mi c tr e at m e nt 
A d diti o n of a n e w crit eri o n t o e x cl u d e 
p arti ci p a nt s w h o ar e s uit a bl e f or li v er 
tr a n s pl a nt ati o n
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
4. 4 E n d of St u d y D efi niti o n
Pr o vi si o n a d d e d f or:

p arti ci p a nt s w h o ar e still r e c ei vi n g 
st u d y i nt er v e nti o n or u n d er g oi n g 
s ur vi v al f oll o w -u p at t h e e n d of 
st u d y t o b e e nr oll e d i n a n e xt e n si o n 
st u d y or n o n -i nt er v e nti o n al st u d y

t h e S p o n s or t o t er mi n at e t h e st u d y 
at a n y ti m e o n c e a c c e s s t o st u d y 
i nt er v e nti o n f or p arti ci p a nt s still 
b e n efiti n g i s pr o vi d e d
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
6. 6. 3. 1 M 7 8 2 4/ Pl a c e b o -r el at e d 
A d v er s e Dr u g R e a cti o n s
F or Gr a d e 3 a d v er s e dr u g r e a cti o n s 
t h at d o n ot r e q uir e tr e at m e nt 
di s c o nti n u ati o n:

D efi niti o n of “tr a n si e nt” a d d e d

N e w crit eri a r el at i n g t o E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p 
P erf or m a n c e St at u s a n d 
e n d o cri n o p at hi e s a d d e d
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
1. 3 S c h e d ul e of A cti viti e s, T a bl e 1 
a n d T a bl e 2
Pr ot o c ol r e q uir e m e nt s cl arifi e d f or vit al 
si g n s a s s e s s m e nt s
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
6. 9. 1 I nf u si o n -r el at e d R e a cti o n s 
I n cl u di n g I m m e di at e 
H y p er s e n siti vit y, T a bl e 1 3
D efi niti o n of “ pr ol o n g e d” a d d e d
T o a d dr e s s r e g ul at or y a g e n c y 
f e e d b a c k
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L B T C P h as e I 賞几II G e m cit a bi n e Pl us Cis pl ati n Wit h oI. Wit h o ut
M S 2 0 0 6 4 7 0 0 5 5
Bi ntr af us p aIf a
A p p e n di x 1 3
S p o ns or Si g n at ur e P a g e
St u d y Titl e:
A P h as e II /III,
M ulti c e nt er,
R a n d o mi z e d,
Pl a c e b o ­ C O ntr Oll e d St u d y of G e m cit a bi n e Pl us
Cis pl ati n Wi 血or Wit h o ut Bi ntr af us p alf a ( M 7 8 2 4) as
First ­ 1i n e Tr e at m e nt of Bili ar y Tr a ct C a n c er
R e g u 看at or y A g e n c y I d e ntif yi n g 
N u m b ers
E u dr a C T: 2 0 1 9 ­ 0 0 1 9 9 2 ­ 3 5
Cli ni c al Tri als. g o v: N C T O 4 0 6 6 4 9 1
C 看i ni c al St u d y Pr ot o c oI 1 4 J ul y 2 0 2 1 N ersi o n 5. 0
V ersi o n:
I a p pr o v e 血e d esi g n of 血e cli ni c al st u d y:
S i 親l 耕皿e
N a m e, a C a d e mi c d e gr e e:
F u n cti o n / TitI e :
I nstit uti o n :
A d dr ess:
T el e p h o n e n u m b er:
F a x n u m b er:
E ­ m ail a d dr ess:
Pr ot o c oI L e a d
M er c k Bi o p h a m a C o., Lt d.
( A 餓Ii at e of M er c k K G a A, D a mst a dt, G e m a n y)
D o c u m e nt N o. 
O 匂e ct N o. 
2 1 1 / 2 1 3
C CI
C CI
C CI
P P D
P P D
P P D
P P D


C CI
C CI
C CI
P P D
P P D
P P DP P D
P P D
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4) 
1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n Wit h or Wit h o ut
M S 2 0 0 6 4 7 _ 0 0 5 5
Bi ntr af us p alf a
2 1 3 / 2 1 3
A p pe n di x 1 5
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A 
P hase 
II/III, 
M ultice nter, 
Ra n d o mize d, 
Place b o -c o ntr olle d 
St u d y  
of 
Ge mcita bi ne 
Pl us 
Cis plati n Wit h or Wit h o ut B i ntraf us p alfa ( M 7 8 24 ) as 
First -li ne Treat me nt of Biliar y Tract Ca ncer
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
E u dra C T: 2 0 1 9 - 0 0 1 9 9 2- 3 5
Cli nical Trials. g o v: N C T 0 4 0 6 6 4 9 1
Cli nic al 
St u d y 
Pr ot oc ol 
Versi o n:
1 4 J ul y 2 0 2 1/ Versi o n 5. 0
Site N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per t he 
cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil 
f or 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n a n d 
s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct a n d 
a n y ot her fi na ncial ties wit h the S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olel y for 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h a n y 
necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  sp o us e 
a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet 
Healt h 
A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o.
O bject N o.
C CI
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SAP_001.pdf: 
Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 /1 0 8  
 
 
I nte gr ate d A n al ysis Pl a n  
 
 
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 6 4 7 _ 0 0 5 5  
Title:  
A P hase II/III, M ultice nt er, Ra n d o mize d, Place b o -c o ntr olle d St u d y of 
Ge mcita bi ne Pl us Cis plati n Wit h or Wit h o ut Bi ntraf us p alfa ( M 7 8 2 4 ) as 
First -li ne Treat me nt of Biliar y Tract Ca ncer 
St u d y P h ase  
P hase II/III 
I n vesti g ati o n al 
Me dici n al Pr o d uct(s)  
Bi ntraf us p alfa  
Cli nic al St u d y Pr ot oc ol 
Versi o n  
1 4 J ul y  2 0 2 1 / Versi o n 5 . 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or  
C o or di n ati n g A ut h or s  
 
 
I nte gr ate d A n al ysis Pl a n  
D ate a n d Versi o n  
1 st Fe br uar y  2 0 2 2 , Versi o n 4   
I nte gr ate d A n al ysis Pl a n 
Re vie wers  
F u n cti o n  
N a m e  
 M er c k H e alt h c ar e  
 
 M er c k H e alt h c ar e 
 
 
, M er c k H e alt h c ar e 
 
 E M D S er o n o 
 
 
 
, E M D S er o n o 
 
 E M D S er o n o 
  
, M er c k H e alt h c ar e 
 
, M er c k H e alt h c ar e 
  
 
 
 
 
 E M D S er o n o 
 
, M er c k H e alt h c ar e 
 
 
 
 E M D S er o n o 
 
 E M D S er o n o 
 
 
 
 
 
 
T his d oc u me nt is t he pr o pert y of Merc k K g a A, D ar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot –  i n f ull or part –  be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut e x press 
per missi o n of Merc k K g a A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 1  b y M erc k K g a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.  
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Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 /1 0 8  
 
 
A p pr o v al P a ge   
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 6 4 7 _ 0 0 5 5  
A P hase II/III, M ultice nt er, Ra n d o mize d, Place b o -c o ntr olle d St u d y of Ge m cita bi ne Pl us Cis plati n 
Wit h or Wit h o ut Bi ntraf us p alfa ( M 7 8 2 4 ) as First-li ne Treat me nt of Biliar y Tract Ca ncer  
A p pr o val of t he I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n 
E L D O R A D O vi a e Si g nat ure. Wit h t he a p pr o val, t he Merc k res p o nsi ble f or eac h of t he a nal ys es 
als o ta kes res p o nsi bilit y t h at all re vie wers’ c o m me nts are a d dresse d a de q uat el y.  
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d oc u me nt.  
  
 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 /1 0 8  
 
 
1  
T a ble of C o nte nts   
  
 
      
A p pr o val Pa ge  
2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b br e viati o ns a n d Defi niti o n of Ter ms  ....................................8  
3  
M o dificati o n Hist or y  ..........................................................................1 2  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  .............................................1 5  
5  
O bjecti ves a n d E n d p oi nts  ...................................................................1 5  
6  
O ver vie w of Pla n ne d A nal yses  ...........................................................1 8  
6. 1  
Safet y M o nit ori n g C o m mittee  ............................................................2 0  
6. 2  
Safet y a n d Efficac y A nal ysis f or O pe n -la bel Safet y R u n-i n Part .......2 1  
6. 3  
I n d e pe n de nt Data M o nit ori n g C o m mittee ..........................................2 1  
6. 4  
I nteri m A nal ysis f or A da ptati o n Decisi o n ..........................................2 2  
6. 5  
I nteri m a n d Pri mar y A nal ysis .............................................................2 2  
7  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli nical St u d y Pr ot o c ol  ......2 2  
7. 1  
O ver vie w of Pla n ne d A nal yses after Trial Disc o nti n uati o n  ...............2 2  
7. 2  
C O VI D -1 9 I m pa ct  ..............................................................................2 4  
8  
A nal ysis P o p ulati o ns a n d S u b gr o u ps ..................................................2 5  
8. 1  
Defi niti o n of A nal ysis P o p ulati o ns  .....................................................2 5  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ..........................................2 8  
9. 1  
Data Ha n dli n g After C ut -off Date  ......................................................2 9  
9. 2  
Defi niti o n of Bas eli ne a n d C ha n ge fr o m Baseli ne  .............................2 9  
9. 3  
St u d y Da y / St u d y Treat me nt Da y  ......................................................3 0  
9. 4  
Defi niti o n of D urati o n a n d ‘ti me si nce’ Varia bles  .............................3 0  
9. 5  
C o n versi o n Fact ors  .............................................................................3 1  
9. 6  
Date o f Last C o ntact ...........................................................................3 1  
9. 7  
Ti me Wi n d o w  .....................................................................................3 1  
9. 8  
Defi niti o n of O n -treat me nt Peri o d ......................................................3 1  
9. 9  
I m p utati o n of Missi n g Data ................................................................3 2  
9. 1 0  
Sc ori n g of H R Q O L Dat a  ....................................................................3 4  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 /1 0 8  
 
 
9. 1 1  
Prese ntati o n of C o nti n u o us a n d Q ualitati ve Varia bles  .......................3 4  
9. 1 2  
Si g nifica nce Le v el  ..............................................................................3 4  
9. 1 3  
P o oli n g of Ce nters  ..............................................................................3 4  
9. 1 4  
U nsc he d ule d Ass ess me nts  ..................................................................3 5  
9. 1 5  
St u d y Treat me nt  ..................................................................................3 5  
9. 1 6  
Preferre d Ter m f or a nal ysis of W orl d Healt h Or ga nizati o n’s Dr u g 
Dicti o nar y ( W H O -D D) c o de d data  .....................................................3 5  
9. 1 7  
T u m or Assess me nts  ............................................................................3 5  
9. 1 8  
Re -scree ne d Partici p a nts .....................................................................3 6  
9. 1 9  
S oft ware  ..............................................................................................3 6  
1 0  
St u d y Partici pa nts  ...............................................................................3 6  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................3 6  
1 0. 2  
Pr ot oc ol De viati o ns  ............................................................................3 8  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................3 9  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis P o p ulati o n  .......4 0  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................4 0  
1 1. 1  
De m o gra p hics  .....................................................................................4 0  
1 1. 2  
Me dical Hist or y  ..................................................................................4 2  
1 1. 3  
Ot her B aseli ne C haracteristics  ............................................................4 2  
1 1. 3. 1  
Disease Hist or y  ...................................................................................4 2  
1 1. 3. 2  
S ki n Stat us Hist or y  .............................................................................4 3  
1 1. 3. 3  
T u m or Bi o ps y  .....................................................................................4 4  
1 1. 3. 4  
P D -L 1 T est  ..........................................................................................4 4  
1 1. 4  
Pre vi o us A ntica ncer T hera p y  .............................................................4 4  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................4 5  
1 2. 1  
Pre vi o us a n d C o nc o mita nt Me dicati o ns  .............................................4 5  
1 2. 2  
Pre me dicati o ns  ....................................................................................4 6  
1 2. 3  
C o nc urre nt Pr oce d ures  ........................................................................4 6  
1 2. 4  
S u bse q ue nt A ntica ncer T hera p y  .........................................................4 7  
1 3  
St u d y Treat me nt: C o m plia nce a n d E x p os ure  .....................................4 8  
1 4  
Efficac y A nal yses  ...............................................................................5 1  
1 4. 1  
O verall S ur vi val ( Pri mar y E n d p oi nt)  ..................................................5 2  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 /1 0 8  
 
 
1 4. 1. 1  
Pri mar y O bj ecti ve : Deri vati o n a n d a nal ysis of O verall S ur vi val .......5 2  
1 4. 1. 2  
Se nsiti vit y A nal ys es of O verall S ur vi val  ............................................5 5  
1 4. 2  
Pr o gressi o n -Free S ur vi val Acc or di n g t o R E CI S T 1. 1 ( Sec o n dar y 
E n d p oi nt)  ............................................................................................5 7  
1 4. 2. 1  
Mai n A nal ysis f or P F S ........................................................................5 8  
1 4. 2. 2  
Se nsiti vit y A nal ysis f or P F S  ...............................................................6 0  
1 4. 3  
O bjecti ve Res p o nse Rate Acc or di n g t o R E CI S T 1. 1 ( Sec o n dar y 
E n d p oi nt)  ............................................................................................6 1  
1 4. 3. 1  
Mai n A nal ysis f or O R R  ......................................................................6 3  
1 4. 3. 2  
Se nsiti vit y A nal ysis f or O R R  .............................................................6 5  
1 4. 4  
D urati o n of Res p o nse Acc or di n g t o R E CI S T 1. 1 ( Sec o n dar y 
E n d p oi nt)  ............................................................................................6 6  
1 4. 4. 1  
Mai n A nal ysis f or D O R  ......................................................................6 7  
1 4. 4. 2  
Se nsiti vit y A nal ysis f or D O R  .............................................................6 7  
1 4. 5  
D ura ble Res p o nse Acc or di n g t o R E CI S T 1. 1 ( Sec o n dar y 
E n d p oi nt)  ............................................................................................6 7  
1 4. 5. 1  
Mai n A nal ysis f or D R R  ......................................................................6 8  
1 4. 5. 2  
Se nsiti vit y A nal ysis f or D R R  .............................................................6 8  
1 5  
Safet y A nal yses  ..................................................................................7 1  
1 5. 1  
A d verse E v e nts  ...................................................................................7 2  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................7 4  
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 /1 0 8  
 
 
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y Treat me nt  ......7 6  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................7 7  
1 5. 2. 1  
Deat hs  .................................................................................................7 7  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................7 8  
1 5. 2 . 3 
D ose -li miti n g T o xicit y ( Pri mar y E n d p oi nt Safet y R u n-i n) ................7 8  
1 5. 2. 4  
Blee di n g E v e nts  ..................................................................................7 8  
1 5. 2. 5  
A d verse E v e nts of S peci al I nt erest  .....................................................7 9  
1 5. 2. 6  
T hree -tier A p pr oac h t o S u m marizi n g a n d A nal yzi n g A d verse 
E ve nts  .................................................................................................8 2  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................8 4  
1 5. 4  
Vital Si g ns  ..........................................................................................9 0  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................9 0  
1 7  
Refere n ces  .........................................................................................1 0 5  
1 8  
A p pe n dices  .......................................................................................1 0 5  
1 8. 1. 1  
A p pe n di x 1 - Defi niti o n of I m p orta nt Pr ot oc ol De viati o ns  ..............1 0 5  
1 8. 1. 2  
A p pe n di x 2 - R ules f or I de ntificati o n of Pre vi o us or C o nc o mita nt 
Me dicati o ns/ Pr oce d ures  ....................................................................1 0 6  
1 8. 1. 3  
A p pe n di x 3 - Defi niti o n of N CI -C T C A E Gra di n g  ...........................1 0 6  
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Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 /1 0 8  
 
 
1 8. 1. 4  
A p pe n di x 4 –  A da ptati o n Pla n  ..........................................................1 0 6  
1 8. 1. 5  
A p pe n di x 5 –  C ycle X Da y 1/ D a y 8/ Da y 1 5 d eter mi nati o n  .............1 0 6  
1 8. 1. 6  
A p pe n di x 6 –  S u bse q ue nt I m m u ne C hec k p oi nt I n hi bit ors  ...............1 0 8  
 
 
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Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 /1 0 8  
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms   
A b bre vi ati o n  
Defi niti o n  
1 L  
First -li ne 
A d a M 
A nal ysis Data M o del  
A E  
A d verse E ve nt  
A E SI  
A d verse E ve nts of S pecial I nterest  
A L T  
Ala ni ne A mi n otra nsferase  
A L P  
Al kali ne P h os p hatase  
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  
Area u n der t he c o nce ntrati o n -ti me c ur ve 
A U C 0 -t 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he last 
sa m pli n g ti me at w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit 
of q ua ntificati o n  
A U C 0 -∞ 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o e xtra p olate d 
t o i nfi nit y 
A T C  
A nat o mical T hera pe utic C he mical  
B L Q  
Bel o w t he l o wer li mit of q ua ntificati o n  
B MI  
B o d y Mass I n de x  
B S A  
B o d y S urface Area  
B T C  
Biliar y Tract Ca ncer  
C C A  
C h ola n gi ocarci n o ma  
C E OI  
T he c o nce ntrati o n o bser ve d i m me diatel y at t he e n d of i nf usi o n  
CI  
C o nfi de nce I nter val  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n  
C M H  
C oc hra n -Ma ntel -Hae nszel  
C R  
C o m plete Res p o nse  
Cr Cl  
Creati ni ne Cleara nce  
C S R  
Cli nical St u d y Re p ort  
ct D N A 
Circ ulati n g t u m or D N A  
C PI  
C hec k p oi nt I n hi bit ors  
C tr o u g h 
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g 
(c orres p o n di n g t o pre-d ose or  tr o u g h c o nce ntrati o n f or m ulti ple 
d osi n g)  
C V  
C oefficie nt of Variati o n ( %)  
D B P  
Diast olic Bl o o d Press ure  
D C R  
Disease C o ntr ol Rate  
DI  
D ose I nte nsit y  
D L T  
D ose -li miti n g T o xicities  
D O R  
D urati o n of Res p o nse  
D R R  
D ura ble Res p o nse  Rate  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 /1 0 8  
 
 
E C G  
Electr ocar di o gra m  
E C O G P S  
Easter n C o o perati ve O nc ol o g y Gr o u p P erf or ma nce S tat us 
e CR F  
Electr o nic Case Re p ort F or m  
e DI S H  
E val uati o n of Dr u g -I n d uce d Seri o us He pat ot o xicit y 
E D R  
Earl y Discre pa nc y Rate  
H B V  
He patitis B Vir us  
H C V  
He patitis C Vir us  
H G B  
He m o gl o bi n  
H L G T  
Hi g h Le vel Gr o u p T er ms  
H L T  
Hi g h Le vel T er m  
I A 
I nteri m A nal ysis 
I A P 
I nte grate d A nal ysis Pla n 
I C 
I m m u ne Cells 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I D M C  
I n de pe n de nt Data M o nit ori n g C o m mittee 
I P D 
I m p orta nt Pr ot oc ol De viati o ns 
ir A E 
I m m u ne-relate d A d verse E ve nt 
I R C 
I n de pe n de nt Re vie w C o m mittee 
I T T 
I nte nt-t o-treat 
I X R S 
I nteracti ve Res p o nse S yste m 
λ Z  
T er mi nal first or der (eli mi nati o n) rate c o nsta nt  
L D R  
Late Discre pa nc y Rate  
Ma x  
Ma xi m u m  
L L N  
L o wer Li mit of N or mal  
M C H  
Mea n C or p usc ular He m o gl o bi n  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 /1 0 8  
 
 
M C H C  
Mea n C or p usc ular He m o gl o bi n C o nce ntrati o n  
M C V  
Mea n C or p usc ular V ol u me  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
Mi n  
Mi ni m u m  
M N  
Mietti ne n & N ur mi ne n  
M SI  
Micr osatellite I nsta bilit y  
M S S  
Micr osatellite Sta ble  
N C  
N ot Calc ulate d  
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 d  
N ot deter mi ne d  
N D  
N o Disease  
O R R  
O bjecti ve Res p o nse Rate  
O R R 2 L  
O bjecti ve Res p o nse Rate o n S u bse q ue nt Li ne of A ntica ncer Treat me nt  
O S   
O verall S ur vi val  
P A  
Pri mar y A nal ysis  
P D   
Pr o gressi ve Disease  
P F S  
Pr o gressi o n -free S ur vi val 
P K  
P har mac o ki netic(s)  
P R  
Partial Res p o nse  
P T  
Preferre d T er m  
Q 1  
First Q uartile  
Q 3  
T hir d Q uartile  
R B C  
Re d Bl o o d Cell  
R DI  
Relati ve D ose I nte nsit y  
R E CI S T 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1  
R M S T  
Restricte d Mea n S ur vi val Ti me  
R N A  
Ri b o n ucleic Aci d  
S A E  
Seri o us A d verse E ve nt  
S A F  
Safet y A nal ysis Set  
S A F RI  
Safet y R u n -i n 
S A P  
Statistical A nal ysis Pla n  
S B P  
S yst olic Bl o o d Press ure  
S D  
Sta ble Disease  
S D T M  
St u d y Data T a b ulati o n M o del  
SI  
I nter nati o nal S yste m of U nits 
S M C  
Safet y M o nit ori n g C o m mittee  
S M Q  
Sta n dar dize d Me d D R A Q ueries  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 1 /1 0 8  
 
 
S o C  
Sta n dar d of Care  
S O C  
S yste m Or ga n Class  
St D  
Sta n dar d De viati o n  
t1/ 2 
A p pare nt ter mi nal (eli mi nati o n) half -life 
T 4  
T h yr o xi ne  
T BI LI  
T otal Bilir u bi n  
T C  
T u m or Cells  
T E A E  
Treat me nt -e mer ge nt A d verse E ve nt  
T G F -β  
Tra nsf or mi n g Gr o wt h Fact or -Beta  
T M B  
T u m or M utati o nal B ur de n  
T M T B  
T otal Meas ure d T u m or B ur de n  
T N M  
T u m or, L y m p h N o des, Metastasis  
T S H  
T h yr oi d -Sti m ulati n g H or m o ne  
U L N  
U p per Li mit of N or mal  
V A S  
Vis ual A nal o g Scale  
W B C  
W hite Bl o o d Cells  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 2 /1 0 8  
 
 
3  
M o dific ati o n Hist or y   
U ni q u e 
I d e ntifi er 
f or I A P 
V er si o n  
D at e of I A P 
V er si o n  
A ut h or s  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1  
 
N ot A p pli c a bl e  
2  
- 
C h a n g e cli ni c al st u d y pr ot o c ol v er si o n t o v er si o n 4  
- 
I n s e cti o n 6, up d at e d o v er all st u d y d e si g n d e s cri pti o n a s 
p er pr ot o c ol u p d at e v er si o n 3  
- 
I n s e cti o n 6, u p d at e d t h e a n al y si s p o p ul ati o n f or i nt eri m 
a n al y si s a d a pt ati o n t o fir st 1 5 0 r a n d o mi z e d a nti bi oti c s 
n aï v e p arti ci p a nt s  
- 
U p d at e d o v er vi e w of pl a n n e d a n al y si s  i n T a bl e 2  
- 
A d d e d s e cti o n 7. 2  C O VI D -1 9 I m p a ct  
- 
I n s e cti o n 8. 2, f or s u b gr o u p d efi niti o n , u p d at e d ‘ di s e a s e 
st at u s at i niti al di a g n o si s’ b y ‘ di s e a s e st at u s at st u d y e ntr y’, 
a n d gr o u p ‘ u n k n o w n’ c at e g or y wit h ‘l o c all y a d v a n c e d 
c at e g or y ’ 
- 
I n s e cti o n 9. 1, s p e cifi e d o ut c o m e s of a d v er s e e v e nt s ar e 
n ot aff e ct e d b y t h e d at a c ut -off r ul e s  
- 
I n s e cti o n 9. 2 a n d 9. 3 , u p d at e d d efi niti o n of b a s eli n e 
m e a s ur e m e nt t o c o n si d er i n t h e r a n d o mi z e d p art a n d 
a d d e d T a bl e 5  
- 
I n s e cti o n 9. 8, a d d e d d efi niti o n of o n-tr e at m e nt p eri o d f or 
i m m u n e-r el at e d a d v er s e e v e nt s 
- 
U p d at e d s e cti o n s 1 0. 1 “ Di s p o siti o n of p arti ci p a nt s a n d 
Di s c o nti n u ati o n s”,  1 0. 2. 1  “I m p ort a nt Pr ot o c ol D e vi ati o n s” 
“ A d v er s e E v e nt s” i n cl u di n g C O VI D-1 9 a n al y s e s d et ail s  
- 
A d d e d K a pl a n -M ei er pl ot s of ti m e t o st u d y tr e at m e nt s  
di s c o nti n u ati o n a n d ti m e t o st u d y di s c o nti n u ati o n i n 
s e cti o n 1 0. 1  
- 
I n s e cti o n 1 1. 1, u p d at e d d efi niti o n of B MI wit h h ei g ht i n c m 
c o n v ert e d i n m²  
- 
I n s e cti o n 1 1. 3. 1, a d d e d c at e g or y ‘ ot h er s’ f or m ol e c ul ar 
a b n or m alit y li sti n g  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 3 /1 0 8  
 
 
U ni q u e 
I d e ntifi er 
f or I A P 
V er si o n  
D at e of I A P 
V er si o n  
A ut h or s  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
- 
I n s e cti o n 1 1. 4, u p d at e d pr e vi o u s a nti c a n c er t h er a p y 
d e s cri pti o n  
- 
I n s e cti o n 1 2. 4, u p d at e d li st of t y p e of a nti c a n c er dr u g 
t h er a p y a n d a d d e d a p p e n di x 6  
- 
U p d at e d t h e w h ol e s e cti o n 1 3 e s p e ci all y b y r e m o vi n g 
d e s cri pti o n b y c y cl e  
- 
I n se cti o n, 1 4. 2. 1, u p d at e d ‘N o b a s eli n e a s s e s s m e nt ’ 
d efi niti o n t o c o n si d er o nl y c a s e s wit h n o t u m or s c a n 
r e c or d e d b ef or e r a n d o mi z ati o n 
- 
I n s e cti o n 1 4. 2. 1, u p d at e d d efi niti o n of ‘L o st t o f oll o w -u p ’ t o 
a d d p arti ci p a nt s w h o di s c o nti n u e d/ c o m pl et e d t h e st u d y 
wit h o u t a n e v e nt 
- 
I n s e cti o n s 1 4. 1. 2, 1 4. 2. 2 a n d 1 4. 3. 2, a d d e d s e n siti v e 
a n al y si s f or 
str atifi e d t e st t o 
b e 
p erf or m e d 
u si n g 
r a n d o mi z ati o n str at a fr o m e C R F 
- 
I n s e cti o n 1 4. 3, c h a n g e d ‘ m or e t h a n 2 8 d a y s aft er’ b y “ at 
l e a st f or 4 w e e k s a p art’ i n t h e d efi niti o n of Be st  O v er all 
R e s p o n s e  b a s e d o n c o nfir m e d r e s p o n s e s (f or C R a n d P R 
r e s p o n s e s) 
- 
I n s e cti o n 1 4. 3. 1, u p d at e d ‘N o b a s eli n e a s s e s s m e nt ’ 
d efi niti o n t o c o n si d er o nl y c a s e s wit h n o t u m or s c a n 
r e c or d e d b ef or e  r a n d o mi z ati o n a n d r e m o v e d ‘N o I R C 
r e vi e w’ c at e g or y  
- 
I n s e cti o n 1 4. 6, u p d at e d ‘N o b a s eli n e a s s e s s m e nt ’ 
d efi niti o n t o c o n si d er o nl y c a s e s wit h n o t u m or s c a n 
r e c or d e d b ef or e  r a n d o mi z ati o n a n d r e m o v e d ‘N o I R C 
r e vi e w’ c at e g or y  
- 
I n s e cti o n 1 5. 1. 1, r e pl a c e d ‘ Tr e at m e nt-r el at e d A n e mi a” b y 
“ A n e mi a” a n d a d d e d s p e cific li sti n g s  
- 
I n s e cti o n 1 5. 1. 1, a d d e d c h e m ot h er a p y r el at e d T E A E s 
bl e e di n g e v e nt s a n al y si s  
- 
I n s e cti o n s 1 5. 1, 1 5. 2. 3 a n d 8. 1, cl arifi e d d efi niti o n of 
D o s e -li miti n g T o xi cit y ( D L T) t o c o n si d er e d e v al u ati o n fr o m 
i n v e sti g at or a n d S M C r e vi e w 
- 
I n s e cti o n 1 5. 2. 5. 1, u p d at e d ‘ti m e r el at e d t o fir st o n s et’ t o 
‘ti m e r el at e d t o fir st o n s et of e a c h st u d y tr e at m e nt’ 
- 
I n s e cti o n 1 5. 2. 5. 2, u p d at ed d efi niti o n of I m m u n e -r el at e d 
a d v er s e e v e nt s  
- 
U p d at e titl e of 1 5. 2. 5. 3 fr o m “ P ot e nti al T G F β -m e di at e d 
s ki n a d v er s e e v e nt s” t o “ T G F -β i n hi biti o n m e di at e d s ki n 
a d v er s e e v e nt s”  
- 
I n s e cti o n 1 5. 2. 5. 3 a d d e d li st of pr e-s p e cifi e d P T f or 
p ot e nti al 
T G F -β i n hi biti o n 
m e di at e d s ki n 
A e s , 
a n d 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 4 /1 0 8  
 
 
U ni q u e 
I d e ntifi er 
f or I A P 
V er si o n  
D at e of I A P 
V er si o n  
A ut h or s  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
c h a n g e d t h e fr e q u e n c y t a bl e b y P T t o fr e q u e n c y t a bl e b y 
w or st gr a d e  
- 
I n s e cti o n 1 5. 2. 5. 4, a d d e d fr e q u e n c y t a bl e f or a n e mi a a n d 
tr e at m e nt-r el at e d a n e mi a 
- 
I n s e cti o n 1 5. 3, u p d at e d T a bl e 1 1  f or N CI-C T C gr a d a bl e 
p ar a m et er s, T a bl e 1 2 f or n o n N CI -C T C p ar a m et er s a d d 
a d d e d d efi niti o n of c orr e ct e d c al ci u m , W B C diff er e nti al 
c o u nt s f or a b s ol ut e v al u e  a n d e sti m at e d cr e ati ni n e 
cl e ar a n c e  
- 
U p d at e d  s e cti o n “ T hr e e -Ti er A p pr o a c h t o S u m m ari zi n g 
a n d A n al y zi n g A e s”  
3  
 
 
- 
I n 
s e cti o n 
7.2 , 
a d d e d 
d e s cri pti o n f or 
C O VI D-1 9 
v a c ci n ati o n  
- 
U p d at e I A P wit h a d diti o n al e x p a n si o n crit eri o n i ntr o d u c e d 
i n pr ot o c ol v er si o n 5. 0  
4  
 
 
- 
S e cti o n 6: a d d e d “ O v er vi e w of Pl a n n e d A n al y s e s aft er 
Tri al Di s c o nti n u ati o n”  
- 
S RI a n al y si s s et r e n a m e d a s S A F RI a cr o s s t h e d o c u m e nt  
f or cl arit y 
- 
T h e d e s cri pti o n of b e st o v er all re s p o n s e  w a s p arti all y 
c h a n g e d t o O R R t o b e c o n si st e nt wit h t h e st u d y pr ot o c ol  
- 
A b br e vi ati o n B O R h a s b e e n r e pl a c e d b y B e st O v er all 
R e s p o n s e a s p er g ui d a n c e v. 3. 0 o n o bj e cti v e r e s p o n s e 
d efi niti o n  
- 
S e cti o n 8. 2: r e m o v e d s u b gr o u p s t h at will n ot b e i n cl u d e d 
a n y m or e i n t h e a n al y s e s f or t h e a b br e vi at e d C S R d u e t o 
d at a n ot a v ail a bl e  
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 5 /1 0 8  
 
 
U ni q u e 
I d e ntifi er 
f or I A P 
V er si o n  
D at e of I A P 
V er si o n  
A ut h or s  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
- 
S e cti o n 1 2. 1: a d d e d d e s cri pti o n of li sti n g o n C O VI D -1 9 
v a c ci n ati o n  
- 
S e cti o n 1 5. 1. 2: 
m o difi e d t a bl e of T E A E s l e a di n g t o 
tr e at m e nt di s c o nti n u ati o n/i nt err u pti o n/ m o difi c ati o n a d di n g 
tr e at m e nt d o s e r e d u cti o n s f or c h e m ot h er a p y r e gi m e n s 
a n d pr o vi di n g fr e q u e n ci e s of T E A E s a n d tr e at m e nt r el at e d 
T E A E s l e a di n g t o i nf u si o n r at e r e d u cti o n s 
of 
a n y 
tr e at m e nt. 
- 
S e cti o n 1 5. 2. 5. 4: a d d e d o v er vi e w t a bl e of a n e mi a e v e nt s  
- 
S e cti o n 1 5. 3: r e m o v e d cr e ati ni n e cl e ar a n c e fr o m gr a d a bl e 
p ar a m et er s. 
A d d e d 
A cti v at e d 
P arti al  T hr o m b o pl a sti n 
Ti m e/ st a n d ar d  
t hr o m b o pl a sti n  
ti m e  
a s  
gr a d a bl e 
p ar a m et er. R e m o v e d cr e ati ni n e cl e ar a n c e d eri v ati o n a s 
t h er e i s n o n e e d t o d eri v e t hi s p ar a m et er at a n a l y si s l e v el 
gi v e n t h at all t h e cr e ati ni n e cl e ar a n c e u nit s c a n b e 
c o n v ert e d i n t hi s st u d y , t h er ef or e t h er e i s n o i s s u e of 
mi s si n g  cr e ati ni n e cl e ar a n c e v al u e s.  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n   
T he p ur p ose of t his  i nte grate d a nal ysis pla n (I A P)  is t o d oc u me nt t ec h nical a n d det aile d 
s pecificati o ns f or t he i nteri m a n d pri mar y  a nal ysis of data c olle cte d f or pr ot oc ol M S 2 0 0 6 4 7 _ 0 0 5 5 . 
Es peciall y, t he p ur p ose of t his versi o n 3 is t o u p date t he a nal ysis pla n as per pr ot oc ol versi o n 5 . 0. 
Res ults of t he a nal yses d escri be d i n t his I A P will b e i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R ). 
A d diti o nall y, t he pla n n e d a n al ys es i de ntifie d i n t his 
I A P ma y  be i ncl u de d i n re g ulat or y 
s u b missi o ns or f ut ure ma n uscri pts. A n y p ost-h o c or u n pla n ne d a nal yses perf or me d t o pr o vi de 
res ults f or i ncl usi o n i n t he CS R  b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d 
i n t he CS R .  
T he I A P is base d u p o n S ecti o n 9 ( Statistical C o nsi derati o ns) of t he st u d y pr ot oc ol a n d is pre p are d 
i n c o m plia nce wit h I nter nati o nal C o u ncil f or Har m o nizati o n (I C H) G ui deli ne E 9. It descri bes 
a nal ys es pla n ne d i n t he pr ot oc ol . Details of t he I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) 
a nal ysis will be d e vel o pe d i n a se parate statistical a nal ysis pla n ( S A P). 
5  
O bjecti ves a n d E n d p oi nts   
T a ble 1  
St u d y O bjecti ves a n d E n d p oi nts   
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P S e cti o n  
O p e n -l a b el, S af et y R u n -i n 
 
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a 2 4 0 0  m g Q 3 W i n 
c o m bi n ati o n wit h g e m cit a bi n e a n d ci s pl ati n i n l o c all y a d v a n c e d or 
m et a st ati c B T C  
 
Pri m ar y  
 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 6 /1 0 8  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P S e cti o n  
T o a s s e s s if bi ntr af u s p alf a 
2 4 0 0  m g Q 3 W i s s af e a n d 
t ol er a bl e a n d t o c o nfir m t hi s 
d o s e a s t h e r e c o m m e n d e d 
P h a s e  II d o s e f or t h e 
r a n d o mi z e d, d o u bl e-bli n d p art 
of t h e st u d y  
O c c urr e n c e of D L T s d uri n g t h e D L T 
e v al u ati o n p eri o d  
1 5. 2. 3  
S e c o n d ar y  
 
T o a s s e s s t h e s af et y pr ofil e of 
bi ntr af u s p alf a i n c o m bi n ati o n 
wit h g e m cit a bi n e a n d ci s pl ati n  
•  
O c c urr e n c e of T E A E s a n d 
tr e at m e nt-r el at e d A E s 
•  
O c c urr e n c e of a b n or m aliti e s 
( Gr a d e ≥ 3) i n l a b or at or y t e st s  
1 5. 1 , 1 5. 2 , 1 5. 3  
R a n d o mi z e d, D o u bl e -bli n d P art  
 
T o a s s e s s t h e f oll o wi n g it e m s wit h bi ntr af u s p alf a i n c o m bi n ati o n wit h 
g e m cit a b i n e pl u s ci s pl ati n v er s u s pl a c e b o wit h g e m cit a bi n e pl u s ci s pl ati n 
i n p arti ci p a nt s wit h a d v a n c e d or m et a st ati c B T C w h o h a v e n ot r e c ei v e d 
c h e m ot h er a p y/i m m u n ot h er a p y i n t h e a d v a n c e d/ m et a st ati c s etti n g  
 
Pri m ar y  
 
T o a s s e s s O S  
O S  
1 4. 1  
S e c o n d ar y  
 
T o a s s e s s P F S  
P F S a c c or di n g t o R E CI S T  1. 1 a s 
a s s e s s e d b y t h e I n v e sti g at or a  
1 4. 2  
T o a s s e s s O R R  
C o nfir m e d o bj e cti v e r e s p o n s e 
a c c or di n g t o R E CI S T  1. 1 a s a s s e s s e d 
b y t h e I n v e sti g at or a  
1 4. 3  
T o a s s e s s D O R  
D O R a s s e s s e d b y c o nfir m e d 
c o m pl et e r e s p o n s e or p arti al r e s p o n s e 
u ntil d e at h or pr o gr e s si o n of di s e a s e 
a c c or di n g t o R E CI S T  1. 1 a s a s s e s s e d 
b y t h e I n v e sti g at or a  
1 4. 4  
T o a s s e s s D R R  
D ur a bl e c o nfir m e d r e s p o n s e of at 
l e a st 6 m o nt h s a c c or di n g t o 
R E CI S T  1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at ora  
1 4. 5  
T o a s s e s s t h e s af et y pr ofil e of 
bi ntr af u s p alf a or pl a c e b o i n 
c o m bi n ati o n wit h g e m cit a bi n e 
pl u s ci s pl ati n  
O c c urr e n c e of T E A E s a n d 
tr e at m e nt-r el at e d A E s, i n cl u di n g 
a d v er s e e v e nt s of s p e ci al i nt er e st  
1 5. 1  
T o c h ar a ct eri z e t h e P K pr ofil e of 
bi ntr af u s p alf a  
•  
P K pr ofil e  of bi ntr af u s p alf a i n 
t er m s of Ce oi  a n d C tr o u g h f or 
p arti ci p a nt s i n t h e M 7 8 2 4 ar m  
•  
P K pr ofil e of bi ntr af u s p alf a i n 
t er m s of A U C0 -t, A U C0 -∞, Cm a x , tm a x , 
a n d t ½  f or p arti ci p a nt s i n t h e s af et y 
r u n-i n p art of t h e st u d y o nl y 
1 6. 1  
T o e v al u at e t h e i m m u n o g e ni cit y 
of bi ntr af u s p alf a a n d t o 
c orr el at e it t o e x p o s ur e  
I m m u n o g e ni cit y a s m e a s ur e d b y 
a nti dr u g a nti b o d y ( A D A) a s s a y s at 
b a s eli n e a n d o n -tr e at m e nt f or 
p arti ci p a nt s i n t h e bi ntr af u s p alf a ar m  
1 6. 4  
 
 
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 7 /1 0 8  
 
 
A E s = a d v er s e e v e nt s, A U C 0 -t= ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e z er o t o t h e l a st s a m pli n g ti m e 
at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n, A U C 0 -∞= A U C fr o m ti m e z er o e xtr a p ol at e d t o 
i nfi nit y, b a s e d o n t h e pr e di ct e d v al u e f or t h e c o n c e ntr ati o n at t h e l a st s a m pli n g ti m e, B T C = bili ar y tr a ct c a n c er, 
C e oi = c o n c e ntr ati o n 
o b s er v e d i m m e di at el y 
at t h e 
e n d 
of i nf u si o n, 
C m a x = m a xi m u m 
o b s er v e d c o n c e ntr ati o n, 
C tr o u g h= c o n c e ntr ati o n o b s er v e d i m m e di at el y b ef or e n e xt d o si n g, D L T = d o s e -li miti n g t o xi cit y, D O R = d ur ati o n of r e s p o n s e, 
D R R = d ur a bl e r e s p o n s e r at e, 
 I L =It e m Li br ar y, I R C =I n d e p e n d e nt R e vi e w C o m mitt e e, 
, 
O R R = o bj e cti v e r e s p o n s e r at e, 
O S = o v er all 
s ur vi v al, 
P F S = pr o gr e s si o n -fr e e 
s ur vi v al, 
P K = p h ar m a c o ki n eti c s, 
 
 
Q 3 W = o n c e 
e v er y 
3 
w e e k s, 
 
 
R E CI S T 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 8 /1 0 8  
 
 
1. 1 = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 1. 1, t ½ = a p p ar e nt t er mi n al h alf -lif e, T E A E s =tr e at m e nt-
e m er g e nt a d v er s e e v e nt s, t m a x =ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al.   
a  
If t h e st u d y i s n ot e x p a n d e d t o P h a s e III, t u m or -b a s e d effi c a c y e n d p oi nt s will al s o b e a s s e s s e d a s p er t h e I R C.  
6  
O ver vie w of Pl a n ne d A n al yses   
T he st u d y c o nsist s of a n o pe n -la bel, safet y r u n-i n part f oll o we d b y a ra n d o mize d, d o u ble-bli n d, 
place b o -c o ntr olle d P hase II/III p art:  
•  T he m ultice nter, o pe n -la bel safet y r u n-i n part will meas ure t he safet y a n d t olera bilit y of first-
li ne (1 L ) bi ntraf us p alf a i n c o m bi nati o n wit h ge mcita bi ne a n d cis plati n. A t otal of 6  t o 1 2 d ose d 
partici pa nts  will be e nr olle d i n eac h of t w o se p arat e re gi o nal c o h orts ( Asia n sites a n d n o n-Asia n 
sites).  
 
