A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) as First-line Treatment of Biliary Tract Cancer
Phase: PHASE2
Conditions: Biliary Tract Cancer, Cholangiocarcinoma, Gallbladder Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

Bi ntr af us p alf a ( M 7 8 2 4)
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
C CI
C CI