T he ra n d o mize d, m ultice nter, d o u ble -bli n d, place b o -c o ntr olle d P hase II/III part will e val uate 
w het her 1 L bi ntraf us p alf a i n c o m bi nati o n wit h t he c urre nt sta n d ar d of care (S o C ) ( ge mcita bi ne 
pl us cis plati n) i m pr o ves  o verall s ur vi val ( O S ) c o m pare d t o place b o, ge mcita bi ne, a n d cis plati n.  
U p t o  3 0 0 partici pa nts will be ra n d o mize d a n d t he a nal ysis f or t he a d a ptati o n decisi o n will be 
c o n d ucte d i n t he first 1 5 0 ra n d o mize d a nti bi otics naï ve partici pa nts i n P hase II . T hereaft er, i n t he 
a nal ysis f or t he a d a ptati o n decisi o n, if t he I D M C r ec o m me n ds e x pa nsi o n base d o n t he pre -
s pecifie d criteria, t he st u d y will be e x pa n de d i nt o P hase III wit h a t otal sa m ple size of  5 0 0 
partici pa nts . If t he st u d y is n ot e x pa n de d t o P hase III, it will be c o m plete d as a P hase II st u d y 
(see A p p e n di x 4 ). 
Ra n d o mizati o n will be stratifie d acc or di n g t o t he f oll o wi n g fact ors:  
o  T y pe of biliar y tract ca n cer ( B T C ) ( base d o n 3 a nat o mical l ocati o ns, i.e., i ntra he patic 
c h ola n gi ocarci n o ma  ( C C A), e xtra he patic C C A i ncl u di n g a m p ulla of Vater’s ca ncer, 
a n d gall bla d der ca ncer)  
o  M etastatic at dia g n osis  vs ot hers, 
w here “ ot hers” i ncl u des partici p a nts 
wit h 
u nresect a ble , l ocall y a d v a nce d dise ase at dia g n osis  a n d partici pa nts wit h resect a ble 
disease at dia g n osis w h o ha ve u n der g o ne  pri or s ur gical resecti o n wit h c ur ati ve i nte nt  
o  Asia sites vers us n o n -Asi a sites  
Statistical a nal yses will be perf or me d o n t he b asis of C DI S C St u d y Data Ta b ulati o n M o del 
(S D T M ) data , use d as s o urce f or C DI S C A nal ysis Data M o de ( A Da M ) d ata creati o n . T hes e S D T M 
data c o nt ai n as clea n as p ossi b le e C R F dat a, as well as e xter nal data i ncl u di n g la b orat or y d ata, 
bi o mar ker data, electr o car di o gra m data, a n d t u m or assess me nt b y t h e I n de pe n d e nt Re vie w 
C o m mittee (I R C).   
E x ce pt f or t he o pe n -l a bel safet y r u n-i n a nal yses, all data will be i ncl u de d u p t o a cli nical c ut -off 
date w hic h is deter mi ne d b y t he n u m ber of e v e nts re q uire d f or t he a n al ysis. T he cli nical c ut -off 
date will be t he date o n w hic h a p pr o xi matel y t he n u m ber of e ve nts is e x pecte d base d o n t he e ve nt 
pr ojecti o ns. T he fi nal n u m ber of e ve nts mi g ht  de viate fr o m t he pla n ne d n u m ber, e. g. d ue t o 
clea ni n g acti vities. T he data c ut -off date will n ot b e a dj uste d retr os p ecti vel y i n t his case.  
Ta ble 2  a n d T a ble 3  dis pla y a n o ver vi e w of t he a n al yses t o b e pr o vi de d f or t his st u d y.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 9 /1 0 8  
 
 
 
T a ble 2  
O ver vie w of A n al yses  
P art  
A n al y si s  
D at a C ut -Off P oi nt  
O p e n -l a b el s af et y r u n-
i n 
S af et y/ Effi c a c y a n al y si s  
W h e n t h e l a st p arti ci p a nt of t h e o p e n -l a b el p art of t h e st u d y 
h a s r e a c h e d a mi ni m u m f oll o w -u p ti m e of 1 2 m o nt h s , T h e 
a n al y si s m a y  b e c o n d u ct e d at ti m e of p h a s e II P A or p h a s e 
III I A  
R a n d o mi z e d, P h a s e  II  
I nt eri m a n al y si s 
a d a pt ati o n  
W h e n 8 0 P F S e v e nt s  p er I R C  h a v e o c c urr e d  a n d t h e fir st 
1 5 0 r a n d o mi z e d a nti bi oti c s n aï v e p arti ci p a nt s h a v e at l e a st 
1 9 w e e k s of f oll o w -u p  
R a n d o mi z e d  P h a s e  II  
P ri m ar y a n al y si s* 
W h e n 6 0 % of t ot al P h a s e II p arti ci p a nt s   h a v e m e et O S  
e v e nt s  
R a n d o mi z e d  P h a s e  III  
Int eri m a n al y si s  
W h e n 2 1 0 O S  e v e nt s h a v e o c c urr e d  
R a n d o mi z e d, P h a s e  III  P ri m ar y a n al y si s 
W h e n 3 3 4  O S e v e nt s h a v e o c c urr e d  
* O nl y if st u d y i s n ot e x p a n d e d i nt o P h a s e III wit h N = 5 0 0.  
P F S = pr o gr e s si o n -fr e e s ur vi v al; O S =o v er all s ur vi v al.  
 
 
T a ble 3  
O ver vie w of E n d p oi nts f or E ac h A n al ys is 
E n d p oi nt s  
O p e n -l a b el 
S af et y R u n -i n 
P h a s e II  
P h a s e III  
S af et y/ Effi c a c y 
A n al y si s  
Int eri m A n al y si s  
A d a pt ati o n  
P ri m ar y 
A n al y si s a  
Int eri m 
A n al y si s  
P ri m ar y 
A n al y si s  
Di s p o siti o n  
✓ 
✓ 
✓ 
✓ 
✓ 
Pr ot o c ol d e vi ati o n s  
✓ 
✓ 
✓ 
✓ 
✓ 
R a n d o mi z ati o n d et ail s  
 
✓ 
✓ 
✓ 
✓ 
D e m o gr a p hi c s a n d ot h er s 
b a s eli n e c h ar a ct eri sti c s  
✓ 
✓ 
✓ 
✓ 
✓ 
M e di c al hi st or y  
✓ 
 
✓ 
✓ 
✓ 
Pr e vi o u s a n d c o n c o mit a nt 
m e di c ati o n s  
✓ 
 
✓ 
✓ 
✓ 
Pr e vi o u s a nti c a n c er 
tr e at m e nt 
✓ 
✓ 
✓ 
✓ 
✓ 
S u b s e q u e nt a nti c a n c er 
tr e at m e nt 
✓ 
✓ 
✓ 
✓ 
✓ 
Tr e at m e nt e x p o s ur e a n d 
c o m pli a n c e  
✓ 
✓ 
✓ 
✓ 
✓ 
O S  
✓b  
✓ 
✓ 
✓ 
✓ 
P F S R E CI S T 1. 1 p er I R C  
 
✓ 
✓ 
 
 
P F S R E CI S T 1. 1 p er 
I n v e sti g at or 
✓b  
 
✓ 
✓ 
✓ 
O R R  R E CI S T 1. 1 p er I R C  
 
✓ 
✓ 
 
 
O R R  R E CI S T 1. 1 p er 
I n v e sti g at or 
✓b  
✓ 
✓ 
✓ 
✓ 
O R R 2 L  
 
 
✓ 
✓ 
✓ 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 0 /1 0 8  
 
 
E n d p oi nt s  
O p e n -l a b el 
S af et y R u n -i n 
P h a s e II  
P h a s e III  
S af et y/ Effi c a c y 
A n al y si s  
Int eri m A n al y si s  
A d a pt ati o n  
P ri m ar y 
A n al y si s a  
Int eri m 
A n al y si s  
P ri m ar y 
A n al y si s  
D O R  R E CI S T 1. 1 p er I R C  
 
✓b  
✓ 
✓ 
✓ 
D O R R E CI S T 1. 1 p er 
I n v e sti g at or 
 
 
✓ 
✓ 
✓ 
D R R  
 
 
✓ 
✓ 
✓ 
F oll o w -u p ti m e P F S  
 
✓ 
✓ 
✓ 
✓ 
F oll o w -u p ti m e O S  
 
 
✓ 
✓ 
✓ 
S af et y ( T E A E, S A E, 
A E SI …)  
✓ 
✓ 
✓ 
✓ 
✓ 
3 -Ti er a p pr o a c h  
 
 
 
✓ 
✓ 
L a b or at or y e v al u ati o n  
✓ 
✓ 
✓ 
✓ 
✓ 
Vit al si g n s  
✓ 
 
✓ 
✓ 
✓ 
Ot h er s af et y 
( E C G/ E C O G) 
✓ 
 
✓ 
✓ 
✓ 
P K  
✓ 
 
✓ 
✓ 
✓ 
A E SI = a d v er s e e v e nt s of s p e ci al i nt er e st; O R R = o bj e cti v e  r e s p o n s e r at e; 
O RR 2 L = o bj e cti v e  r e s p o n s e r at e o n 
s u b s e q u e nt  
li n e  
of  
a nti c a n c er  
tr e at m e nt; 
D O R = d ur ati o n  
of 
r e s p o n s e;  
D R R = d ur a bl e  
r e s p o n s e; 
E C G = el e ctr o c ar di o gr a m s; I A =i nt eri m a n al y si s; 
 I R C= i n d e p e n d e nt 
r e vi e w 
c o m mitt e e; 
  
  
  
 
  
  
 
  
pr o gr e s si o n-fr e e  
s ur vi v al;  
P A= pri m ar y  
a n al y si s;  
P F S = pr o gr e s si o n -fr e e  
s ur vi v al; 
P K = p h ar m a c o ki n eti c s; 
; 
O S =o v er all s ur vi v al; 
R E CI S T 1. 1 = re s p o n s e e v al u ati o n 
c rit eri a i n s oli d tu m or s v er si o n 1. 1; T E A E =  T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt s; S A E = s eri o u s a d v er s e e v e nt s.  
a  A n al y si s will b e p erf or m e d o nl y if st u d y i s n ot e x p a n d e d i nt o P h a s e III. 
b  D u e t o t h e s m all n u m b er of p arti ci p a nt s or e v e nt s e x p e ct e d, a n al y si s of t h e s e e n d p oi nt s will b e b a s e d o n fi g ur e s 
a n d li sti n g s  a s d e s cri b e d i n t h e c orr e s p o n di n g s e cti o n s b el o w.  T h e li st of t a bl e s, li sti n g s a n d fi g ur e s t o b e pr o vi d e d at 
e a c h a n al y si s i s d e s cri b e d i n a  s e p ar at e d o c u m e nt.  
6. 1  
S afet y M o nit ori n g C o m mittee   
A Safet y M o nit ori n g C o m mittee ( S M C ) will be res p o nsi ble f or safet y e v al u ati o ns of t he o p e n  la b el 
safet y r u n-i n p art. Details ca n be f o u n d i n t he S M C C harter. 
T he S M C will e val uate safet y base d o n t h e d ose-li miti n g t o xicities (D L Ts ) o bser ve d i n e ac h of t he 
Asia n  a n d n o n -Asi a n c o h ort s d uri n g t he safet y r u n -i n part of t he st u d y o nce t he 6t h e val ua ble 
partici pa nt of eac h c o h ort has c o m plete d t h e D L T o bser vati o n peri o d. O nce all partici pa nts i n a 
c o h ort ha ve c o m plete d t he D L T p eri o d or dis c o nti n ue d fr o m st u d y pre m at urel y, a dat a s na ps h ot 
will be ta ke n f or pr o visi o n of S M C o ut p uts. T here will be n o data c ut -off a p plie d.  
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 1 /1 0 8  
 
 
Data res ults f or S M C will be pr o vi de d usi n g p atie nt pr ofile s. N o Statistical A nal ysis Pla n will be 
writte n.  
6. 2  
S afet y a n d Effic ac y A n al ysis f or O pe n -l a bel S afet y R u n-i n 
P art   
A nal ysis of s afet y a n d efficac y e n d p oi nts will be perf or me d f or t he o p e n -l a bel safet y r u n-i n part 
base d o n T able 3  a b o ve a n d tri g gere d b y t he data c ut-off  p oi nt dis pla ye d i n Ta ble 2 . 
D ue t o t he s mall n u m ber of partici pa nts e x pecte d i n t he o pe n -la bel safet y r u n-i n part, efficac y dat a 
will n ot be s u m marize d b y ti me-t o-e ve nt a n al yses. I nst ea d, dat a will be prese nte d t hr o u g h gra p hs 
(s wi m mer, waterfall a n d s pi der pl ots) wit h t he rele va nt i nf or mati o n.  
N ote t hat t h e f oll o wi n g data  will n ot be a nal yze d at t he ti me of t his safet y/efficac y a nal ysis. 
H o we ver, a p o ole d a nal ysis t o get her wit h t he ra n d o mize d partici pa nts will be perf or me d . 
N ote t hat s o me e n d p oi nts (e .g .: pr ot oc ol d e viati o ns, me dical hist or y , etc) ma y  o nl y be detaile d via 
listi n gs. 
6. 3  
I n de pe n de nt D at a M o nit ori n g C o m mittee  
T o e ns ure partici p a nts’ safet y, a n I n de p e n de nt Data M o nit ori n g  C o m mittee (I D M C) will be 
esta blis he d f or peri o dic re vie w of safet y data t hr o u g h o ut t he ra n d o mize d d o u ble -bli n d part of t he 
st u d y. B ot h d ata fr o m t he safet y r u n-i n p art a n d t h e ra n d o mize d part will be s u m marize d. Res ults 
fr o m safet y r u n-i n part will be prese nte d o verall a n d will n ot be s plit b y Asia n/ n o n-Asia n c o h ort.  
I n a d diti o n, t he I D M C will re vie w efficac y a n d safet y data fr o m t h e  first 1 5 0 partici pa nts of t he 
ra n d o mize d, d o u ble-bli n d part of t he st u d y  d uri n g i nteri m a nal ys is (I A) f or a da ptati o n t o P hase III 
sa m ple siz e e xte nsi o n (see Secti o n 6. 4 ). T he I D M C will rec o m me n d t o t he st u d y tea m w het her t o 
c o nti n ue t he st u d y as a P hase II st u d y o nl y or t o e x pa n d i nt o P hase III.  
F or eac h I D M C  me eti n g , t he i n de pe n de nt statisticia n will pre pare t he o ut p uts ( usi n g pr o gra ms 
pre pare d  b y t he bli n de d tea m base d o n d u m m y treat me nt ar ms) i n a gree me nt wit h t he  I D M C 
C harter a n d tra ns mit t he a nal ys es, ta b ulati o ns, a n d listi n gs t o t he I D M C o nl y f or t he meeti n g.  T h e 
i n de pe n de nt statisticia n will be a vaila ble at t he I D M C meeti n g s h o ul d a n y q uesti o ns fr o m t he 
I D M C me m b ers aris e re gar di n g t h e data a n d/ or a n al yses. 
T he f ull me m bers hi p, ma n date, a n d pr o cesses of t he I D M C will be detaile d i n t he I D M C C harter . 
A s pecific statistical a n al ysis pla n will be pre p are d f or t he I D M C.  
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 2 /1 0 8  
 
 
6. 4  
I nteri m A n al ysis f or A d a pt ati o n  Decisi o n   
T he a nal ysis f or a da ptati o n decisi o n will be c o n d ucte d i n t he first 1 5 0  ra n d o mize d a nti bi otics  nai ve 
partici pa nts w he n 8 0  P F S e ve nts ha ve occ urre d a n d o nce at least 1 9 wee ks of f oll o w -u p f or t he 
first 1 5 0 ra n d o mize d a nti bi otics  nai ve partici pa nts is reac h e d.  
I n case m ulti ple partici pa nts are ra n d o mize d o n t h e sa me da y as t he 1 5 0t h partici pa nt, t he a n al ysis 
f or a da pt ati o n decisi o n will i ncl u de all a nti bi otics nai ve partici pa nts ra n d o mize d u p t o t his da y.  
B ot h data fr o m t he s afet y r u n -i n part a n d t he ra n d o mize d part will be s u m marize d. Res ults fr o m 
safet y r u n-i n p art will be prese nte d o v erall, a n d will n ot be s plit b y Asia n/ n o n -Asia n c o h ort.  
Efficac y a n al ysis will be perf or me d o n t he first 1 5 0 ra n d o mize d a nti bi otics naï ve partici pa nts, all 
ot hers a nal ysis i ncl u di n g safet y will be perf or me d o n all partici pa nts ra n d o mize d till c ut-off date.  
T his I A will tri g ger t he d ecisi o n t o e x pa n d t he st u d y i nt o Phase III  if t he f oll o wi n g criteri a are met:  
•  O d ds rati o of a c o nfir me d O R R ( O R O R R ) is ≥ 1. 6  or P F S hazar d rati o  (H R P F S ) is < 0. 7 5, a n d, 
•  t he pr o ba bilit y of s u ccess e x cee ds a pres pecifie d t hres h ol d (s uccess is d efi ne d as pr ojecte d O S 
H R bel o w a pres p ecifie d t hres h ol d at t he pri mar y a nal ysis). Det ails will be s pecifie d i n a n 
a p pe n di x t o t he I D M C c h arter a n d I D M C statistical a nal ysis pla n.  
Ot hers a nal ysis will be perf or me d as s u m marize d i n  T a ble 3. D ata relati ve t o partici pa nts’ d urati o n 
of res p o nse will n ot be s u m marize d i n a ta ble b ut dis pla ye d t hr o u g h a s wi m mer pl ot a n d a s pi der 
pl ot.  
6. 5  
I nteri m a n d Pri m ar y A n al ysis   
F or P hase II P A  (if a p pli ca ble ), a n d P hase III I A a n d P A  (if a p plica ble), a n al yses will be pr o vi de d  
as s u m mariz e d i n T a ble 3 , tri g gere d b y t he data c ut-off  p oi nt dis pla ye d i n Ta ble 2 .  
7  
C h a n ges t o t he Pl a n ne d 
A n al yses i n t he 
Cli nic al 
St u d y 
Pr ot oc ol   
7. 1  
O ver vie w of Pl a n ne d A n al yses after Tri al Disc o nti n u ati o n   
T he e xter nal I D M C re vie we d t he d ata c o ncer ni n g 1 2 partici pa nts i n s afet y r u n -i n a n d 2 9 7 
ra n d o mize d partici pa nts i n t he P hase II part of st u d y f or a da ptati o n decisi o n, wit h a dat a c ut-off 
date of 2 0 t h Ma y 2 0 2 1. Base d o n t he t otalit y of t h e effi cac y a n d safet y dat a a vaila ble, t h e I D M C 
di d n ot s u p p ort t he c o nti n uati o n of t he cli nical trial. Base d o n t his rec o m me n dati o n, t he S p o ns or 
has ma de t he decisi o n t o disc o nti n ue t his cli nical  trial. 
T heref ore, t he a n al ys es descri be d i n Secti o n 6  will n ot be perf or me d as pla n ne d, b ut o ne pri mar y 
a nal ysis will be perf or m e d f or a n a b bre viate d C S R. T he a nal y ses c o nsi dere d rele va nt f or t his 
p ur p ose are liste d bel o w:  
•  Partici pa nt dis p ositi o n  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 3 /1 0 8  
 
 
•  I m p ort a nt pr ot oc ol de viati o ns 
•  E nr oll me nt details ( N u m ber or ra n d o mize d b y re gi o n a n d c o u ntr y, n u m ber or ra n d o mize d b y 
stratificati o n fact or at ra n d o mizati o n a n d differe n ce bet w ee n str atificati o n fact or c ollecte d i n 
e-C R F vs I X R S)  
•  De m o gra p hics, me dical hist or y a n d ot her baseli ne c haracteristics ( disease hist or y, E C O G 
perf or ma n ce stat us, hei g ht, wei g ht, B S A a n d B MI at baseli ne, s ki n stat us hist or y)  
•  Pre vi o us a n d c o nc o mita nt me dicati o ns, pr oce d ures, f oll o w -u p treat me nts  
•  Treat me nt 
e x p os ure 
a n d 
c o m plia nce 
(e. g. 
d urati o n 
of treat me nts, 
n u m ber 
of 
i nf usi o ns/fracti o ns, c u m ulati ve d ose, c he m ot hera p y d ose re d u cti o ns, t hera p y dela ys, i nf usi o n 
rate re d ucti o ns, i nf usi o n te m p orar y i nterr u pti o n) 
•  Efficac y a nal ys es:  
o  O verall s ur vi val ( O S)  
▪ O verall S ur vi val –  F orest pl ot of hazar d rati o b y s u b gr o u ps  
o  P F S per R E CI S T 1. 1 as assesse d b y I R C  
▪ P F S per R E CI S T 1. 1 as assesse d b y I R C  - F orest pl ot of hazar d rati o b y 
s u b gr o u ps 
o  O R R per R E CI S T 1. 1 as assesse d  b y I R C  
▪ Cr oss ta b ulati o n B est O verall Res p o nse  per R E CI S T 1. 1 as assesse d b y I R C vs 
I n v esti gat or 
▪ T u m or s hri n ka ge i n tar get lesi o ns  
▪ O R R per R E CI S T 1. 1 as assess e d b y I R C  - F orest pl ot of o d ds rati o b y 
s u b gr o u ps 
o  F oll o w -u p d urati o n ( P F S a n d O S)  
o  D urati o n of res p o ns e 
•  Safet y a nal yses ( o ver vie w of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es), seri o us T E A Es 
( S A E),  
treat me nt-relate d  
T E A Es,  
T E A Es  
lea di n g  
t o  
treat me nt 
disc o nti n uati o n/i nterr u pti o n/ m o dificati o n, T E A Es Lea di n g t o deat h, a d verse e ve nts of s peci al 
i nterest ( A E SI), T E A Es ass ociate d t o C O VI D-1 9, vital si g ns, E C O G, cli nical la b orat or y 
e val uati o ns)  
Data fr o m t he c ut off of 2 0 t h Ma y 2 0 2 1 were t he b asis f or t he decisi o n t o disc o nti n ue t he trial a n d 
will be use d f or t he pri m ar y a n al ysis f or a b bre viat e d C S R.  Efficac y  a n al ysis will be perf or me d o n 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 4 /1 0 8  
 
 
t he first 1 5 0 ra n d o mize d a nti bi otics naï ve partici pa nts, all ot hers a nal yses i ncl u di n g safet y will be 
perf or me d o n all partici p a nts ra n d o mize d till c ut -off date.  
I n cas e a n e w safet y si g n al is o bser ve d, a n a d diti o nal a nal ysis will be d o ne at t he e n d of st u d y a n d 
i ncl u de d i n C S R a d de n d u m. I n t he ot her cases, n o f urt her a n al yses will be pla n ne d. 
7. 2  
C O VI D -1 9 I m p act   
N o c ha n ges t o t he pla n ne d a nal ysis of t he  efficac y e n d p oi nts will be perf or me d d ue t o t he i m pact 
of C O VI D -1 9 o ut br ea k.  
I nste a d, a d diti o nal o ut p uts (s u m mar y ta bles a n d listi n gs) will be ge nerate d t o assess p ote ntial 
i m pacts of C O VI D-1 9 i n t his st u d y, i ncl u di n g: 
•  O ver vie w ta bl e of t he i m pact b y C O VI D -1 9  
•  L isti n g of partici p a nts affecte d b y C O VI D -1 9  
•  T a ble of i n direct C O VI D -1 9 i m pact  
•  T a ble of C O VI D -1 9 relat e d pr ot oc ol de viati o ns  
•  L isti n g of C O VI D-1 9 rel ate d pr ot oc ol de viati o ns  
•  T a ble of treat me nt -e mer ge nt a d verse e ve nt s ( T E A Es) ass ociate d t o C O VI D -1 9  
•  L isti n g of A Es relate d t o C O VI D-1 9  
•  Listi n gs of vacci nes f or C O VI D -1 9  
Partici pa nts will be cate g orize d base d o n t he C O VI D -1 9 st u d y peri o d defi n e d as:  
•  Pre -pa n de mic ti me peri o d: partici pa nts w h o starte d t he treat me nt bef ore t he start of C O VI D -1 9 
pa n de mic.  
•  D uri n g -pa n de mic ti me p eri o d: partici pa nts w h o starte d t he treat me nt o n t h e sa me date or after 
t he start of C O VI D-1 9 pa n de mic  
•  P ost -pa n de mic ti me peri o d:  t he e n d of p a n de mic is c o nsi dere d n ot yet reac he d a n y w here a n d 
will be defi ne d later  
T he start of C O VI D -1 9 p a n de mic is defi ne d b y c o u ntr y as t he earliest dat e of eit her t he date of t he 
first deat h fr o m C O VI D-1 9 occ urre d i n eac h c o u ntr y acc or di n g t o t he p u blis he d data b y E ur o pea n 
Ce ntre  
f or  
Diseas e  
Pre ve nti o n  
a n d  
C o ntr ol  
o n  
2 6t h  
J u ne  
2 0 2 0 
( htt ps:// w w w.ec dc.e ur o pa.e u/e n/ p u blicati o ns-data/ d o w nl oa d -t o da ys-data -ge o gra p hic -
distri b uti o n -c o vi d-1 9 -cas es -w orl d wi de) or 1 1 t h Marc h 2 0 2 0 ( w he n t h e W H O declare d C O VI D 1 9 
pa n de mic).  
Details of t he a n al ys es are pr o vi de d i n Secti o ns 1 0. 1 , 1 0. 2 , 1 5. 1. 1 . 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 5 /1 0 8  
 
 
8  
A n al ysis P o p ul ati o ns  a n d S u b gr o u ps   
8. 1  
Defi niti o n of A n al ysis P o p ul ati o ns   
Scree ni n g A n al ysis Set  
T he scree ni n g anal ysis set i ncl u des all partici pa nts, w h o si g ne d t he i nf or m e d c o nse nt, re gar dless 
of t he partici pa nt’s ra n d o mizati o n a n d st u d y i nter ve nti o n stat us i n t he st u d y. 
S afet y R u n -I n A n al ysis Set  
T he safet y r u n -i n ( SA F RI) a n al ysis s et i ncl u des all partici pa nts fr o m t he safet y r u n-i n part w h o 
were a d mi nistere d a n y d ose of a n y st u d y i nter ve nti o n.  
D ose -li miti n g T o xicit y  A n al ysis Set  
T he d ose -li miti n g t o xicity ( D L T)  a n al ysis s et i ncl u des all partici pa nts w h o e x perie nce d at least 
o ne D L T (eit her b y I n v esti gat or or b y S M C) or w h o c o m plete d t he safet y r u n -i n, i.e., t he 2 1-da y 
D L T e val uati o n peri o d, recei vi n g at least o ne  i nf usi o n of bi ntraf us p alfa  a n d of b ot h ge mcita bi n e 
a n d cis plati n a n d  n ot b ei n g wit h dr a w n d uri n g t h e D L T e v al uati o n peri o d f or reas o ns ot her t ha n 
t o xicit y. 
I nte nt-t o-Tre at A n al ysis Set  
T he i nte nt-t o-treat (I T T) a nal ysis set i ncl u des all ra n d o mize d partici p a nts . Partici pa nt s will be 
a nal yze d acc or di n g t o t he treat me nt assi g ne d at ra n d o mizati o n as per t he i nte nt -t o-treat pri nci ple.  
T he I T T a n al ysis s et will be use d f or all a nal yses of d e m o gra p hics a n d b aseli ne c haracteristics, 
effic ac y, P R O s, a n d bi o mar kers . 
S afet y A n al ysis Set  
T he safet y ( S A F) a nal ysis set i ncl u des all partici p a nts fr o m t he I T T a n al ysis set  w h o recei v e d at 
least o ne d ose of st u d y tr eat me nt. 
Partici pa nts will be classifie d acc or di n g t o t he treat me nt assi g n e d at ra n d o mizati o n u nless t he 
i nc orrect treat me nt(s) was/ were recei ve d t hr o u g h o ut t he d osi n g peri o d i n w hic h cas e partici pa nts 
will be classifie d acc or di n g t o t he first st u d y treat me nt recei v e d .    
P h ar m a c o ki netic A n al ysis Set  
T he p har m ac o ki netic ( P K) a nal ysis set ( P K A S) i ncl u des all participa nts (fr o m safet y r u n-i n p art 
a n d ra n d o mize d part) w h o recei ve d at least o ne  d ose  of bi ntraf us p alfa , a n d w h o pr o vi de d at least 
o ne  sa m ple wit h a meas ura ble c o nce ntrati o n of bi ntraf us p alfa  after start of treat me nt , wit h o ut 
i m p orta nt pr ot oc ol de viati o ns or e ve nts dee me d t o affect P K e val uati o n .  
All P K a nal ys es will be base d o n t his a nal ysis set.  Refer t o Secti o n 1 6. 1  f or pr ot oc ol de viati o ns 
a n d ha n dli n g rele v a nt t o P K.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 6 /1 0 8  
 
 
T a ble 4  s u m marizes t he use of t he a n al ysis sets i n t he differe nt a nal yses. 
 
T a ble 4   
O ver vie w of t he A n al ysis Set s Use d i n t he A n al yses  
A n al y s e s  
S cr e e ni n g  
S A F RI  
D L T  
I T T 
S A F  
Di s p o siti o n  
✓ 
 
 
 
 
Pr ot o c ol d e vi ati o n  
 
✓ 
 
✓ 
 
D e m o gr a p hi c s  
 
✓ 
 
✓ 
 
B a s eli n e a s s e s s m e nt s  
 
✓ 
 
✓ 
 
Pr e vi o u s a n d c o n c o mit a nt 
t h er a pi e s 
 
✓ 
 
✓ 
 
C o m pli a n c e a n d e x p o s ur e  
 
✓ 
 
 
✓ 
Effi c a c y  
 
✓ 
 
✓ 
 
S af et y a n d t ol er a bilit y: d o s e -
li miti n g t o xi cit y 
 
✓ 
✓ 
 
 
S af et y a n d t ol er a bilit y: ot h er 
e n d p oi nt s  
 
 
 
 
✓ 
P h ar m a c o ki n eti c s  
 
 
 
 
 
D L T = d o s e -li miti n g  t o xi cit y; 
  I T T =i nt e nti o n-t o-tr e at;  
P K = p h ar m a c o ki n eti c;  
S A F =s af et y ; 
S A F RI = S af et y R u n -i n. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 7 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 8 /1 0 8  
 
 
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
T his secti o n descri bes a n y ge n eral s p ecificati o ns n ot i ncl u de d i n s u bse q ue nt secti o ns.  
T he s pecificati o ns f or P K data h a n dli n g/ a nal ysis are pres e nte d i n  Secti o n 1 6. 1 . U nless ot her wise 
i n dicate d, all ge neral (i. e., dis p ositi o n of partici pa nts a n d disc o nti n uati o ns, pr ot oc ol de viati o ns, 
de m o gra p hics a n d ot her baseli ne c haracteristics, a n d pre vi o us or c o nc o mita nt me dicati o n),  safet y 
a n d effic ac y a nal yses will be prese nte d se p arat el y f or t he t w o treat me nt ar ms ( bi n traf us p alfa a n d 
place b o , s h ort f or t he c o m bi nati o ns of bi ntraf us p alfa +  c he m ot hera p y a n d place b o  +  
c he m ot hera p y) i n t he ra n d o mize d, d o u ble-bli n d part a n d per c o h ort  ( Asia n/ n o n-Asia n)  f or t he 
safet y r u n-i n p art. 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
2 9 /1 0 8  
 
 
T hr o u g h o ut t he d o c u me nt, the ter m “c o h ort” ( Asia n, N o n -Asia n) will be us e d f or t he s afet y r u n  i n 
w hereas t he ter m “ar m” (b i ntraf us p alfa, place b o ) will be use d f or t he ra n d o mize d, d o u ble -bli n d 
part.  
U nless ot h er wise s pecifie d, c o m paris o ns will be prese nte d f or bi ntraf us p alf a  vers us place b o.  
9. 1  
D at a H a n dli n g After C ut -off D ate   
B y its nat ur e, dat a after c ut -off m a y be i nc o m plete a n d s u bject t o f urt her c ha n ge a n d will n ot b e 
use d f or s u m mar y statistics, statistical a nal yses, listi n gs or i m p utati o ns.  
St o p dates a n d o utc o mes of a d verse e ve nts are n ot affecte d b y t his r ule, e. g., a st o p date of a n A E 
a n d its relate d o utc o me w hic h starts pri or t o t he c ut -off b ut st o ps after dat e of c ut -off, will n ot be 
c ha n ge d.  
9. 2  
Defi niti o n of B aseli ne a n d C h a n ge fr o m B aseli ne   
I n t he safet y r u n-i n part, t he last n o n -missi n g meas ure me nt pri or t o t h e first st u d y tr eat me nt 
a d mi nistrati o n will be us e d as t he “ Baseli ne” meas ure me nt. If a n ass ess me nt t hat is pla n ne d t o be 
perf or me d bef ore treat me nt per pr ot oc ol is p erf or me d o n t he sa me d a y as t he start of treat me nt, 
res pecti vel y, b ut t he ass ess me nt ti me is n ot a vaila ble, it will be ass u me d t hat it was perf or me d 
pri or a n d will be c o nsi dere d as bas eli ne.  
I n t he ra n d o mize d part, t he last n o n-missi n g meas ure me nt pri or t o ra n d o mizati o n or pri or t o t he 
start of st u d y treat me nt will ser ve as t he baseli ne meas ure me nt, de pe n di n g of t he t y pe of a nal ysis. 
Details are gi v e n i n t he ta ble bel o w:  
 
T a ble 5  
B aseli ne D ate t o be U se d i n t he A n al yses f or R a n d o miz ati o n Part  
A n al y si s  
D at e of st art of 
st u d y  tr e at m e nt 
D at e of 
r a n d o mi z ati o na  
Di s p o siti o n  
 
✓ 
Pr ot o c ol d e vi ati o n s  
 
✓ 
D e m o gr a p hi c s a n d ot h er s b a s eli n e 
c h ar a ct eri sti c s  
 
✓ 
M e di c al hi st or y  
 
✓ 
Pr e vi o u s a n d c o n c o mit a nt 
m e di c ati o n s, Pr e vi o u s/ S u b s e q u e nt 
a nti c a n c er t h er a p y  
✓ 
 
Tr e at m e nt e x p o s ur e a n d c o m pli a n c e  
✓ 
 
Effi c a c y ( O S, P F S, O R R …)  
 
✓ 
S af et y ( T E A E, S A E, A E SI …)  
✓ 
 
L a b or at or y e v al u ati o n  
✓ 
 
Vit al si g n s  
✓ 
 
Ot h er s af et y ( E C G/ E C O G)  
✓ 
 
P K  
✓ 
 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 0 /1 0 8  
 
 
A n al y si s  
D at e of st art of 
st u d y  tr e at m e nt 
D at e of 
r a n d o mi z ati o na  
a  If t h e l a st n o n-mi s si n g m e a s ur e m e nt pri or t o r a n d o mi z ati o n i s n ot a v ail a bl e, t h e l a st m e a s ur e m e nt pri or t o t h e fir st 
st u d y tr e at m e nt a d mi ni str ati o n will b e u s e d wit h t h e e x c e pti o n of pr e -r a n d o mi z ati o n a s s e s s m e nt s u s e d f or t h e d eri v ati o n 
of effi c a c y e n d p oi nt s ( e. g. t u m or a s s e s s m e nt at b a s eli n e, w hi c h will b e s et t o mi s si n g, if n ot d o n e pri or t o r a n d o mi z ati o n).  
F or t he p ur p oses of t h e descri pti o n of bas eli ne c h aracteristics o n t he I T T A n al ysis S et, t h e bas eli ne 
val ue of all safet y para meters s uc h as vital sig ns will be defi n e d as t he last n o n -missi n g 
meas ure me nt pri or t o ra n d o mizati o n. Si milarl y, s u b gr o u p classificati o n bas e d o n b aseli ne v al ues 
will be deri ve d usi n g t he last n o n -missi n g meas ure me nt pri or t o ra n d o mizati o n.  
If a n assess me nt t hat is pla n ne d t o be perf or me d b ef ore ra n d o mizati o n, or treat me nt per pr ot oc ol 
is perf or me d o n t he s a me da y as t he ra n d o mizati o n or start of treat me nt, res pecti vel y, b ut t h e 
assess me nt ti me is n ot a vaila ble, it will be ass u me d t hat it was perf or me d pri or a n d will be 
c o nsi dere d f or d eri vati o n of baseli ne. If a sc he d ul e d pre -d os e meas ure me nt act uall y occ urre d p ost -
d ose, t he n t h e c orres p o n di n g me as ure m e nt will b e a n al yze d si milar t o a n u nsc he d ule d p ost -d os e 
meas ure me nt.  
A bs ol ute a n d perce nt c h a n ges fr o m baseli ne are d efi ne d as:   
•  A bs ol ute c ha n ge = ti me p oi nt val ue –  baseli ne val u e  
•  P erce nt c h a n ge = 1 0 0 * ( ti me p oi nt val ue –  baseli ne val ue) / bas eli ne val ue  
9. 3  
St u d y D a y / St u d y Tre at me nt D a y   
I n t he safet y r u n-in part, Da y 1 is t he d a y of start of st u d y treat me nt, t h e d a y bef ore is Da y -1 ( n o 
Da y 0 is defi ne d).  
I n t he ra n d o mize d d o u ble-bli n d part, Da y 1 is eit her t he da y of ra n d o mizati o n or t he da y of start 
of st u d y tr eat me nt de pe n di n g of t he a nal ysis, as d etail e d i n Ta ble 5 5  of t his d oc u me nt.  
9. 4  
Defi niti o n of D ur ati o n a n d ‘ti me si nce’ V ari a bles   
D urati o n i n d a ys will be calc ul ate d b y t h e differe nce of start a n d st o p date + 1 if n ot ot her wis e 
s pecifie d. F or e x a m ple, d urati o n of res p o nse ( da ys) = d ate of P D/ deat h/ce ns ori n g –  date of 
res p o nse + 1. 
T he ti me si nce a n e ve nt (e. g. ti me si nce i nitial ca nc er dia g n osis) will be calc ulate d as refere n ce 
date mi n us date of e v e nt. I n ge neral, t he refere nce date will be st u d y d a y 1. 
T he ti me t o a n e ve nt will be calc ulate d b y t he differe n ce b et wee n t h e ti me of e ve nt a n d t he 
refere nce d ate + 1 if n ot ot her wise s p ecifie d. F or e x a m ple, s ur vi val ti me ( da ys) = date of deat h - 
st u d y da y 1 + 1. 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 1 /1 0 8  
 
 
9. 5  
C o n versi o n F act ors   
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o wee ks, m o nt hs or  years :  
•  1 wee k = 7 d a ys,  
•  1 m o nt h = 3 0. 4 3 7 5 da ys  
•  1 year = 3 6 5. 2 5 da ys  
9. 6  
D ate of L ast C o nt act   
T he date of last c o ntact will be deri ve d f or parti ci pa nts  w h o are  n ot k n o w n t o ha ve di e d at t he 
a nal ysis c ut -off usi n g t he latest c o m plete date pri or t o or at t he data c ut -off date fr o m t he f oll o wi n g: 
•  All partici pa nt ass ess me nt dates ( bl o o d dra ws [la b orat or y, P K], vital si g ns, E C O G perf or ma nce 
stat us, E C G, t u m or assess me nts, q ualit y of life assess me nts)  
•  Start a n d e n d dates of a ntica ncer t hera pi es a d mi nistere d aft er disc o nti n uati o n of st u d y tr eat me nt  
•  A E start a n d e n d d ates  
•  Last k n o w n ali ve date i n “ S u bject Stat us / S ur vi val F oll o w -U p” e C R F pa ge ( d o n ot use t he 
f oll o w-u p date)  
•  St u d y treat me nt start a n d e n d dates 
•  Ra n d o mizati o n date  
•  Date of disc o nti n uati o n ta ke n fr o m t he “ St u d y T er mi nati o n” e C R F pa ge ( d o n ot use if reas o n 
f or disc o nti n uati o n is l ost t o f oll o w-u p or deat h)  
O nl y dates ass ociat e d wit h act ual e x a mi nati o ns of t he partici pa nt re p orte d i n t he e C R F will be 
use d i n t he d eri vati o n.  D ates ass oci ate d wit h a tec h nical o perati o n u nrelat e d t o partici pa nt stat us 
s uc h as t he date a bl o o d sa m ple was pr ocesse d will n ot be use d.  
9. 7  
Ti me Wi n d o w   
N ot a p plica ble  
9. 8  
Defi niti o n of O n -tre at me nt Peri o d  
T he o n -treat me nt peri o d is defi ne d as t he ti me fr o m t he date of  first st u d y tr eat me nt a d mi nistrati o n 
t o t he date of l ast st u d y treat me nt a d mi nistrati o n + 3 0 da ys or t he c ut-off date or deat h or t he 
earliest dat e of s u bse q u e nt a ntica n cer t hera pies mi n us 1 da y, w hi c he v er occ urs first, u nless 
ot her wise state d. F or partici pa nts wit h treat me nt o n g oi n g at t he cut -off date, all data fr o m t he date 
of first st u d y treat me nt a d mi nistrati o n u p  t o t he c ut-off date will be c o nsi dere d u n der t he o n -
treat me nt peri o d. 
 
F or i m m u ne -relate d A Es as liste d i n Secti o n 1 5. 2. 5. 2 , a n e x pa n de d o n-tr eat me nt peri o d will be 
use d as a defa ult f or a n y a nal ysis:  Ti me fr o m t he first st u d y i nter ve nti o n t o t he last st u d y 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 2 /1 0 8  
 
 
i nter ve nti o n date + 9 0 da ys, deat h O R t o t he earliest date of s u bse q ue nt a nti ca ncer t hera p y mi n us 
1 da y, w hic he v er occ urs first, u nless ot her wise state d.  
A n y  s yst e mic a ntica ncer t hera p y, a n y a ntica n cer s ur ger y a n d a n y a ntica ncer ra di ot hera p y as 
d oc u me nte d i n t h e ” A nti -ca ncer tr eat me nt after dis c o nti n uati o n”  e C R F pa ge will be c o nsi dere d as 
s u bse q ue nt a ntica n cer t hera p y ( palliati ve b o ne-directe d ra di ot hera p y a n d ur ge nt palliati ve 
s ur geries, dia g n ostic bi o psies a n d ste nti n g/ perc uta ne o us tra ns he p atic biliar y drai n a ge f or t he 
p ur p ose of releasi n g biliar y tract o bstr uct i o n occ urri n g d uri n g t h e o n-treat me nt peri o d will be 
d oc u me nte d i n t he “ C o nc urre nt pr oce d ures” e C R F pa ge).  
9. 9  
I m p ut ati o n of Missi n g D at a  
U nless ot her wise s pecifi e d all data will be e val uate d as o bser ve d, a n d n o i m p utati o n met h o d f or 
missi n g val ues will be us e d.  
Missi n g statistics, e. g. w he n t he y ca n n ot b e calc ulate d, will be pres e nte d as “ n d ” f or “ n ot 
deter mi ne d. F or e x a m ple, if n = 1, t he meas ure of varia bilit y [e. g. St D] ca n n ot be c o m p ute d a n d 
will be prese nte d as “ n d”.  
Partial dates, w hic h are n ot t o be i m p ute d acc or di n g t o t h e I A P, will be prese nte d i n t he f or mat 
li ke “ _ _ _ _ _ Y Y Y Y”. If v al ues are i m p ute d acc or di n g t o t he I A P, i m p ute d v al ues will be prese nte d 
i n partici pa nt data listi ngs a n d i m p ute d i nf or mati o n will be fla g ge d.  
I n c o m plete dates will be ha n dle d as s pecifie d i n t he f oll o wi n g ta bl e: 
 
T a ble 6  
I m p ut ati o n R ules f or I nc o m plete D ates 
A g e C al c ul ati o n  
I n c o m pl et e d at e s ( d at e of i nf or m e d c o n s e nt, d at e of birt h) f or t h e c al c ul ati on of a g e will 
b e i m p ut e d a s f oll o w s:  
•  I n c a s e of mi s si n g d a y f or at l e a st o n e d at e, b ut m o nt h a n d y e ar a v ail a bl e f or b ot h d at e s: 
t h e d a y of i nf or m e d c o n s e nt a n d t h e d a y of birt h will b e s et t o 1. 
•  I n c a s e of mi s si n g m o nt h f or at l e a st o n e d at e, b ut y e ar a v ail a bl e f or b ot h d at e s, t h e 
d a y a n d t h e m o nt h of i nf or m e d c o n s e nt a n d t h e d a y a n d m o nt h of birt h will b e s et t o 1.  
•  I n all ot h er c a s e s, t h e i n c o m pl et e d at e s will n ot b e i m p ut e d.  
Di s e a s e hi st or y  
I n c o m pl et e d at e s f or di s e a s e hi st or y ( e. g. i niti al di a g n o si s d at e, d at e of d o c u m e nt e d, l o c all y 
a d v a n c e d, i n o p er a bl e or m et a st ati c di s e a s e di a g n o si s, d at e of r e s p o n s e or pr o gr e s si o n i n 
pri or tr e at m e nt) will b e i m p ut e d a s f oll o w s:  
•  If t h e d a y i s mi s si n g, it will b e i m p ut e d t o t h e 1 st d a y of t h e m o nt h.  
•  If b ot h d a y a n d m o nt h ar e mi s si n g, t h e m o nt h a n d d a y will b e i m p ut e d a s J a n u ar y 1
st  
•  If t h e d at e i s c o m pl et el y mi s si n g, n o i m p ut ati o n will b e p erf or m e d. 
A d v er s e e v e nt s  
I n c o m pl et e A E-r el at e d d at e s will b e i m p ut e d a s f oll o w s: 
•  I n c a s e t h e o n s et d at e i s mi s si n g c o m pl et el y or mi s si n g p arti all y b ut t h e o n s et m o nt h 
a n d y e ar, or t h e o n s et y e ar ar e e q u al t o t h e st art of st u d y tr e at m e nt t h e n t h e o n s et d at e 
will b e i m p ut e d b y t h e mi ni m u m of st art of st u d y tr e at m e nt a n d A E r e s ol uti o n d at e (if 
n ot mi s si n g).  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 3 /1 0 8  
 
 
•  I n all ot h er c a s e s, t h e mi s si n g o n s et d a y or mi s si n g o n s et m o nt h will b e i m p ut e d b y 1. 
•  I n c o m pl et e st o p d at e s will b e i m p ut e d b y t h e l a st d a y of t h e m o nt h (if d a y i s mi s si n g 
o nl y), if n ot r e s ulti n g i n a d at e l at er t h a n t h e d at e of t h e p arti ci p a nt’ s d e at h. I n t h e l att er 
c a s e, t h e d at e of d e at h will b e u s e d t o i m p ut e t h e i n c o m pl et e st o p d at e.  
•  I n all ot h er c a s e s, t h e i n c o m pl et e st o p d at e will n ot b e i m p ut e d.  
Pr e vi o u s  
a n d 
c o n c o mit a nt 
m e di c ati o n  
 
I n c o m pl et e d at e s f or pr e vi o u s a n d c o n c o mit a nt m e di c ati o n s will b e i m p ut e d a s f oll o w s:  
•  F or st art d at e of m e di c ati o n  
o  
If t h e d a y i s mi s si n g, it will b e i m p ut e d t o t h e 1st d a y of t h e m o nt h.  
o  
If b ot h d a y a n d m o nt h ar e mi s si n g, t h e m o nt h a n d d a y will b e i m p ut e d a s 
J a n u ar y 1 st.  
o  
If t h e d at e i s c o m pl et el y mi s si n g, n o i m p ut ati o n will b e p erf or m e d.  
•  F or e n d d at e m e di c ati o n:  
o  
If t h e d a y i s mi s si n g, it will b e i m p ut e d t o t h e l a st d a y of t h e m o nt h.  
o  
If b ot h d a y a n d m o nt h ar e mi s si n g, t h e m o nt h a n d d a y will b e i m p ut e d as 
D e c e m b er 3 1 st  
o  
If t h e d at e i s c o m pl et el y mi s si n g, n o i m p ut ati o n will b e p erf or m e d. 
N ot e: I n c a s e t h e i m p ut ati o n r e s ult s i n a d at e l at er t h a n t h e d at e of t h e p arti ci p a nt' s 
d e at h, t h e n t h e d at e of d e at h will b e u s e d t o i m p ut e t h e i n c o m pl et e st o p d at e.  
S u b s e q u e nt 
A nti c a n c er T h er a p y  
I n c o m pl et e d at e s f or t h e st art d at e of s u b s e q u e nt a nti c a n c er t h er a p y ( dr u g t h er a p y, 
r a di ot h er a p y, s ur g er y) will b e i m p ut e d a s f oll o w s a n d will b e u s e d f or d et er mi ni n g 
c e n s ori n g d at e s f or effi c a c y a n al y s e s a n d i n t h e d eri v ati o n  of t h e e n d of t h e o n -tr e at m e nt 
p eri o d:  
•  If o nl y d a y i s mi s si n g, it will b e i m p ut e d a s t h e l a st d a y of t h e m o nt h u nl e s s t h e e n d d at e 
of s u b s e q u e nt a nti c a n c er t h er a p y i s b ef or e t h at d at e. I n t h at c a s e, t h e i n c o m pl et e 
a nti c a n c er t h er a p y st art d at e will b e i m p ut e d a s t h e e n d d at e of t h e a nti c a n c er t h er a p y.  
•  If b ot h d a y a n d m o nt h ar e mi s si n g, n o i m p ut ati o n will b e p erf or m e d.  
I n c o m pl et e s u b s e q u e nt a nti c a n c er t h er a p y st o p d at e s will n ot b e i m p ut e d.  
D e at h  
F or t h e p ur p o s e s  of s ur vi v al a n al y s e s, p arti all y mi s si n g d e at h d at e s will b e i m p ut e d a s 
f oll o w s: 
•  If o nl y t h e d a y i s mi s si n g, t h e d e at h d at e will b e i m p ut e d t o t h e m a xi m u m of t h e ( n o n-
i m p ut e d) d a y aft er t h e d at e of l a st k n o w n ali v e d at e a n d t h e 1 5t h d a y of t h e m o nt h  
•  Ot h er wi s e it will n ot b e i m p ut e d  
P har mac o ki netic para met ers will be calc ulate d usi n g t he act ual ela ps e d ti me si nce d osi n g. W he n 
t he act ual sa m pli n g ti me is missi n g, calc ulati o ns will be perf or me d usi n g t he sc h e d ule d ti me. 
Ot her wise, t h ere will be n o f urt her i m p utati o n of missi n g d ata. C o n ce ntrati o ns will be set t o 
missi n g i n s u m mar y ta bl es if t he val ue is re p orte d as n o res ult.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 4 /1 0 8  
 
 
9. 1 0  
Sc ori n g of H R Q O L D at a   
U nless ot her wise s p ecifie d, 
H R Q O L q u esti o n naires 
will be sc ore d  usi n g t heir p u blis he d 
a d mi nistrati o n a n d sc ori n g ma n ual. F or ite ms wit h missi n g res p o nses, t he res p o nse will be 
ma na ge d as p er t he sc ori n g ma n u al. See Secti o n 1 6. 3  f or details. 
9. 1 1  
Prese nt ati o n of C o nti n u o us a n d Q u alit ati ve V ari a bles   
C o nti n u o us ( n o n -P K) varia bles will be s u m marize d usi n g descri pti ve statistics i.e. ,  
•  N u m ber of partici pa nts ( N), n u m ber of partici pa nts wit h missi n g val ues  
•  Mea n, sta n dar d de viati o n ( St D)  
•  Me dia n, 2 5t h perce ntile - 7 5t h perce ntile ( Q 1 -Q 3)  
•  Mi ni m u m ( Mi n), a n d ma xi m u m ( Ma x)  
If t here are n o missi n g val ues, t he n u m ber of partici pa nts wit h missi n g val ues s h o ul d be set t o 0. 
Mea n, Me dia n, Q 1, Q 3, Mi n, Ma x ha ve t he sa m e precisi o n as S D T M data ( n u m ber of di gits) f or 
n o n -deri ve d data. Statistics o n deri ve d d ata will be r o u n de d t o reas o na ble di gits, w hereas ma xi mal 
di gits will be a vaila ble i n A Da M datas ets. S D is t o be prese nt e d wit h o ne di git m ore t ha n mea n.  
If n ot ot herwise s p ecifie d, p -val ue will be prese nte d usi n g t he S A S f or mat “ p val ue 6. 4” usi n g 4 
deci mals. H R a n d o d ds r ati o will be dis pla ye d wit h 2 deci mals.  
Q ualitati ve varia bles will be s u m marize d b y c o u nts a n d perce nta ges. U nless ot her wise state d, t he 
calc ulati o n o f pr o p orti o ns will be bas e d o n t h e n u m ber of partici pa nts i n t he a n al ysis s et of i nterest. 
T heref ore, c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he de n o mi n at or a n d prese nte d as a 
se parat e cat e g or y.  
Perce nta ges will be re p orte d t o o ne deci mal plac e.  
Descri pti ve statistics b y n o mi nal visit or ti me p oi nt, e. g. f or la b orat or y m eas ure me nts, will i ncl u de 
o nl y dat a fr o m s c he d ule d visits. U nsc he d ule d visits will be i ncl u de d i n t he deri vati o n of b aseli ne 
or w orst o n -treat me nt val ues. 
9. 1 2  
Si g nific a nce Le vel   
T he o verall si g nifica nce le vel is 2. 5 % o ne -si de d. Statistical tests are des cri be d i n Secti o n 1 4 . 
9. 1 3  
P o oli n g of C e nters   
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss sites.  T he 
“site” f act or will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal yses d ue t o t he hi g h 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 5 /1 0 8  
 
 
n u m ber of partici pati n g sites i n c o ntrast t o t he a ntici pate d s mall n u m ber of partici p a nts  at eac h 
site. 
9. 1 4  
U nsc he d ule d Assess me nts   
As per data b ase d efi niti o n, u nsc he d ule d safet y assess me nts are al wa ys li n ke d t o a sc he d ule d 
ti me p oi nt (eac h u ns c he d ule d assess me nt is li n ke d t o t he pre vi o us sc h e d ule d ti me p oi nt). Safet y 
data retrie ve d fr o m a n u nsc he d ule d ti me p oi nt ( vital si g ns , electr ocar di o gra m [E C G ] a n d la b orat or y 
data) will be a n al yze d acc or di n g t o t he f oll o wi n g sce nari o:  
•  F or s hift ta ble s, t he y will be ta ke n i nt o acc o u nt i n t he defi niti o n of t he w orst assess me nt d uri n g 
st u d y 
•  F or descri pti o n at eac h ti me p oi nt  p ost -baseli ne, t he first a vaila ble res ult (i n c hr o n ol o gical or der) 
per ti me p oi nt will be ta ke n i nt o acc o u nt i n t he a n al ysis i n cas e of m ulti ple val ues  
•  F or d escri pti o n at baseli ne, t he last a vaila ble res ult bef ore t he first a d mi nistrati o n of st u d y 
treat me nt will be ta ke n i nt o acc o u nt i n t he a n al ysis i n case of m ulti ple val ues  (see S ecti o n 9. 2 ) 
F or i m m u n o ge nicit y a n al ysis, u nsc he d ule d visits will als o be ta ke n i nt o acc o u nt i n t he a n al ysis  
f oll o wi n g t he sa m e r ules as detaile d a b o v e. 
F or P K a nal ysis, u nsc he d ule d sa m ples will n ot be li n ke d t o a sc he d ule d ti me p oi nt a n d will be 
e x cl u de d fr o m s u m maries.  
9. 1 5  
St u d y Tre at me nt   
I n t his st u d y, bi ntraf us p alfa , place b o, a n d c h e m ot hera pies are c o nsi dere d as st u d y tr eat me nts. T he 
date of first st u d y treat me nt a d mi nistrati o n will be defi ne d as t he earliest a d mi nistrati o n date of 
a n y treat me nts ( bi ntraf us p alfa , pla ce b o or c h e m ot hera pies). T h e dat e of last st u d y treat me nt 
a d mi nistrati o n  will be defi ne d as t he latest a d mi nistrati o n date of a n y tr eat me nts ( bi ntraf us p alfa , 
place b o or c he m ot hera pi es).  
9. 1 6  
Preferre d Ter m f or a n al ysis of W orl d He alt h Or g a niz ati o n’s 
Dr u g Dicti o n ar y ( W H O -D D) c o de d d at a   
F or data c o de d acc or di n g t o W H O Dr u g B 3  (e. g., c o nc o mita nt me dicati o ns), s u m maries will be 
d o ne o n t he preferre d ter m ( P T) le vel w here t he P T  c orres p o n d s t o c o des e n di n g in 0 1 0 0 1. Wit h 
t his a p pr oac h, variati o ns of salt f or ms of acti ve i n gre die nts will be a nal yz e d u n der t he sa me t er m, 
e. g. di p he n h y dra mi ne a n d di p he n h y dra mi ne h y dr oc hl ori de will be a nal yz e d as t he sa me P T,  
di p he n h y dra mi ne.  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 6 /1 0 8  
 
 
9. 1 8  
Re -scree ne d P artici p ants   
Re -scree ne d p artici pa nts will be o nl y c o u nte d o n ce i n t he scree ni n g a nal ysis set, c o nsi deri n g t he 
latest scree ni n g (scree ni n g wit h latest i nf or me d c o nse nt).  
9. 1 9  
S oft w are   
All statistical a nal ys es will be perf or me d usi n g statistical s oft ware S A S ® ( Statistical A nal ysis 
S yste m, S A S -I nstit ute, Car y N C, U S A, 
Wi n d o ws Versi o n 9. 4 or hi g h er) i n t he S A S Gri d 
e n vir o n me nt.  
T he c o m p uter pr o gra m
 Versi o n 8. 0, or hi g h er 
 
 U S A) will b e use d t o deri ve P K p ara meters a p pl yi n g n o n-c o m part me ntal a nal ysis . 
1 0  
St u d y P artic ip a nts   
T he s u bsecti o ns i n t his secti o n i ncl u de s pecifi cati o ns f or re p orti n g parti ci pa nt dis p ositi o n a n d 
st u d y treat me nt/st u d y dis c o nti n uati o ns. A d diti o nall y, pr oce d ures f or re p orti n g p r ot o c ol de viati o ns 
are pr o vi d e d.  
1 0. 1  
Dis p ositi o n of P artici p a nts a n d Disc o nti n u ati o ns   
Descri pti ve statistics will be use d t o s u m marize partici pa nt  dis p ositi o n base d o n t he e C R F d ata.  
All partici pa nts wit hi n t he scree ni n g a nal ysis set will be c o nsi dere d.  
T he n u m ber a n d perce nt a ge of partici pa nts i n eac h of t he f oll o wi n g dis p ositi o n cate g ories will be 
prese nte d b y c o h ort/ar m a n d t otal. Perce nta ges will be calc ulate d bas e d o n t he n u m ber of 
partici pa nts i n t he S A F RI  / I T T a n al ysis set, e x ce pt f or t he n u m ber of scree ne d a n d re s cree ne d 
partici pa nts w here n o perce nta ge will be pr o vi de d :  
•  T otal n u m ber of partici pa nts scree n e d (i.e. , all partici pa nts w h o ga v e i nf or me d c o nse nt)  
•  N u m ber of partici pa nt s w h o disc o nti n ue d fr o m t he st u d y pri or t o ra n d o mizati o n ( or pri or t o first 
st u d y treat me nt a d mi nistrati o n f or safet y r u n-i n part) o verall a n d gr o u pe d b y t he mai n reas o n 
(e. g. t he s pecific faile d i ncl usi o n or e x cl usi o n criteria, a d verse e v e nt, l ost t o f oll o w -u p, d eat h, 
pr o gressi ve dise ase, wit h dra wal of c o nse nt  a n d ot her) 
•  N u m ber of re -scree n e d p artici pa nt s 
•  N u m ber of partici pa nt s w h o recei ve d at least o ne d ose of st u d y treat me nt ( bi ntraf us p alfa a n d/ or 
c he m ot hera pi es)  o verall a n d b y c o h ort f or saf et y r u n -i n part 
•  N u m ber of ra n d o mize d partici pa nts o verall a n d b y treat me nt ar m f or ra n d o mize d, d o u ble -bli n d 
part  
T he e n d of tr eat me nt stat us will be s u m marize d b y:  
•  N u m ber of ra n d o mize d partici pa nts w h o di d n ot recei ve a n y st u d y tr eat me nt b y treat me nt ar m.  
Gl o bal Versi o n I D: C CI
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 7 /1 0 8  
 
 
•  N u m ber of partici pa nts wit h bi ntraf us p alfa / place b o) o n g oi n g at t he data c ut-off date o verall 
a n d b y c o h ort/treat me nt ar m  
•  N u m ber of partici pa nts wit h cis plati n o n g oi n g at t he data c ut -off date o verall a n d b y 
c o h ort/treat me nt ar m  
•  N u m ber of p artici pa nts wit h ge m cita bi ne o n g oi n g at t he data c ut -off d ate o verall a n d b y 
c o h ort/treat me nt ar m  
•  N u m ber of partici pa nts off bi ntraf us p alfa/ place b o , gr o u pe d b y mai n reas o n (treat me nt 
c o m plete d as per pr ot oc ol, pr o gressi ve disease  ( P D), deat h, a d verse e v e nt, l ost t o f ollo w -u p, 
pr ot oc ol n o n -c o m plia nce, wit h dre w c o nse nt, ot her)  
•  N u m ber of partici pa nts off cis plati n, gr o u pe d b y mai n reas o n (treat me nt c o m plete d as p er 
pr ot oc ol, pr o gressi ve dise ase, d eat h, a d verse e v e nt, l ost t o f oll o w -u p, pr ot oc ol n o n -c o m plia nce, 
wit h dre w c o ns e nt, ot her)  
•  N u m ber of partici pa nts off g e mcita bi ne, gr o u pe d b y mai n reas o n (treat me nt c o m plete d as per 
pr ot oc ol, pr o gressi ve dise ase, d eat h, a d verse e v e nt, l ost t o f oll o w -u p, pr ot oc ol n o n -c o m plia nce, 
wit h dre w c o nse nt, ot her)  
T he e n d of st u d y stat us will be  s u m marize d b y: 
•  N u m ber of partici pa nts wit h bi ntraf us p alf a/ place b o  o n g oi n g at t he e n d of st u d y  o v erall a n d b y 
c o h ort/treat me nt ar m  
•  N u m ber of partici pa nts 
wit h 
cis plati n o n g oi n g at t he e n d of st u d y o verall a n d b y 
c o h ort/treat me nt ar m  
•  N u m ber of partici pa nts  wit h g e mcita bi ne o n g oi n g at t he e n d of st u d y o verall a n d b y 
c o h ort/treat me nt ar m  
•  N u m ber of p artici pa nt s w h o c o m plete d/ disc o nti n ue d st u d y partici pati o n , wit h t he ass ociate d 
mai n reas o n ( st u d y c o m plete d acc or di n g t o pr ot oc ol, a d verse e ve nt, l ost t o f oll o w-u p, pr ot oc ol 
n o n -c o m plia nce, d eat h, wit h dre w c o nse nt, ot her ) 
I n a d diti o n, t he n u m ber of partici pa nt s scree ne d a n d ra n d o mize d i n eac h a nal ysis set as defi ne d i n 
Secti o n 8. 1 1  will be pr o vi de d  o verall , b y re gi o n, b y c o u ntr y wit hi n re gi o n , a n d b y site .   
F or t h e ra n d o mize d, d o u ble -bli n d part, t he res ults of t he ra n d o mizati o n al g orit h m (acc or di n g t o 
IX R S) will be s u m marize d as f oll o ws: 
•  N u m ber a n d p erce nta ge of ra n d o mize d partici pa nts o verall, b y re gi o n, b y c o u ntr y wit hi n re gi o n  
•  N u m ber a n d p erce nta ge of ra n d o mize d partici pa nts b y ra n d o mizati o n strat a ( I X R S) 
•  N u m ber a n d p erce nta ge of ra n d o mize d partici pa nts b y ra n d o mi zati o n strat a ( C R F)  
•  Listi n g of partici p a nts f or w h o m strat u m b y I X R S is differe nt fr o m strat u m b y C R F 
•  Cr oss ta b ulati o n: partici pa nts ra n d o mize d vs. treat e d  a n d c orres p o n di n g listi n g  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 8 /1 0 8  
 
 
T he listi n g of partici pa nt  dis p ositi o n will i ncl u de all partici pa nt s (i.e., i ncl u di n g scree ni n g fail ures, 
b ut n ot re -scree ne d p artici pa nt s (at t heir scree n fail ure ti me) w h o will be liste d i n a se parate listi n g). 
T he listi n g will i nc l u de t he f oll o wi n g i nf or m ati o n: c o h ort/ pla n ne d ar m ( partici pa nts ha vi n g act u al 
ar m differe nt fr o m  pla n ne d ar m will be fla g ge d a n d dis pla ye d i n a se parat e listi n g), partici pa nt  
i de ntifier, date of i nf or m e d c o nse nt, p artici pa nt c o nti n ue be y o n d scree ni n g  yes/ n o  (if n ot reas o n 
f or n ot t o c o nti n ue ), d ate of ra n d o mizati o n (i n ra n d o mize d part), date of first/last st u d y tr eat me nt 
(f or bi ntraf us p alfa/ place b o , cis plati n, a n d g e mcita bi ne), date a n d  reas o n off-treat me nt, date a n d 
reas o n off-st u d y, p o p ulati o n fla gs. W he n t he reas o n s uc h as reas o n off -treat me nt is cate g orize d as 
“ Ot her, s pecif y” or “ Wit h dre w c o nse nt fr o m treat me nt, s pecif y”, t he ver bati m te xt as e ntere d i n 
t he e C R F will be pres e nte d i n t he listi n g.  
If a n y re-s cree ne d partici pa nt s are o bser ve d, t he y will be prese nte d i n a s pecific listi n g t hat will 
i ncl u de: c o h ort/ pla n ne d ar m, partici pa nt  i de ntifier (i de ntifier at i ncl usi o n i n t he st u d y), dat e of 
i nf or me d c o nse nt at i ncl usi o n, date of first  st u d y treat me nt, i nitial partici pa nt  i de ntifier (i de ntifier 
at scree n fail ure), d ate of i nf or me d c o ns e nt at scree n fail ure, date a n d reas o n of scree n fail ure . N ote 
if partici pa nts are scree n e d se veral ti mes, all scree ni n g atte m pts will be liste d. 
F or t he I D M C me eti n gs, Ka pla n -Mei er’s pl ots of ti me t o st u d y treat me nts disc o nti n uati o n a n d 
ti me t o st u d y disc o nti n uati o n will be pr o vi de d (if m ore t ha n 1 0 e ve nts will be o bser ve d). 
I n a d diti o n, f or t he assess me nt of C O VI D-1 9 i m pact o n t his st u d y, a n o ver vie w ta ble will be 
prese nte d b y tr eat me nt ar m wit h t he f oll o wi n g i nf or mati o n:  
•  Partici pa nts  p ote ntiall y affect e d b y C O VI D -1 9 (i. e. , partici pa nts w h o start e d treat me nt a fter 
start of t he C O VI D-1 9 pa n de mic, or w h o starte d treat me nt pri or t o start of t he C O VI D -1 9 
pa n de mic a n d are still o n g oi n g aft er t he start of t he pa n de mic)  
•  Partici pa nts wit h at least o ne C O VI D -1 9 i m pact    
•  Partici pa nts wit h at le ast o ne C O VI D -1 9 i m pact i n t he f oll o wi n g cate g ori es: a d verse e ve nts, 
deat h, pr ot oc ol de viati o ns, misse d dr u g a d mi nistrati o n, treat me nt a d mi nistrati o n m o dificati o ns, 
misse d t u m or assess me nts, 
misse d visits, tele  visits re placi n g o n -site visits, treat me nt 
disc o nti n uati o n, st u d y disc o nti n uati o n  
•  N u m ber of partici p a nts wit h misse d t u m or assess me nts, dela ye d t u m or assess me nts, misse d 
visits, tele -visits re placi n g o n -site visits ( 1 / 2 / 3 / > 3) 
T he fre q u e nc y distri b uti o n of partici pa nts w h o starte d t he treat me nt bef ore , d uri n g  or after  the 
pa n de mic p er c o u ntr y -s p ecific start of C O VI D-1 9 st u d y peri o d (see Secti o n  7. 2  f or det ails o n t he 
C O VI D -1 9 cate g orizati o n b y st u d y peri o d) will be als o dis pla ye d.  
Listi n gs of C O VI D -1 9 i m pact will be pr o vi de d:  
•  Partici pa nts affecte d b y 
C O VI D -1 9 
wit h f oll o wi n g i nf or mati o n: c o h ort/ pla n ne d ar m, 
partici pa nt i de ntifier, first a n d last date of treat me nt a d mi nistrati o n, date of t he e ve nt, visit, 
cate g or y, e ve nt, e v e nt descri pti o n/reas o n  
1 0. 2  
Pr ot oc ol De vi ati o ns   
A n alysis Set: S A F RI  / I T T 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
3 9 /1 0 8  
 
 
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
I m p ort a nt pr ot oc ol de viati o ns (I P Ds) are pr ot o c ol de viati o ns t hat mi g ht si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t h e st u d y dat a or t h at mi g ht si g nifica ntl y affect a 
partici pa nt's ri g hts, safet y, or well -bei n g.  
I P Ds will be d efi ne d i n a s pecific d o c u me nt (see A p pe n di x 1 ). T he y c o ul d i ncl u de, b ut are n ot 
li mite d t o: 
•  Partici pa nts w h o are d os e d o n t he st u d y d es pite n ot satisf yi n g t he e nr ol me nt criteria  
•  Partici pa nts w h o de vel o p wit h dra wal crite ria w hilst o n t he st u d y b ut are n ot wit h dra w n 
•  Partici pa nts w h o recei ve t he wr o n g st u d y treat me nt or a n i nc orrect d ose  
•  Partici pa nts w h o recei ve a n e x cl u de d c o nc o mita nt me dicati o n 
•  Fail ure t o c olle ct data n ecessar y t o i nter pret pri mar y e n d p oi nts  
•  Fail ure t o c o llect necessar y k e y safet y data 
•  De viati o n fr o m G o o d Cli nical Practice  
•  A n y ot her pr ot oc ol d e viati o n t hat mi g ht si g nifica ntl y affect t he c o m plete ness, acc urac y, a n d/ or 
relia bilit y of t he st u d y d ata or t h at mi g ht si g nifica ntl y affect a partici p a nt's ri g hts, s afet y, or 
well -bei n g  
I P Ds will be i de ntifie d f or all partici pa nts b y eit h er site m o nit ori n g, me di cal re vie w pr ocess es or 
pr o gra m mi n g a n d c o nfir me d pri or t o or at t he Data Re vie w Meeti n g at t he latest.  
All I P Ds will be  d oc u me nte d i n S D T M datasets w het her i de ntifie d t hr o u g h site m o nit ori n g, 
me dical re vie w or pr o gra m mi n g.  
A d diti o nal cli nicall y i m p orta nt pr ot oc ol d e viati o ns ma y be i d e ntifie d d uri n g t he c o urse of t h e st u d y 
b ut will n ot re q uire a me n d me nt t o t his I A P.   
I P Ds will be s u m marize d f or 
•  De viati o ns fr o m  t he i ncl usi o n a n d e x cl usi o n criteria 
•  De viati o ns p ost -i ncl usi o n 
T he f oll o wi n g s u m mar y ta ble a n d listi n g will be pr o vi de d:  
•  Fre q u e nc y ta ble p er reas o n of I P Ds, s e parate d f or pre -/ p ost i ncl usi o n de viati o ns 
•  Listi n g of all pr ot oc ol de viati o ns (i ncl u di n g  C O VI D -1 9  mi n or  P D ) w hic h will i ncl u de: 
c o h ort/ pla n ne d ar m, partici pa nt i de ntifier, cate g or y of t he d e viati o n (e. g. i ncl usi o n/e xcl usi o n), 
a descri pti o n of t he de vi ati o n , if i m p orta nt or n ot ( yes/ n o). T h e listi n g will be e nric he d b y t he 
varia ble “ C O VI D -1 9 R elate d Pr ot oc ol De viati o ns” fla g gi n g all pr ot o c ol de viati o ns d ue t o 
C O VI D -1 9.  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 0 /1 0 8  
 
 
1 0. 2. 2  
Re as o ns 
Le a di n g t o t he 
E xcl usi o n fr o m 
a n 
A n al ysis 
P o p ul ati o n   
A fre q u e nc y t a ble per reas o n of e x cl usi o n fr o m t he D L T a n d P K a n al ysis sets  as well as a listi n g 
will be pr o vi de d. A listi n g of partici p a nts i ncl u de d i n t he I T T a nal ysis set b ut e x cl u de d fr o m t he 
S A F a nal ysis set will als o be pr o vi de d . 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
A n alysis Set: S A F RI  / I T T 
1 1. 1  
De m o gr a p hics   
De m o gra p hic c haracteristics a n d p h ysical meas ure me nts will be s u m marize d descri pti vel y usi n g 
t he f oll o wi n g inf or m ati o n fr o m t he Scree ni n g/ Bas eli ne Visit e C R F pa ges.  
De m o gra p hic c haracteristics will be s u m marize d usi n g t he f oll o wi n g i nf or mati o n:  
•  Se x : m ale, fe male, u n differe ntiate d 
•  Et h nicit y: His pa nic or Lati n o, n ot His pa nic or Lati n o; J a pa nese, n ot J a pa nese  
•  Race:  
o  F or partici p a nts re p orti n g o ne race o nl y: W hite, Blac k or Africa n A meri ca n, Asia n, 
A merica n I n dia n or Alas ka Nati ve, Nati ve Ha waiia n or ot her Pacific Isla n der, N ot 
c ollecte d at t he site, Ot h er.  
o  F or partici pa nts re p orti n g m ulti ple races, all c o m bi nati o ns will be re p orte d u n der ‘ M ore 
t ha n o ne race” cate g or y.  
•  A ge ( years): s u m mar y st atistics  
•  A ge cat e g ories:  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 1 /1 0 8  
 
 
o  < 6 5 years,  
o  ≥ 6 5 years  
▪ 6 5 -7 4 years,  
▪ 7 5 -8 4 years,  
▪ ≥ 8 5 years  
•  Ge o gra p hic R e gi o n: N ort h A merica, Lati n  A merica, E ur o pe, Asi a  & Pacific  
•  B o d y S urface Area ( B S A) ( m 2) at Bas eli ne 
•  Hei g ht ( c m)  at Bas eli ne  
•  Wei g ht ( k g)  at Bas eli ne  
•  B o d y Mass I n d e x ( B MI) ( k g/ m 2) at Baseli ne 
•  E C O G Perf or ma n ce stat us : 
o  0: F ull y acti ve, a ble t o carr y o n all pre -disease p erf or ma nce wit h o ut restricti o n  
o  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 s e de ntar y nat ure, e. g., li g ht h o us e w or k, office w or k  
o  2: A m b ulat or y a n d ca pa ble of all selfcare b ut u n a 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 o re t ha n 5 0 % of wa ki n g h o urs 
o  3: Ca pa ble of o nl y li mite d selfcare, 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  
o  4: C o m pletel y dis a 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  
o  5: Dea d  
S p ecificati o ns f or c o m p utati o n  (at A DaM l e v el):  
o  A ge [ years]: ( date of gi v e n i nf or me d c o ns e nt - dat e of birt h + 1) / 3 6 5. 2 5  
T he i nte ger p art of t he calc ulate d a ge will be us e d f or re p orti n g p ur p oses.  N ote f or 
rescree ne d p artici pa nts, t heir latest i nf or me d c o nse nt date will be use d. 
o  B MI ( k g/ m 2) = wei g ht( k g)/[ hei g ht( cm) ²/ 1 0 0 0 0] 
o  B S A ( m²) = ([ hei g ht ( c m) x wei g ht ( k g)] / 3 6 0 0) ½  
o  I n v esti gat or site c o d es will be use d f or t he det er mi nati o n of t he partici pa nt ’s ge o gra p hic 
re gi o n. 
De m o gra p hic c haract eristics  i ncl u di n g c o h ort/ pla n ne d ar m, partici pa nt  i de ntifier, se x, race 
(i ncl u di n g all re p orte d races i n case of “ m ulti ple” races, a n d det ails i n case of “ ot her” race), 
et h nicit y, ge o gra p hic re gi o n, a ge, b o d y mass i n de x, b o d y s urface area, wei g ht a n d h ei g ht will be 
prese nte d i n a listi n g .  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 2 /1 0 8  
 
 
1 1. 2  
Me dic al Hist or y   
Rele va nt past a n d o n g oi n g me dical c o n diti o ns at Baseli ne will be s u m marize d fr o m t he “ Me dical 
Hist or y Det ails” e C R F pa ge, usi n g t he latest a vaila ble versi o n of t he Me dical Dicti o nar y f or 
Re g ulat or y A cti vities ( Me d D R A), P T  as e ve nt cat e g or y a n d Me d D R A s yst e m or ga n class ( S O C) 
b o d y ter m as B o d y S yste m cate g or y.  
Me dical hist or y will be dis pla ye d i n 
fre q ue nc y ta bles, or dere d b y pri mar y S O C a n d P T i n 
al p ha betical or d er . E ac h partici p a nt will be c o u nte d o nl y o nce wit hi n eac h P T or S O C.  
Listi n g of me di cal hist or y i ncl u di n g c o h ort/ pla n ne d ar m, partici pa nt  i de ntifier, a ge, se x, race, 
preferre d t er m, re p orte d me dical hist or y ter m, start /e n d date s, rel ate d st u d y c o n diti o n, o n g oi n g at 
scree ni n g a n d t o xicit y gra de ( w h e n me dical hist or y is o n g oi n g) will be pres e nte d.  
1 1. 3  
Ot her B aseli ne C h ar acteristics   
1 1. 3. 1  
Dise ase Hist or y   
I nf or mati o n o n dise ase c haracteristics c ollecte d o n t he “ Disease Hist or y” e C R F p a ge will be 
s u m marize d as f oll o ws: 
•  Biliar y tract ca n cer ( B T C) s u bt y pe a n d t u m or hist ol o g y: 
o  Intr a he p atic C C A  
▪ I ntr a he p atic c h ola n gi ocarci n o ma  
▪ C o m bi ne d he pat ocell ular  c h ola n gi ocarci n o ma  
▪ Ot hers  [carci n osarc o ma, ot her] 
o  E xtra he patic C C A  
▪ Peri hilar C C A  
• 
A de n ocarci n o ma [a de n ocarci n o ma, a de n ocarci n o ma ( biliar y t y pe, 
i ntesti nal t y p e, gastric f o ve olar t y pe), m u ci n o us a de n ocarci n o ma, clear 
cell a de n o carci n o ma, si g net ri n g cell carci n o ma]  
• 
S q ua m o us [s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma]  
• 
O t hers 
▪ Distal C C A  
• 
A de n ocarci n o ma [a de n ocarci n o ma, a de n ocarci n o ma ( biliar y t y pe, 
i ntesti nal t y p e, gastric f o ve olar t y pe), m u ci n o us a de n ocarci no ma, clear 
cell a de n o carci n o ma, si g net ri n g cell carci n o ma]  
• 
S q ua m o us [s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma]  
• 
Ot hers  
o  Gall bla d der ca ncer  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 3 /1 0 8  
 
 
▪ A de n ocarci n o ma [a de n o carci n o ma, a de n ocarci n o ma ( biliar y t y pe, i ntesti nal 
t y pe, 
gastric f o ve olar t y p e), 
m uci n o us 
a d e n ocarci n o ma, 
clear 
cell 
a de n ocarci n o ma, si g net ri n g cell carci n o ma]  
▪ S q ua m o us [s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma]  
▪ Ot hers  
o  A m p ulla of Vater’s ca n cer  
▪ A de n ocarci n o ma [a de n o carci n o ma, a de n ocarci n o ma (i n vasi ve i ntesti nal t y pe, 
pa ncreatic o bilia r y t y pe), clear cell carci n o ma, he pat oi d a de n o carci n o ma, 
m uci n o us carci n o ma, si g net ri n g cell carci n o ma]  
▪ S q ua m o us [s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma]  
▪ Ot hers  
•  Hist ol o g y gra d e ( Well differe ntiat e d, M o deratel y differe ntiate d, P o orl y differe ntiat e d, Gra de 
ca n n ot b e ass esse d)  
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs)  
•  Ti me si nce d oc u me nte d, l ocall y a d va nce d or metastatic disease ( m o nt hs)  
•  Ti me si nce last pr o gressi o n of disease pri or t o st u d y e ntr y ( m o nt hs)  
•  T N M classificati o n at i nitial dia g n osis a n d at st u d y e ntr y: eac h T, N, M cate g or y will be 
descri be d ( T X, T 0, N 1, etc.)  
•  M olec ular a b n or malities:  
o  F G F R 1/ F G F R 2/ F G F R 3 ( m utate d, wil d  t y pe) 
o  I D H 1/ I D H 2 ( m utate d, wil d t y p e) 
•  M SI  stat us: M SI h i g h, M SI lo w, M S S, u n k n o w n  
De dicate d listi n gs will als o be pr o vi de d wit h t he f oll o wi n g i nf or mati o n : 
•  C o h ort/ pla n ne d ar m, p artici pa nt  i de ntifier, a ge, s e x, race, B T C cl assificati o n, t u m or hist ol o g y, 
date of i nitial ca ncer dia g n osis ( m o nt hs), date of d oc u me nte d, l ocall y a d v a nce d or metastatic 
disease ( m o nt hs), dat e o f last disease pr o gressi o n ( m o nt hs), T N M classificati o n at i nitial 
dia g n osis, T N M cl assificati o n at st u d y e ntr y  a n d M SI stat us 
•  M olec ular a b n or malit y (res ult f or F G F R 1 ( m utat e d/ wil d t y p e), F G F R 2 ( m utate d/ wil d t y pe), 
F G F R 3 ( m utate d/ wil d t y pe), I D H 1 ( m utate d/ wil d t y p e) a n d I D H 2 ( m utate d/ wil d t y pe) , ot hers 
( n or mal/a b n or mal)) 
1 1. 3. 2  
S ki n S t at us H ist or y  
S ki n stat us hist or y is c oll ecte d o n t he “ S ki n Stat us Hist or y” e C R F pa ge a n d will be s u m marize d 
b y t he fre q u e nc y a n d p erce nta ge of partici pa nt s h a vi n g t he f oll o wi n g hist or y of: 
•  Fre q u e nt s u n b ur n ( Yes, N o, U n k n o w n)  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 4 /1 0 8  
 
 
•  Eas y s u n b ur n ( Y es, N o, U n k n o w n)  
•  S ki n ca ncer ( Yes, N o, U n k n o w n) 
•  Si g nifica nt U V e x p os ure ( Yes, N o, U n k n o w n)  
•  P h ot ose nsiti vit y d ue t o s ki n dis or der ( Yes, N o, U n k n o w n)  
•  P h ot ose nsiti vit y d ue t o m e dicati o n ( Yes, N o, U n k n o w n)  
•  Fa mil y hist or y of s ki n ca ncer i n first d e gree relati ve (i.e. , pare nts, si bli n gs a n d / or c hil dre n) ( Yes, 
N o, U n k n o w n)  
•  N u m ber of p artici pa nt s h a vi n g hist or y of t he s ki n c o n diti o ns a b o ve ( N o c o n diti o n, 1 c o n diti o n, 
2 c o n diti o ns, 3 or m ore c o n diti o ns)  
A listi n g of s ki n stat us hist or y will be pr o vi de d.  
1 1. 4  
Pre vi o us A ntic a ncer T her a p y   
Pre vi o us a ntica ncer treat me nts a n d pr oce d ures are c ollecte d u n d er t he “ Pri or A nti -Ca ncer Dr u g 
T hera pies Details”  a n d “ Pri or A nti -Ca ncer S ur geries Details” e C R F p a ges.  
T he n u m be r a n d perce nt a ges of partici pa nts i n eac h of t he f oll o wi n g a ntica ncer t hera p y cate g ories 
will be ta b ulate d:  
•  Partici pa nts wit h at least o ne t y p e of pre vi o us a ntica ncer tr eat me nt or pr oce d ure (i.e. , dr u g 
t hera p y, ra di ot hera p y or s ur ger y) 
•  Partici pa nts wit h at  least o ne pre vi o us a ntica ncer dr u g t hera p y  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 5 /1 0 8  
 
 
•  Partici pa nts wit h at least o ne pre vi o us a ntica ncer ra di ot hera p y  
•  Partici pa nts wit h at least o ne pre vi o us a ntica ncer s ur ger y  
T he f oll o wi n g d etails f or pre vi o us s yste mic a ntica ncer dr u g t h era p y will als o be s u m mar ize d: 
•  Partici pa nts wit h at least o ne pre vi o us a dj u va nt t h era p y  
•  Partici pa nts wit h at least o ne pre vi o us ne o a dj u va nt t hera p y  
•  Partici pa nts wit h at least o ne pre vi o us t hera p y f or metastatic or l ocall y a d v a nce d dise ase  
•  N u m ber of a n y pre vi o us a ntica ncer t hera p y li nes f or metastatic or l ocall y a d va nce d disease (as 
cate g orical varia bl e)  
•  Best res p o ns e t o last treat me nt re gi me n 
Pre vi o us a ntica ncer dr u gs, pre vi o us a ntica n cer ra di ot hera p y, a n d pre vi o us a ntica ncer s ur ger y will 
be prese nt e d i n se parate listi n gs:  
•  T he pre v i o us a ntica ncer dr u g listi n g will c o ntai n c o h ort/ pla n ne d ar m, p artici pa nt i de ntifier, a ge, 
se x, race, re gi me n I D/na me , i nte nt of t hera p y, best res p o nse, date of pr o gressi o n, me dicati o n 
na me, preferre d ter m, start date, e n d dat e .  
•  T he pre vi o us a ntica ncer ra di ot hera p y listi n g will c o ntai n c o h ort/ pla n ne d ar m, partici pa nt 
i de ntifier, a ge, s e x, race, start date, e n d d ate, l ocati o n of ra di ot hera p y. 
•  T he pre vi o us a ntica n cer s ur ger y listi n g will c o ntai n c o h ort/ pla n ne d ar m, p artici pa nt i de ntifier, 
a ge, se x, race, n a m e a n d l ocati o n of s ur ger y,  d ate of s ur ger y,  c urati ve i nte nt of s ur ger y ( yes/ n o), 
a n d o utc o me of s ur ger y.   
1 2  
P re vi o us  or  C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
A n alysis set: S A F RI  / I T T 
1 2. 1  
Pre vi o us a n d C o nc o mit a nt M e dic ati o ns   
C o nc o mita nt a n d pre vi o us me dicati o ns are re p orte d o n t he “ C o nc o mita nt Me dicati o ns Details” 
e C R F pa ge.  
C o nc o mit a nt tre at me nts  are me dicati o ns, ot h er t ha n st u d y treat me nt, w hic h are ta ke n b y 
partici pa nts a n y ti me d uri n g t he o n -tr eat me nt peri o d, see Secti o n 9. 8 . 
Pre vi o us me dic ati o ns  are me dicati o ns, ot her t ha n st u d y treat me nt a n d pre -me dicati o ns f or st u d y 
treat me nts, w hic h start e d bef ore  first a d mi nistrati o n of st u d y tr eat me nts.  
A me dicati o n ma y b e cl assifie d as b ot h c o nc o mita nt a n d pre vi o us. T he res pecti ve fla gs will be 
deri ve d bas e d o n start a n d e n d date.  
C o nc o mita nt a n d pre vi o us t reat me nt eac h will be s u m marize d b y n u m ber a n d p erce nta ge of 
partici pa nts. A T C -2 n d le vel a n d preferre d ter m will be ta b ulate d as gi ve n fr o m t he W H O -D D 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 6 /1 0 8  
 
 
dicti o nar y m ost c urre nt versi o n. If a n y pre vi o us or c o n c o mita nt me dicati o n is classifie d i nt o 
m ulti ple A T C classes, t he me dicati o n will be s u m marize d se paratel y u n der eac h of t hese A T C 
classes. T he s u m mar y ta bles will be s orte d b y decreasi n g fre q u e nc y of dr u g class a n d decreasi n g 
fre q ue n c y of dr u g na me i n a gi ve n dr u g class. I n case of e q ual fre q ue nc y re gar din g dr u g class 
(res pecti vel y dr u g na me), al p ha betical or der will be use d. I n case a n y s pecific me dicati o n d oes n ot 
ha ve a n A T C classificati o n le vel 2 c o de d ter m, it will be s u m marize d u n der “ U na vaila ble A T C 
classificati o n” cate g or y. Eac h p artici pa nt will o n l y b e c o u nt e d o nce wit hi n a gi ve n dr u g cl ass a n d 
wit hi n a gi ve n dr u g n a me, e ve n if he/s he recei ve d t he sa me me dicati o n at differe nt ti mes.  
S pecific r ules will be use d t o defi ne if a me di cati o n/ pr oce d ure is c o nsi dere d as a pre vi o us, 
c o nc o mita nt or b ot h pre v i o us a n d c o nc o mita nt me dicati o n/ pr oce d ure as det aile d i n A p pe n di x 2 .  
Pre vi o us a n d c o n c o mita nt 
me dicati o ns 
will b e pres e nte d i n listi n g s 
w hic h 
will i ncl u de: 
c o h ort/ pla n ne d ar m, partici pa nt  i de ntifier, a ge, se x, race, preferre d ter m , me dicati o n na me as 
pr o vi de d b y t h e in vesti gat or , start date, e n d d ate, d ose, d ose u nits, fre q ue n c y, r o ute, reas o n f or t he 
me dicati o n.  
A se parate listi n g of c o nc o mita nt C O VI D -1 9 vacci nati o ns will be pr o vi de d, t his listi n g will i ncl u de 
t he sa me i nf or mati o n as c o nc o mita nt me dicati o ns listi n g : c o u ntr y a n d sta n d ar dize d dr u g gr o u pi n g 
( S D G) s u b gr o u p i nf or mati o n will als o be pr o vi de d.  
1 2. 2  
Pre me dic ati o ns   
Pre me dicati o ns are me d i cati o ns a d mi nistere d per pr ot oc ol o n t he sa me da y as, b ut pri or t o, t he 
st u d y treat me nt.  
T he n u m ber of partici pa nt s recei vi n g preme dicati o n f or 
bi ntraf us p alfa/ place b o  will b e 
s u m marize d f or eac h treat me nt visit base d o n “ St u d y Treat me nt P re me dicati o n details” e C R F 
pa ge.  T he n u m b er of p artici pa nts recei vi n g pre me dicati o n f or c he m ot hera p y (cis plati n a n d/ or 
ge m cita bi ne) 
will be s u m marize d f or eac h tr eat me nt visit base d o n  t he “C he m ot hera p y 
Pre me dicati o n details” e C R F pa ge.  
Perce nta ges will be cal c ulate d o n t he n u m ber of partici pa nt s w h o recei ve d a d ose of bi ntraf us p 
alfa/ place b o  ( or a c he m ot hera p y d ose, res pecti vel y) at t he ass ociat e d visit.   
Listi n gs of pre me dicati o n f or bi ntraf us p alf a/ place b o  a n d of pre m e dicati o n f or c he m ot hera p y will 
be pr o vi de d a n d  t he y will i ncl u de: c o h ort/ pla n ne d ar m, p artici pa nt  i de ntifier, a ge, se x, race, 
me dicati o n na me,  visit, date/ti me of st u d y tr eat me nt, d ose, d ose u nits, a n d r o ute. 
1 2. 3  
C o nc urre nt  P r oce d ures   
C o nc urre nt pr oce d ures  are re p orte d  acc or di n g t o t he “C o nc o mita nt Pr oce d ures Details”  e C R F 
pa ge.   
C o nc urre nt pr oce d ures will be pres e nte d i n a listi n g w hic h will i ncl u de c o h ort/ pla n n e d ar m, 
partici pa nt  i de ntifier, a ge, se x, race, na me of pr oce d ure  (as pr o vi de d b y t he in vesti gat or) , start date, 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 7 /1 0 8  
 
 
e n d date, i n dicati o n, reas o n f or pr oce d ure a n d t y pe of s peci me n c ollecte d . A fla g will be dis pla ye d 
t o i de ntif y eac h pr oce d ure as pri or t o treat me nt or o n -treat me nt.  
1 2. 4  
S u bse q ue nt A ntic a ncer T her a p y   
A ntica ncer  treat me nt aft er disc o nti n uati o n of st u d y dr u g will be s u m marize d acc or di n g t o  t he 
" A nti-ca ncer Treat me nt After 
Disc o nti n uati o n”, “ Ra di ot hera p y 
After Disc o nti n uati o n” a n d 
“ S ur ger y After Disc o nti n uati o n” f or a ntica ncer  s ur ger y e C R F p a ges . 
T he n u m ber of partici p a nt s i n eac h of t he f oll o wi n g a ntica n cer  treat me nt cat e g ories will be 
ta b ulate d: 
•  Partici pa nts wit h at least o ne s u bse q ue nt a ntica ncer  treat me nt or pr oce d ure (i.e., dr u g t hera p y, 
ra di ot hera p y or s ur ger y) 
•  Partici pa nts wit h at least o ne s u bse q ue nt a ntica ncer  dr u g t hera p y  
•  Partici pa nts wit h at least o ne s u bse q ue nt a ntica ncer  ra di ot hera p y 
•  Partici pa nt s wit h at least o ne s u bse q ue nt a ntica ncer  s ur ger y 
•  I n a d diti o n, t he n u m ber a n d perce nta ge of p artici pa nts w h o recei v e d s u bse q ue nt i m m u ne 
c hec k p oi nt i n hi bit ors ( C PI) (a vel u ma b, 
ni v ol u ma b, 
pe m br oliz u ma b, la m br oliz u ma b, 
atez oliz u ma b, d ur val u ma b, tre meli m u ma b or i pili m u ma b) a n d tar gete d t hera p y will be 
ta b ulate d b y treat me nt ar ms. T he fi nal list of s u bse q ue nt C PI a n d tar get e d t hera p y will be 
pr o vi de d u p o n me dical re vie w of all s u bse q ue nt a ntica ncer t hera pies a n d will be liste d i n 
A p pe n di x 6 .  
•  T he n u m ber a n d p erce nta ge of partici pa nts wit h a n y a ntica ncer dr u g t hera p y will als o be 
prese nte d b y t y pe ( base d o n me dical re vie w res ults):  
•  C yt ot o xic t hera p y  
•  I m m u ne C PI 
•  M o n ocl o nal a nti b o dies t hera p y  ot her t ha n C PI  
•  Tar gete d t h era p y wit h s mall m olec ules  
•  Ot her  
T he best res p o nse t o t he f irst s u bse q ue nt a ntica ncer t hera p y will be descri be d ( C R/ P R/ S D / P D/ 
N o n -C R/ N o n -P D/ N ot E val ua ble ( N E)/ N A/ U n k n o w n) as well as t h e best o verall res p o ns e a m o n g 
all a nti -ca ncer dr u g t h era pies.  
T he s u bse q u e nt a nti -ca n cer  dr u g  t hera pies will als o be s u m marize d bas e d o n t he n u m ber a n d 
perce nt a ge of p artici pa nts b y A T C -2 n d le vel a n d preferre d ter m. A partici pa nt will be c o u nte d 
o nl y o nce wit hi n a gi ve n A T C  class a n d wit hi n a preferre d t er m , e v e n if he/s he recei ve d t he s a me 
me dicati o n at differe nt ti mes. T he s u m mar y will be s orte d o n decreasi n g fre q ue nc y of A T C -2 n d 
le vel a n d d ecreasi n g fre q ue nc y of preferre d t er m  wit hi n  a gi ve n A T C dr u g class. I n cas e of e q ual 
fre q ue n c y re gar di n g A T C -2 n d le vel (res pecti vel y preferre d ter m ), al p ha betical or der will be use d. 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 8 /1 0 8  
 
 
S u bse q ue nt C PI a n d s u bse q ue nt tar gete d t hera p y will be s u m marize d. A partici pa nt will be 
c o u nte d o nl y o n ce wit hi n a C PI/tar gete d t hera p y, e ve n if h e/s he recei ve d t he sa me me dicati o n at 
differe nt ti mes. T he s u m mar y will be s orte d o n d ecreasi n g fre q ue n c y of C PI/ta r gete d t hera p y. I n 
case of e q ual fre q u e nc y re gar di n g C PI/tar gete d t hera p y le vel (res pecti vel y preferre d ter m), 
al p ha betical or d er will be use d.  
I n a d diti o n, t he a ntica ncer  treat me nt aft er disc o nti n uati o n of st u d y treat me nt will be pr o vi de d i n 
t w o listi n gs: 
•  F or dr u g t hera p y : c o h ort/ pla n ne d ar m, partici pa nt i de ntifier, a ge, se x, race, preferre d ter m  / dr u g 
na me, re gi me n n a me , start date, e n d dat e a n d best res p o nse  
•  F or ra di ot hera p y a n d s ur ger y: c o h ort/ pla n ne d ar m, partici pa nt i de ntifier, a ge, se x, race, t y p e o f 
t hera p y, start date, e n d d ate, ra di ot hera p y site or  na me of s ur ger y/l ocati o n , if s ur ger y o utc o me 
a n d was t he s ur ger y c urati ve i n i nte nt ( yes/ n o ) 
1 3  
St u d y  Tre at me nt:  C o m pli a nce a n d E x p os ure   
A n alysis set: S A F RI  / S A F 
Partici pa nts will be treate d wit h bi ntraf us p alf a/ place b o  (bi ntraf us p alfa  or p lace b o f or t he 
ra n d o mize d part, bi ntraf us p alfa f or t h e o pe n-la bel part) i n c o m bi nati o n wit h cis plati n a n d 
ge m cita bi ne . Bi ntraf us p alfa/ place b o  will be gi ve n at a flat d ose of 2 4 0 0  m g o nce e v er y 3 wee ks  
or c orres p o n di n g pl ace b o . G e mcita bi ne will be gi ve n at a d ose of 1 0 0 0 m g/ m² a n d cis plati n at a 
d ose of 2 5  m g/ m² o n D a ys 1  a n d 8 of e v er y 2 1 -da y c ycl e f or 8 c ycl es . If c h e m ot hera p y ca n not be 
a d mi nistere d o n Da y 1 or Da y  8 of a gi ve n c ycle (f or safet y or t olera bilit y reas o ns), t he misse d 
d ose ma y be a d mi nistere d o n Da y  1 5 of t hat c ycl e. A d mi nistrati o n details , i ncl u di n g d urati o n o f 
treat me nt, of all st u d y dr u gs  are gi ve n i n Secti o n 6  of t he st u d y pr ot oc ol.  
All d osi n g calc ulati o ns  bel o w  a n d s u m mari es 
will be base d o n t he “ St u d y Treat me nt 
A d mi nistrati o n Details” , “ Ge mcita bi ne A d mi nistrati o n Details” a n d “ Cis plati n A d mi nistrati o n 
Details” e C R Fs pa ge s. D osi n g calc ul ati o ns f or t he t w o c h e m ot hera p ies will be b ase d o n t he 
c orres p o n di n g e C R F p a ges me nti o ne d pre vi o usl y, a n d t he pla n ne d d ose ( pre pare d b y t he u n bli n de d 
p har macist) will be ca pt ure d i n t he dr u g pre parati o n f or m.  
 
D ur ati o n of 
T her a p y a n d 
N u m ber of I nf usi o ns f or 
Bi ntr af us p alf a/ P l ace b o a n d 
C he m ot her a p y  
A n i nf usi o n is re gar de d as bei n g a d mi nistere d if t h e act ual d ose recei ve d is > 0.  
T he  o ver all d ur ati o n  of eac h st u d y treat me nt will be calc ul ate d as f oll o ws:  
•  D urati o n of bi ntraf us p alfa/ place b o ( wee ks) = ( dat e of last d ose –  date of first d ose + 2 1) / 7  
•  D urati o n of cis plati n/ ge m cita bi ne ( wee ks) = ( date of last d ose –  date of first d ose +  x) / 7 w here 
x will be e q ual t o 2 1 if partici pa nt o nl y recei ve da y 1 at t he last c ycle, x = 1 4 if t he last d ose 
recei v e d is at da y 8, a n d x = 7 if t he last d ose recei ve d is at da y 1 5  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
4 9 /1 0 8  
 
 
N ote: C ycl e X d a y 1, d a y 8 a n d d a y 1 5 are i d e ntifie d base d o n visit na me as per t he pr ot oc ol 
sc he d ule d acti vities (see A p pe n di x 5 ) 
I n c o m plete/ Missi n g dat es of last d ose will be i m p ute d as s pecifie d i n T a ble 6 . 
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d per c o h ort/ar m:  
•  D urati o n of t hera p y ( wee ks) f or eac h treat me nt s e parat el y ( bi ntraf us p alfa/ place b o, cis plati n, 
ge m cita bi ne), b y s u m mar y statistics a n d b y cate g ories ( < 3 wee ks, 3 t o 6 wee ks, 6 t o 9 wee ks, 
u p t o ≥4 8 wee ks)  
•  N u m ber of i nf usi o ns recei ve d f or eac h treat me nt s e p arat el y ( bi ntraf us p alf a/ place b o, cis plati n, 
ge m cita bi ne), b y s u m mar y statistics a n d b y cate g ories ( 1, 2, u p t o 1 6 d oses)  
 
C u m ul ati ve D os e, D ose I nte nsit y, a n d Rel ati ve D ose I nte nsit y  
Bi ntraf us p alf a/ place b o a n d c he m ot hera p y calc ulati o ns a n d s u m maries will  be base d o n t he 
“ A d mi nistrati o n Details” e C R F pa ges f or eac h t hera p y.  
C u m ulati ve d ose, d ose i nte nsit y a n d relati ve d os e i nte nsit y of c h e m ot hera pies will be calc ulat e d 
f or eac h c h e m ot hera p y a ge nt se p aratel y (cis plati n a n d ge mcita bi ne). 
T he c u m ul ati ve d ose  of bi ntraf us p alfa/ place b o a n d c he m ot hera pies per partici pa nt i n a gi ve n ti me 
peri o d will be t he s u m of t he act u al d ose le vels t h at t he p artici pa nt recei ve d wit hi n t hat peri o d (i.e., 
t otal d ose a d mi nistere d [ m g or m g/ m 2]). 
D ose I nte nsit y ( DI)  
•  F or bi ntraf u s p alfa/ place b o: 
o  O verall DI ( m g/ 3 wee ks) = [ o verall c u m ulati ve d os e ( m g)]/[ o verall d urati o n ( wee ks)/ 3]  
•  F or c h e m ot hera pi es : 
o  O verall DI ( m g/ m²/ 3 wee ks) = [ o verall c u m ulati ve d ose ( m g)/ B S A ( m²)]/[ o verall 
d urati o n ( wee ks)/ 3]  
N ote: i n cas e t he B S A is missi n g i n  t he gi ve n ti me peri o d, t he latest pre vi o us B S A a vaila ble will 
be use d.  
 Rel ati ve d ose i nte nsit y ( R DI)   
•  F or bi ntraf us p alfa/ place b o a n d c he m ot hera pies:  
o  O verall R DI ( %) = 1 0 0 x [ o verall DI]/ pla n ne d d ose i nte nsit y  
w here t he d os e pla n ne d is 2 4 0 0 m g f or bi ntraf us p alfa/ place b o, 2 0 0 0 m g/ m² f or ge mcita bi ne a n d 
5 0 m g/ m² f or cis plati n.  
 T he f oll o wi n g s u m mar y ta ble will be pr o vi de d  f or bi ntraf us p alfa/ place b o  a n d c he m ot hera p i es b y 
treat me nt ar m: 
•  D urati o n of t hera p y ( wee ks)  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 0 /1 0 8  
 
 
•  T otal n u m ber of i nf usi o ns recei v e d  
•  C u m ulati ve d ose ( m g  or m g/ m² )  
•  D I (m g/ 3 wee ks or m g/ m²/ 3 wee ks )  
•  R DI  ( %) as c o nti n ue varia ble, a n d cate g orize d as  
o   < 8 0 %  / 8 0 %-9 0 % / > 9 0 % f or bi ntraf us p alfa/ place b o  
o   < 5 0 % / 5 0 % -7 5 % / > 7 5 % f or c h e m ot hera p y  
T w o listi n gs will be pres e nte d:  
•  A listi n g of st u d y tr eat me nt e x p os ure data , w hic h will pr o vi de: c o h ort/ pla n ne d ar m, partici pa nt  
i de ntifier, a ge, se x, race, visit , i nf usi o n start date a n d ti me, i nf usi o n e n d dat e a n d ti me, i nf usi o n 
rate ( m L/ hr), v ol u me i nf use d (f or bi ntraf us p alf a/ place b o ), act ual d ose (f or c he m ot hera p y), 
a d mi nistrati o n m o dificati o n a n d reas o n f or m o dificati o n, c ha n ge i n a d mi nistrati o n detail, a n d 
treat me nt dela y ( da ys). 
•  A n a d diti o nal listi n g of treat me nt e x p os ure a n d c o m plia nce  w hic h  will i ncl u de  c o h ort/ pla n ne d 
ar m, partici pa nt  i de ntifi er, a ge, se x, race, d urati o n of t hera p y ( wee ks), t otal n u m ber of i nf usi o ns 
recei v e d, c u m ulati ve d os e of t hera p y , DI , a nd R DI  ( %). 
D ose M o dific ati o n  
Per pr ot oc ol, d ose m o dificati o n  f or bi ntraf us p alf a/ place b o  is n ot all o we d. N o s u m maries will be 
pr o vi de d.  
C he m ot hera p y d ose re d ucti o ns as rec or de d o n t he “ Ge mcita bi ne A d mi nistrati o n Details” a n d 
“ Cis plati n A d mi nistrati o n Details” pa ges of t he e C R F (i.e. , a ns w er t o t h e q uesti o n “Is t here a 
c ha n ge i n d ose? ” = “ D ose a dj uste d”) will be use d f or a nal ysis. T he n u m be r of partici pa nts wit h at 
least o ne d ose re d u cti o n, reas o ns f or d ose re d ucti o n (A d verse E ve nt / Ot her) , as well as a 
cate g orizati o n of t he n u m ber of i nf usi o ns wit h d ose re d uce d ( 1 / 2 / ≥ 3) will be s u m marize d f or 
eac h re gi me n  b y treat me nt ar m .  
T her a p y De l a ys 
T hera p y d ela ys will be d eri ve d f or bi ntraf us p alf a/ place b o as f oll o ws:  
T hera p y d ela ys f or bi ntraf us p alf a/ place b o  = st art date of c urre nt i nf usi o n –  start dat e of t h e 
pre vi o us i nf usi o n –  2 1  
C he m ot hera p y a d mi nistrati o n dela ye d as rec or de d o n t he “ Ge mcita bi n e A d mi nistrati o n Details” 
a n d “ Cis plati n A d mi nistrati o n Details” pa ges of t he e C R F (i.e., a ns w er t o t he q uesti o n “ Was t he 
Cis plati n/ Ge mcita bi ne a d mi nistrati o n dela ye d? ” = “ Yes”) will be use d  f or a nal ysis.  
T he f oll o wi n g will be s u m marize d i n a ta ble  f or bi ntraf us p alf a/ place b o  a n d c he m ot hera p y f or eac h 
treat me nt ar m: 
•  N u m ber of partici pa nt s wit h at least o ne dela y 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 1 /1 0 8  
 
 
•  N u m ber of partici pa nt s wit h n o dela y 
•  N u m ber of del a ys per partici pa nt ( 1 dela y, 2 dela ys, 3 dela ys, ≥ 4 d ela ys)  
•  L o n gest dela y  p er partici pa nt  ( 1-2 da ys, 3 -8 d a ys, 9 -1 5 da ys, ≥1 6 da ys) ( o nl y f or bi ntraf us p 
alfa/ place b o)  
Te m p or a r y I nf usi o n I nterr u pti o ns  
Te m p orar y i nterr u pti o ns of bi ntraf us p alfa/ place b o  a n d c he m ot hera p y i nf usi o n as rec o r de d o n t he 
“ A d mi nistrati o n Details” pa ges of t he e C R F will be use d f or a n al ysis. T he n u m ber of partici pa nt s 
wit h at least o ne st u d y dr u g te m p orar y i nf usi o n i nterr u pti o n, reas o n f or i nf usi o n te m p orar y 
i nterr u pti o n (A d vers e E ve nt  / Ot her), as well as a categ orizati o n of t he n u m ber of te m p orar y 
i nf usi o n i nterr u pti o ns ( 1 / 2 / ≥3) will be s u m marize d b y tr eat me nt ar m f or b ot h bi ntraf us p 
alfa/ place b o  a n d c h e m ot hera p y.  
I nf usi o n R ate Re d ucti o ns 
I nf usi o n rat e re d ucti o ns as rec or de d o n t he “A d mi nistrati o n Details” e C R F pa ge s will b e use d f or 
a nal ysis. T h e n u m ber of partici pa nt s wit h at least o ne i nf usi o n rate re d ucti o n, reas o n f or i nf usi o n 
rate re d u cti o ns (A d verse E ve nt  / Ot her), as w ell as a cate g orizati o n of t he n u m ber of i nf usi o n rate 
re d ucti o ns ( 1 / 2 / ≥3) will be s u m marize d  b y treat me nt ar m f or b ot h bi ntraf us p alf a/ place b o  a n d 
c he m ot hera p y.  
1 4  
Effic ac y A n al yses   
A n alysis Sets: S A F RI  / I T T 
De pe n di n g o n t he d ecisi o n t o e x pa n d or n ot t he st u d y i nt o P hase  III sa m ple siz e, all efficac y 
e n d p oi nts will be c o nsi d ere d eit her as t he pri mar y a nal ysis or a se nsiti vit y a nal ysis acc or di n g t o 
T a ble 7 . Data relate d t o i n ves ti gat or’s t u m or assess me nts will be c ollecte d o n t he “ Assess me nt of 
disease base d o n i ma gi n g (acc or di n g t o R E CI S T 1. 1)” e C R F p a ge . 
T a ble 7  
Defi niti o n of P ri m a r y a n d S e nsiti vit y A n al ysis of E ffic ac y T u m or -rel at e d 
E n d p oi nts acc or di n g t o t he A d a pt ati o n D ecisi o n  
A d a pt ati o n d e ci si o n  
Pri m ar y A n al y si s  
S e n siti vit y A n al y si s t o t h e t y p e of 
t u m or a s s e s s m e nt (I n v e sti g at or v s 
I R C) 
E x p a n si o n i nt o P h a s e III ( 5 0 0 
p arti ci p a nt s)  
Effi c a c y e n d p oi nt a s a s s e s s e d b y t h e 
i n v e sti g at or 
Effi c a c y e n d p oi nt a s a s s e s s e d b y t h e 
I R C i n t h e fir st 1 5 0 r a n d o mi z e d 
a nti bi oti c s n aï v e p arti ci p a nt s i n P h a s e 
II 
N o e x p a n si o n  
Effi c a c y e n d p oi nt a s a s s e s s e d b y t h e 
I R C 
Effi c a c y e n d p oi nt a s a s s e s s e d b y t h e 
i n v e sti g at or 
M ulti plicit y a dj ust me nt f or pri m ar y a n d ke y sec o n d ar y e n d p oi nts  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 2 /1 0 8  
 
 
O ut of t he sec o n d ar y e n d p oi nts, P F S  as well as o bjecti ve res p o ns e rate are c o nsi dere d as ke y 
sec o n dar y e n d p oi nts. 
If t h e st u d y is n ot e x pa n de d i nt o P hase  III sa m ple siz e, t he statistical test f or t he pri mar y e n d p oi nt 
will be per f or me d at o ne-si de d al p ha of 0. 0 2 5. Ot her wise, t w o se q ue ntial t ests (i nteri m a n d pri mar y 
a nal ys es) will be perf or m e d f or t he pri mar y a n d k e y sec o n dar y e n d p oi nts.  
A hierarc hical testi n g pr oce d ure will be a p plie d t o t he c o nfir mat or y tests f or t he pri mar y a n d  ke y 
sec o n dar y e n d p oi nts. T he h y p ot h esis f or t he pri m ar y e n d p oi nt  (O S ) will b e teste d usi n g a gr o u p 
se q ue ntial a p pr oac h i n a n i nteri m a nal ysis a n d a fi nal a nal ysis at a  si g nifi ca nce le vel of 0. 0 2 5  o n e -
si de d. If t he n ull h y p ot hesis f or t he pri mar y e n d p oi nt is rejecte d, t he h y p ot hesis f or t he first ke y 
sec o n dar y e n d p oi nt (P F S ) will be teste d c o nfir mat or y usi n g t he s a me i nf or mati o n fracti o n f or a 
gr o u p s e q ue ntial a p pr oac h . Fi nall y, if t his last n ull h y p ot hesis is rejecte d t he n t he last ke y 
sec o n dar y e n d p oi nts ( o bjecti ve res p o ns e rat e) will be teste d li ke wise.  
T he gr o u p s e q ue ntial a p pr oac h f or testi n g O S, P F S a n d o bjecti ve res p o ns e will use al p ha -s pe n di n g 
f u ncti o n of La n-De Mets a p pr oac h acc or di n g t o t he act ual n u m ber of o bser ve d e ve nts re gar di n g 
t he t otal e ve nt n u m ber pla n ne d f or t he pri mar y a nal ysis f or O S ( 3 3 4 e ve nts), i.e. , t he sa me 
i nf or mati o n fracti o n wit h O S will be use d f or P F S a n d o bjecti ve res p o nse. O’ Brien -Fle mi n g 
b o u n daries are use d f or O S a n d P oc oc k b o u n daries are use d f or P F S a n d o bjecti ve res p o nse 
( Gli m m 2 0 1 0). 
Pre -s pecif yi n g t he or der of t he h y p ot hes es t o be teste d, t he fa mil y wise err or rate f or t his a p pr oac h 
t o se q ue ntiall y rejecti ve m ulti ple test pr oce d ure ( Ma urer 1 9 9 5) is c o ntr oll e d at 2. 5 % o ne-si de d 
al p ha le vel . 
1 4. 1  
O ver all S ur vi v al ( Pri m ar y E n d p oi nt)   
1 4. 1. 1  
Pri m ar y 
O bjecti ve: 
Deri v ati o n a n d a n al ysis of 
O ver all 
S ur vi v al   
O ver all s ur vi v al is defi ne d as t he ti me fr o m st u d y da y 1 t o t he d ate of d eat h d ue t o a n y ca us e: 
O S  ( m o nt hs) = ( date of e ve nt or ce ns ori n g –  d ate of st u d y da y 1 + 1)/ 3 0. 4 3 7 5.  
T he date of e ve nt / ce ns ori n g is de fi ne d i n Ta ble 8 . 
 
T a ble 8  
S ur vi v al E ve nt / Ce ns ori n g  
S ur vi v al St at u s  
D at e of E v e nt/ c e n s ori n g  
C e n s ori n g  
P arti ci p a nt s w h o di e d b ef or e or at c ut -off d at e  
D at e of d e at h  
N o  
P arti ci p a nt s h a v e  n ot di e d b ef or e or at c ut -off d at e  
D at e  of l a st c o nt a ct  
Y e s  
T he date of l ast c o ntact will be defi ne d f oll o wi n g Secti o n 9. 6 . 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 3 /1 0 8  
 
 
K a pl a n -Meier A n al ysis  
T he a nal ysis of O S will be perf or me d wit h a Ka pla n -Meier met h o d. Ka pla n -Meier esti mates 
( pr o d uct-li mit esti mates) will be prese nte d b y treat me nt gr o u p t o get her wit h a s u m mar y of 
ass ociate d statistics i ncl u di n g  t he me dia n O S wit h t w o-si de d 9 5 % CIs. I n partic ular, O S rates wit h 
t heir t w o-si de d 9 5 % CI s at 3, 6, 9,  1 2 a n d 2 4 m o nt hs at least will be prese nte d, as well as t h e 
n u m ber of partici pa nts at ris k a n d faile d. T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me yer a n d Cr o wle y  a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d 
a b o ve will be deri ve d usi n g t he l o g -l o g tr a nsf or mati o n acc or di n g t o Kal bfleisc h a n d Pre ntice  
(c o nft y pe =l o gl o g defa ult o pti o n i n S A S P R O C LI F E T E S T) wit h bac k tr a nsf or mati o n t o a CI o n 
t he u ntra nsf or me d scale. T he esti mate of t he sta n d ar d err or will be c o m p ute d usi n g Gree n w o o d’s 
f or m ula. 
Fre q u e nc y ( n u m ber a n d perce nt a ge) of partici pa nts wit h a n e ve nt ( deat h) a n d c e ns ori n g reas o ns 
will als o be prese nte d b y treat me nt gr o u p. Ce ns ori n g reas o ns are t he f oll o wi n g: 
•  Ali ve  (a d mi nistrati ve ce ns ori n g) 
•  Wit h dra wal of c o nse nt  
•  L ost t o f oll o w -u p  
L ost t o f oll o w -u p will i ncl u de t he f oll o wi n g parti ci pa nts : 
•  L ost t o f ol l o w-u p stat us is c ollecte d o n t he e C R F pa ge pri or t o t he a nal ysis c ut -off  
•  Partici pa nts wit h t he last c o ntact date > 1 4 wee ks pri or t o t he a nal ysis c ut -off date ( d urati o n of 
1 4 wee ks is base d o n t he assess me nt sc he d ule of e ver y 3 m o nt hs f or s ur vi val f oll o w -u p i nter val 
+ 2 -wee k wi n d o w)  
Ali ve will i ncl u de ce ns ore d partici pa nts w h o di d n ot wit h dra w fr o m c o nse nt a n d were n ot l ost t o 
f oll o w-u p base d o n t he pre vi o us defi niti o n.  
A partici pa nt listi n g will be pr o vi de d i n cl u di n g t he f oll o wi n g i nf or mati o n: c o h ort/ pla n ne d ar m, 
partici pa nt i de ntifier, a ge, se x, race, d ate of st u d y da y 1, date of e v e nt/ce ns ori n g, e ve nt/ce ns ori n g 
reas o n, ti me t o e ve nt/ce ns ori n g. 
O S will als o be prese nte d gra p hicall y wit h Ka pla n -Meier fi g ures.  
F oll o w -u p D ur ati o n  
A Ka pla n -Meier a nal ysis f or O S f oll o w -u p d urati o n will als o be perf or me d re v ersi n g t he O S 
ce ns ori n g a n d e ve nt i n di cat ors. T his a n al ysis will be base d o n t h e mai n Ka pla n -Meier a nal ysis of 
O S descri be d a b o v e.  
Str atifie d L o g -r a n k Test  
O S will be c o m pare d bet wee n t he t w o treat me nt gr o u ps  ( bi ntraf us p alf a vs place b o) usi n g a o ne -
si de d stratifie d l o g-ra n k t est.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 4 /1 0 8  
 
 
T he f oll o wi n g n ull h y p ot hesis will be teste d:  
𝐻0
𝑂𝑆: 𝜆𝐵
𝑂𝑆(𝑡) = 𝜃𝜆𝑃
𝑂𝑆(𝑡),𝜃≥1  vers us 𝐻1
𝑂𝑆: 𝜆𝐵
𝑂𝑆(𝑡) = 𝜃𝜆𝑃
𝑂𝑆(𝑡),𝜃< 1  
W here 𝜆⋅
𝑂𝑆(𝑡) re prese nts t he hazar d at ti me 𝑡 a n d 𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he treat me nt gr o u ps B  (bi ntraf us p alfa ) a n d P  ( place b o). 
C o x’s Re gressi o n M o del  
T he treat me nt effect  o n O S  will be esti mate d usi n g a C o x’s p r o p orti o nal h azar ds m o del stratifie d 
b y t h e ra n d o mizati o n data ( B T C s u bt y pe, Asia n/ N o n-Asia n  a n d diseas e stat us at i nitial dia g n osis) 
t hr o u g h t he H R  c o m p utati o n . Ra n d o mizati o n strata will be ta ke n as s p ecifi e d a n d d o c u me nte d i n 
t he IX R S. Eac h strat u m will defi ne a se p arate baseli ne hazar d f u ncti o n ( usi n g t he ' S T R A T A' 
state me nt i n S A S P R O C P H R E G), i.e., f or t he i-t h strat u m t he hazar d f u ncti o n is e x presse d as: h(i; 
t) = h(i, 0;  t) e x p( x), w here h(i, 0;  t) defi nes t he baseli ne hazar d f u ncti o n f or t he i-t h strat u m a n d 
x defi nes t he treat me nt gr o u p ( 0  =  place b o , 1 =  bi ntraf us p alfa ) a n d  is t he u n k n o w n re gressi o n 
para meter.  
Ties will be h a n dle d b y re placi n g t h e pr o p orti o nal hazar ds m o d el b y t he discrete l o gistic m o del 
( Ties = Discrete o pti o n i n S A S P R O C P H R E G). 
A ta ble i ncl u di n g t h e Ka pla n -Meier esti mates  a n d t he C o x’s pr o p orti o nal hazar ds m o del res ults 
will be pr o vi de d.  
Met h o ds f or e v al u ati n g t he v ali dit y of m o del ass u m pti o ns  
Sc h oe nfel d resi d uals f or t he stratifie d C o x pr o p orti o nal hazar ds m o del will be pl otte d i ncl u di n g a 
L O E S S c ur ve t o i n vesti gat e gra p hic all y vi olati o ns fr o m t he pr o p orti o nal hazar ds ass u m pti o n; a 
n o n -zer o sl o pe is e vi de nce of de viati o n fr o m pr o p orti o nal hazar ds . Sc h oe nfel d resi d uals will be 
c o m p ute d i n S A S usi n g t he P H R E G pr oce d ure a n d usi n g t he O U T P U T stat e me nt a n d t he k e y w or d 
R E S S C H. Wit h pr o p orti o nal hazar ds t he L O E S S c ur ve s h o ul d be p arallel t o t he x -a xis.  
T he pr o p orti o nal hazar ds  ass u m pti o n will be f or mall y teste d usi n g Sc h oe nfel d’s resi d ual test 
( Sc h oe nfel d, 1 9 8 0; T her nea u & Gra m bsc h, 2 0 0 0).  Lar ge de part ures fr o m pr o p orti o nal  hazar ds  
will be e vi de nce d b y a p -val ue <  0. 0 5; n ote h o we ver t hat t he test will n ot be se nsiti ve t o detect 
n o n -li near de vi ati o ns fr o m P H. 
I n a d diti o n, t he pr o p orti o nal hazar ds  ass u m pti o n will be c hec k e d vis uall y b y pl otti n g f or eac h 
ra n d o mizati o n strat u m 
lo g( -l o g( S(t))) v ers us l o g(t),  
w here S(t) is t he esti mate d s ur vi val f u ncti o n at ti me t b y tr eat me nt ar m.  
If t h ese met h o ds s h o w lar ge de part ures fr o m pr o p orti o nal hazar ds, t he n O S  will als o be a nal yze d 
base d o n restri cte d mea n s ur vi val ti me ( R M S T) differe nc es ( Z ha n g, 2 0 1 3). See  Secti o n 1 4. 1. 2 . 
M ulti v ari a ble C o x Re gressi o n  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 5 /1 0 8  
 
 
M ulti varia ble C o x re gressi o n a nal ysis will be carrie d o ut t o assess a n d a dj ust t he treat me nt effect 
f or rele v a nt baseli ne fact ors of p ote ntial pr o g n ostic i m pact. Rele va nt  baseli ne fact ors will be 
defi ne d as t he s u b gr o u ps defi ne d i n Secti o n 8. 2 . T he f oll o wi n g cate g orizati o ns will be c o nsi dere d 
f or t h ose s u b gr o u ps wit h m ulti ple defi niti o ns: 
•  Bl o o d -bas e d a n d/ or t u m or -base d T M B at b aseli ne, gr o u pe d i n q uartiles  
o  T M B l o w ( Q 1 + Q 2) (refere nce l e vel)  
o  T M B hi g h ( Q 3 + Q 4)  
•  P D -L 1 e x pressi o n o n t u m or cells ( T C)  at bas eli ne 
o  < 1 % (refere nce le vel)  
o   ≥ 1 %  
•  P D -L 1 e x pressi o n o n i m m u ne cells (I C) at b aseli ne  
o  <  1 % (refere nce le vel)  
o   ≥ 1 %  
A ste p wise selecti o n pr oce d ure will ser ve t o i de ntif y e x pla nat or y v aria bl es of p ote ntial pr o g n ostic 
val ues a d diti o nal t o t he ra n d o mizati o n strata w hic h will be i ncl u de d i n all m o dels d uri n g t h e 
selecti o n pr oce d ure, t he ste p wise selecti o n met h o d i n S A S ( P R O C P H R E G) will be use d. T he 
le vel of si g nifica nce f or a n e x pla nat or y varia bl e t o e nter t he m o del will be set t o 0. 1 5 a n d t he 
si g nifica n ce le v el f or re m o vi n g t o 0. 4 0. T he C o x's p r o p orti o nal h azar d m o del is defi ne d as: h(t) = 
h( 0;  t) e x p( X b), w here h( 0; t) defi nes t he baseli ne hazar d f u ncti o n a n d X defi nes t he vect or of 
e x pla nat or y varia bl es a n d b t he u n k n o w n vect or of re gressi o n para m eters. T he hazar d rati os of all 
selecte d e x pla nat or y vari a bles a n d of treat me nt effects will be re porte d i ncl u di n g 2 -si de d 9 5 % CIs. 
N o i nteracti o ns will be c o nsi dere d. P ost -baseli ne fact ors will n ot be c o nsi d ere d f or t he m o del.  
1 4. 1. 2  
Se nsiti vit y A n al yses  of O ver all S ur vi v al   
T o assess t he r o b ust ness of t he O S a nal ysis, t he f oll o wi n g se nsiti vit y a n al ysis will be c o n d ucte d:  
•  A n u nstratifie d a n al ysis will be perf or me d t o c o m pare O S  bet w ee n t he t w o treat me nt gr o u ps  
a n d t o esti mate t he treat me nt effect . T his a nal ysis will be perf or me d as d escri be d i n S ecti o n 
1 4. 1. 1 . 
•  T he pri mar y a n al ysis will be re peate d b y ce ns ori n g partici pa nts  w h o recei ve d s u bse q ue nt 
i m m u ne c hec k p oi nt i n hi bit or t hera p y s uc h as a vel u ma b, ni v ol u ma b, pe m br oliz u ma b, 
atez oliz u ma b, d ur val u ma b, tre meli m u ma b or i pili m u ma b after disc o nti n ui n g t he st u d y 
treat me nt at t he date of t h e first d ose of s u bse q ue nt i m m u ne c hec k p oi nt i n hi bit or t hera p y mi n us 
1 da y. T he fi nal list of s u bse q ue nt i m m u ne c h ec k p oi nt i n hi bit or t hera p y will be pr o vi de d u p o n 
me dical re vie w of all s u bse q ue nt a nti -ca ncer t hera pies.  
•  T he meas ur e me nt of tr eat me nt effect o n O S str atifie d b y t he ra n d o mizati o n data will be 
re peat e d usi n g ra n d o mizati o n strata as s pecifie d a n d d oc u me nte d i n t he e C R F. 
If t he a n al ysis of O S base d o n C o x’s re gressi o n m o del has bee n s h o w n t o n ot meet t he pr o p orti o nal 
hazar ds ass u m pti o n, t he n t he f oll o wi n g a n al ysis will be perf or me d.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 6 /1 0 8  
 
 
Restricte d Me a n S ur vi v al Ti me ( R M S T)  
T he R M S T met h o d ol o g y is a p plica ble i n de pe n de ntl y of t he pr o p orti o nal haz ar ds ( P H) ass u m pti o n 
a n d ca n b e use d, at a mi ni m u m, as a se nsiti vit y a nal ysis t o e x pl ore t he r o b ust ness of t he pri mar y 
a nal ysis res ults.  
As it pertai ns t o t he c ut -off p oi nt (τ) t o e val u ate t h e R M S T, it is n ote d t hat t he c ut -off p oi nt s h o ul d 
n ot e x cee d t he mi ni m u m  of t he lar gest o bser ve d ti me f or b ot h treat me nt ar ms s o t hat t he R M S T of 
all treat me nt ar ms bei n g e val uate d ca n be a d e q uatel y esti mate d a n d c o m paris o n bet w ee n 
treat me nts is f easi ble; τ s h o ul d be cli nicall y mea ni n gf ul a n d cl oser t o t h e e n d of t he st u d y f oll o w-
u p s o t hat t he maj orit y of s ur vi val o utc o mes will be c o vere d b y t he ti me i nter val. T he R M S T u p 
t o ti me τ ca n t he n b e i nter prete d as t he e x pecte d s ur vi val ti me restri cte d t o t he c o m m o n f oll o w-u p 
ti me τ a m o n g all patie nts. T he selecti o n of τ s h o ul d e ns ure t hat t he R M S T e val uati o n will n ot g o 
be y o n d t he ma xi m u m ti me p oi nt w here t he e val uati o n ca n be perf or me d w hile als o ta ki n g i nt o 
acc o u nt a lar ge peri o d of ti me t hat is e x pecte d t o pr o vi de a mea ni n gf ul ass ess me nt of treat me nt 
effect. T o a v oi d ar bitrar y sel ecti o n of t he c o m m o n c ut -off τ f or b ot h treat me nt ar ms, t hr ee sets of 
a nal ys es will be perf or m e d:  
•  τ1 = mi ni m u m of (lar gest o bser ve d s ur vi val ti me f or bi ntraf us p alfa ar m, lar gest o bser ve d 
s ur vi val ti me f or place b o ar m).  
•  τ2 = mi ni m u m of (lar gest s ur vi val e ve nt ti me f or bi ntraf us p alf a ar m, lar gest s ur vi val e ve nt 
ti me f or place b o ar m).  
•  τ3 = mi d p oi nt bet wee n τ 1 a n d τ 2. 
I n t his se cti o n, ‘s ur vi val’ is mea nt t o de n ote O S. 
T he treat me nt effect b et wee n t he bi ntraf us p alfa ar m a n d t h e place b o ar m will be assess e d bas e d 
o n t he differe n ce i n R M S T. T he ass o ciate d 9 5 % CI f or t h e differe n ce i n mea ns a n d o ne -si de d p-
val ue will be ge nerate d. R M S T as a f u ncti o n of τ a n d t he ass ociate d treat m e nt effect bet wee n t he 
t w o treat me nt ar ms will be plotte d a gai nst ti me τ  (fr o m τ = 0 t o t he lar gest o bser ve d s ur vi val ti me 
acr oss b ot h ar ms) . 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 7 /1 0 8  
 
 
1 4. 2  
Pr o gressi o n -Free S ur vi v al  Acc or di n g t o R E CI S T 1. 1  
(Sec o n d ar y  E n d p oi nt)   
Pr o g ressi o n -F ree S ur vi v al  ti me is defi ne d as t he ti me fr o m st u d y da y 1 u ntil t he first 
d oc u me ntati o n of pr o gressi o n of disease or deat h d ue t o a n y ca us e, w hic he ver occ ur s first. 
P F S = ( date of P D or deat h or ce ns ori n g –  date of st u d y da y 1 + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
Ce ns ori n g r ul es f or pri m ar y a n d se nsiti vit y a nal ys es are s u m marize d i n Ta ble 9 . 
 
T a ble 9  
Ce ns ori n g R ules f or Pri m a r y a n d Se nsiti vit y A n al ysis of P F S  
Sit u ati o n  
Pri m ar y A n al y si s / S e n siti vit y 
A n al y si s t o t h e t y p e of t u m or 
a s s e s s m e nt  
S e n siti vit y A n al y si s 2  
( Pri m ar y A n al y si s P F S c o u nti n g all 
e v e nt s ( P D a n d d e at h) r e g ar dl e s s of 
t h e st art of a n e w a nti c a n c er t h er a p y 
a n d i g n ori n g t h e n u m b er of mi s si n g 
e v al u a bl e t u m or a s s e s s m e nt s b ef or e 
pr o gr e s si o n or d e at h)  
N o P D a n d n o 
d e at h  
N e w a nti c a n c er 
t h er a p y i s n ot 
i niti at e d 
C e n s or e d at l a st t u m or 
a s s e s s m e nt*  
C e n s or e d at l a st t u m or a s s e s s m e nt*  
N e w a nti c a n c er 
t h er a p y i s i niti at e d 
C e n s or e d at l a st t u m or 
a s s e s s m e nt* b ef or e n e w 
a nti c a n c er t h er a p y  
C e n s or e d at l a st t u m or a s s e s s m e nt*  
N o b a s eli n e 
a s s e s s m e nt or 
n o e v al u a bl e 
p o st -b a s eli n e 
a s s e s s m e nt  
N o d e at h or d e at h 
> 1 2 w e e k s aft er 
st art of st u d y 
tr e at m e nt 
C e n s or e d o n st u d y d a y 1  
C e n s or e d o n st u d y d a y 1  
D e at h ≤1 2 w e e k s 
aft er st art of st u d y 
tr e at m e nt 
Pr o gr e s s e d at d at e of d e at h  
 
Pr o gr e s s e d at d at e of d e at h  
 
P D or d e at h  
Aft er ≤1 mi s si n g 
t u m or a s s e s s m e nta  
Pr o gr e s s e d at d at e of 
d o c u m e nt e d P D or d e at h, 
w hi c h e v er c a m e fir st  
Pr o gr e s s e d at d at e of d o c u m e nt e d 
P D or d e at h, w hi c h e v er c a m e fir st  
Aft er ≥2  s u b s e q u e nt 
mi s si n g t u m or 
a s s e s s m e nt s a  
C e n s or e d at l a st t u m or 
a s s e s s m e nt* b ef or e t h e 
mi s si n g a s s e s s m e nt s.  
Pr o gr e s s e d at d at e of d o c u m e nt e d 
P D or d e at h, w hi c h e v er c a m e fir st  
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 8 /1 0 8  
 
 
Sit u ati o n  
Pri m ar y A n al y si s / S e n siti vit y 
A n al y si s t o t h e t y p e of t u m or 
a s s e s s m e nt  
S e n siti vit y A n al y si s 2  
( Pri m ar y A n al y si s P F S c o u nti n g all 
e v e nt s ( P D a n d d e at h) r e g ar dl e s s of 
t h e st art of a n e w a nti c a n c er t h er a p y 
a n d i g n ori n g t h e n u m b er of mi s si n g 
e v al u a bl e t u m or a s s e s s m e nt s b ef or e 
pr o gr e s si o n or d e at h)  
B ef or e st art e d n e w 
a nti c a n c er t h er a p y b  
Pr o gr e s s e d at d at e of 
d o c u m e nt e d P D or d e at h, 
w hi c h e v er c a m e fir st  
Pr o gr e s s e d at d at e of d o c u m e nt e d 
P D or d e at h, w hi c h e v er c a m e fir st  
Aft er st art e d n e w 
a nti c a n c er t h er a p y b  
C e n s or e d at l a st t u m or 
a s s e s s m e nt* b ef or e n e w 
a nti c a n c er t h er a p y  
Pr o gr e s s e d at d at e of d o c u m e nt e d 
P D or d e at h, w hi c h e v er c a m e fir st  
* wit h o ut c o m e C R, P R, S D  or N o n -C R/ N o n -P D . If n o a d e q u at e t u m or a s s e s s m e nt, c e n s or e d o n  st u d y d a y 1 . 
a  N o a s s e s s m e nt s i n 8 4  d a y s d uri n g t h e fir st 9  m o nt h s of f oll o w -u p or 1 6 8 d a y s aft er t h e fir st 9  m o nt h s of f oll o w -u p . 
b  D efi niti o n of n e w a nti c a n c er t h er a p y t o b e c o n si d er e d i s gi v e n i n S e cti o n 9. 8 . 
1 4. 2. 1  
M ai n A n al ysis f or P F S   
Mai n a nal ysis f or P F S will be base d o n partici pa nts’ t u m or res p o nses eit her as asses se d b y t he 
i n vesti gat or or b y t h e I R C acc or di n g t o t he r ule d efi ne d i n Ta ble 7 . 
K a pl a n -Meier A n al ysis  
T he a nal ysis of P F S will be perf or me d wit h a Ka pla n -Mei er met h o d. Ka pla n -Mei er esti mates 
( pr o d uct-li mit esti mates) will be prese nte d b y treat me nt gr o u p t o get her wit h a s u m mar y of 
ass ociate d statistics i ncl u di n g t he me di a n P F S wit h t w o -si de d 9 5 % CIs. I n partic ular, P F S rates 
wit h t heir t w o -si de d 9 5 % CIs at 3, 6, 9, 1 2, 1 8 a n d 2 4 m o nt hs at l east ( de pe n di n g o n t he act ual 
data)  will be prese nt e d, as well as t he n u m ber of partici pa nts at ris k a n d faile d. T he CIs f or t h e 
me dia n will be calc ul ate d acc or di n g t o Br o o k me yer a n d Cr o wle y  a n d t h e CIs f or t he s ur vi val 
f u ncti o n esti mates at t he ti me p oi nts defi ne d a b o ve will be deri ve d usi n g t he l o g -l o g tra nsf or mati o n 
acc or di n g t o Kal bfleisc h a n d Pre ntice  (c o nft y p e =l o gl o g defa ult o pti o n i n S A S PR O C  LI F E T E S T) 
wit h bac k tra nsf or mati o n t o a CI o n t he u ntra nsf or me d scale. T h e esti mate of t he sta n dar d err or 
will be c o m p ute d usi n g Gree n w o o d’s f or m ula.  
Fre q u e nc y ( n u m ber a n d perce nt a ge) of p artici pa nts wit h a n d wit h o ut a n e ve nt, o verall a n d per 
e ve nt t y pe ( P D or deat h) will be prese nte d b y treat me nt ar m. Ce ns ori n g reas o ns will be descri be d 
b y treat me nt ar m, as f oll o ws:  
•  A d mi nistrati ve ce ns ori n g ( o n g oi n g i n t he st u d y wit h o ut a n e ve nt)  
•  N o baseli ne ass ess me nt  i.e n o t u m or sca n rec or de d bef ore  ra n d o mizati o n 
•  N o e val ua ble p ost -b aseli ne assess me nt  
•  Start of ne w a ntica ncer t h era p y 
•  E ve nt after 2 or m ore missi n g or n o n -e val ua ble p ost -baseli ne assess me nts  
•  Wit h dra wal of c o nse nt  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
5 9 /1 0 8  
 
 
•  L ost t o f oll o w -u p  
 
L ost t o f oll o w -u p will i ncl u de t he f oll o wi n g parti ci pa nts:  
•  L ost t o f oll o w -u p stat us is c ollecte d o n t he “ Treat me nt T er mi nati o n ” e C R F  pa ge or t h e “ St u d y 
T er mi nati o n ” e C R F p a ge pri or t o t he a nal ysis c ut -off  
•  Partici pa nts wit h ce ns ori n g date > 1 4 wee ks pri or t o t he a nal ysis c ut -off d ate ( d urati o n of 1 4 
wee ks is base d o n t he ass ess me nt sc he d ule of e v er y 3 m o nt hs f or s ur vi val f oll o w -u p i nter val + 
2 -wee k wi n d o w)  a n d p artici pa nt o n g oi n g wit h o ut e ve nt  
•  Partici pa nts w h o disc o nti n ue d/c o m plete d t he st u d y wit h o ut a n e v e nt  
A partici pa nt listi n g will be pr o vi de d i n cl u di n g t he f oll o wi n g i nf or mati o n: c o h ort/ pla n ne d ar m, 
partici pa nt i de ntifier, a ge, se x, race, d ate of st u d y da y 1, date of e v e nt/ce ns ori n g, e ve nt/ce ns ori n g 
reas o n, ti me t o e ve nt/ce ns ori n g.  
P F S will als o be prese nte d gra p hicall y wit h Ka pla n -Meier fi g ures.  
F oll o w -u p D ur ati o n  
A pl ot will be ge n erate d t o c o m pare pla n ne d a n d act ual rel ati ve da y of t u m or assess me nts b y 
treat me nt ar m. A Ka pla n-Meier a n al ysis f or P F S f oll o w -u p d urati o n will als o be perf or me d 
re versi n g t he P F S ce ns ori n g a n d e v e nt i n dicat ors. T his a nal ysis will be base d o n t he mai n Ka pla n -
Meier a n al ysis of P F S descri be d a b o v e.  
Str atifie d L o g -r a n k Test  
P F S will be c o m pare d b et wee n t he t w o treat me nt gr o u ps ( bi ntraf us p alfa vs  place b o) usi n g a o n e -
si de d stratifie d l o g-ra n k t est.  
T he f oll o wi n g n ull h y p ot hesis will be tes te d: 
𝐻0
𝑂𝑆𝜆: 𝐵𝑂
𝑆𝑡𝜃(𝜆) = 𝑃𝑂𝑆
𝑡𝜃𝐻(𝑂),𝑆≥1  vers us 𝜆1
𝐵𝑂𝑆: 𝑡𝜃
𝜆𝑃𝑂(𝑆) = 𝑡𝜃𝜆
𝑂𝑆𝑡(𝑡),𝜃< 1  
W here 𝜆⋅
𝑃𝐹𝑆(𝑡) re prese nts t he hazar d at ti me 𝑡 a n d 𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he treat me nt gr o u ps M  (bi ntraf us p alfa ) a n d P  (place b o ). 
Tests will be c o nsi dere d as c o nfir mat or y if c o n diti o ns o n m ulti plicit y a dj ust me nts state d i n t he 
i ntr o d ucti o n of Secti o n 1 4  are f ulfille d.  
C o x’s Re gressi o n M o del  
T he treat me nt effect o n P F S will be e sti mate d usi n g a str atifie d C o x’s pr o p orti o nal hazar ds m o del 
f oll o wi n g t he met h o d ol o g y des cri be d i n Secti o n 1 4. 1. 1 . 
Met h o ds f or e v al u ati n g t he v ali dit y of m o del ass u m pti o ns  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 0 /1 0 8  
 
 
P ote ntial de part ure fr o m t he m o del ass u m pti o ns will be assesse d f oll o wi n g t he met h o d ol o g y 
descri be d i n Secti o n 1 4. 1. 1 . 
M ulti v ari a ble C o x Re gressi o n  
M ulti varia ble C o x re gressi o n a nal ysis  f or P F S will be carr i e d o ut t o assess a n d a dj ust t he treat me nt 
effect f or rele v a nt baseli ne fact ors of p ote ntial pr o g n ostic i m pact. It will be c o n d ucte d i n t he sa me 
wa y as des cri be d i n Secti o n 1 4. 1. 1 . 
1 4. 2. 2  
Se nsiti vit y A n al ysis f or P F S   
T he f oll o wi n g  t w o s e nsiti vit y a nal yses will be c o n d ucte d: 
•  P F S c o u nti n g all e v e nts ( P D a n d deat h) re gar dless of t he start of a ne w a nti ca ncer t hera p y a n d 
i g n ori n g t he n u m ber of missi n g e val ua ble t u m or assess me nts bef ore pr o gressi o n or deat h 
•  Mai n a nal ysis descri be d f or t he sec o n d ar y e n d p oi nt P F S  will als o be perf or me d o n t u m or 
res p o nses bas e d o n i n vesti gat or or I R C assess me nt acc or di n g t o Ta ble 7 . N o f or mal test will 
be perf or me d.  
•  T he meas ur e me nt of tr eat me nt effect o n P F S  stratifie d b y t he ra n d o mizati o n data will be 
re peat e d usi n g ra n d o mizati o n strata as s pecifie d a n d d oc u me nte d i n t he e C R F. 
T h ese se nsiti vit y a n al ys es will be s u p p orte d wit h Ka pla n -Mei er pl ots a n d partici pa nt -listi n gs. 
Pr o g ressi ve Dise ase b y I n vesti g at or vs I R C  
F or all partici pa nts wit h b ot h t u m or assess me nt per i n vesti gat or a n d I R C, a s u m mar y of t he I R C 
assess me nt vers us i n vesti gat or assess me n t will be pr o vi de d i ncl u di n g n u m b ers of c o nc or da nt a n d 
disc or da nt assess me nts as well as t he n u m ber of cases w here P D was assesse d at differe nt 
ti me p oi nts b y I R C a n d i n vesti gat or. T a ble 1 0  o utli nes t he p ossi ble o utc o mes b y i n vest i gat or a n d 
I R C.  
T a ble 1 0  
P ossi ble O utc o mes f or I n vesti g at or vs I R C  
 
I R C 
I n v e sti g at or 
 
P D  
N o P D  
P D  
a = a 1 + a 2 + a 3  
b  
N o P D  
c  
d  
a 1: n u m b er of a gr e e m e nt s o n ti mi n g a n d o c c urr e n c e of P D  
a 2: n u m b er of a gr e e m e nt s o n P D b ut i n v e sti g at or d e cl ar e s P D l at er t h a n I R C 
a 3: n u m b er of a gr e e m e nt s o n P D b ut i n v e sti g at or d e cl ar e s P D e arli er t h a n I R C  
N = a + b + c + d.  
T h e ti mi n g a gr e e m e nt of pr o gr e s si o n h a s t o b e d efi n e d a s a wi n d o w of 7 d a y s  
T he f oll o wi n g m eas ur es of a gree me nt a n d disc or da nce will be calc ulate d f or eac h treat me nt ar m: 
•  T otal e ve nt discre p a nc y rate: ( b +c) / N  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 1 /1 0 8  
 
 
•  T otal e ve nt a gree me nt rate: (a + d) / N  
•  Rate of u nc o nfir m e d i n vesti gat or P Ds: b / (a + b)  
•  Earl y Discre pa nc y Rat e ( E D R): (a 3 + b) / (a + b)  
•  Lat e Discre pa nc y R ate ( L D R): (a 2 +c) / (a 2 +a 3 + b +c)  
•  O verall Discre pa n c y Rat e: (a 2 +a 3 + b +c) / N  
T he E D R re pres e nts t he p ositi ve pre dicti ve v al u e of i n vesti gat or assess me nt a n d q ua ntifies t he 
fre q ue n c y wit h w hic h t he i n vesti gat or declares pr o gressi o n earlier t ha n I R C wit hi n eac h ar m as a 
pr o p orti o n of t he t otal n u m ber of i n vesti g at or-assesse d P Ds.  
T he L D R q ua ntifies t h e fre q ue nc y wit h w hic h t he i n vesti gat or d eclares pr o gressi o n later t ha n I R C 
as a pr o p orti o n of t he t ot al n u m ber of discre pa n cies wit hi n t he ar m.  
Disc or da nce metrics are calc ulate d f or eac h treat me nt ar m a n d, f or eac h  metric, t he differe nce i n 
disc or da nce bet wee n t he bi ntraf us p alfa  a n d place b o  ar ms is use d t o e val u ate p ote ntial bias. If t he 
disc or da nce is si milar acr oss t he treat me nt ar ms , t he n t his s u g gests t he a bse nce of e v al uati o n bias 
fa v ori n g a partic ul ar ar m. A ne gati ve differe ntial disc or da nce f or E D R a n d/ or a p ositi ve 
differe ntial disc or d a nce f or L D R ma y be i n dicati v e of i n vesti gat or e v al uati o n bias i n fa v or of t he 
bi ntraf us p  alfa ar m.  
1 4. 3  
O bje cti ve Res p o nse 
R ate 
A cc or di n g t o 
R E CI S T 
1. 1 
(Sec o n d ar y  E n d p oi nt)   
O bjecti ve R es p o nse R ate  ( O R R) 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 2 /1 0 8  
 
 
O R R is defi ne d as t he pr o p orti o n of partici pa nts h a vi n g a best o verall res p o nse of C R or  P R. F or 
c o nfir me d O R R, c o nfir m e d C R or P R will be use d.  
B est o verall res p o ns e  will be assesse d base d o n o verall res p o nses re p orte d at differe nt e val u ati o n 
ti me p oi nts fr o m ra n d o mizati o n u ntil t he first d oc u me nte d disease pr o gressi o n acc or di n g t o 
R E CI S T  1. 1 , ta ki n g re q uire me nts f or c o nfir mati o n i nt o acc o u nt as detail e d bel o w. O nl y t u m or 
assess me nts perf or m e d bef ore or at start of a n y s u bse q ue nt a ntica ncer t hera pies (see Secti o n 9. 8  
f or s u bse q ue nt a ntic a ncer t hera pi es t o b e c o nsi dere d) will be c o nsi dere d i n t he assess m e nt of best 
o verall res p o nse . Cli nical deteri or ati o n will n ot be c o nsi dere d as d o c u me nte d disease pr o gressi o n. 
B est o ver all res p o nse  b ase d o n c o nfir me d res p o nse s: 
•  C R = at least t w o deter mi nati o ns  of C R at least 4 wee ks a p art a n d b ef ore pr o gressi o n  
N ote: it is reas o na ble t o c o nsi der C R-N E -C R or C R -P R -C R as C R as l o n g as t he s ec o n d C R 
is at least 4 wee ks a p art t he first ti me p oi nt.  
•  P R = at least t w o deter mi nati o ns of P R or better ( P R f oll o we d b y P R  or P R f oll o we d b y C R) at 
least 4 wee ks a part a n d b ef ore pr o gressi o n (a n d n ot q ualif yi n g f or a C R)  
N ote: It is reas o na ble t o c o nsi der P R -N E -P R or P R -S D -P R as P R pr o vi de d  t he sec o n d P R is 
at least 4 wee ks a part t he first ti me p oi nt  
•  S D = at least o ne S D assess me nt ( or better) ≥ 6 wee ks after start date a n d bef ore pr o gressi o n 
(a n d n ot q ualif yi n g f or C R or P R) 
•  N o n -C R/ N o n -P D  = at le ast o ne n o n -C R/ n o n -P D assess me nt  ( or better) ≥ 6 wee ks aft er start 
date  a n d bef ore pr o gressi o n wit h n o meas ura ble disease  at baseli ne (a n d n ot q ualif yi n g  f or C R  
or P R ) 
N o n -C R/ n o n -P D is s pecific t o I R C ass ess me nt , i.e., it d oes n ot a p pl y f or  t he In v esti gat or 
assess me nt  as i n vesti gat or s h o ul d i ncl u de o nl y partici pa nts wit h meas ura ble dise ase at 
baseli ne  as per i ncl usi o n/e x cl usi o n criteria . 
•  P D = pr o gressi o n ≤ 1 2  wee ks after st art date (a n d n ot q ualif yi n g f or C R, P R, S D  or n o n -C R/ n o n -
P D ) 
•  N D = at least o ne N D assess me nt  
N ote: O verall res p o ns e is rate d as “ N o Disease” ( N D) w he n t he I R C is n ot a ble t o i d e ntif y 
a n y diseas e at baseli ne (t ar get or n o n -t ar get l esi o ns). N D is s pecifi c t o I R C assess me nt, i.e., 
it d oes n ot a p pl y f or t he In v esti gat or assess m e nt  as i n vesti gat or s h o ul d i ncl u de o nl y 
partici pa nts wit h meas ur a ble disease at baseli ne  as per i ncl usi o n/e xcl us i o n criteria. 
•  N E = all assess me nts are N E a n d/ or n o ( or n ot e v al ua ble) t u m or ass ess me nts o n -treat me nt, or 
partici pa nt d oes n ot meet a n y of t he res p o nses a b o ve  
B est o ver all res p o nse  b ase d o n u nc o nfir me d res p o nses:  
•  C R = at least o ne deter mi nati o n of C R  d oc u m e nte d bef ore pr o gressi o n  
•  P R = at least o ne deter mi nati o n of P R  d oc u me nte d bef ore pr o gressi o n  (a n d n ot q ualif yi n g f or 
a n C R ) 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 3 /1 0 8  
 
 
•  S D = at least o ne S D assess me nt ≥ 6 wee ks after start date a n d bef ore pr o gressi o n ( a n d n ot 
q ualif yi n g f or C R or P R ) 
•  N o n -C R/ N o n -P D = at least o ne n o n -C R/ n o n -P D assess me nt ≥ 6 wee ks after start date a n d b ef ore 
pr o gressi o n wit h n o meas ura ble diseas e ( a n d n ot q ualif yi n g f or C R  or P R ) 
N o n -C R/ n o n -P D is s pecific t o I R C ass ess me nt , i.e., it d oes n ot a p pl y f or  t he In v esti gat or 
assess me nt  as i n vesti gat or s h o ul d i ncl u de o nl y partici pa nts wit h meas ura ble dise ase at 
baseli ne as per i ncl usi o n/e x cl usi o n criteria.  
•  P D = pr o gressi o n ≤ 1 2 wee ks after st art date (a n d n ot q ualif yi n g f or C R, P R, S D or n o n -C R/ n o n -
P D)  
•  N D = at least o ne N D asse ss me nt  
N ote: O verall res p o ns e is rate d as “ N o Disease” ( N D) w he n t he I R C is n ot a ble t o i d e ntif y 
a n y diseas e at baseli ne (t ar get or n o n -t ar get l esi o ns). N D is s pecifi c t o I R C assess me nt, i.e., 
it d oes n ot a p pl y f or In v esti gat or ass ess me nt  as i n vesti gat or s h o ul d i ncl u de o nl y partici pa nts 
wit h meas ura ble disease at baseli ne as p er i ncl usi o n/e xcl usi o n criteria.  
•  N E = all assess me nts are N E or partici pa nt  has a missi n g ( or n ot e val ua ble) baseli ne t u m or 
assess me nt a n d/ or n o ( or n ot e val ua ble) t u m or assess me nts o n -treat me nt, or partici pa nt  d o es 
n ot meet a n y of t he res p o nse s a b o ve  
Dise ase C o ntr ol R ate  ( D C R) 
D C R is defi ne d as t he pr o p orti o n of partici pa nt s ha v i n g a best o verall res p o nse  of C R  or P R, S D  
or N o n -C R/ N o n -P D . F or c o nfir me d D C R, c o nfir me d C R or P R or S D or N o n -C R/ N o n -P D will be 
use d . 
1 4. 3. 1  
M ai n A n al ysis f or O R R   
Mai n a nal ysis f or O R R will be base d o n p artici p a nts’ t u m or res p o ns es eit her as assesse d b y t h e  
i n vesti gat or or b y t h e I R C acc or di n g t o t he r ule d efi ne d i n Ta ble 7 . 
N u m ber a n d perce nta ge of partici p a nt s wit h best o verall res p o nse  of c o nfir me d C R, P R, S D, n o n -
C R/ n o n -P D, P D,  N D a n d N E as well as  t he O R R  a n d t he D C R  will be ta b ulate d b y treat me nt ar m. 
T he O R R a n d D C R will be prese nt e d wit h a t w o -si de d 9 5 % CI usi n g t he Cl o p per-Pears o n met h o d 
(e x act CI f or a bi n o mial pr o p orti o n as c o m p ute d b y defa ult b y t he S A S F R E Q pr oce d ure usi n g t he 
E X A C T o pti o n).  
T he ass oci ati o n of tr eat m e nt effect a n d O R will be teste d b y t he g e neral ass o ciati o n statistic of t he 
C oc hra n -Ma nt el -Hae nszel test ( C M H) wit h t he ra n d o mizati o n strata ta ke n i nt o acc o u nt. T he n ull 
h y p ot hesis of n o ass ociati o n i n a n y of t he ra n d o mizati o n strata is teste d a gai nst t he alter nati ve, 
w hic h s pecifies t hat t here is a n ass ociati o n bet wee n treat me nt a n d t u m or res p o nse at least i n o ne 
ra n d o mizati o n strat u m. A  o ne -si de d C M H test will be perf or me d at a n o v erall  al p ha le vel  of 0. 0 2 5 . 
If t he st u d y is e x pa n de d i nt o P hase  III, testi n g will be perf or m e d as e x plai ne d i n t he i ntr o d ucti o n 
of Secti o n 8. 1 . 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 4 /1 0 8  
 
 
T he stratifie d o d ds rati o i n ter ms of c o nfir me d O R will als o be esti mate d al o n g wit h its 9 5 % CI t o 
assess t he treat me nt effect. T he o d ds rati o is defi ne d as t he o d ds of c o nfir me d O R wit h test 
treat me nt di vi de d b y t he o d ds of c o nfir me d O R wit h c o ntr ol treat me nt. T he Bresl o w-Da y test will 
be use d t o c h ec k t h e h o m o ge n eit y of t he o d ds rati o acr oss t he ra n d o mizati o n strata. It tests t he n ull 
h y p ot hesis t hat o d ds rati os i n all strata are e q ual a gai nst t he alter nati ve h y p ot hesis t hat t he o d ds 
rati o is differe nt i n at le ast o ne strat u m. 
I n case t he n ull h y p ot hesis of h o m o ge neit y of o d ds rati os acr oss strata is n ot rejecte d at t he al p ha 
le vel of 5 % t w o-si de d, t he c o m m o n o d ds rati o will be deter mi ne d usi n g t he Ma ntel -Hae nszel 
esti mate ( b y t h e F R E Q pr oce d ure usi n g C M H o pti o n i n S A S); if t he n ull h y p ot hesis of 
h o m o ge n eit y of o d ds rati o acr oss all strata is reject e d, t he o d ds rati o per str at u m will be calc ulate d 
wit h t he c orres p o n di n g e x act CI.  
T he i n di vi d ual perce nta ge of c ha n ge i n t he s u m of dia meter  of  all tar get lesi o ns (l o n gest di a meter 
f or n o n-n o d al lesi o ns a n d s h ort a xis f or n o d al tar get lesi o ns) si nce baseli ne f or eac h tr eat me nt ar m 
will be dis pla ye d o ver ti me o n a s pi der pl ot, t o get her wit h t he first o cc urre nce of ne w lesi o n , t he 
partici pa nt  off -treat me nt. T his s pi der pl ot will be pr o d uce d f or t he w h ole safet y r u n-i n a nal ysis set 
a n d it will be restricte d t o partici pa nts wit h P R o r better at a n y ti me d uri n g t h e st u d y  f or t he 
ra n do mize d a nal ys es . T he perce nt c h a n ge i n t he s u m of dia meters of all tar get lesi o ns bet wee n 
baseli ne a n d t he best p ost -baseli ne assess me nt (i.e. , l o west c ha n ge si n ce b aseli ne) f or eac h 
treat me nt ar m will als o b e dis pla ye d o n a waterfall gra p h.  
F or s pi der pl ots a n d waterfall pl ots , t he perce nt c ha n ge fr o m baseli ne i n t he s u m of dia meters of 
all tar get lesi o ns will be dis pla ye d f or vali d ti me p oi nt assess me nts o nl y. F or t he p ur p os e of t his 
a nal ysis, a v ali d ti me p oi nt assess me nt is defi ne d as a c o m p lete assess me nt of all tar get lesi o ns 
re p orte d at bas eli ne. F urt her, s plit a n d c oalesce d l esi o ns m ust  be  ta ke n i nt o acc o u nt a p pr o pri atel y 
t o deter mi ne if a ti me p oi nt assess me nt is vali d t o deri ve t he perce nt c ha n ge fr o m baseli ne i n t he 
s u m of dia meters. Al l s u m of dia meters s h o ul d b e use d, i ncl u di n g t he o nes be y o n d first P D (f or 
waterfall pl ot s, t he best p ost-baseli ne s u m of dia meters will be use d e v e n if occ urri n g be y o n d P D).  
F or w aterfall pl ot s, t he perce nt c ha n ge fr o m bas eli ne t o t he 6 -wee k assess me nt, a s well as t he 
perce nt c ha n ge fr o m bas eli ne t o t he best p ost -baseli ne s u m of dia meters , will be dis pla ye d f or eac h 
partici pa nt.  
Listi n g s of t u m or assess me nt will be pr o vi de d wit h t he f oll o wi n g i nf or mati o n: c o h ort/ pla n ne d ar m, 
partici pa nt  i de ntifier, a ge, sex, race, date of ra n d o mizati o n  ( date of first st u d y tr eat me nt 
a d mi nistrati o n  f or n o n-ra n d o mize d part), dat e of start of s u bs e q ue nt a ntica ncer  t hera p y, d ate of 
deat h w he n deat h occ urs, best o verall res p o nse  base d o n c o nfir me d a n d u nc o nfir me d res p o ns es , 
visit, date(s) of i ma gi n g, descri pti o n of tar get lesi o ns (size, site, t y pe, met h o d , s plit/ mer ge d, 
res p o nse), n o n-tar get lesi o ns (stat us, site, t y p e, met h o d, res p o nse), a n d ne w lesi o ns (site, t y p e, 
met h o d), s u m of lesi o n dia meters, perce nt c ha n ge i n tar get l esi o ns fr o m baseli ne, a n d o v erall 
res p o nse of partici pa nt . N ote t hat res p o nse of tar get a n d n o n-tar get lesi o ns is n ot a p plica ble at 
baseli ne.  
M ulti v ari a ble L o gistic Re gressi o n  
M ulti varia ble l o gistic re gressi o n a nal ysis will be perf or me d o n c o nfir me d b est o verall res p o nse  t o 
assess a n d a dj ust t he treat me nt effect f or rel e va nt baseli ne fact ors of p ote ntial pr o g n ostic i m pact. 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 5 /1 0 8  
 
 
T he s u b gr o u p vari a bles defi ne d i n Secti o n 8. 2  will be i ncl u de d i n t he m o del. A ste p wise sel ecti o n 
pr oce d ure will ser ve t o i de ntif y e x pla nat or y v aria bles of p ote ntial pr o g n ostic val ues a d diti o nal t o 
t he ra n d o mizati o n strata w hic h will be i ncl u de d i n all m o dels d uri n g t he selecti o n pr oce d ure. T he 
le vel of si g nifica n ce f or a n e x pla nat or y v aria ble to e nter t he m o del is set t o 0. 1 5 ( p -val ue of Sc ore 
test) a n d t he si g nifica n ce le vel f or re m o vi n g it is set t o 0. 4 0 ( p-val ue of Wal d test). O nce t his 
pr oce d ure st o ps, t he fact or 'treat me nt gr o u p' will be a d d e d t o t he l ast selecte d m o del i n or der t o 
e val uate t h e effect of treat me nt o n best o verall res p o nse  w he n a dj uste d f or t h e selecte d e x pla nat or y 
varia bles. T he o d d rati os of all selecte d e x pla nat or y vari a bles a n d of treat me nt effects will be 
re p orte d i ncl u di n g 2-si de d 9 5 % CI . N o i nteracti o ns will be c o nsi d ere d. P ost-baseli ne fact ors will 
n ot be c o nsi dere d f or t he m o del.  
N o n -e v al u a ble best o ver all res p o nse  
A s u m mar y t a ble of t he reas o ns f or n o n -e v al ua ble best o verall res p o nse  base d o n c o nfir me d 
res p o nses will be pr o vi de d b y ra n d o mize d ar m. T h e f oll o wi n g reas ons will be use d i n hi erarc hical 
or der:  
•  N o baseli ne ass ess me nt , i.e n o t u m or sca n rec or de d bef ore ra n d o mizati o n 
•  N o p ost -baseli ne ass ess me nts d ue t o deat h wit hi n 6 wee ks after start d ate  
•  N o p ost -baseli ne ass ess me nts d ue t o ot her reas o ns  
•  All p ost -baseli ne assess me nts ha ve o verall res p o nse ‘N o n -e val ua ble ’ 
•  Ne w a ntica ncer t hera p y starte d bef ore first e val ua ble p ost -baseli ne assess m e nt  
•  S D ( or better) of i ns uffici e nt d urati o n ( < 6 wee ks after start date  wit h o ut f urt her e val ua bl e t u m or 
assess me nt) 
N ote: special cases w here best o verall res p o nse  is N E d ue t o b ot h earl y S D a n d late P D will be 
classifie d i nt o t his cate g or y 
•  N o n -C R/ n o n -P D of i ns ufficie nt d urati o n ( < 6 wee ks after start d ate  wit h o ut f urt her e val u a ble 
t u m or assess me nt) (if a p pears i n t he dat a  
•  P D t o o late  (> 1 2 wee ks  after start dat e ) 
•   “ N ot deter mi ne d ” cat e g ories ma y be a d d e d, if a p plica ble  
A listi n g of reas o ns f or n o n -e val ua ble b est o verall res p o nse  base d o n c o nfir me d res p o nses will 
als o be create d i ncl u di n g: c o h ort/ pla n n e d ar m, partici pa nt i de ntifier, a ge, se x, race, dat e of 
ra n d o mizati o n (ra n d o mize d p hase o nl y), date of first a n d last d ose, date(s) of i ma gi n g, o verall 
res p o nse a n d t h e reas o n f or c o nfir me d b est o verall res p o nse  n o n -e val ua ble.  
1 4. 3. 2  
Se nsiti vit y A n al ysis f or O R R   
•  N u m ber a n d perce nta ge of partici pa nts wit h best o verall res p o nse  of u n c o nfir me d C R, P R, S D, 
n o n -C R/ n o n -P D, P D, N D a n d N E as well as t h e O R R a n d t h e D C R  b as e d o n u n c o nfir me d 
res p o nses will be ta b ulat e d b y tr eat me nt ar m. T he O R R a n d D C R will be prese nte d wit h a t w o -
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 6 /1 0 8  
 
 
si de d 9 5 % CI usi n g t he Cl o p per-Pears o n met h o d (e x act CI f or a bi n o mial pr o p orti o n as 
c o m p ute d b y d efa ult b y t he S A S F R E Q pr oce d ure usi n g t he E X A C T o pti o n).  
•  Mai n  a nal ysis descri be d f or t he s ec o n dar y e n d p oi nt O R R  base d o n c o nfir me d res p o nses  will 
als o be perf or me d o n t u m or res p o nses base d o n i n vesti gat or or I R C assess me nt acc or di n g t o 
Ta ble 7 . N o f or mal test will be perf or me d. 
o  I n a d diti o n, a s u m mar y of t he best o verall res p o nse  as a dj u dicate d b y I R C vers us 
I n v esti gat or assess me nt i ncl u di n g n u m bers of c o n c or da nt a n d disc or da nt assess me nts, 
a n d a listi n g of i nc o nsiste ncies will be pr o vi de d.  
•  T he meas ure me nt of str atifie d o d ds rati o i n ter ms of c o nfir me d O R will be re peate d usi n g 
ra n d o mizati o n strata as s pecifie d a n d d o c u me nte d i n t he e C R F. 
1 4. 4  
D ur ati o n of Res p o nse Acc or di n g t o R E CI S T 1. 1 (Sec o n d ar y 
E n d p oi nt)   
D ur ati o n of res p o nse ( D O R)  is defi ne d f or partici pa nt s wit h a c o nfir me d o bjecti ve res p o nse, as 
t he ti me fr o m first d o c u m e ntati o n of c o nfir me d o bj ecti ve res p o nse ( C R or P R  base d o n c o nfir me d 
res p o nses) t o t he d ate of first d oc u me ntati o n of o bjecti ve P D or deat h d ue t o a n y ca use w hic he v er 
occ urs first : 
D O R = ( dat e of P D or d eat h  or ce ns ori n g –  d ate of c o nfir me d o bjecti ve res p o nse + 1)/ 3 0. 4 3 7 5 
( m o nt hs). 
T he ce ns ori n g r ules f or D O R are as descri be d f or P F S  ( pri mar y defi niti o n in Ta ble 9 ) i n Secti o n 
1 4. 2 . 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 7 /1 0 8  
 
 
1 4. 4. 1  
M ai n A n al ysis f or D O R   
Pri mar y a nal ysis f or D O R will be bas e d o n p artici pa nts’ t u m or res p o nses eit her as assesse d b y t he  
i n vesti gat or or b y t h e I R C acc or di n g t o t he r ule d efi ne d i n Ta ble 7 . 
D O R of  C R/ P R  base d o n c o nfir me d  res p o nses acc or di n g t o R E CI S T 1. 1 will be descri b e d  b y 
treat me nt ar m. As C R/ P R  base d o n c o nfir me d res p o nses  i n v ol ves ha vi n g at least t w o o bjecti ve 
res p o nses, t he date of occ urre nce of t he first C R/ P R will be use d as t he d ate of o bjecti ve res p o ns e.  
T he a nal ysis of D O R will be perf or m e d wit h a Ka pla n -Mei er met h o d. Ka pla n -Mei er esti mates 
( pr o d uct-li mit esti mates) will be prese nte d b y treat me nt gr o u p t o get her wit h a s u m mar y of 
ass ociate d statistics i ncl u di n g t he me dia n D O R wit h t w o -si de d 9 5 % CIs. I n partic ular, D O R  rates 
wit h t heir t w o -si de d 9 5 % CIs at 3, 6, 9, 1 2 a n d 2 4 m o nt hs at least will be prese nte d, as well as t he 
n u m ber of partici pa nts at ris k a n d faile d. T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me yer a n d Cr o wle y  a n d the CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d 
a b o ve will be deri ve d usi n g t he l o g -l o g tr a nsf or mati o n acc or di n g t o Kal bfleisc h a n d Pre ntice  
(c o nft y pe =l o gl o g defa ult o pti o n i n S A S P R O C  LI F E T E S T) wit h bac k tr a nsf or mati o n t o a CI o n 
t he u ntra nsf or me d scale. T he esti mate of t he sta n d ar d err or will be c o m p ute d usi n g Gree n w o o d’s 
f or m ula. 
T he ti me t o a n d d urati o n of res p o nse per partici pa nt  ha vi n g a n  o bjecti v e res p o nse (i ncl u di n g 
dela ye d res p o nse, s ee S ecti o n 1 4. 1 0  bel o w)  b ase d o n c o nfir m e d res p o ns es  will be dis pla ye d i n 
s wi m mer gra p hs. Ka pl a n -Meier fi g ure s will als o be pr o vi de d.  
Listi n gs will be pr o vi de d wit h t he f oll o wi n g i nf or mati o n: pla n ne d ar m, partici pa nt  i de ntifier, a ge, 
se x, race, date of ra n d o mizati o n, date of first res p o nse, date of last t u m or assess me nt, ce ns ore d 
(yes/ n o ), date of e ve nt/ce ns ori n g, e v e nt/ce ns ori n g reas o n a n d  d urati o n of res p o nse.  
1 4. 4. 2  
Se nsiti v it y A n al ysis f or D O R   
•  Mai n a nal ysis des cri be d f or t he s ec o n dar y e n d p oi nt D O R will als o be p erf or me d fr o m t u m or 
res p o nses bas e d o n i n vesti gat or or I R C assess me nt acc or di n g t o Ta ble 7 . N o f or mal test will 
be perf or me d.  
•  Mai n a nal ysis des cri be d f or t he s ec o n dar y e n d p oi nt D O R will als o be p erf or me d fr o m t u m or 
res p o nses bas e d o n u nc o nfir me d res p o ns es f or b ot h i n vesti gat or a n d I R C. 
1 4. 5  
D ur a ble Res p o nse Acc o r di n g t o R E CI S T 1. 1 ( Sec o n d ar y 
E n d p oi nt)   
D ur a ble Res p o nse R ate ( D R R)  is defi n e d as t he n u m ber of partici pa nt s h a vi n g a D O R lasti n g > 
6 m o nt hs, o ut of t he t otal n u m ber of partici p a nts. 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 8 /1 0 8  
 
 
1 4. 5. 1  
M ai n A n al ysis f or D R R   
Mai n a nal ysis f or D R R will be base d o n p artici p a nts’ t u m or res p o ns es eit her as assesse d b y t h e 
i n vesti gat or or b y t h e I R C acc or di n g t o t he r ule d efi ne d i n Ta ble 7 . 
T he D R R will be pr o vi de d  per treat me nt ar m  wit h a t w o -si de d 9 5 % CI usi n g t he Cl o p per-Pears o n 
met h o d (e x act CI f or a bi n o mial pr o p orti o n as c o m p ute d b y defa ult b y t he F R E Q pr oce d ure usi n g 
t he E X A C T o pti o n).   
T he ass ociati o n bet w ee n D R R a n d treat me nt as well as t he ma g nit u de of t he treat me nt effect 
(stratifie d o d ds rati o o btai ne d fr o m C M H met h o d) will be assesse d usi n g t he sa me met h o d ol o g y 
as descri be d i n Secti o n 1 4. 3. 1 . 
1 4. 5. 2  
Se nsiti vit y A n al ysis f or D R R   
Mai n a nal ysis descri be d f or t he sec o n d ar y e n d p oi nt D R R will als o be perf or me d 
fr o m t u m or 
res p o nses bas e d o n i n vesti gat or or I R C ass ess me nt acc or di n g t o Ta ble 7 . N o f or mal test will be 
perf or me d.  
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
6 9 /1 0 8  
 
 
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 0 /1 0 8  
 
 
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 1 /1 0 8  
 
 
1 5  
S afet y A n al yses   
A n alysis set: S A F RI  / S A F  
T he  f oll o wi n g s u bsecti o ns i ncl u de s pecifi cati o ns f or s u m marizi n g s afet y e n d p oi nts t hat are 
c o m m o n acr oss cli nical st u dies s uc h as A E , la b orat or y tests a n d vital si g ns. 
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 2 /1 0 8  
 
 
1 5. 1  
A d verse E ve nts   
Treat me nt -e mer ge nt a d v erse e ve nts are t h ose e v e nts wit h o nset dates occ urri n g d uri n g t he o n -
treat me nt peri o d or if t he w orse ni n g of a n e ve nt is d uri n g t he o n-treat me nt peri o d. 
C ha n ges i n t o xicit y gra d e, seri o us ness or o utc o m e of A Es are rec or de d as se parate e ntri es i n t he 
e C R F wit h ass ociate d e n d a n d start dates (start date e q uals e n d date of pre vi o us e ntr y). S uc h e ntries 
re p orti n g t he sa me e ve nt i n s uc h i m me diatel y c o ns ec uti ve peri o ds will be c o nsi dere d as o ne e ve nt 
i n t he a nal ysis. T hese e v e nts will be ke pt as se parate rec or ds i n t he data base i n or der t o mai ntai n 
t he f ull detaile d hist or y of t he e ve nts. T he start date of t he i nitial rec or d i n t he se q ue nce is ta ke n 
as t he start dat e of t he e ntire e ve nt, si milarl y t he e n d date of t he l ast e ve nt i n t he se q ue nce is ta ke n 
as t he e n d date of t h e e ntire e ve nt. T h e o verall o utc o me of t he A E  is t he o ut c o me of t he last e ve nt 
i n t he se q ue nce. D urati o n of t he A E a n d t he T E A E fla g will be a dj uste d acc or di n gl y i n t he a nal ysis. 
All a nal yses descri be d  i n t his secti o n will be base d o n T E A Es , u nless ot her wise s pecifie d , a n d will 
be descri b e d b y treat me nt ar m.  T he A E listi n gs will i ncl u de al l A Es. A Es o utsi de t he o n -treat me nt 
peri o d ( pri or or after) will be fla g ge d i n listi n gs.  
I n c o m plete A E-relate d d ates will be ha n dle d as st ate d i n Secti o n 9. 9  (Ta bl e 6 ). 
D ose -li miti n g T o xicit y A d verse E ve nts  are t h os e A Es re p orte d o n t he “ A d verse E ve nt Details” 
e C R F pa ge wit h t he “Is t his a d verse e ve nt a d ose li miti n g t o xicit y” or “Is t his a d verse e ve nt a d ose 
li miti n g t o xicit y u p o n S M C re vie w? ” fiel ds tic ke d “ Yes”. 
Bi ntr af us p alf a/ pl ac e b o Rel ate d A d verse E ve nts  are t h ose A Es wit h relati o ns hi p t o bi ntraf us p 
alfa/ place b o  re p orte d b y t he I n v esti gat or as relate d (i.e., a ns wer t o t he q uesti o n “ Relati o ns hi p wit h 
st u d y treat me nt ” = “ Rel ate d” o n “ A d verse E v e nt Details” e C R F pa ge)  a n d t h ose of u n k n o w n 
relati o ns hi p (i.e., n o a ns wer t o t he q uesti o n “ Relati o ns hi p wit h M 7 8 2 4”).  
C he m ot her a p y Rel ate d A d verse E ve nts  are t h ose A Es wit h relati o ns hi p t o g e mcita bi ne or 
cis plati n defi ne d as f oll o ws:  
•  F or g e mcita bi ne re p ort e d b y t he I n vesti gat or as relate d (i.e., a ns w er t o t he q uesti o n 
“ Relati o ns hi p wit h Ge mcita bi ne ” = “ Relate d ” or “ missi n g” o n “ A d verse E v e nt Details” e C R F 
pa ge)  
•  F or cis plati n re p orte d b y t he I n v esti gat or as relate d (i.e., a ns wer t o t he q uesti o n “ Relati o ns hi p 
wit h Cis plati n ” = “ Relate d” or “ missi n g” o n “ A d verse E ve nt D etails” e C R F pa ge)  
Tre at me nt -rel ate d A d v erse E v e nts  are bi ntraf us p alfa/ place b o  a n d/ or c he m ot hera p y rel ate d 
a d verse e ve nts.  
Seri o us A d verse E ve nts are t h ose A Es re p orte d o n t he “ A d verse E v e nts Det ails”  e C R F pa ge, wit h 
t he “ Seri o us A d verse E v e nt” fiel d tic ke d “ Yes ”.  
A d verse E ve nts Le a di n g t o D ose Re d ucti o n of C he m ot her a p y are t h ose A Es lea di n g t o d ose 
re d ucti o n of g e m cita bi ne or cis plati n defi ne d as f oll o ws:   
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 3 /1 0 8  
 
 
•  F or g e mcita bi n e c o nsi der a ns wer t o t he q u esti o n “ Acti o n(s) ta ke n wit h Ge mcita bi ne” = “ D ose 
re d uce d ” o n “ A d v erse E ve nt Details” e C R F p a ge) 
•  F or cis plati n c o nsi der a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h Cis plati n” = “ D ose re d u ce d” 
o n “ A d vers e E ve nt D etails” e C R F pa ge)  
A d verse E ve nts Le a di n g t o Te m p or ar y Disc o nti n u ati o n  of Bi ntr af us p alf a/ pl ace b o  are t h ose 
A Es lea di n g t o te m p orar y disc o nti n uati o n of bi ntraf us p alf a/ place b o  (a ns wer t o t he q uesti o n 
“ Acti o n(s) ta ke n wit h St u d y treat me nt ” = “ Dr u g i nterr u pte d” o n “ A d verse E ve nt Details” e C R F 
pa ge).  
A d verse E ve nts Le a di n g t o Te m p or ar y Disc o nti n u ati o n of C he m ot her a p y  are t h ose A Es 
lea di n g t o te m p or ar y disc o nti n uati o n of ge mcita bi ne or cis plati n defi ne d as f oll o ws: 
•  F or ge mcita bi n e c o nsi der a ns wer t o t he q u esti o n “ Acti o n(s) ta ke n wit h Ge mcita bi ne” = “ Dr u g 
i nterr u pte d” o n “ A d vers e E ve nt Details” e C R F p a ge 
•  F or cis plati n c o nsi der a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h Cis plati n” = “ Dr u g 
i nterr u pte d” o n “ A d vers e E ve nt Details” e C R F p a ge 
A d verse E ve nts Le a di n g t o Per m a ne nt Disc o nti n u ati o n of Bi ntr af us p a lf a/ pl ace b o are t h os e 
A Es lea di n g t o per m a ne nt disc o nti n uati o n of bi ntraf us p alf a/ place b o  (i.e., a ns wer t o t he q u esti o n 
“ Acti o n(s) ta ke n wit h St u d y treat me nt ” = “ Dr u g wit h dra w n” o n “ A d verse E ve nt Details” e C R F 
pa ge).  
A d verse  E ve nts  Le a di n g  t o Per m a ne nt Dis c o nti n u ati o n  of C he m ot her a p y  are t h ose A Es 
lea di n g t o p er ma ne nt dis c o nti n uati o n of ge mcita bi ne or cis plati n  defi ne d as f oll o w s: 
•  F or ge mcita bi n e c o nsi der a ns wer t o t he q u esti o n “ Acti o n(s) ta ke n wit h Ge mcita bi ne” = “ Dr u g 
wit h dra w n ” o n “ A d vers e E ve nt Details”  e C R F p a ge  
•  F or cis plati n c o nsi der a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h Cis plati n” = “ Dr u g 
wit h dra w n ” o n “ A d vers e E ve nt Details” e C R F p a ge  
A d verse E v e nts L e a di n g t o D e at h  are t h ose  A Es lea di n g t o d eat h (as rec or de d o n t he “ A d verse 
E ve nt Details” e C R F pa ge, cha n ge i n gra d e = “ N o” a n d o utc o me = “ Fatal ”, or Gra d e = “ Gra de 5 
or deat h relat e d t o A E” or Seri o us a d v erse e v e nt = “ Yes ” a n d seri o us n ess criteria i ncl u de “ Res ults 
i n deat h”). 
A d verse E ve nts of S peci al I nterest are t h ose A Es i de ntifie d acc or di n g to a pre -s pecifie d s earc h 
list of Me d D R A Preferre d Ter ms ( P Ts). Cate g ories of A E SI i n cl u de: 
•  I nf usi o n-relat e d Reacti o ns (I R R s) 
•  I m m u ne-relat e d A d verse E ve nts (ir A E s) 
•  S ki n A E s p ossi bl y relate d t o tra nsf or mi n g gr o wt h fact or b eta (T G F -β ) i n hi biti o n 
•  A ne mia  
A ne mi a  e ve nts are t h ose A Es bel o n gi n g t o t he Me d D R A H L T A nae mias N E C, H L T A nae mias 
hae m ol ytic i m m u ne, H L T A nae mias hae m ol ytic N E C or P T = Hae m o gl o bi n decrease d.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 4 /1 0 8  
 
 
Blee di n g e ve nts  are t h ose A Es bel o n gi n g t o t he Me d D R A S M Q Hae m orr ha ge ter ms (e x cl u di n g 
la b orat or y terms) . 
1 5. 1. 1  
All A d verse E ve nts   
A d verse e v e nts will be s u m marize d b y w orst se v erit y (acc or di n g t o Nati o nal Ca ncer I nstit ute - 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts [ N CI -C T C A E]  v ersi o n 5. 0 ) per partici pa nt , 
usi n g  t he latest versi o n  of  Me d D R A , P T  as e ve nt cate g or y a n d Me d D R A pri mar y S O C b o d y ter m 
as B o d y S yste m cate g or y.   
U nless ot her wise state d , A Es  will be dis pla ye d i n ter ms of fre q ue n c y t a bles: P T s a n d pri mar y 
S O C s i n al p ha betical or d er.  
Eac h p artici pa nt will b e c o u nte d o nl y o n ce wit hi n eac h P T or S O C.  If a partici pa nt  e x perie n ce s 
m ore t ha n o n e A E wit hi n a P T or S O C f or t he sa me rec or di n g p eri o d, o nl y t he A E wit h t he 
str o n gest relati o ns hi p or t he w orst se v erit y, as a p pr o priate, will be i ncl u de d i n t he s u m maries of 
relati o ns hi p a n d se verit y. 
If a n a d v erse e ve nt is re p orte d f or a gi v e n partici p a nt m ore t ha n o nce d uri n g treat me nt, t he w orst 
se verit y a n d t he w orst relati o ns hi p t o st u d y treat me nt will be ta b ulate d. I n case a partici pa nt  ha d 
e ve nts wit h missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he n o n -missi n g gra des will be 
dis pla ye d.  
A ta ble prese nti n g t he o verall s u m mar y of A Es will be prese nte d i ncl u di n g t he fre q ue n c y ( n u m ber 
a n d perce nta ge) of partici pa nts wit hi n  eac h of t he f oll o wi n g cate g ories : 
•  T E A Es  
•  Treat me nt -relate d T E A Es 
•  Bi ntraf us p alfa/ place b o  relate d T E A Es  
•  C he m ot hera p y  rel ate d T E A Es  
•  Seri o us T E A Es  
•  Treat me nt -relate d s eri o us T E A Es 
•  Bi ntraf us p alfa/ place b o  relate d seri o us T E A Es  
•  C he m ot hera p y rel ate d seri o us T E A Es  
•  T E A Es N CI -C T C A E se v erit y gra de ( 3, 4)  
•  Treat me nt -relate d T E A Es N CI-C T C A E s e verit y gra de ( 3, 4)  
•  Bi ntraf us p alfa/ place b o  relate d T E A Es N CI -C T C A E se verit y gra de ( 3, 4)  
•  C he m ot hera p y rel ate d T E A Es N CI -C T C A E se verit y gr a de (3, 4)  
•  T E A Es lea di n g t o deat h  
•  Treat me nt -relate d T E A Es lea di n g t o deat h 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 5 /1 0 8  
 
 
•  Bi ntraf us p alfa/ place b o  relate d T E A Es lea di n g t o deat h 
•  C he m ot hera p y rel ate d T E A Es lea di n g t o deat h  
•  A E SI s a n d b i ntraf us p alfa/ place b o relate d A ESI :  
o  I R Rs (see S ecti o n   1 5. 2. 5. 1  f or defi niti o n) 
o  ir A Es (see S ecti o n 1 5. 2. 5. 2  f or defi niti o n) 
o  T G F -β i n hi biti o n me diate d s ki n a d verse e ve nts  
o  A ne mia  
•  T E A E s, blee di n g e v e nts (see Secti o n 1 5. 1  f or defi niti o n) 
•  Bi ntraf us p alfa/ place b o relate d T E A Es, blee di n g e ve nts  
•   C he m ot hera p y rel ate d T E A Es, blee di n g e ve nts  
 Fre q u e nc y t a bles f or T E A Es c orres p o n di n g t o eac h cate g or y i n t he o v er vi e w ta ble a b o v e will be 
pr o vi de d b y:  
•  Me d D R A pri mar y S O C ( or dere d al p ha beticall y) a n d P T ( or dere d al p ha beticall y), (e x ce pt f or 
A E SI ) 
T E A E s, treat me nt-relate d T E A Es, bi ntraf us p alfa/ place b o -rel ate d T E A Es  a n d c he m ot hera p y-
relate d T E A E s will  als o be s u m marize d  b y w orst gra de , a n d t he m ost fre q ue nt P T  (at least 5 %) 
will  be prese nt e d gra p hic all y  b y w orst gra de a n d P T  wit h bar c hart fi g ures.  
Re q uire me nt s f or Cli nic altri als. g o v a n d E u dr a C T 
S u m mar y ta ble f or n o n -s eri o us T E A Es e x cl u di n g S A Es a p pl yi n g fre q ue nc y t hres h ol d of 5 % will 
be pr o vi de d.  
Listi n gs of a d v erse e ve nt s will c o ntai n t he f oll o wi n g i nf or m ati o n: c o h ort/ pla n ne d ar m, partici pa nt  
i de ntifier, a ge, se x, race, dates of first a n d l ast a d mi nistrati o ns  of st u d y treat me nt, P T , re p ort e d 
ter m f or t he A E, start date, e n d date, d urati o n of A E (i n da ys), d a y rel ati ve t o t he first i nf usi o n, 
da y relati ve  t o t he m ost rece nt i nf usi o n pri or t o A E o nset, relati o ns hi p t o st u d y treat me nt, t o xicit y 
gra de, acti o n(s) ta ke n, o utc o me, seri o us n ess ( yes/ n o ), A E SI i nf usi o n-relate d (yes/ n o ), A E SI 
i m m u ne-relate d (yes/ n o ), T G F -β i n hi biti o n me diate d s ki n A E SI ( yes/ n o ), a nemia A E SI ( yes/ n o ).  
T he f oll o wi n g listi n gs will be pr o vi de d  wit h t he rele va nt i nf or mati o n : 
•  Listi n g of all A E s ( w h et h er treat me nt-e mer ge nt or n ot) . T E A Es will be fla g ge d. 
•  Listi n g of T E A Es . 
•  Listi n g of n o n -T E A E s f or A Es occ urri n g after e nr oll me nt ( date of first si g nat ure of i nf or me d 
c o nse nt/ date of first si g n at ure of first i nf or me d c o nse nt) b ut pri or t o t he first d ose of st u d y 
treat me nt.   
•  Listi n g of A E s wit h o nset or w orse ni n g aft er t he o n -treat me nt peri o d. 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 6 /1 0 8  
 
 
E v al u ati o n of P ote nti al Effect of A D A o n S afet y of B i ntr af us p alf a 
T he ta ble pr o vi di n g o verall s u m mar y of A Es , as descri be d a b o ve will als o be pr o vi de d b y A D A 
stat us (e ver p ositi ve, ne v er p ositi ve). 
Listi n gs of all A Es a n d all I R Rs f or e ver -p ositi ve A D A partici pa nts ( pre-e xisti n g, tra nsie nt 
treat me nt-e mer ge nt, persiste nt -treat me nt e mer ge nt) 
will be pre pare d i ncl u di n g partici pa nt 
i de ntifier a n d s h o wi n g t h e date(s) of t he p ositi ve A D A res ult t o get h er wit h t he A Es or I R Rs. F or 
t he A Es a n d I R Rs, start a n d st o p date will be s h o w n al o n g wit h gra de. A d verse e ve nts rec or de d 
d uri n g t he peri o d of  t w o wee ks pri or t o t he p ositi ve A D A val ue u ntil t w o wee ks after t he p ositi ve 
A D A val ue will be fla g ge d.  
E v al u ati o n of C O VI D -1 9 effects o n A Es  
T he direct effect  of C O VI D -1 9 f or A Es will be assesse d b y mea ns of:  
•  A n o ver vie w ta ble of treat me nt -e mer ge nt A Es ass ociate d t o C O VI D -1 9 b y Me d D R A pri mar y 
S O C, hi g h le vel gr o u p ter ms ( H L G T), hi g h le vel ter ms ( H L T) a n d P Ts ( or dere d 
al p ha beticall y).  
•  A listi n g of C O VI D -1 9 relate d A Es. T he f oll o wi n g i nf o r m ati o n will be pr o vi de d: 
o  Partici pa nt  I D, c o u ntr y, a ge, s e x, race 
o  Date of first, last treat me nt wit h st u d y dr u g  
o  C O VI D -1 9 -ass ociate d A E start date ( da y), C O VI D -1 9 ass ociat e d A E st o p date ( da y)  
o  A E preferre d ter m, ver bati m  
o  T o xicit y gra de  
o  Seri o us ness  
o  Relati o ns hi p t o treat me nt  
o  Acti o n ta ke n  
o  O utc o me  
T he C O VI D -1 9 relate d A Es will be i de ntifie d as s pecifie d i n t he “ C O VI D -1 9 Data a n d Re p orti n g 
f or Merc k O n g oi n g St u dies ma na ge d b y I Q VI A” d oc u me nt versi o n 1. 1. 
T he o ver vie w ta bl e will be pr o vi de d if m ore t ha n 3 treat me nt-e mer ge nt A Es will be o bser ve d i n 
t he a nal ysis p o p ulati o n. 
1 5. 1. 2  
A d verse 
E ve nts 
Le a di n g 
t o Disc o nti n u ati o n  of 
St u d y 
Tre at me nt   
Fre q u e nc y ta bles s u m marizi n g t he f oll o wi n g acti o n s ta ke n wit h st u d y treat me nt will be prese nte d 
b y P T a n d pri mar y S O C i n al p ha betical or d er:  
•  T E A Es lea di n g t o te m p orar y dr u g i nterr u pti o n  (at least o ne of t he st u d y treat me nts) 
•  Bi ntraf us p alfa/ place b o  relate d T E A Es lea di n g t o te m p orar y dr u g i nterr u pti o n 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 7 /1 0 8  
 
 
•  C he m ot hera p y rel ate d T E A Es lea di n g t o te m p orar y dr u g i nterr u pti o n  
•  T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  ( of at least o ne of t he st u d y tr eat me nts) 
•  Bi ntraf us p alfa/ place b o  relate d T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n 
•  C he m ot hera p y rel ate d T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  
•  T E A Es lea di n g t o i nf usi o n rate re d ucti o n  ( of at least o ne of t he st u d y tr eat m e nts) 
•  Treat me nt relate d T E A Es lea di n g t o i nf usi o n rate re d ucti o n 
•  T E A Es lea di n g t o d ose  re d ucti o ns ( of at least o ne of t he c he m ot hera p y re gi me ns) 
•  C he m ot hera p y rel ate d T E A Es lea di n g  t o d ose  re d ucti o ns 
I n a d diti o n, t he i nci de nces f or a b o ve ite ms will be s u m marize d i n a n o ver vie w ta ble. 
A listi n g of T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n will als o be pr o vi de d wit h t he 
rele va nt i nf or m ati o n. 
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 5. 2. 1  
De at hs   
All deat hs, deat hs wit hi n 3 0 da ys aft er t he last d os e of st u d y tr eat me nt, deat h wit hi n 6 0 da ys aft er 
t he first d ose of st u d y tr eat me nt (f or all partici pa nt s, t he first d ose will be t he first d os e of t he a n y 
st u d y treat me nt) as well as t he pri mar y reas o n f or deat h will be ta b ulat e d base d o n i nf or mati o n 
fr o m t he “ D eat h” e C R F pa ges. 
T he f oll o wi n g s u m maries will be pr o vi de d:  
•  N u m ber of deat hs  
•  N u m ber of deat hs wit hi n 3 0 da ys after l ast d ose of st u d y treat me nt  
•  N u m ber of deat hs wit hi n 6 0  da ys after first d ose of st u d y treat me nt  
•  Pri mar y reas o n f or d eat h   
o  Pr o gressi ve disease a n d/ or disease relate d c o n diti o n  
o  E ve nt u nrelate d t o st u d y treat me nt  
o  E ve n t relate d t o st u d y treat me nt 
o  U n k n o w n  
I n a d diti o n, date a n d ca use of d eat h will be pr o vi de d i n a n i n di vi d ual p artici pa nt data listi n g 
t o get her wit h t he f oll o wi n g i nf or m ati o n: c o h ort/ra n d o mize d ar m, partici p a nt  i de ntifier, a n al ysis 
sets t o w hic h t he partici pa nt bel o n gs t o, a ge, se x, race, date s of  first/last d oses of  st u d y tr eat me nt, 
n u m ber of i nf usi o ns, da y relati ve t o t he first a n d t he last i nf usi o n, a ut o ps y (yes/ n o/ u n k n o w n ), A Es 
wit h fatal o utc o me ( list P Ts  of A Es wit h o u tc o me = Fat al, as well as Gra de 5  A Es  or Seri o us A Es 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 8 /1 0 8  
 
 
res ulti n g i n d eat h), fla g f or deat h wit hi n 3 0 da ys of last d ose of st u d y treat me nt a n d f la g f or d eat h 
wit hi n 6 0 da ys of first d ose of st u d y tr eat me nt.  
1 5. 2. 2  
Seri o us A d verse E ve nts   
T he n u m ber of p artici pa nt s wit h S A Es will be descri be d b y S O C a n d P T: 
•  S A Es  
•  Treat me nt -relate d S A Es  
•  Bi ntraf us p alfa/ place b o -relate d S A Es 
•  C he m ot hera p y -relate d S A Es 
Bar c harts pre s e nti n g S A Es, treat me nt-relate d S A Es, bi ntraf us p alfa/ place b o -rel ate d S A Es a n d 
c he m ot hera p y-rel ate d S A Es of t he m ost fre q ue nt P T (at least 5 %) will be dis pla ye d b y w orst gra de 
a n d P T. 
A l isti n g of S A Es will als o be pr o vi de d (see Secti o n 1 5. 1. 1 ).  
1 5. 2. 3  
D ose -li miti n g T o xicit y ( Pri m ar y E n d p oi nt S afet y R u n -i n)  
Criteria t o defi n e D L T are s pecifie d i n pr ot oc ol secti o n 6. 6. 2.  D L T will o nl y be defi n e d i n t he 
o pe n -la bel safet y r u n-i n p hase. 
A ta ble of t he occ urre nce of D L T A E  ( d efi ne d i n Secti o n 1 5. 1 ) will be pr o vi de d i ncl u di n g: 
•  N u m ber a n d perce nta ge of partici pa nts  w h o e x perie nce d a D L T d uri n g t h e D L T e val uati o n 
peri o d  per i n vesti gat or a n d per S M C  
•  N u m ber of D L Ts per partici pa nt e x perie nce d d uri n g t h e D L T e v al uati o n p eri o d ( 1 / 2 / ≥3)  p er 
i n vesti gat or a n d per S M C 
•  D L T e x perie n ce d d uri n g t he D L T e val u ati o n peri o d per i n vesti gat or a n d per S M C b y S O C  a n d 
P T  base d o n t he latest a v aila ble Me d D R A versi o n.  
A listi n g of D L Ts will als o be pr o vi de d wit h t he rele va nt i nf or mati o n (s ee  Secti o n 1 5. 1. 1 ).  
1 5. 2. 4  
Blee di n g E ve nts   
Blee di n g e v e nts are d efi n e d  i n Secti o n 1 5. 1 . Blee di n g e v e nts a n d trial dr u g relate d blee di n g e v e nts  
(treat me nt-relate d, bi ntraf us p alf a/ place b o -relat e d a n d c h e m ot hera p y-relat e d) will be s u m marize d 
i n a fre q ue nc y ta ble pres e nti n g S O C a n d P T s orte d b y al p ha betical or der. T he w orst gra de per 
partici pa nt, per S O C , a n d per P T will be re p ort e d:   
•  A n y gra de (i ncl u di n g missi n g gra d e)    
•  Gra de 1  
•  Gra de 2  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
7 9 /1 0 8  
 
 
•  Gra de 3  
•  Gra de 4  
•  Gra de 5  
1 5. 2. 5  
A d verse E ve nt s of S peci al I nterest   
1 5. 2. 5. 1  
I nf usi o n-Rel ate d  
Re acti o n  
i ncl u di n g 
I m me di ate 
H y perse nsiti vit y   
I R Rs are defi ned as a d v erse e v e nts wit h P Ts acc or di n g t o a pre -s pecifie d Me d D R A searc h list, 
a n d are di vi de d i nt o t w o s u bcate g ories: “ Reacti o ns” a n d “ S i g ns a n d s y m pt o ms” base d o n t he 
te m p oral relati o ns hi p bet wee n t he d a y of t he i nf usi o n a n d o nset of t he e v e nt : 
Re acti o ns of I R R s: s h o ul d be c o nsi dere d w he n t h e o nset is o n t he da y of i nf usi o n ( d uri n g or after 
t he i nf usi o n if ti mi n g relate d t o t he i nf usi o n is a vaila ble) or t he d a y aft er t he i nf usi o n (irres pecti ve 
of res ol uti o n date) f or a n y i nf usi o n -rel ate d reacti o n, dr u g h y perse nsiti vit y, a na p h ylactic reacti o n, 
h y perse nsiti vit y a n d/ or T y p e  1 h y p erse nsiti vit y.  
Si g ns a n d s y m pt o ms of I R Rs a n d h y perse nsiti vit y/ aller gic re a cti o ns:  s h o ul d be c o nsi dere d 
w he n t he o nset is o n t he da y of i nf usi o n ( d uri n g or after t he i nf usi o n  if ti mi n g rel ate d t o t he i nf usi o n 
is a vaila ble) a n d res ol ve d c o m pletel y, wit h t he e n d date o n t he s a me da y of t he i nf usi o n or t he d a y 
after f or a n y of t he f oll o wi n g: p yre xia, c hills, fl us hi n g, h y p ote nsi o n, d ys p nea, w heezi n g, bac k pai n, 
a b d o mi nal pai n a n d urticaria .  
N ote: all i nf usi o ns (i .e., of bi ntraf us p alf a / place b o a n d c he m ot hera pies) h a v e t o be c o nsi dere d.  
I R Rs, o verall a n d b y s u b cate g ories, will be s u m marize d b y t he f oll o wi n g v aria bles: 
•  N u m ber of partici pa nt s wit h at least o ne I R R b y t he w orst  N CI -C T C A E  t o xicit y gra de ( gra d e 
1/ gra d e 2/ gra d e 3/ gra d e 4/ gra de 5/ missi n g gra de)  
•  N u m ber of partici pa nt s wit h I R R lea di n g t o per ma ne nt treat me nt disc o nti n uati o n of eac h st u d y 
treat me nts 
•  Ti me relate d t o first o nset (i nf usi o n 1/ i nf usi o n 2/ i nf usi o n 3/ i nf usi o n 4 or later) of eac h st u d y 
treat me nt. T he e ve nts will be assi g ne d t o t he act ual dr u g i nf usi o ns t hat t he partici pa nt recei ve d, 
n ot t o t he pla n ne d dates. A n I R R is assi g ne d t o a dr u g i nf usi o n if its o nset is o n t he sa me dat e 
( b ut n ot bef ore d osi n g w he n ti mi n g relat e d t o t he i nf usi o n is a vaila ble) or t h e da y f oll o wi n g t he 
dr u g i nf usi o n.  
A fre q u e nc y ta ble of I R R A Es b y w orst gra d e, S O C, a n d P T will als o be pr o vi de d.  
A listi n g of I R Rs will be pr o vi de d wit h t he rele va nt i nf or mati o n (see Se cti o n 1 5. 1. 1 ). O ne 
a d diti o nal listi n g will dis pla y t he st u d y dr u g a d mi nistrati o n details t o get her wit h t he I R R i ncl u di n g 
a d mi nistrati o n date ( da y) /ti me, reas o n f or m o dificati o n, t y pe of m o dificati o n, m o dificati o n start 
ti me, use of pre-m e dicati o n, I R R A E P T, I R R A E gra de, I R R A E start d a y /  st o p da y, a n d I R R A E 
ti mi n g relate d t o i nf usi o n (if a vaila ble).  
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824)      1L BTC Phase II/III Gemcitabine Plus Cisplatin With or Without 
Bintrafusp alfa 
MS200647_0055  
 
 
 
                                                              Version 4  
 
 
 
80/108 
 
 
15.2.5.2 
Immune-related Adverse Events  
irAEs will be identified programmatically. AEs which satisfy all the following criteria will be 
flagged as immune-related: 
• The AE PT matches a PT on the list of pre-selected MedDRA terms. 
• The AE onset or worsening occurs after the first bintrafusp alfa/placebo infusion and no more 
than 90 days after last bintrafusp alfa/placebo dose, or to the earliest date of subsequent 
anticancer therapy minus 1 day, whichever occurs first, unless otherwise stated. 
• On the “AE” eCRF page, the question “Were corticosteroids, Immunosuppressants, hormonal 
therapy (e.g. Thyroid) or Insulin applied?” has the answer “Yes” selected. 
• On the “imAE SPECIFIC QUESTIONS” eCRF page, either: 
1. The question “Does any of the following provide a clear etiology for the event, other than 
immune related AE?” has the answer “No” selected, indicating that the AE is not 
attributable to underlying cancer disease/PD, prior or concomitant medications/procedures, 
nor another medical condition such as an infection or pre-existing disease. 
OR  
2. The “imAE SPECIFIC QUESTIONS” eCRF page indicates that a biopsy was performed 
and the question “Is the histopathology/biopsy consistent with an immune-mediated 
event?” has the answer “Yes” selected. 
Where criteria (1) through (3) are met, and entries for condition (4) are missing, the following 
rules will be applied:  
• If the answer to “Does any of the following provide a clear etiology for the event, other than 
immune related AE?” (4a) is missing, the event will be considered as irAE (irrespective of 
biopsy results).  
• If the answer to “Is the histopathology/biopsy consistent with an immune-mediated event?” 
(4b) is missing, or if no biopsy was performed, and condition (4a) is not satisfied, i.e., “Yes” is 
selected (i.e., at least one (clear) etiology of the event is provided) as the answer to the question 
“Does any of the following provide a clear etiology for the event, other than immune related 
AE?”, the event will be considered as a non-irAE. 
PTs will be compiled into categories (subcategories): Immune-related rash, Immune-related 
colitis, Immune-related pneumonitis, Immune-related hepatitis, Immune-related nephritis and 
renal dysfunction, Immune-related endocrinopathies (adrenal insufficiency, hypogonadism, 
pituitary dysfunction, Type 1 diabetes mellitus, thyroid disorders), and Other immune-related 
adverse events (Anemia, Encephalitis, GVHD, Guillain-Barre Syndrome, Myasthenic syndrome, 
Myocarditis, Myositis, Neurologic events, Pancreatitis, Uveitis, Vasculitis, Other). PTs belonging 
to the category “Immune related endocrinopathies – Thyroid disorders” will also be compiled into 
sub-subcategories: Hyperthyroidism, Hypothyroidism, Thyroiditis. 
irAEs will be summarized by the following variables: 
• Any irAEs 
Global Version ID: 78691_4104630_4852608


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 1 /1 0 8  
 
 
•  ir A Es b y t h e w orst gra d e 
•  ir A Es lea di n g t o per ma n e nt treat me nt disc o nti n uati o n of eac h st u d y treat me nts  
•  Seri o us ir A Es  
A fre q ue n c y ta ble of ir A Es b y 
w orst gra de, 
cate g or y, s u bcate g or y (f or im m u ne -relat e d 
e n d ocri n o pat hies  a n d ot her i m m u ne -relate d a d v erse e ve nts), s u b-s u bcate g or y (f or im m u ne -relate d 
e n d ocri n o pat hies –  t h yr oi d dis or ders) a n d P T will als o be pr o vi de d.  
A listi n g of ir A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n , i ncl u di n g a d diti o nal 
i nter ve nti o ns f or ir A Es (e. g. bi o psies, s ur gical pr oce d ures, me dical pr oce d ures) (see Sect i o n 
1 5. 1. 1 ). 
1 5. 2. 5. 3  
T G F -β i n hi biti o n me di ate d s ki n a d verse e ve nts   
T o i de ntif y p ote ntial s ki n A E s p ossi bl y rel ate d t o T G F -β i n hi biti o n, Me d D R A P T q ueries will be 
use d t o searc h f or s ki n A Es of i nterest i n t he cli nical data base. A listi n g c o ntai ni n g t hes e pre -
s pecifie d P T searc h ter ms will be ge nerate d. P Ts will be c o m pile d i nt o  t w o cate g ories: Narr o w 
defi niti o n,  a n d Br oa d defi niti o n:  
N arr o w  defi niti o n : 
•  Kerat oa ca nt h o ma  
•  S q ua m o us cell carci n o ma of s ki n  
Br o a d defi niti o n h as a d diti o n al P Ts : 
•  H y p er kerat osis  
•  Acti nic kerat osis  
•  Basal cell carci n o ma  
•  Li p s q ua m o us cell carci n o ma  
•  B o we n´s disease  
F urt her details (e. g. Me d D R A P T q ueries ) are re g ularl y u p date d b ase d o n t he c urre nt M e d D R A 
versi o n.  
T he o verall s u m mar y of s ki n T E A E will i ncl u de t he f oll o wi n g cate g ories f or narr o w a n d br oa d 
defi niti o n:  
•  All s ki n T E A E s 
•  All s ki n T E A E s b y w orst gra de  
•  S ki n T E A E s lea di n g t o p er ma ne nt treat me nt disc onti n uati o n  of eac h st u d y treat me nt  
•  Seri o us s ki n T E A Es  
Fre q u e nc y ta bl e f or s ki n T E A Es b y w orst gra de will be pr o vi de d b y Me d D R A P Ts (i ncl u di n g b ot h 
narr o w a n d br oa d d efi niti o n P Ts).  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 2 /1 0 8  
 
 
A listi n g of s ki n A E s will als o be pr o vi de d . T his listi n g will s pecificall y i ncl u de, f or t he A Es 
i de ntifie d fr o m t he P T list, t he n u m ber of lesi o ns, if a bi o ps y or a n e x cisi o n was d o ne a n d if it 
c o nfir me d t he dia g n osis, a n d t he l ocati o n f or eac h lesi o n c o mi n g fr o m e C R F pa ge “ T G F β 
M E DI A T E D S KI N R E A C TI O N”  if a v aila ble. 
1 5. 2. 5. 4  
A ne mi a   
A ne mia e v e nts are defi ne d i n Secti o n 1 5. 1 . A ne mia e ve nts a n d trial dr u g relate d a ne mia e ve nts 
(treat me nt-relate d, bi ntraf us p alf a/ place bo -relat e d a n d c h e m ot hera p y-relat e d) will be s u m marize d 
i n a fre q ue nc y ta ble pres e nti n g S O C a n d P T s orte d b y al p ha betical or der. T he w orst gra de per 
partici pa nt, per S O C, a n d per P T will be re p orte d.  A ta ble dis pla yi n g t h e o verall s u m mar y of  
A ne mia  A Es b y treat me nt ar m will be  als o prese nt e d . 
A listi n g of a n e mia a d v erse e ve nt will be pr o vi de d wit h t he rele va nt i nf or mati o n (see Secti o n 
1 5. 1. 1 ).  
 De dicate d listi n gs m a y als o be gi ve n:  
•  T E A E  
ane mia ≥ gra d e 3  
•  Seri o us T E A E a ne mia wit h ≥ gra d e 3   
1 5. 2. 6  
T hree -tier A p pr o ac h t o S u m m arizi n g a n d A n al yzi n g A d verse 
E ve nts   
T he 3 -tier a p pr oac h is a s yste matic wa y t o s u m marize a n d a n al yze a d v erse e ve nts i n cli nical 
st u dies. A Es are cate g oriz e d i n differe nt tiers a n d a nal yze d usi n g differe nt le vels of statistical 
a nal ysis. All a n al ys es will be perf or m e d o n T E A Es  o nl y.  
T he 3 -tier a p pr oac h will be perf or me d o nl y if t he st u d y is e x pa n de d i n P hase  III. 
Ris k Me as u res  
T he f oll o wi n g statistics will be pr o vi de d t o  s u m marize safet y data: 
•  Cr u de R ate : is cal c ulat e d as t he n u m b er of partici pa nts wit h  a s pecific A E o ut of t he t otal 
n u m ber of partici p a nts at ris k e x presse d as perce nt a ge.  
•  E x p os ure A dj uste d I nci de nce R ate ( E A I R): is defi ne d as t he n u m ber of partici pa nts wit h a 
s pecific A E o ut of t h e t otal e x p os ure-ti me a m o n g t he partici pa nts i n t he tr eat me nt ar m at ris k 
of t he i nitial occ urre nce of t he e ve nt. If a partici p a nt has m ulti ple e ve nts, t he e x p os ure peri o d 
of t he fir st e ve nt will be use d. F or a partici pa nt wit h n o e ve nt, t h e e x p os ure peri o d will be 
ce ns ore d at t he last f oll o w -u p ti me f or t he A E s u m marizati o n peri o d. E AI R will be meas ure d 
i n 1 0 0 partici pa nt years, u nless a differe nt pr o vi des a m ore reas o n a ble n u m ber of  di gits f or 
re p orti n g p ur p ose.  
Tier 1, 2, a n d 3 Ide ntific ati o ns  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 3 /1 0 8  
 
 
All A Es will be classifi e d i nt o Tier 2 or Tier 3 b ase d o n t he R ule -of -4. If t here are 4 or m ore 
partici pa nts wit h t he re p orte d preferre d ter m i n a n y treat me nt gr o u p t hat preferre d ter m will be 
i ncl u de d i n Tier 2. Ot her wise it will be i ncl u de d i n Tier 3. 
F urt her t o t his, Tier 1 A Es will be i de ntifie d fr o m a list of pre-selecte d Me d D R A ter ms ( usi n g t he 
latest versi o n of M e d D R A a vaila ble). I n case t hese e ve nts f ulfill t he R ule-of -4, Tier 1 a nal y sis 
met h o ds will be use d. Ot her wise, a nal yses will be d o ne acc or di n g t o Tier  3. T he f oll o wi n g list of 
pre -sele cte d c o m p osite ter ms base d o n s pecifie d Me d D R A q ueries will be use d : 
•  I m m u ne-relat e d a d verse e ve nts 
o  I m m u ne-relat e d p ne u m o nitis 
o  I m m u ne-relat e d c olitis 
o  I m m u ne-relat e d he patitis 
o  I m m u ne-relat e d e n d ocri n o pat hies 
▪ T h yr oi d dis or d ers  
• 
H y p ot h yr oi dis m  
• 
H y p ert h yr oi dis m  
• 
T h yr oi ditis  
▪ A dre nal i ns uffi cie nc y  
▪ T y pe 1 Dia betes M ellit us  
▪ Pit uitar y d ysf u ncti o n  
▪ H y p o g o n a dis m  
o  I m m u ne-relat e d ne p hritis a n d re nal d ysf u ncti o n 
o  I m m u ne-relat e d ras h 
o  Ot her i m m u ne -rel ate d a d verse e v e nts 
 
•  I nf usi o n-relat e d reacti o ns 
o  Reacti o ns  
o  Si g ns a n d S y m pt o ms  
•  T G F -β  i n hi biti o n me diate d s ki n reacti o ns  
•  A ne mia , as defi ne d i n S ecti o n 1 5. 2. 5. 4  
•  Blee di n g a d v erse e ve nts  
•  I m paire d w o u n d h eali n g  
S u m m ar y st atistics  
T he f oll o wi n g s u m maries will be prese nte d:  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 4 /1 0 8  
 
 
F or t he pre -s pecifie d ter ms  
•  N u m ber of partici pa nts a n d perce nt a ge b y 
pre -s pecifi e d ter ms i n eac h treat me nt ar m  
acc o m pa ni e d b y t he differe nce i n cr u de rat e bet wee n treat me nt ar ms w it h 9 5 % CI. T he CI will 
be ge nerate d usi n g  t he Mietti ne n  &  N ur mi ne n ( M N) met h o d . CI will n ot be pr o vi de d f or t er ms 
n ot f ulfilli n g t he r ule -of -4 . 
•  F orest pl ot s h o wi n g cr u de rat e a n d cr u de rate differe nce f or eac h pre -s pecifie d ter m i n Tier 1 
wit h 9 5 % M N CI  
•  N u m ber of partici p a nts, n u m ber of partici pa nt -ye ars a n d E AI R wit h 9 5 % CI usi n g P oiss o n 
met h o d b y pre -s pecifie d ter ms i n eac h treat me nt ar m. I n a d diti o n, t he differe n ce i n E AI R 
bet wee n treat me nt ar ms al o n g wit h 9 5 % CI will be s h o w n . T he CI f or E AI R differe nce will be 
esti mate d base d o n M N or e q ui vale nt statistical met h o ds de pe n di n g o n t heir c o m p utati o nal 
efficie n c y. CIs will n ot be pr o vi de d f or ter ms bel o n gi n g t o Tier 3.  
•  F orest pl ot s h o wi n g E AI R a n d E AI R differe n ce f or eac h pre -s pecifie d ter m i n Tier 1 wit h 9 5 % 
CI  
F or t he a n y T E A Es:  
•  N u m ber of partici p a nts a n d perce nta ge b y P T i n Ti er s 2 a n d 3 a n d o v erall i n eac h treat me nt ar m 
acc o m pa ni e d b y t he differe nce i n cr u de rate bet w ee n treat me nt ar ms wit h 9 5 % CI. CI will be 
ge n erat e d usi n g M N met h o d . CI will n ot be pro vi de d f or ter ms b el o n gi n g t o Tier 3.  
•  F orest pl ot s h o wi n g c r u de rate a n d cr u de rate differe nce f or eac h Tier 2 T E A Es wit h 9 5 % M N 
CI  
•  N u m ber of partici p a nts, n u m ber of partici pa nt -ye ars a n d E AI R wit h 9 5 % CI usi n g P oiss o n 
met h o d b y P T i n Tiers 2 a n d 3  i n eac h treat me nt ar m. I n a d diti o n, t he differe n ce i n E AI R 
bet wee n treat me nt ar ms al o n g wit h 9 5 % CI will be s h o w n . T he CI f or E AI R differe nce will be 
esti mate d base d o n M N or e q ui vale nt statistical met h o ds de pe n di n g o n t heir c o m p utati o nal 
efficie n c y. CIs will n ot be pr o vi de d f or ter ms bel o n gi n g t o Tier 3.  
•  F orest pl ot s h o wi n g E AI R a n d E AI R differe nce f or eac h Tier 2 T E A Es wit h 9 5 % CI  
N o m ulti plicit y a dj ust me nt will be a p plie d f or t he a nal ysis of T E A Es.  
F or prese ntati o n of tier 2 a n d 3 e ve nts i n t he mai n b o d y of t h e C S R te xt, a c ut of 5 % i n a n y of t h e 
treat me nt ar ms will be a p plie d, w hile t he c orres p o n di n g e n d-of -te xt ta ble will pr o vi de all of tier 2 
a n d 3 e ve nts.  
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n   
Baseli ne a n d o n -treat me nt la b orat or y v al ues (i ncl u di n g c orres p o n di n g n or mal ra n ges), c o n v erte d 
i nt o sta n dar d u nits, will be use d f or s u m mar y statistics a n d s hift ta bles.  
La b orat or y res ults will be classifie d acc or di n g t o t he N CI -C T C A E criteri a versi o n 5. 0  a n d as 
s pecifie d i n A p pe n di x 3 . A d diti o nal la b orat or y res ults t hat are n ot part of N CI -C T C A E will be 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 5 /1 0 8  
 
 
cate g orize d as f oll o ws: bel o w n or mal li mits, wit hi n n or mal li mits, a n d a b o ve n or mal li mits 
(acc or di n g t o t he ori gi nal la b orat or y n or mal ra n ges). 
All a nal ys es descri be d i n t his secti o n will be descri be d b y treat me nt ar m if n ot ot her wise s pecifi e d.  
Q ua ntitati ve data will be s u m marize d usi n g descri pti ve statistics ( mea n, St D , me dia n, Q 1, Q 3, 
Mi n , a n d Ma x ) of act ual baseli ne val ues , o n-tr eat me nt val ues, a n d c ha n ges fr o m baseli ne t o eac h 
o n -treat me nt visit o ver ti me.  Refer t o Secti o n 9. 1 4  f or f urt her i nf or mati o n a b o ut ha n dli n g of 
u n sc he d ule d assess me nts. Q ualitati ve data base d o n refere nce ra n ges will be descri be d acc or di n g 
t o t he cate g ories (i.e., A b n or mal , N or mal). 
S u m mar y ta bles o ver ti me will prese nt s u m mar y st atistics f or c o nti n u o us a n d cate g orical varia bles 
b y ti me p oi nt.  
T he f o ll o wi n g fi g ures will be pr o vi de d: 
•  B o x pl ots of t he la b orat or y val u es b y ti me p oi nt  
•  B o x pl ots of t he c ha n ge fr o m baseli ne b y ti me p oi nt  
B o x pl ots f or la b orat or y para meters w here t o xicit y gra des are defi ne d b as e d o n t he rati o of t he 
para meter val ue a n d t he u p per li mit of n or mal ( U L N) will be dis pla ye d usi n g t he rati o of t he 
meas ure d v al ue o ver U L N. T his c o m prises al kali ne p h os p hatase ( A L P), ala ni ne a mi n otra nsferas e 
( A L T), as partat e a mi n otra nsferase ( A S T), Acti vate d Partial T hr o m b o plasti n Ti me (a P T T), 
bilir u bi n, a n d creati ni ne.  
L a b or at or y p ar a meters wit h N CI -C T C gr a des a v ail a ble  
La b orat or y p ara m eters wit h N CI -C T C gra des a v aila ble will be a nal yze d wit h t heir res pecti ve N CI -
C T C na me a n d directi o n of a b n or malit y. F or para meters t hat are gra de d wit h  b ot h l o w a n d hi g h 
val ues , s uc h as p otassi u m ( h y p o kal e mia/ h y p er kale mia), t he t o xicities will be s u m marize d 
se parat el y. L o w dir ecti o n t o xicit y (e. g. h y p o kal e mia) gra d es at b aseli ne a n d p ost -baseli ne will be 
set t o 0 w he n t he v aria bles are d eri ve d f or s u m mari zi n g hi g h dir ecti o n t o xicit y (e. g. h y per kale mia), 
a n d vice versa.  
T he f oll o wi n g s u m maries will be dis pla ye d:  
•  N u m ber a n d p erce nta ge of partici pa nt s b y w orst o n-treat me nt gra de ( > = 1, > = 3, > = 4) 
•  S hift i n t o xicit y gra di n g fr o m baseli ne t o hi g h est o n -treat me nt t o xicit y gra d e 
T he defi niti o ns of t he N CI -C T C A E t o xicit y gra di n g versi o n 5. 0 are pr o vi d e d i n A p pe n di x 3 .  
 
T a ble  1 1  
N CI -C T C Gr a d a ble P a r a meters  
P ar a m et er  
P ar a m et er C o d e  
N a m e i n N CI -C T C  
Dir e cti o n of 
A b n or m alit y  
Bi o c h e mi str y  
 
 
 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 6 /1 0 8  
 
 
P ar a m et er  
P ar a m et er C o d e  
N a m e i n N CI -C T C  
Dir e cti o n of 
A b n or m alit y  
Al a ni n e 
A mi n otr a n sf er a s e  
A L T  
Al a ni n e a mi n otr a n sf er a s e  
i n cr e a s e d 
Hi g h  
Al b u mi n  
A L B  
H y p o al b u mi n e mi a  
L o w  
Al k ali n e P h o s p h at a s e  
A L P  
Al k ali n e p h o s p h at a s e i n cr e a s e d  
Hi g h  
A m yl a s e  
A M Y L A S E  
S er u m a m yl a s e i n cr e a s e d  
Hi g h  
A s p art at e 
A mi n otr a n sf er a s e  
A S T  
A s p art at e a mi n otr a n sf er a s e  
i n cr e a s e d 
Hi g h  
Bilir u bi n t ot al  
BI LI  
Bl o o d bilir u bi n i n cr e a s e d  
Hi g h  
C al ci u m a  
C A  
H y p er c al c e mi a/ H y p o c al c e mi a a  
Hi g h/ L o w  
Cr e ati ni n e  
C R E A T  
Cr e ati ni n e i n cr e a s e d  
Hi g h  
G a m m a Gl ut a m yl 
Tr a n sf er a s e  
G G T  
G G T i n cr e a s e d  
Hi g h  
Gl u c o s e  
G L U C  
H y p o gl y c e mi a b   
L o w  
L a ct at e 
D e h y dr o g e n a s e  
L D H  
Bl o o d l a ct at e d e h y dr o g e n a s e 
i n cr e a s e d 
Hi g h  
Li p a s e  
LI P A S E T  
Li p a s e i n cr e a s e d  
Hi g h  
M a g n e si u m  
M G  
H y p er m a g n e s e mi a/ H y p o m a g n e s e mi a  
Hi g h/ L o w  
P ot a s si u m  
K  
H y p er k al e mi a/ H y p o k al e mi a  
Hi g h/ L o w  
S o di u m  
S O DI U M  
H y p er n atr e mi a/ H y p o n atr e mi a  
Hi g h/ L o w  
Cr e ati n e Ki n a s e  
C K  
C P K i n cr e a s e d  
Hi g h  
H e m at ol o g y  
 
 
 
E o si n o p hil s  
E O S  
E o si n o p hili a  
Hi g h  
L y m p h o c yt e s  
L Y M  
L y m p h o c yt e c o u nt d e cr e a s e d/ 
L y m p h o c yt e c o u nt i n cr e a s e d  
L o w/ Hi g h  
N e utr o p hil s  
N E U T  
N e utr o p hil c o u nt d e cr e a s e d  
L o w  
L e u k o c yt e s  
W B C  
W hit e bl o o d c ell d e cr e a s e d / 
L e u k o c yt o si s  
L o w/ Hi g h  
H e m o gl o bi n  
H G B  
A n e mi a/ H e m o gl o bi n i n cr e a s e d  
L o w/ Hi g h  
Pl at el et c o u nt  
P L A T  
Pl at el et c o u nt d e cr e a s e d  
L o w  
C o a g ul ati o n  
 
 
 
A cti v at e d P arti al 
T hr o m b o pl a sti n Ti m e c 
A P T T  
A cti v at e d p arti al t hr o m b o pl a sti n 
ti m e pr ol o n g e dc 
Hi g h  
A cti v at e d P arti al 
T hr o m b o pl a sti n 
Ti m e / st a n d ar d 
t hr o m b o pl a sti n ti m ec 
A P T T S T N D  
A cti v at e d p arti al t hr o m b o pl a sti n ti m e 
pr ol o n g e d / st a n d ar d t hr o m b o pl a sti n 
ti m ec 
Hi g h  
Pr ot hr o m bi n 
I nt er n ati o n al 
N or m ali z e d R ati o c 
I N R 
I N R i n cr e a s e dc 
Hi g h  
a  B a s e d o n c orr e ct e d c al ci u m ( s e e A p p e n di x 3 ). 
b  H y p er gl y c e mi a i s d efi n e d a s p er N CI -C T C A E V 5. 0 b ut gr a d e s c a n n ot b e c o m p ut e d b a s e d o n gl u c o s e v al u e s o nl y.  
c R e p ort e d o n t h e “ C o a g ul ati o n” e C R F p a g e . 
F or c alci u m, C T C A E gra di n g is base d o n C orrecte d Calci u m a n d I o nize d Calci u m ( C A L CI O), if 
a vaila ble. C orrecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws:  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 7 /1 0 8  
 
 
o  C orrecte d Cal ci u m ( m g/ d L) = Calci u m ( m g/ d L) –  0. 8 [ Al b u mi n ( g/ d L) -4]  
or  
o  C orrecte d calci u m ( m m ol/ L) = meas ure d t otal calci u m ( m m ol/ L) + 0. 0 2 ( 4 0 –  ser u m 
al b u mi n [ g/ L])  
L a b or at or y p ar a meters wit h N CI -C T C gr a des n ot a v ail a ble  
 
T a ble  1 2   
N o n -N CI -C T C Gr a d a ble P a r a meters  
P ar a m et er ( L B T E S T)  
 
Bi o c h e m i str y 
 
Bilir u bi n dir e ct  
BI LI DI R  
Bilir u bi n I n dir e ct  
BI LI N DI R  
C hl ori d e  
C L  
C -R e a cti v e Pr ot ei n  
C R P  
P h o s p h at e a  
P H O S  
T ot al Pr ot ei n  
P R O T  
Ur e a Nitr o g e n  
B U N  
Cr e ati ni n e Cl e ar a n c e  
C R E A T C L R  
H e m at ol o g y  
 
A b s ol ut e R eti c ul o c yt e s  
R E TI  
B a s o p hil s  
B A S O  
B a s o p hil s/ L e u k o c yt e s  
B A S O L E  
E o si n o p hil s/ L e u k o c yt e s  
E O S L E  
Er yt hr o c yt e s ( R B C)  
R B C  
H e m at o crit  
H C T  
L y m p h o c yt e s/ L e u k o c yt e s  
L Y M L E  
M e a n C or p u s c ul ar H e m o gl o bi n  
M C H  
M e a n C or p u s c ul ar H G B C o n c e ntr ati o n  
M C H C  
M e a n C or p u s c ul ar V ol u m e  
M C V  
M o n o c yt e s  
M O N O  
M o n o c yt e s/ L e u k o c yt e s  
M O N O L E  
N e utr o p hil s/ L e u k o c yt e s  
N E U T L E  
R eti c ul o c yt e s/ Er yt hr o c yt e s  
R E TI R B C  
C o a g ul ati o n  
 
Pr ot hr o m bi n Ti m e b  
P T  
a P h o s p h at e i s a gr a d a bl e p ar a m et er a s p er N CI -C T C A E V 5. 0 b ut gr a d e s c a n n ot b e c o m p ut e d b a s e d o n p h o s p h at e 
r e s ult s o nl y. 
b R e p ort e d o n t h e “ C o a g ul ati o n” e C R F p a g e . 
F or W B C differe nti al c o u nts  ( ne utr o p hil, l y m p h oc yt e c o u nts), t he a bs ol ute val ue will be us e d 
w he n re p ort e d.  W he n o nl y p erce nta ges are a v aila ble (t his is mai nl y i m p orta nt f or ne utr o p hils a n d 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 8 /1 0 8  
 
 
l y m p h oc ytes, beca use t h e C T C A E gra di n g is b ase d o n t he a bs ol ute c o u nts), t he a bs ol ute val u e is 
deri ve d as f oll o ws:  
Deri ve d differe ntial a bs ol ute c o u nt = ( W B C c o u nt) * ( Differe ntial % v al ue / 1 0 0)  
F or all n o n -gra da ble p ara meters, t he f oll o wi n g s u m maries will be dis pla ye d:  
•  N u m ber a n d p erce nta ge of partici pa nts b y l o w est o n -treat me nt val u e (cl assifie d as n or mal, hi g h, 
l o w) 
•  N u m ber a n d perce nta ge of partici pa nts b y hi g hest o n -treat me nt val ue (cl assifie d as n or mal, 
hi g h, l o w)  
•  S hift fr o m baseli ne t o hi g hest/l o west o n -treat me nt val ue (classifi e d as n or m al, hi g h, l o w) 
Se parate listi n gs of h e m at ol o g y, bi oc h e mistr y a n d c oa g ulati o n will be create d. Eac h listi n g will 
i ncl u de: c o h ort/ pla n ne d ar m, partici pa nt  i de ntifier, a ge, se x, race, first d ose date, last d ose date, 
la b orat or y p ara m eter ( u nits), visit, date/ti me (st u d y d a y), SI val ue, c h a n ge  i n SI v al ue fr o m 
baseli ne, L L N,  U L N,  in dicat or of n or mal ra n ge (lo w, n or mal, h i g h), t o xicit y gra d e acc or di n g t o 
N CI -C T C A E (w h e n  a p plica ble)  a n d hi g hest/l o w est o n -treat me nt val ue fl a g. Baseli ne a n d p ost -
baseli ne val ues after t h e o n -treat me nt peri o d will be fla g ge d.  
Li ver f u ncti o n tests  
A L T, A S T, a n d total b ilir u bi n will be use d t o assess p ossi ble dr u g i n d uce d li ver t o xicit y.  T h e rati os 
of test res ult o ver U L N will be calc ulat e d a n d clas sifie d f or t hese t hree para meters d uri n g t h e o n-
treat me nt peri o d. 
T he n u m ber a n d perce nt a ge of partici pa nt s wit hi n eac h of t he f oll o wi n g li ver f u ncti o n cate g ories 
d uri n g t he o n -treat me nt p eri o d will be descri b e d: 
•  A L T < 3 × U L N, A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 1 0 × U L N, A L T ≥ 2 0 × U L N  
•  A S T < 3 × U L N, A S T ≥ 3 × U L N, A S T ≥ 5 × U L N, A S T ≥ 1 0 × U L N, A S T ≥ 2 0 × U L N  
•  ( A L T a n d A S T) < 3 × U L N, ( A L T or A S T) ≥ 3 × U L N, ( A L T or A S T) ≥ 5 × U L N, ( A L T or A S T) 
≥ 1 0 × U L N, ( A L T or A S T) ≥ 2 0 × U L N  
•  BI LI < 2 × U L N, BI LI ≥ 2 × U L N  
•  C o nc urre nt A L T ≥ 3 × U L N a n d BI LI  ≥ 2 × U L N  
•  C o nc urre nt A S T ≥ 3 × U L N a n d BI LI ≥ 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d BI LI ≥ 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d BI LI ≥ 2 × U L N a n d A L P > 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d BI LI ≥ 2 × U L N a n d A L P ≤ 2 × U L N or missi n g  
C o nc urre nt meas ur e me nts are t h ose occ urri n g o n t he sa me date.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
8 9 /1 0 8  
 
 
Cate g ories will be c u m ulati ve, i.e., a partici pa nt wit h a n ele vati o n of A S T ≥1 0 × U L N will als o 
a p pear i n t he cate g ories ≥5 × U L N a n d ≥3 × U L N.  
A pl ot of pea k A L T  v ers us pea k t otal bilir u bi n, b ot h relati ve t o t he U L N  will be pr o vi de d. T his 
e DI S H pl ot (e val uati o n of dr u g -i n d uce d seri o us he pat ot o xicit y) will be di vi de d i nt o 4 q ua dra nts 
b y t h e li nes t hr o u g h A L T = 3 × U L N a n d total b ilir u bi n = 2 × U L N. T he left l o wer q u a dra nt is t he n 
c o nsi dere d n or mal or i nsi g nifica nt ele vati o ns i n li v er c h e mistries, t he u p per left q ua dra nts i n dicate 
partici pa nts wit h p ossi ble Gil bert’s c h olestasis; t he ri g ht u p per q ua dra nt are t he p ossi ble H y’s La w 
partici pa nts ; t he ri g ht l o wer q ua dra nt s h o ws p ossi ble Te m ple’s C or ollar y ( partici pa nts wit h A L T ≥ 
3 x U L N b ut n ot satisf yi n g H y’s La w).  T he s a me pl ot will be pr o vi de d f or A S T.  
I n a d diti o n, a listi n g of all t otal bilir u bi n, A L T, A S T a n d A L P val ues f or p artici pa nts wit h a p ost -
baseli ne t otal bilir u bi n ≥ 2 × U L N, A L T ≥ 3 × U L N or A S T ≥ 3 × U L N will be pr o vi de d.  
Uri n al ysis  / uri n al ysis micr os c o pic e v al u ati o n, a ne mi a, h or m o n e tests, ser u m, ser ol o g y, 
c a ncer a nti ge n 1 9. 9  
All test res ults f or uri nal ysis / uri nal ysis micr osc o pic e val uati o n, h or m o n e tests, ser u ms a n d 
ser ol o g y p ara m eters will be liste d  i n de dicate d listi n gs:  
•  Uri nal ysis p ara met ers:  
o  Uri nal ysis f ull para m eters: p h ysic al a p peara n ce, p H, s pecific gra vit y, pr otei n, gl uc ose, 
ket o nes, nitrite, le u k oc yt e esterase, bl o o d, ur o bili n o ge n, bilir u bi n, c ol or  
o  Uri nal ysis micr osc o pi c para meters: er yt hr oc yt es ( R B C), le u k oc yt es ( W B C), epit helial 
cells, b acteria, cr ystals, casts 
•  A ne mia para met ers: re d cell v o l u me distri b uti o n wi dt h sta n dar d de viati o n ( R D W-S D), re d cell 
distri b uti o n c oefficie nt of variati o n ( R D W -C V), t otal ir o n bi n di n g ca pacit y, tra nsferri n, ir o n, 
ferriti n, vita mi n B 1 2, ser u m f olate, a bs ol ute retic ul oc ytes 
•  H or m o n e para m eters: th yr o xi ne free ( Free T 4), th yr otr o pi n ( th yr oi d -sti m ulati n g h o r m o ne; 
T S H)  
•  Ca ncer a nti ge n 1 9. 9  ( C A 1 9-9)  
•  Ser u m para meters: K re bs v o n de n L u n ge n -6 ( K L -6), surfacta nt p r otei n A ( S P-A), surfacta nt 
p r otei n D ( S P-D) ( o nl y f or J a pa nese sites)  
•  S er ol o g y p ara met ers: h e p atitis B v ir us ( H B V), h e p atitis C v ir us ( H C V), h e patitis C R N A 
Pre g n a nc y test  
Res ults f or pre g n a nc y a n d p ost -me n o pa usal stat us as c ollect e d o n t he “ Pre g n a nc y T est” e C R F pa ge 
will als o be liste d:  
•  Pre g n a nc y para met ers ( ser u m or hi g hl y s e nsiti ve uri ne h u ma n c h ori o nic g o na d o tr o pi n [h C G ]) 
•  P ost -me n o pa usal stat us  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 0 /1 0 8  
 
 
1 5. 4  
Vit al Si g ns   
T he f oll o wi n g s u m maries will be pre pare d f or vital si g ns:  b o d y te m p erat ure, p ulse rate, s yst olic 
bl o o d press ure ( S B P), diast olic  bl o o d press ure ( D B P), res pirati o n rate a n d o x y ge n s at urati o n 
c o nsi deri n g o nl y p artici p a nts wit h p ost -baseli ne v al ues d uri n g o n -treat me nt peri o d: 
•  S u m mar y statistics o ver ti me  
T he  f oll o wi n g p ot e ntiall y cli nicall y si g nifica nt a b n or malities will be s u m marized : 
•  ≤ 9 5 m m H g a n d decrease fr o m baseli ne ≥ 2 0 m m H g i n s yst olic bl o o d press ure  
•  ≥ 1 4 0 m m H g a n d i ncreas e fr o m baseli ne ≥ 2 0 m m H g i n s yst olic bl o o d press ure  
•  ≤ 4 5 m m H g a n d decrease fr o m baseli ne ≥ 2 0 m m H g i n diast olic bl o o d press ure  
•  ≥ 9 0 m m H g a n d i ncreas e fr o m b aseli ne ≥ 2 0 m m H g i n diast olic bl o o d press ure  
•  ≤ 5 0 beats/ mi n  a n d decrease fr o m bas eli ne ≥ 2 0 b eats/ mi n  i n heart rate 
•  ≥ 1 0 0 beats/ mi n  a n d i ncrease fr o m baseli ne ≥ 2 0 beats/ mi n  i n heart rate 
•   <  2 0  breat hs/ mi n a n d decreas e fr o m b aseli ne ≥ 5  breat hs/ mi n i n res pirat or y rate  
•  ≥ 2 0  breat hs/ mi n a n d i ncrease fr o m baseli ne ≥ 5  breat hs/ mi n i n res pirat or y rate  
•  ≥ 1 0 % wei g ht i ncrease  
•  ≥ 1 0 % wei g ht decreas e  
A listi n g of vital si g ns will be pr o vi de d  i ncl u di n g c o h ort/ pla n ne d ar m, parti ci pa nt  i de ntifier, a ge, 
se x, race, vital si g n p ara meter, visit , ti me p oi nt, d ate, ti me, v al ue,  u nit , a n d c ha n ge fr o m bas eli ne . 
Baseli ne v al ues a n d p ost -baseli ne val ues c ollecte d after t he o n -treat me nt peri o d will be fla g ge d.  
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns   
E C G  
Si n gle 1 2 -le a d E C Gs will be o btai ne d as o utli ne d i n t he Sc he d ul e of Acti vities ( Ta ble 1) i n t he 
pr ot oc ol, a n d 
E C G 
p ara meters 
will 
be 
descri be d 
fr o m t he 
d ata c ollect e d 
o n t he 
“ Electr o car di o gra m” e C R F pa ge. S hift ta ble f or E C G i nter pret ati o n val ue at bas eli ne t o t he val ue 
at e n d of treat me nt will be pr o vi de d.   
A listi n g of E C G val ues will be pr o vi de d i ncl u di n g c o h ort/ pla n ne d ar m , partici pa nt  i de ntifier, a ge, 
se x, race, E C G para meter a n d u nit, visit /ti me (st u d y da y), E C G date, v al ue, c ha n ge fr o m bas eli ne. 
Baseli ne val ues a n d p ost -baseli ne v al ues c ollecte d after t he o n -treat me nt peri o d will be fla g ge d. 
Q ualitati ve E C G res ults will als o be pr o vi de d.  
E C O G Perf or m a nce St at us  
T he  E C O G Perf or ma nce Stat us will be deri ve d fr o m t he data c ollecte d o n t he “ E C O G Perf or ma n ce 
Stat us” e C R F pa ge.  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 1 /1 0 8  
 
 
T he E C O G s hift fr o m baseli ne t o t he hi g hest sc ore d uri n g t he o n -treat me nt peri o d will be 
s u m marize d.  
E C O G perf or ma nce stat us will als o be prese nt e d i n a listi n g at eac h ti me p oi nt.  
1 6  
A n al yses of Ot her E n d p oi nts   
1 6. 1  
P h ar m ac o ki netics   
T he a nal yses d escri b e d i n t his secti o n will be perf or me d b y t he Cli nical P K/ P har mac o d y na mics 
gr o u p ( C P K) of Tra nslati o nal Me dici ne, Merc k Healt hcare K Ga A, Dar mst a dt, Ger ma n y, or b y a 
C o ntract Researc h Or ga niz ati o n selecte d b y t he S p o ns or. P har mac o ki netic listi n gs a n d i n di vi d ual 
data will be pres e nte d b ase d o n t he Safet y A nal ysis Set. S u m maries a n d statistical a nal yses will 
be base d o n t he P K A S. I nte grate d a n al ys es acr oss st u dies, s uc h as t he P o p ulati o n P K a nal ysis, will 
be descri b e d se paratel y fr o m t his I A P a n d prese nt e d se pa ratel y fr o m t he m ai n C S R. 
P har mac o ki netic c o n ce ntrati o ns/ P K para meters m e nti o ne d herei n refer t o t h ose of bi ntraf us p alfa . 
1 6. 1. 1  
Missi n g/ n o n -q u a ntifi a ble/ u nsc he d ule d P K D at a H a n dli n g   
C o nce ntr ati o ns Bel o w t he L o w er Li mit of Ass a y Q u a ntific ati o n  
P har mac o ki netic c o nce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n ( B L Q) will be set t o zer o 
f or cal c ulati n g p ara m eters a n d descri pti ve statistics. 
P har mac o ki netic c o n ce ntrati o ns t hat are B L Q  a n d occ ur bef ore t he l ast q ua ntifia ble data p oi nt will 
be ta ke n as zer o f or calc ul ati n g P K para meters of si n gle d ose pr ofiles. C o nce ntrati o ns t hat are B L Q 
a n d occ ur after t he last q ua ntifia ble data p oi nt will n ot be c o nsi dere d i n t he calc ulati o n of t he 
ter mi nal first or der rate c o nsta nt ( λZ ). 
U nsc he d ule d S a m ples  
F or P K a nal ysis, u nsc he d ule d sa m ples will n ot be li n ke d t o a sc he d ule d ti me p oi nt a n d will be 
e x cl u de d fr o m s u m maries.  
De vi ati o ns, Missi n g C o nce ntr ati o ns, a n d A n o m al o us V al ues  
P har mac o ki netic para met ers will be calc ulate d usi n g t he act ual ela ps e d ti me si nce d osi n g. W he n 
t he act ual sa m pli n g ti me is missi n g, calc ulati o ns will be perf or me d usi n g t he sc h e d ule d ti me. 
Ot her wise, t h ere will be n o f urt her i m p utati o n of missi n g d ata. C o n ce ntrati o ns will be set t o 
missi n g i n s u m mar y ta bl es if t he val ue is re p orte d as n o res ult.  
P har mac o ki netic c o n ce ntrati o ns w hic h are err o ne o us d ue t o a pr ot oc ol vi olati o n (as defi ne d i n t he 
cli nical st u d y pr ot oc ol a n d/ or Secti o n 8. 1 ), d oc u me nte d ha n dli n g err or, or a nal yti cal err or (as 
d oc u me nte d i n t he pr ot oc ol de viati o n l o g, bi oa nal ytical data, a n d/ or bi oa nal ytical re p ort) ma y b e 
e x cl u de d fr o m t he P K a nal ysis if a gree d u p o n pri or t o perf or mi n g t he P K a nal ysis. I n t his case t he 
rati o nale f or e x cl usi o n will be pr o vi de d i n t he C S R. A n y ot her P K c o nce ntrati o ns t hat a p pear 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 2 /1 0 8  
 
 
i m pla usi ble t o t he P har mac o ki neticist/ P K
 Data A nal yst will n ot b e e x cl u de d 
fr o m t he a nal ysis. A n y i m pla usi ble data will be d oc u me nte d i n t he C S R. 
E x cl usi o ns f or c o nce ntrati o n data descri pti ve statistics:  
- 
P ositi ve pre -d ose val ues o n Da y 1  
- 
C o nce ntrati o n o bser ve d at t he e n d of i nf usi o n  ( CE OI ) < l o wer li mit of q ua ntificati o n 
( L L O Q) 
- 
I n case of misse d d ose, e x cl u de all c o nce ntrati o ns u ntil i nte n de d d osi n g is res u me d  
- 
C o nce ntrati o n o b ser ve d at t he e n d of t he d osi n g i nter val ( C tr o u g h) val ues i n case sa m ples 
are ta k e n at least 7 da ys l ate or earl y  
E x cl usi o ns f or N o n -C o m part me ntal A nal ysis ( N C A):  
- 
P ositi ve pre -d ose val ues o n Da y 1  
- 
C E OI  < L L O Q  
- 
I n case of misse d d ose, e x cl u de all c o nce ntratio ns u ntil i nte n de d d osi n g is res u me d  
A n y  
ot her  
P K  
c o nce ntr ati o ns  
t hat  
a p pear  
i m pla usi ble  
t o  
t he 
P har mac o ki neticist/ P K/
 Data A nal yst will n ot be e x cl u de d fr o m t he a nal ysis. 
A n y i m pla usi ble data will be d oc u me nte d i n t he C S R.  
If a P K para meter ca n n ot be deri ve d fr o m a partici pa nt’s c o nce ntr ati o n data, t he para meter will be 
c o de d as N C ( n ot calc ul ate d) ( N ote t hat N C val u es will n ot be ge nerate d be y o n d t he da y t hat a 
partici pa nt disc o nti n ues t he treat me nt). F or statistical a nal ys es (i.e. , d escri p ti ve statistics), P K 
para meters c o de d as N C will be set t o missi n g.  
If a n i n di vi d ual partici pa nt has a k n o w n biase d esti mate of a P K para meter ( d ue f or e x a m ple t o a 
de viati o n fr o m t he assi g n e d d ose le vel), t his partici pa nt/ val ue will be e x cl u de d fr o m t he d escri pti ve 
statistics base d o n t he P K a nal ysis s et a n d i nstea d t he res ult will be liste d o nl y.  
Rele va nt decisi o ns o n partici pa nt i ncl usi o n i n t he P K a nal ysis set will be ma de i n a t w o -ste p 
pr ocess:  
3.  Bef ore dat a base l o c k i n a bli n de d data re vie w meeti n g.  
4.  A fter d ata bas e l oc k a n d u n bli n di n g, t he P K a n al ysis set m a y be u p dat e d base d u p o n 
u n bli n de d data rele v a nt t o P K.  
1 6. 1. 2  
Descri pti ve P K A n al ysis   
Prese nt ati o n of P K C o n ce ntr ati o n D at a  
Listi n gs  
I n di vi d ual P K sa m ple ti mes, ti me de viati o ns, a n d c o nce ntrati o n data will be liste d b y part, 
partici pa nt, re gi o nal c o h ort ( Asia n or n o n -Asia n), st u d y da y, a n d n o mi nal ti me. C o nce ntrati o n 
listi n gs will be base d o n t he safet y r u n-i n a nal ysis set f or t he safet y r u n-i n part a n d t he S A F f or t he 
ra n d o mize d, d o u ble-bli n d part. P har mac o ki netic c o nce ntr ati o ns will be re p orte d wit h t he sa me 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 3 /1 0 8  
 
 
precisi o n as t he s o ur ce data pr o vi de d b y t he bi oa nal yti cal la b orat or y. Act ual el a pse d s a m ple 
c ollecti o n ti mes will be r o u n de d t o t w o deci mal places wit h u nits of h o urs f or re p orti n g p ur p oses 
i n listi n gs. 
T a bles  
P har mac o ki netic  c o nce ntrati o n data f or t he first d ose i n t he safet y r u n -i n p art will be prese nte d i n 
ta bles a n d d escri pti vel y s u m marize d f or t he P KA S  b y re gi o n al c o hort, o verall ( b ot h c o h orts 
c o m bi ne d), a n d n o mi nal ti me usi n g: n u m ber of n o n -missi n g o bser vati o ns ( n), arit h metic mea n 
( Mea n), ge o metric me a n ( Ge o Mea n), St D, St D of l o g -tr a nsf or m e d data (l o g St D), c o effici e nt of 
variati o n ( C V %), ge o metric c oeffi cie nt of vari ati o n ( Ge o C V %), Mi n, me dia n ( Me dia n), a n d Ma x. 
S u m maries of pre -d ose a n d e n d -of -i nf usi o n c o n ce ntrati o ns ( ot her t ha n first d osi n g i nter val) f or t he 
safet y r u n-i n part, as w ell as all pre-d ose a n d e n d -of -i nf usi o n c o n ce ntr ati o ns i n t he ra n d o mize d, 
d o u ble -bli n d part, will be c o vere d b y t h e para meter s u m maries o nl y.  
A d diti o nal ta ble(s) will s u m marize P K c o nce ntrati o ns wit h f urt her stratificati o n b y et h nicit y (e. g., 
J a pa nese, n o n-J a pa nese Asia n, all Asia n, n o n-Asia n, C hi nese mai nla n d, n o n -C hi nese mai nla n d 
Asia n),  base d o n t he P K A S. A d diti o nal ta ble(s) will s u m marize P K c o nce ntrati o ns wit h f urt her 
stratificati o n b y A D A s u bsets e ver p ositi ve a n d ne ver p ositi ve, a n d a d diti o nall y “ Treat me nt 
e mer ge nt ( A L L)” v ers us “ A D A N o n -Treat me nt -e mer ge nt”, b ase d o n t he P K A D A. A d dit i o nal 
ta ble(s) will s u m marize P K c o nce ntrati o ns wit h f urt her s u b-stratificati o n b y n A b s u bsets e ver 
p ositi ve a n d ne v er p ositi ve, bas e d o n t he P K N A B. F or n A b s u bs ets, s u m maries will b e d o ne f or 
e ver p ositi ve i n eit her of 2 n A b assa ys ( P D -L 1 a n d T G F ß rece pt o r ne utralizati o n; see Secti o n 1 6. 4 . 
A d diti o nal ta ble(s)  ma y s u m marize  P K c o nce ntrati o n at t he ti me p oi nts wit h A D A meas ure me nt 
wit h stratificati o n b y t he A D A res ults ( Ne gati ve or P ositi ve, see Secti o n 1 6. 4 ) at eac h ti me p oi nt 
base d o n t he P K A D A. A d diti o nal ta ble(s) ma y s u m marize P K c o nce ntrati o ns wit h f urt her 
stratificati o n b y a nti bi otics stat us s u b gr o u ps. O nl y s u b gr o u p sa m ple siz e wit h a mi ni m u m of 3 
partici pa nt s will be dis pla ye d. 
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce d ata pr o vi de d b y t he bi oa nal ytical la b orat or y a n d r o u n de d f or re p orti n g 
p ur p oses o nl y. T he f oll o wi n g c o n ve nti o ns will  be a p plie d w he n re p orti n g descri pti ve statistics of 
P K c o nce ntrati o n dat a:  
Mea n, Mi n, Me dia n, Ma x , Ge o Mea n:  
 
3 si g nifica nt di gits  
St D , l o g St D:  
 
 
 
            4 si g nifica nt di gits  
C V % %, Ge o C V % : 
 
 
 
 
1 deci mal place  
Fi g ures  
I n di vi d ual P K c o n ce ntr ati o n-ti me pr ofiles s h o wi n g all partici pa nts b y re gi o nal  c o h ort will be 
creat e d f or serial s a m pli n g (i.e. , s afet y r u n-i n part, first d ose) usi n g t he act u al ti me p oi nts a n d t he 
n u meric c o nce ntr ati o n data. Arit h metic mea n , Ge o Mea n a n d M e dia n c o nce ntrati o n -ti me pr ofiles 
b y  re gi o nal c o h ort a n d o v erall ( b ot h c o h orts)  f or s erial sa m pli n g (i.e., s afet y r u n-i n part, first d ose) 
will be pr o vi de d usi n g s c he d ule d ( n o mi nal) ti me p oi nts a n d t he n u meric c o nce ntr ati o n data. All 
c o nce ntr ati o n -ti me pl ots f or P K data will be prese nted b ot h o n a li near a n d o n a se mi -l o garit h mic 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 4 /1 0 8  
 
 
scale. Mea n a n d Ge o Mea n P K pl ots will i ncl u de St D  or l o g St D  err or bars w he n pl otte d o n a li near 
scale. Pl ots of i n di vi d ual data will b e prese nte d base d o n t he s afet y r u n-i n a nal ysis set, a n d 
s u m mar y pl ots will be base d o n t he P K A S .. Fi g ures of pre-d ose a n d e n d -of -i nf usi o n c o nce ntrati o ns 
ot her t ha n first d osi n g i nt er val will be c o v ere d b y t he para m eter s u m mari es o nl y.  
A d diti o nal fi g ures will prese nt Mea n, Ge o M ea n, a n d Me dia n P K c o nce ntrati o n -ti me pr ofiles wit h 
f urt her str atificati o n b y et h nicit y (e. g., J a pa n ese, n o n-J a pa nese Asia n, all Asia n, n o n-Asia n, 
C hi nese mai nla n d, n o n -C hi nese mai nla n d Asia n), base d o n t he P K A S. A d diti o nal fi g ures will 
prese nt Mea n, G e o Mea n, a n d Me di a n P K c o n ce ntr ati o n -ti me pr ofiles wit h f urt her str atificati o n b y 
A D A s u bsets e ver p ositi ve a n d ne ver p ositi ve, a n d a d diti o nall y “ Treat me nt e mer ge nt ( A L L)” a n d 
“ A D A N o n-Treat me nt -e mer ge nt”, bas e d o n t he P K A D A.  A d diti o nal b o x -w his ker pl ots ma y b e 
prese nte d of P K c o nce ntr ati o n at t he ti me p oi nts wit h A D A meas ure me nt wit h stratificati o n b y t h e 
A D A res ults ( Ne gati ve or P ositi ve, see Secti o n 1 6. 4 ) at eac h ti me p oi nt base d o n t he P K A D A.  
A d diti o nal fi g ures will prese nt Mea n, Ge o Mea n a n d Me dia n P K c o nce ntrati o n -ti me pr ofiles wit h 
f urt her s u b-stratificati o n b y n A b s u bsets e v er p ositi ve a n d ne v er p ositi ve ( s ee Secti o n 1 6. 4  b ase d 
o n t he P K N A B. A d diti o nal fi g ure(s) of i n di vi d ual data o verlai d will be prese nte d wit h f urt her 
stratificati o n b y A D A s u b gr o u ps (e ver p ositi ve a n d ne ver p ositi ve). O nl y s u b gr o u p sa m ple siz e 
wit h a mi ni m u m of 3 partici pa nts will be dis pla ye d.  
1 6. 1. 3  
P h ar m ac o ki netic N o n -C o m p art me nt a l A n al ysis   
T he P K para meters liste d bel o w will be cal c ulate d f or bi ntraf us p alf a (if esti ma ble) usi n g t he act ual 
ti me ela pse d fr o m d osi n g ( or usi n g sc h e d ule d ti me if act ual ti me is n ot a vaila ble, e. g., a n y a n al ys es 
pri or t o fi nal a nal ysis)  b y n o n -c o m p art me ntal met h o ds . P har mac o ki netic c o nce ntr ati o ns will be 
a nal yze d wit h t he sa me precisi o n as t he s o urce data pr o vi de d b y t h e bi oa nal yti cal la b orat or y. 
Act ual ela ps e d sa m ple c ollecti o n ti mes will be a nal yze d u nr o u n d e d ( m a xi m u m of 1 4 si g nifica nt 
di gits). T he pre -d ose sa m ples will be c o nsi dere d as if t he y ha d bee n ta ke n si m ulta ne o usl y wit h t he 
start of i nf usi o n (i.e., ti me zer o). 
C E OI  
T he c o nce ntr ati o n o bser ve d i m me diatel y at t he e n d of i nf usi o n. 
T his will be ta ke n directl y fr o m t he o bser ve d bi ntraf us p alfa 
c o nce ntr ati o n -ti me data. 
C tr o u g h 
T he c o n ce ntr ati o n o bser ve d i m me diatel y b ef ore ne xt d osi n g 
(c orres p o n di n g t o pre-d ose or tr o u g h c o nce ntrati o n f or m ulti ple 
d osi n g). T his will be t a k e n directl y fr o m t he o bser ve d bi ntraf us p 
alfa c o n ce ntr ati o n -ti me data. 
A U C 0 -t 
Area u n der t he c o nce ntr ati o n -ti me c ur ve ( A U C) fr o m ti me zer o 
(i.e., i nf usi o n start ti me) t o t he last sa m pli n g ti me (tlast) at w hic h 
t he c o nce ntr ati o n is at or a b o ve t he l o wer li mit of q ua ntificati o n. 
(S A F RI  part o nl y; first d ose o nl y).  
A U C 0 -∞ 
T he A U C fr o m ti me zer o (i nf usi o n start ti me) e xtra p olate d t o 
i nfi nit y, bas e d o n t he pre dicte d val ue f or t he c o nce ntrati o n at tlast 
( Clast pre d), as esti mate d usi n g t he li near re gressi o n fr o m λZ  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 5 /1 0 8  
 
 
deter mi nati o n. A U C 0 -∞ = A U C 0 -t+ C last pre d/ λZ . (S A F RI  part o nl y; 
first d ose o nl y). 
t1/ 2 
A p pare nt ter mi nal (eli mi nati o n) half -life, calc ulate d b y l n 2/ λZ . 
(S A F RI  part o nl y; first d ose o nl y).  
λ Z  
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt, deter mi ne d fr o m 
t he ter mi nal sl o pe of t h e l o g-tr a nsf or me d c o n ce ntr ati o n-ti me c ur ve 
usi n g li near re gressi o n o n te r mi nal data p oi nts of t he c ur ve. 
(S A F RI  part o nl y; first d ose o nl y).  
C ma x   
Ma xi m u m o bser ve d c o nce ntrati o n. ( S A F RI  part o nl y; first d ose 
o nl y).  
tma x  
T he ti me t o reac h t h e ma xi m u m o bser ve d c o nce ntrati o n c ollecte d 
d uri n g a d osi n g i nter val ( u nless ot her wise defi n e d, ta ke t he 1st 
occ urre nce i n cas e of m ulti ple/i de ntical C ma x  val ues). ( S A F RI  p art 
o nl y; first d ose o nl y).  
C L  
T otal b o d y cl eara nce. C L = D ose/ A U C 0 -∞. (S A F RI  part o nl y; first 
d ose o nl y).  
V z 
V ol u me 
of 
distri b uti o n 
d uri n g ter mi nal 
p hase f oll o wi n g 
i ntra ve n o us d osi n g. V z = D ose/( A U C 0 -∞* λ Z ). (S A F RI  part o nl y; 
first d ose o nl y). 
T he f oll o wi n g P K para m eters ( S A F RI  part o nl y; first d ose o nl y) will be calc ulate d f or dia g n ostic 
p ur p oses a n d liste d, b ut will n ot be s u m marize d:  
•  T he ti me i nter val ( h) of t he l o g-li near re gressi o n t o deter mi ne λZ  (t1/ 2, I nter val). 
•  T he starti n g ti me p oi nt ( h) of t he ti me i nter val of t he l o g -li near re gressi o n t o deter mi ne z 
( La m b da _z _l o w). 
•  T he e n di n g ti me p oi nt ( h) of t he ti me i nter val of t he l o g -li near re gressi o n t o deter mi ne z 
( La m b da _z _ u p p). 
•  N u m ber of dat a p oi nts (t 1/ 2, N) i ncl u de d i n t he l o g-li near re gressi o n a nal ysis t o deter mi ne λZ . 
•  G o o d ness -of -fit statistic (a dj uste d Rs q) f or calc ulati o n of λZ . 
•  Perce nta ge 
of 
A U C 0 - 
o btai ne d 
b y 
e xtra p olati o n 
( A U C e xtra %), 
calc ulate d 
b y 
( 1 － [ A U C0 -t/ A U C0 -]) × 1 0 0. 
T he re gressi o n a nal ysis ( deter mi nati o n of z) s h o ul d c o ntai n as ma n y data p oi nts as p ossi ble ( b ut 
e x cl u di n g C ma x ) a n d has t o i ncl u de c o nce ntrati o n data fr o m at least 3 differe nt ti me p oi nts, 
c o nsiste nt wit h t he assess me nt of a strai g ht li ne (t he ter mi nal eli mi nati o n p hase) o n t he 
l o g-tr a nsf or me d scale. T he o bser vati o n peri o d o ver w hic h t he re gressi o n li ne is esti mate d s h o ul d 
be at least t w o -f ol d t he res ulti n g t1/ 2 itself. If A U C e xtra % is > 2 0. 0 % a n d/ or a dj uste d Rs q  of λ Z is 
< 0. 8 0 0, a n d/ or t1/ 2, I nter v al is less t h a n t w o-f ol d t h e res ulti n g t1/ 2, t he n λ Z  a n d all deri ve d p ara m eters 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 6 /1 0 8  
 
 
(e. g. t1/ 2, A U C 0 -∞, C L, etc.) will be liste d , fla g ge d, a n d disc usse d/r e vie we d wit h t he Merc k Cli nical 
P K/ 
 Scie ntist o n a case -b y -case basis f or  p ote ntial e xcl usi o n fr o m descri pti ve statistics . 
T he calc ulati o n of t he A U Cs will be perf or me d usi n g t he mi x e d l o g -li near tra pez oi dal met h o d 
(li near u p, l o g d o w n). E xtra p olate d areas will al wa ys be c o m p ute d usi n g t he pre dicte d last 
c o nce ntr ati o n t hat is e sti mate d usi n g t he li near re gressi o n fr o m ter mi nal rate c o nsta nt 
deter mi nati o n.  
Prese nt ati o n of P K P ar a meter D at a  
Listi n gs  
I n di vi d ual P K para met er data will be liste d b y part, partici pa nt, re gi o nal c o h ort, a n d st u d y da y. 
Para meter listi n gs will be base d o n t he S A F RI  a n al ysis set f or t he s afet y r u n-i n part a n d t h e S A F 
f or t he ra n d o mize d, d o u ble-bli n d part. P har mac o ki netic para meters will be  re p orte d t o 3 si g nifica nt 
di gits i n listi n gs.  
T he P h oe ni x Wi n N o nli n n o n -c o m part me ntal C or e O ut p ut will be pr o vi de d i n a se parate listi n g.  
T a bles  
P har mac o ki netic p ara met er d ata will b e prese nte d i n ta bles a n d descri pti vel y s u m marize d f or t he 
P K A S  b y part, re gi o nal c o h ort, o verall b y part ( b ot h c o h orts wit hi n eac h part), o verall (all 
parts/c o h orts), a n d da y usi n g: n, 
Mea n, St D, C V %, 
Mi n, 
Me dia n, 
M a x, Ge o Mea n,  l o g St D, 
Ge o C V %, a n d t he 9 5 % CI f or t he Ge o M ea n. S u m maries will be base d o n t he P K A S. A d diti o nal 
ta ble(s) will s u m marize select para meters wit h f urt her str atificati o n b y A D A s u b gr o u ps e v er 
p ositi ve a n d ne ver p ositi ve.  
A d diti o nal ta ble(s) will s u m marize C tr o u g h a n d C E OI  wit h f urt h er stratificati o n b y et h nicit y (e. g., 
J a pa nese, n o n-J a pa nese Asia n, all Asia n, n o n-Asia n, C hi nese mai nla n d, n o n -C hi nese mai nla n d 
Asia n), base d o n t he P K A S. A d diti o nal ta ble(s) will s u m marize C tr o u g h a n d C E OI  wit h f urt her 
stratificati o n b y A D A s u bsets e ver p ositi ve a n d n e ver p ositi ve, a n d ma y a d diti o nall y s u m marize 
C tr o u g h a n d C E OI  at t h e ti me p oi nts wit h A D A m eas ure me nt wit h stratificati o n b y t h e A D A res ults 
( Ne gati ve or P ositi ve, see Secti o n 1 6. 4 ) at eac h ti me p oi nt, base d o n t he P K A D A. A d diti o nal 
ta ble(s) will s u m marize Ctr o u g h a n d C E OI  wit h f urt h er s u b -stratificati o n b y n A b s u bsets e v er p ositi ve 
a n d ne ver p ositi ve, base d o n t he P K N A B. F or n A b s u bsets, s u m maries will be d o ne f or e ver 
p ositi ve i n eit her of 2 n A b assa ys ( P D L 1 a n d T G F ß rece pt or ne utr alizati o n; P D L 1 +/ T G F ß +, 
P D L 1 +/ T G F ß −, P D L 1 −/ T G F ß +) v ers us n e ver p ositi ve ( P D L 1 −/ T G F ß −).  A d diti o nal ta ble(s) ma y 
s u m marize P K para meters wit h f urt her stratificati o n b y a nti bi otics stat us s u b gr o u ps.  
A d diti o nal ta ble(s) will s u m marize C tr o u g h a n d C E OI  wit h f urt her s u b -stratificati o n b y A D A s u bsets 
e ver p ositi ve a n d ne ver p ositi ve a n d, neste d wit hi n, re gi o nal c o h ort b ase d o n t he P K A D A. 
A d diti o nal ta ble(s) will s u m marize C tr o u g h of A D A e ver p ositi ve partici pa nts  wit h f urt her s u b -
stratificati o n b y A D A s u bgr o u ps “ Treat me nt e mer ge nt ( A L L)” a n d “ A D A N o n -Treat me nt -
e mer ge nt”, b ase d o n t he P K A D A. F or n A b e ver -p ositi ve partici pa nts , ser u m bi ntraf us p al p ha 
C tr o u g h will be descri pti vel y s u m marize d i n a d diti o nal ta ble(s) f or n A b stat us s u b gr o u ps ( p ositi ve 
i n a n y of 2 n A b assa ys), base d o n t he P K N A B. A d diti o nal ta ble(s) will s u m marize C tr o u g h of A D A 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 7 /1 0 8  
 
 
e ver-p ositi ve p artici pa nts  wit h f urt her s u b -str atificati o n b y A D A s u b gr o u ps a n d, neste d wit hi n, 
re gi o nal c o h ort (a n d ma y b e f urt her stratifie d b y et h nicit y as a b o ve), b ased o n t he P K A D A. F or 
n A b e ver -p ositi ve partici pa nts , ser u m bi ntraf us p al p ha Ctr o u g h will be descri pti vel y s u m marize d i n 
a d diti o nal ta ble(s) f or n A b stat us s u b gr o u ps ( p ositi ve i n a n y of 2 n A b assa ys) a n d, nest e d wit hi n, 
re gi o nal c o h ort (a n d ma y be f urt her stratifie d b y et h nicit y as a b o v e), b ase d o n t he P K N A B. 
A d diti o nal ta ble(s) will s u m marize C tr o u g h of A D A Treat me nt -e mer ge nt partici pa nts  a n d n A b 
Treat me nt -e mer ge nt partici pa nts  b y P K da y relati ve t o ser oc o n versi o n, f or all partici pa nts  a n d b y 
re gi o nal c o h ort (a n d ma y b e f urt her stratifie d b y et h nicit y as a b o ve) bas e d o n t he P K A D A a n d 
P K N A B, res pecti vel y. O nl y s u b gr o u p sa m ple siz e wit h a mi ni mal 3 partici pa nts  will be dis pla ye d 
f or a n y of t he a b o ve. 
I n e x p ort datasets, as w ell as i n t he S D T M P P d o mai n, P K paramet ers will be pr o vi de d wit h f ull 
precisi o n a n d will n ot be r o u n de d. Des cri pti ve statistics of P K para meter d ata will be cal c ulate d 
usi n g f ull precisi o n val ues a n d r o u n de d f or re p orti n g p ur p os es o nl y.  
T he f oll o wi n g c o n v e nti o ns will be a p plie d w he n re p orti n g des cri pti ve statistics of P K para meter 
data:  
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI:  
3 si g nifica nt di gits  
St D , l o g St D:  
 
 
 
 
4 si g nifica nt di gits  
C V %, Ge o C V %:  
 
 
 
 
1 deci mal place  
Fi g ures  
I n di vi d ual P K Ctr o u g h a n d C E OI  val ues will be pl otte d a gai nst ac t ual st u d y d a y o n a li near scale, f or 
all partici pa nts b y part a n d re gi o nal c o h ort. Pl ots of i n di vi d ual data will be prese nte d b ase d o n t h e 
safet y r u n-i n a n al ysis s et f or t he safet y r u n-i n p art a n d t he S A F f or t he ra n d o mize d, d o u ble-bli n d 
part.  
Arit h metic mea n ( ± St D) , Ge o Mea n ( ±l o g St D),  a n d M e dia n C tr o u g h a n d C E OI  will be pl otte d v ers us 
n o mi nal st u d y d a y b y part, re gi o nal c o h ort , o verall b y part ( b ot h c o h orts wit hi n eac h part), a n d 
o verall (all parts/c o h orts)  o n a li near scale. S u m maries will be base d o n t he P K A S . A d diti o nal 
fi g ure(s) will be prese nt e d of Mea n ( ± St D), Ge o M ea n ( ±l o g St D), a n d M e dia n C tr o u g h a n d C E OI  wit h 
f urt her str atificati o n b y et h nicit y (e. g., J a pa n ese, n o n-J a pa nese Asia n, all Asia n, n o n-Asia n, 
C hi nese mai nla n d, n o n -C hi nese mai nla n d Asia n), base d o n t he P K A S. A d diti o nal fi g ure(s) will be 
prese nte d wit h f urt her stratificati o n b y A D A s u b gr o u ps (e v er p ositi ve a n d ne ver p ositi ve) , a n d 
a d diti o nall y “ Treat me nt e mer ge nt ( A L L)” a n d “ A D A N o n -Treat me nt -e mer ge nt”, b ase d o n t he 
P K A D A. A d diti o nal fi g ure(s) will pres e nt Mea n, Ge o Mea n, M e d ia n, C tr o u g h a n d C E OI  wit h f urt her 
s u b-stratificati o n b y n A b s u bsets e ver p ositi ve a n d ne ver p ositi ve, bas e d o n t he P K N A B . S u m mar y 
fi g ures of Mea n, Ge o Mea n, or Me dia n  will c o ntai n a f o ot n ote de n oti n g n p er ti me p oi nt.  All Mea n, 
Ge o Mea n, a n d Me dia n  pl ots will o nl y dis pla y ti m e p oi nts wit h n > 2, w hic h will als o be a d d e d as 
f o ot n ote. 
F or A D A tr eat me nt -e m er ge nt (i n d uce d) partici pa nts  wit h at least o ne C tr o u g h meas ure me nt bef ore 
a nd after A D A ser oc o n versi o n, i n di vi d ual C tr o u g h will be pl otte d vers us P K da y relati ve t o 
ser oc o n versi o n (f or rea da bilit y, s plit f urt her i nt o gr o u ps of 1 0 partici pa nts  or fe wer as nee de d), f or 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 8 /1 0 8  
 
 
all partici pa nts  a n d b y re gi o nal c o h ort, base d o n t he S A F. B o x pl ots will  be pre pare d f or C tr o u g h 
vers us P K da y relati ve t o ser oc o n v ersi o n, f or all p artici pa nts  a n d b y re gi o n al c o h ort, b ase d o n t h e 
P K A D A.  
F or n A b treat me nt -e mer ge nt partici pa nts  wit h at least o ne C tr o u g h meas ure me nt bef ore a n d after 
n A b ser oc o n versi o n (earliest of 2 assa ys if p ositi ve i n b ot h), i n di vi d ual C tr o u g h will be pl otte d v ers us 
P K da y rel ati ve t o ser oc o n versi o n (f or rea da bilit y, s plit f urt h er i nt o gr o u ps of 1 0 partici pa nts  or 
fe wer as nee de d), f or all partici pa nts  a n d b y re gi o nal c o h ort, base d o n t he S A F. B o x pl ots will be 
pre pare d f or C tr o u g h vers us P K da y relati ve t o ser oc o n versi o n, f or all partici pa nts  a n d b y re gi o n al 
c o h ort, base d o n t he P K N A B.  
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
9 9 /1 0 8  
 
 
Ti me t o o nset of res p o nse  f or tre at me nt-e mer g e nt  A L L  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 0 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 1 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 2 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 3 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 4 /1 0 8  
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 5 /1 0 8  
 
 
1 7  
Refere nces   
C h ua W, C harles K A, Barac os V E, Clar ke SJ. Ne utr o p hil/l y m p h oc yt e rati o  pre dicts c he m ot hera p y 
o utc o mes i n patie nts wit h a d va nce d c ol orectal ca ncer. Br  J Ca ncer. 2 0 1 1 A pr 1 2; 1 0 4( 8): 1 2 8 8-9 5 . 
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 -4 7.  
Gli m m E, Ma urer  W, Bretz F. Hierarc hi cal testi n g of m ulti ple e n d p oi nts i n gr o u p -se q ue ntial trials. 
Stat Me d. 2 0 1 0 J a n 3 0; 2 9( 2): 2 1 9 -2 8.  
Ka o S C, Pa vla kis N, Har vie R, et al. Hi g h bl o o d n e utr o p hil -t o-l y m p h oc yt e rati o is a n i n dicat or of 
p o or pr o g n osis i n mali g n a nt mes ot heli o ma patie nts u n der g oi n g s yste mic t hera p y. Cli n Ca ncer Res. 
2 0 1 0 Dec 1; 1 6( 2 3): 5 8 0 5 -1 3.  
Ma urer W, H ot h or n L, Le h mac her W. M ulti ple c o m paris o ns i n dr u g cli nical trials a n d precli nical 
assa ys: a pri ori or dere d h y p ot hes es. I n Bi o metrie i n der C he misc h-P har maze ut isc he n I n d ustrie, 
V ol. 6, V oll mar, J. (e d.), 3 – 1 8. St utt gart: Fisc her Verla g, 1 9 9 5.  
Z ha n g X. C o m paris o n of restricte d mea n s ur vi val ti mes bet wee n treat me nts base d o n a  stratifie d 
C o x m o del. D OI 1 0. 1 5 1 5/ ba ms -2 0 1 3 -0 1 0 1 Bi o -Al g orit h ms a n d Me d -S yste ms 2 0 1 3;  9( 4): 1 8 3 – 9.  
E ur o pea n Ce ntre f or Disease Pre ve nti o n a n d C o ntr ol. Data o n C O VI D -1 9 ge o gra p hic distri b uti o n 
b y c o u ntr y. htt ps:/ / w w w.ec dc. e ur o pa. e u/e n/ p u blicati o ns-data/ d o w nl oa d -t o da ys-data -ge o gra p hic -
distri b uti o n -c o vi d-1 9 -cas es -w orl d wi de , accesse d a n d d o w nl oa de d o n 2 6 J u ne 2 0 2 0. 
1 8  
A p pe n dices   
1 8. 1. 1  
A p pe n di x 1  - Defi niti o n of Im p ort a nt P r ot oc ol D e vi ati o ns   
See d oc u me nt: ct p-ms 2 0 0 6 4 7 -0 0 5 5 -ia p-a p pe n di x -i p d-v 2 . d oc x 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 6 /1 0 8  
 
 
1 8. 1. 2  
A p pe n di x 2  - R ules f or 
Ide ntific ati o n of 
P re vi o us or 
C o nc o mit a nt M e dic ati o ns/P r oce d ures   
See 
d oc u me nt: 
ct p-ms 2 0 0 6 4 7 -0 0 5 5 -ia p-a p p e n di x -i de ntificati o n-pre vi o us -c o nc-me dicati o ns -
v 1 . d oc x 
1 8. 1. 3  
A p pe n di x 3  - Defi niti o n of N CI -C T C A E G r a di n g   
See d oc u me nt: ct p-ms 2 0 0 6 4 7 -0 0 5 5 -ia p-a p pe n di x -nci -ctcae-v 2 . xls x. 
1 8. 1. 4  
A p pe n di x 4 –  A d a pt ati o n Pl a n   
See d oc u me nts : ct p-ms 2 0 0 6 4 7 -0 0 5 5 -ia p-a p pe n di x -a da ptati o n -pla n -v 1. d oc x  a n d ct p-ms 2 0 0 6 4 7 -
0 0 5 5 -ia p-a p p e n di x -si m ulati o n-re p ort-v 1. d o c x . 
U p date d si m ulati o n re p ort f oll o wi n g pr ot oc ol versi o n 5. 0: ct p-ms 2 0 0 6 4 7 -0 0 5 5 -ia p-a p pe n di x -
si m ulati o n-re p ort-v 2. d oc x.  
1 8. 1. 5  
A p pe n di x 5  –  C ycle X D a y 1/ D a y 8/ D a y 1 5 deter mi n ati o n   
C ycle X Da y 1 d eter mi nati o n:  
 
Vi sit N a m e  
C y cl e X D a y 1  
W E E K 1 D A Y 1  
C y cl e 1 D a y 1  
W E E K 4 D A Y 2 2  
C y cl e 2 D a y 1  
W E E K 7 D A Y 4 3  
C y cl e 3 D a y 1  
W E E K 1 0 D A Y 6 4  
C y cl e 4 D a y 1  
W E E K 1 3 D A Y 8 5  
C y cl e 5 D a y 1  
W E E K 1 6 D A Y 1 0 6  
C y cl e 6 D a y 1  
W E E K 1 9 D A Y 1 2 7  
C y cl e 7 D a y 1  
W E E K 2 2 D A Y 1 4 8  
C y cl e 8 D a y 1  
W E E K 2 5 D A Y 1 6 9  
C y cl e 9 D a y 1  
W E E K 2 8 D A Y 1 9 0  
C y cl e 1 0 D a y 1  
W E E K 3 1 D A Y 2 1 1  
C y cl e 1 1 D a y 1  
W E E K 3 4 D A Y 2 3 2  
C y cl e 1 2 D a y 1  
W E E K 3 7 D A Y 2 5 3  
C y cl e 1 3 D a y 1  
W E E K 4 0 D A Y 2 7 4  
C y cl e 1 4 D a y 1  
W E E K 4 3 D A Y 2 9 5  
C y cl e 1 5 D a y 1  
W E E K 4 6 D A Y 3 1 6  
C y cl e 1 6 D a y 1  
C ycle X Da y 8 d eter mi nati o n  
 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 7 /1 0 8  
 
 
Vi sit N a m e  
C y cl e X D a y 8  
W E E K 2 D A Y 8  
C y cl e 1 D a y 8  
W E E K 5 D A Y 2 9  
C y cl e 2 D a y 8  
W E E K 8 D A Y 5 0  
C y cl e 3 D a y 8  
W E E K 1 1 D A Y 7 1  
C y cl e 4 D a y 8  
W E E K 1 4 D A Y 9 2  
C y cl e 5 D a y 8  
W E E K 1 7 D A Y 1 1 3  
C y cl e 6 D a y 8  
W E E K 2 0 D A Y 1 3 4  
C y cl e 7 D a y 8  
W E E K 2 3 D A Y 1 5 5  
C y cl e 8 D a y 8  
W E E K 2 6 D A Y 1 7 6  
C y cl e 9 D a y 8  
W E E K 2 9 D A Y 1 9 7  
C y cl e 1 0 D a y 8  
W E E K 3 2 D A Y 2 1 8  
C y cl e 1 1 D a y 8  
W E E K 3 5 D A Y 2 3 9  
C y cl e 1 2 D a y 8  
W E E K 3 8 D A Y 2 6 0  
C y cl e 1 3 D a y 8  
W E E K 4 1 D A Y 2 8 1  
C y cl e 1 4 D a y 8  
W E E K 4 4 D A Y 3 0 2  
C y cl e 1 5 D a y 8  
W E E K 4 7 D A Y 3 2 3  
C y cl e 1 6 D a y 8  
 
C ycle X Da y 1 5 d eter mi nati o n  
 
Vi sit N a m e  
C y cl e X D a y 1 5  
W E E K 3 D A Y 1 5  
C y cl e 1 D a y 1 5  
W E E K 6 D A Y 3 6  
C y cl e 2 D a y 1 5  
W E E K 9 D A Y 5 7  
C y cl e 3 D a y 1 5  
W E E K 1 2 D A Y 7 8  
C y cl e 4 D a y 1 5  
W E E K 1 5 D A Y 9 9  
C y cl e 5 D a y 1 5  
W E E K 1 8 D A Y 1 2 0  
C y cl e 6 D a y 1 5  
W E E K 2 1 D A Y 1 4 1  
C y cl e 7 D a y 1 5  
W E E K 2 4 D A Y 1 6 2  
C y cl e 8 D a y 1 5  
W E E K 2 7  D A Y 1 8 3  
C y cl e 9 D a y 1 5  
W E E K 3 2  D A Y 2 0 4  
C y cl e 1 0 D a y 1 5  
W E E K 3 5  D A Y 2 2 5  
C y cl e 1 1 D a y 1 5  
W E E K 3 8  D A Y 2 4 6  
C y cl e 1 2 D a y 1 5  
W E E K 4 1  D A Y 2 6 7  
C y cl e 1 3 D a y 1 5  
W E E K 4 4  D A Y 2 8 8  
C y cl e 1 4 D a y 1 5  
W E E K 4 7  D A Y 3 0 9  
C y cl e 1 5 D a y 1 5  
W E E K 5 0 D A Y 3 3 0  
C y cl e 1 6 D a y 1 5  
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4)       1 L B T C P h ase II/III Ge mcit a bi ne Pl us Cis pl ati n 
Wit h or 
Wit h o ut 
Bi ntr af us p a lf a 
M S 2 0 0 6 4 7 _ 0 0 5 5   
 
 
 
                                                              Versi o n 4   
 
 
 
1 0 8 /1 0 8  
 
 
1 8. 1. 6  
A p pe n di x 6 –  S u bse q ue nt I m m u ne C hec k p oi nt I n hi bit ors   
As of 3 0 t h J ul y 2 0 2 1, t he list of s u bse q ue nt i m m u ne c h ec k p oi nt i n hi bit ors i ncl u de d i n t he a nal ysis 
is t he f oll o wi n g: 
•  A vel u ma b  
•  Ni v ol u ma b  
•  Pe m br oliz u ma b  
•  La m br oliz u ma b  
•  Atez oliz u ma b  
•  D ur val u ma b  
•  Tre meli m u ma b  
•  I pili m u ma b 
 
Gl o bal Versi o n I D: C CI


Si g nat ure Pa ge f or 
v 1. 0
Si g nat ure Pa ge f or 
v 1. 0
A p pr o val
Cli nical
0 3- Fe b- 2 0 2 2 1 6: 5 1: 4 5 G M T + 0 0 0 0
Gl o bal Versi o n I D: 7 8 6 9 1 _ 4 1 0 4 6 3 0 _ 4 8 5 2 6 0 8
C CI
C CI
P P D